First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane ß-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

Evaluation of a new digital pediatric malnutrition risk screening tool for hospitalized children with congenital heart disease.

BACKGROUND: In a cohort of hospitalized children with congenital heart disease (CHD), a new digital pediatric malnutrition screening tool as a mobile application was validated, and its effectiveness and clinical value were determined as a prospective study. METHODS AND RESULTS: Children with CHD (n = 1125) were screened for malnutrition risk. The incidence of risk and the differences among various age groups and types of CHD were characterized. The optimal threshold for the tool to determine if there is a risk of malnutrition is score 2, while the Youden index was 79.1%, and the sensitivity and specificity were 91.2% and 87.9%, respectively. Based on such criterion, 351 children were at risk of malnutrition accounting for 31.20% of the total. Compared with the non-malnutritional risk group, the median age for the group at risk for malnutrition was younger (8.641 months [4.8, 23.1] vs. 31.589 months [12.4, 54.3], P < 0.01), and the length of stay was longer (12.000 [8.0, 17.0] vs. (8.420 [5.0, 12.0], P < 0.01]. There were significant differences in malnutrition risk among different age groups (χ2 = 144.933, P < 0.01), and children under one year of age exhibited the highest risk for malnutrition and more extended hospital stay (H = 78.085, P < 0.01). The risk of malnutrition among children with cyanotic CHD was higher than in those with non-cyanotic CHD (χ2 = 104.384, P < 0.01). CONCLUSIONS: The new digital pediatric malnutrition screening tool showed high sensitivity and specificity in children with CHD. The tool indicated that the malnutrition risk for young children and children with cyanotic or Bethesda moderate and complex CHD was higher, and the hospitalization time was longer than in the non-risk group. The tool provides a rational approach to targeted nutrition intervention and support and may improve clinical outcomes.

Chromosomal-Scale Genome Assemblies of Two Coastal Plant Species, Scaevola taccada and S. hainanensis-Insight into Adaptation Outside of the Common Range.

While most of the species in Goodeniaceae family, excluding the Scaevola genus, are endemic to Australasia, S. taccada and S. hainanensis have expanded their distribution range to the tropical coastlines of the Atlantic and Indian Oceans. S. taccada appears to be highly adapted to coastal sandy lands and cliffs, and it has become invasive in places. S. hainanensis is found mainly in salt marshes near mangrove forests, and is at risk of extinction. These two species provide a good system to investigate adaptive evolution outside the common distribution range of this taxonomic group. Here, we report their chromosomal-scale genome assemblies with the objective of probing their genomic mechanisms related to divergent adaptation after leaving Australasia. The scaffolds were assembled into eight chromosome-scale pseudomolecules, which covered 90.12% and 89.46% of the whole genome assembly for S. taccada and S. hainanensis, respectively. Interestingly, unlike many mangroves, neither species has undergone whole-genome duplication. We show that private genes, specifically copy-number expanded genes are essential for stress response, photosynthesis, and carbon fixation. The gene families that are expanded in S. hainanensis and contracted in S. taccada might have facilitated adaptation to high salinity in S. hainanensis. Moreover, the genes under positive selection in S. hainanensis have contributed to its response to stress and its tolerance of flooding and anoxic environments. In contrast, compared with S. hainanensis, the more drastic copy number expansion of FAR1 genes in S. taccada might have facilitated its adaptation to the stronger light radiation present in sandy coastal lands. In conclusion, our study of the chromosomal-scale genomes of S. taccada and S. hainanensis provides novel insights into their genomic evolution after leaving Australasia.

Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).

Establishing community-wide DNA barcode references for conserving mangrove forests in China.

BACKGROUND: Mangrove ecosystems have been the focus of global attention for their crucial role in sheltering coastal communities and retarding global climate change by sequestering 'blue carbon'. China is relatively rich in mangrove diversity, with one-third of the ca. 70 true mangrove species and a number of mangrove associate species occurring naturally along the country's coasts. Mangrove ecosystems, however, are widely threatened by intensifying human disturbances and rising sea levels. DNA barcoding technology may help protect mangrove ecosystems by providing rapid species identification. RESULTS: To investigate this potential, 898 plant specimens were collected from 33 major mangrove sites in China. Based on the morphologic diagnosis, the specimens were assigned to 72 species, including all 28 true mangrove species and all 12 mangrove associate species recorded in China. Three chloroplast DNA markers rbcL, trnH-psbA, matK, and one nuclear marker ITS2 were chosen to investigate the utility of using barcoding to identify these species. According to the criteria of barcoding gaps in genetic distance, sequence similarity, and phylogenetic monophyly, we propose that a single marker, ITS2, is sufficient to barcode the species of mangroves and their associates in China. Furthermore, rbcL or trnH-psbA can also be used to gather supplement confirming data. In using these barcodes, we revealed a very low level of genetic variation among geographic locations in the mangrove species, which is an alert to their vulnerability to climate and anthropogenic disturbances. CONCLUSION: We suggest using ITS2 to barcode mangrove species and terrestrial coastal plants in South China. The DNA barcode sequences we obtained would be valuable in monitoring biodiversity and the restoration of ecosystems, which are essential for mangrove conservation.

The effect of different adiposity factors on insulin resistance in obese children and adolescents.

CONTEXT: Insulin resistance (IR) has been common in obese children, but the effect of different adiposity factors on IR is still unclear. OBJECTIVE: To evaluate the associations between IR with body mass index (BMI), waist circumference (WC), body fat mass (BFM), and body fat percentage (BFP) in obese children and adolescents. METHODS: A total of 224 simple obese children were included in this study, including 150 boys and 74 girls, aged 3-18 who were seen in the clinical nutrition outpatient of Xinhua Hospital from September 2012 to December 2019. Basic information, body composition and laboratory tests were collected. RESULTS: Compared with girls, boys had higher height, weight, BMI, WC, and BFM (P < 0.05), but on the contrary, boys' FINS and HOMA- IR were lower than girls' (P > 0.05). With the age increasing, height, weight, BMI, BFM, WC, HC, WHtR, FINS and HOMA-IR increased accordingly (P < 0.05). The results from univariate analysis and multiple linear regression analysis showed that the impact of BMI on IR was slightly lower than BFM, WC and HC, but higher than BFP, with adjusting for the effects of age, sex and lipid metabolism (P < 0.01). CONCLUSION: Overall adipose tissue, especially abdominal adipose tissue, is a powerful marker in inducing IR in obese children and adolescents. In addition, more attention should be paid to WC and BFM than BMI in obese people with IR.

Endoscopic frontal trephination verse the osteoplastic flap in patients with frontal sinus disease after bifrontal craniotomy.

OBJECTIVE: We review the clinical outcome of endoscopic frontal trephination and osteoplastic flap in patients with frontal sinus disease after bifrontal craniotomy. METHODS: The clinical data of patients with frontal sinus disease after bifrontal craniotomy between 2008 and 2018 were studied. RESULTS: Twenty-two patients underwent trephination and 15 patients had osteoplastic flap. The mean operation time was 101.5 min for osteoplactic flap, statistically shorter than that of the trephination (p < 0.05). The blood loss during the trephination was significantly lower than that of the osteoplactis flap (mean, 29.6 ± 11.5 versus 96.3 ± 46.8 ml; p < 0.01). The postoperative hospital stay was 2.2 ± 0.7 days for patients of the trephination and 3.7 ± 1.6 days for patients of the osteoplastic flap, and this difference was statistically significant (p < 0.01). No complication and recurrence in all 37 patients. CONCLUSIONS: Both endoscopic frontal trephination and the osteoplastic flap are safe and highly effective in patients with frontal sinus disease after bifrontal craniotomy. However, the trephination can cause lower blood loss and require shorter postoperative stay while it takes shorter time to complete the osteoplactis flap.

Association between trimester-specific gestational weight gain and childhood obesity at 5 years of age: results from Shanghai obesity cohort.

BACKGROUND: It is still unclear if and at which trimester gestational weight gain is related to childhood adiposity. Thus we aimed to evaluate the association between trimester-specific gestational weight gain and body-fat compositions in Chinese children. METHODS: Maternal gestational weight were measured by trained nurses every 2 to 4 weeks from the first prenatal care, and body-fat compositions of 407 children from the Shanghai Obesity Cohort at 5 years of age were measured by nutritionist through bioelectrical impedance analysis. Overweight/obesity of children was defined according to the criteria of International Obesity Task Force. Logistic and linear regression models adjusted for potential confounders were conducted to evaluate the associations of gestational weight gains with childhood obesity and body-fat compositions. Two-sided P-value < 0.05 was considered statistically significant. RESULTS: Greater gestational weight gain in the 1st-trimester was significantly associated with a higher risk of childhood overweight/obesity [OR: 1.40 (95% CI: 1.06, 1.86)], fat mass index [ß: 0.25 (95% CI: 0.12, 0.38)], body fat percentage [ß: 1.04 (95% CI: 0.43, 1.65)], and waist-to-height ratio [ß: 0.005 (95% CI: 0.002, 0.008)]. A positive but nonsignificant association was found between greater 3rd-trimester gestational weight gain and a higher risk of offspring overweight/obesity, and we speculated that the association between 2nd-trimester gestational weight gain and offspring overweight/obesity is the "U" type. CONCLUSIONS: Weight gain in the first trimester gestation is positively correlated with the risk of childhood overweight/obesity and with body adiposity distributions of children at 5 years of age. Weight gain should be well controlled and monitored from early pregnancy.

A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides.

BACKGROUND: Vupanorsen is a GalNAc3-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia. OBJECTIVES: The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG). METHODS: In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non-high-density lipoprotein cholesterol [non-HDL-C]), and safety were assessed. RESULTS: Absorption of vupanorsen was rapid (median time to maximum concentration [Tmax]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [Cmax]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were - 59.7% and - 69.5% for ANGPTL3, - 41.9% and - 52.5% for TG, and - 23.2% and - 25.4% for non-HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study. CONCLUSIONS: This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04916795.

Osteocalcin has a muscle-protective effect during weight loss in men without metabolic syndrome: a multicenter, prospective, observational study.

Objective: Weight reduction often accompanies muscle loss. Existing studies highlight the involvement of osteocalcin (OC) in energy metabolism and its potential to prevent age-related muscle loss. Nevertheless, these studies predominantly involve individuals with hyperglycemia, yielding conflicting research outcomes. This study investigated the protective role of OC against muscle loss during weight reduction in individuals without metabolic syndrome (MetS). Measures: We enrolled 130 overweight or obese individuals without MetS in a 4-month high-protein, energy-restricted dietary weight management program conducted at two clinic centers. Body composition and laboratory tests were assessed both before and after weight loss. Correlation and regression analysis were made between the changes in metabolic indicators and muscle mass during weight loss. Results: Following weight loss, there was a decrease in body mass index (BMI), percentage of body fat (PBF), visceral fat area (VFA), fasting insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR), glycated haemoglobin (HbA1c), and lipid profile, and increase in the percentage of skeletal muscle (PSM) and vitamin D. There was no change in osteocalcin (OC) during the intervention. Correlation analysis of the relative changes in all metabolic indicators revealed a positive correlation between OC and PSM (r=0.383, p=0.002). Multiple linear regression analysis found that OC has a significant protective effect on muscles during weight loss in males after adjusting for confounding factors (ß=0.089, p=0.017). Conclusion: High-protein, energy-restricted diets demonstrate efficacy in enhancing metabolic indicators within the weight-loss population. Furthermore, OC exhibits a protective effect on muscle mass during weight reduction in individuals without MetS, with this effect being particularly evident in males.

Tri-ponderal mass index as a screening tool for obesity prediction in children aged 6-9 years.

Objective: This study aimed to evaluate the efficiency of tri-ponderal mass index (TMI) in determining obesity in Chinese children aged 6-9 years, using the criteria of percentage of body fat (PBF) and body mass index z-scores (BMI-Z). Methods: The cross-sectional study included 5365 children, aged 6-9 years, who participated in the project survey "Group prevention and treatment of obesity among students and school health promotion in Shanghai" from September 2007 to September 2009. Height, weight, waist circumference, body mass index (BMI), TMI, waist-to-height ratio (WHtR), and PBF were recorded. Statistical analyses including Kolmogorov-Smirnov test, chi-square test, receiver operating characteristics curve, and kappa chi-square test were performed. Results: TMI for both sexes was relatively constant with increasing age, and statistically significant differences were not observed at some ages (P > 0.05 at 6, 7, 8, and 9 years). WHtR showed subtle changes, while BMI and PBF increased significantly with age in boys and girls (P < 0.01). Using BMI-Z criteria as the measure of general obesity, the results indicated that TMI cutoff values for 6-9 years were 14.60 kg/m3 for boys and 14.84 kg/m3 for girls (P < 0.001). Analysis of the agreement between TMI and BMI-Z showed that the kappa statistic was 0.826 in boys and 0.709 in girls (P < 0.001). Conclusion: TMI, as a constant tool, holds great potential as an alternative screening method for identifying children aged 6-9 years who may be at risk of obesity at an early stage.

Evolution of coastal forests based on a full set of mangrove genomes.

Genomic studies are now poised to explore whole communities of species. The ~70 species of woody plants that anchor the coastal ecosystems of the tropics, collectively referred to as mangroves, are particularly suited to this exploration. In this study, we de novo sequenced the whole genomes of 32 mangroves, which we combined with other sequences of 30 additional species, comprising almost all mangroves globally. These community-wide genomic data will be valuable for ecology, evolution and biodiversity research. While the data revealed 27 independent origins of mangroves, the total phylogeny shows only modest increases in species number, even in coastal areas of active speciation, suggesting that mangrove extinction is common. A possible explanation for common extinction is the frequent sea-level rises and falls (SLRs and SLFs) documented in the geological record. Indeed, near-extinctions of species with extremely small population size (N) often happened during periods of rapid SLR, as revealed by the genome-wide heterozygosity of almost all mangroves. Reduction in N has possibly been further compounded by population fragmentation and the subsequent accumulation of deleterious mutations, thus pushing mangroves even closer to extinction. Crucially, the impact of the next SLR will be exacerbated by human encroachment into these mangrove habitats, potentially altering the ecosystems of tropical coasts irreversibly.

Obesity-Induced Insulin Resistance Is Mediated by High Uric Acid in Obese Children and Adolescents.

Objective: This study aimed to evaluate whether serum uric acid (SUA) plays a mediating role in the development of insulin resistance (IR) in obese children and adolescents. Methods: A total of 369 participants aged 4-17 years with obesity who attended the Nutrition Outpatient Clinic for Obesity at Xinhua Hospital from January 2012 to January 2019 were recruited for this retrospective study. We classified participants into two groups on the basis of HOMA-IR values: the low HOMA-IR group (< 3.16) (n = 222) and the high HOMA-IR group (≥ 3.16) (n = 147). Results: The univariate analysis found that the high HOMA-IR group had higher BMI, SUA, and fasting insulin (FINS) (P < 0.05). Multiple linear regression analysis and mediating effect analysis indicated that body mass index (BMI) could directly regulate FINS and HOMA-IR (both P < 0.05). The results from the mediating effect analysis found that UA partially played an indirect role in the link between BMI, FINS and HOMA-IR (both P < 0.05) but had no effect on fasting blood glucose (P > 0.05). Conclusions: SUA should be investigated in obesity and plays a partial mediating role in insulin resistance induced by obesity in obese children and adolescents.

Uric acid is associated with adiposity factors, especially with fat mass reduction during weight loss in obese children and adolescents.

BACKGROUND: Current adult studies suggest that uric acid (UA) is associated with body fat, but the relationship in obese children is unclear. Thus, we aim to evaluate the association between uric acid and body composition of obese children. METHODS: A total of 79 obese children were included in this study, and 52 children (34 boys and 18 girls) underwent a 6-week weight loss camp, including 34 boys and 18 girls. Six-week weight-loss interventions were performed on all participants through aerobic exercise and appropriate dietary control. Laboratory tests and body composition were collected before and after the intervention. RESULTS: Before the intervention, correlation analysis demonstrated that uric acid was positively correlated with height, weight, body mass index (BMI), waist circumference, hip circumference, fat mass (FM), and free fat mass (FFM) with adjusting for age and gender (P < 0.05). After 6 weeks of intervention, the participants gained 3.12 ± 0.85 cm in height, body fat percentage decreased by 7.23 ± 1.97%, and lost 10.30 ± 2.83 kg in weight. Univariate and multivariate analysis indicated that uric acid at baseline was associated with FM reduction during weight loss (P < 0.05). CONCLUSIONS: This study is the first report that uric acid is associated with BMI and FM, and may play an important role in the reduction of FM during weight loss in obese children and adolescents. The interaction between UA and adiposity factors and its underlying mechanisms need to be further explored. TRIAL REGISTRATION: This study was registered in Clinical Trials.gov (NCT03490448) and approved by the Ethics Committee of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.

Development and validation of a pediatric nutritional screening score (PNSS) for hospitalized children.

BACKGROUND AND OBJECTIVES: There is no evidence on the most effective nutritional screening tool for hospitalized children. The objective of this study was to develop and validate a pediatric nutritional screening tool to assess undernutrition risk upon hospital admission. METHODS AND STUDY DESIGN: The study had a two-phase prospective observational design. A novel pediatric nutritional screening score (PNSS) was developed and sensitivity, specificity, and reliability were evaluated by comparing with a complete dietetic assessment. Length of hospital stay, weight loss, disease complications, and nutritional support were recorded. RESULTS: PNSS consisted of three elements: disease with malnutrition risks, changes in food intake, and anthropometric measurements, with a score of 0-2 for each element. The optimal cut-off score to identify patients (n=96) at risk of undernutrition was two. The agreement between PNSS and the complete dietetic assessment was moderate (κ=0.435, 95% CI=0.373-0.498). Sensitivity and specificity values of PNSS were 82% (95% CI=76%-87%) and 71% (95% CI=67%-74%), respectively. Inter-rater agreement had a κ value of 0.596 (95% CI=0.529-0.664, p<0.001). The percentage of children with undernutrition risk was 44.9%. Children with oncologic, gastrointestinal, and cardiac diseases were most likely to be at risk of undernutrition. The at-risk group was associated significantly with longer length of hospital stay and higher percentage of weight loss compared with the not-at-risk group. CONCLUSION: PNSS is the first nutritional screening tool developed for hospitalized children and validated in a large population of patients in China.