Association between weight, weight perception, weight teasing and mental health among adolescents.

BACKGROUND: Adolescent mental health problems are becoming increasingly prevalent, and there are correlations between weight-related concerns and adolescent mental health. The aim of this study is to explore the association between three weight-related factors (actual weight, weight perception, and weight teasing) and mental health problems (depressive symptoms, anxiety symptoms, and loneliness) in Chinese adolescents. METHODS: 10,070 adolescents between the ages of 11-18 from schools in Shanghai, China were selected using a stratified random cluster sampling method. Self-reported questionnaires were collected to investigate weight-related factors and mental health problems. Logistic regression analysis was used to examine the relationship. RESULTS: The prevalence of depressive symptoms, loneliness, mild anxiety symptoms, and moderate to severe anxiety symptoms among adolescents were 18.0%, 53.8%, 26.5%, and 12.3%, respectively, with a higher prevalence found in females. After adjusting for weight perception and weight teasing, actual weight had no harmful impact on adolescents' mental health. Adolescents' perception of being overweight increased the risk of depressive symptoms, loneliness, mild anxiety symptoms, and moderate to severe anxiety symptoms, while the perception of being underweight had a similar but more profound impact (depressive symptoms OR = 1.590, 95% CI: 1.342-1.883; loneliness OR = 1.537, 95% CI: 1.353-1.746; mild anxiety symptoms OR = 1.368, 95% CI: 1.178-1.589; moderate to severe anxiety symptoms OR = 1.780, 95% CI: 1.449-2.186). Experiencing weight teasing more than once a year had a greater effect on adolescents' mental health, especially among adolescents with overweight/obesity (depressive symptoms OR = 2.970, 95% CI: 2.325-3.793; loneliness OR = 3.839, 95% CI: 3.119-4.727; mild anxiety symptoms OR = 2.822, 95% CI: 2.236-3.562; moderate to severe anxiety symptoms OR = 5.212, 95% CI: 3.846-7.065). CONCLUSIONS: The prevalence of mental health problems among adolescents was high, especially loneliness. Weight perception and weight teasing, but not the actual weight, independently influenced adolescent mental health.

Copper-catalyzed thiocyanation of cyclobutanone oxime esters using ammonium thiocyanate.

A copper-catalyzed thiocyanation of cycloketone oxime esters with ammonium thiocyanate has been developed for the first time. This innovative approach allows access to cyano and thiocyano bifunctionally substituted alkanes, which can be further transformed into their respective trifluoromethylthiol-substituted or difluoromethylthiol-substituted alkylnitriles, alkynyl sulfides, and phosphorothioate esters. The readily available nature of ammonium thiocyanate and the cost-effectiveness of the copper catalyst make this method a promising strategy for the synthesis of sulfur-containing alkylnitriles.

Real-time detection of laryngopharyngeal cancer using an artificial intelligence-assisted system with multimodal data.

BACKGROUND: Laryngopharyngeal cancer (LPC) includes laryngeal and hypopharyngeal cancer, whose early diagnosis can significantly improve the prognosis and quality of life of patients. Pathological biopsy of suspicious cancerous tissue under the guidance of laryngoscopy is the gold standard for diagnosing LPC. However, this subjective examination largely depends on the skills and experience of laryngologists, which increases the possibility of missed diagnoses and repeated unnecessary biopsies. We aimed to develop and validate a deep convolutional neural network-based Laryngopharyngeal Artificial Intelligence Diagnostic System (LPAIDS) for real-time automatically identifying LPC in both laryngoscopy white-light imaging (WLI) and narrow-band imaging (NBI) images to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists. METHODS: All 31,543 laryngoscopic images from 2382 patients were categorised into training, verification, and test sets to develop, validate, and internal test LPAIDS. Another 25,063 images from five other hospitals were used as external tests. Overall, 551 videos were used to evaluate the real-time performance of the system, and 200 randomly selected videos were used to compare the diagnostic performance of the LPAIDS with that of laryngologists. Two deep-learning models using either WLI (model W) or NBI (model N) images were constructed to compare with LPAIDS. RESULTS: LPAIDS had a higher diagnostic performance than models W and N, with accuracies of 0·956 and 0·949 in the internal image and video tests, respectively. The robustness and stability of LPAIDS were validated in external sets with the area under the receiver operating characteristic curve values of 0·965-0·987. In the laryngologist-machine competition, LPAIDS achieved an accuracy of 0·940, which was comparable to expert laryngologists and outperformed other laryngologists with varying qualifications. CONCLUSIONS: LPAIDS provided high accuracy and stability in detecting LPC in real-time, which showed great potential for using LPAIDS to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists.

Predicting the severity of white matter lesions among patients with cerebrovascular risk factors based on retinal images and clinical laboratory data: a deep learning study.

Background and purpose: As one common feature of cerebral small vascular disease (cSVD), white matter lesions (WMLs) could lead to reduction in brain function. Using a convenient, cheap, and non-intrusive method to detect WMLs could substantially benefit to patient management in the community screening, especially in the settings of availability or contraindication of magnetic resonance imaging (MRI). Therefore, this study aimed to develop a useful model to incorporate clinical laboratory data and retinal images using deep learning models to predict the severity of WMLs. Methods: Two hundred fifty-nine patients with any kind of neurological diseases were enrolled in our study. Demographic data, retinal images, MRI, and laboratory data were collected for the patients. The patients were assigned to the absent/mild and moderate-severe WMLs groups according to Fazekas scoring system. Retinal images were acquired by fundus photography. A ResNet deep learning framework was used to analyze the retinal images. A clinical-laboratory signature was generated from laboratory data. Two prediction models, a combined model including demographic data, the clinical-laboratory signature, and the retinal images and a clinical model including only demographic data and the clinical-laboratory signature, were developed to predict the severity of WMLs. Results: Approximately one-quarter of the patients (25.6%) had moderate-severe WMLs. The left and right retinal images predicted moderate-severe WMLs with area under the curves (AUCs) of 0.73 and 0.94. The clinical-laboratory signature predicted moderate-severe WMLs with an AUC of 0.73. The combined model showed good performance in predicting moderate-severe WMLs with an AUC of 0.95, while the clinical model predicted moderate-severe WMLs with an AUC of 0.78. Conclusion: Combined with retinal images from conventional fundus photography and clinical laboratory data are reliable and convenient approach to predict the severity of WMLs and are helpful for the management and follow-up of WMLs patients.

Body Weight, Weight Self-Perception, Weight Teasing and Their Association with Health Behaviors among Chinese Adolescents-The Shanghai Youth Health Behavior Survey.

Weight-related status has been associated with the physical and psychological health of adolescents. This cross-sectional study evaluated three different kinds of weight-related statuses (Body Mass Index (BMI), weight self-perception and weight teasing from others) among Chinese adolescents and identified their associations with health risk behaviors (lack of healthy dietary behavior, unhealthy dietary behavior, binge eating behavior, lack of physical activity (PA), sedentary behaviors (SB) and sleep disturbance). A stratified random cluster sampling method was used to select 10,070 students aged 11−18 years old from schools in Shanghai. Self-reported questionnaires were collected, weight-related statuses were divided into three categories and six specific health risk behaviors were classified into two groups: positive or negative. Overall, 27.82% of the adolescents were classified as being overweight and obese (35.61% of boys and 18.21% of girls), 43.45% perceived themselves as too heavy and 30.46% experienced weight teasing in the past. Among overweight or obese participants, 50.55% have been teased about their weight, and 77.48% perceived themselves as too heavy. Weight perception and weight teasing were significantly associated with health risk behaviors rather than the actual body weight status based on BMI, especially regarding binge eating behavior (body weight status (BMI): p > 0.05, underweight perception: OR = 1.18, 95%CI 1.03−1.34; weight teasing for more than once a year: OR = 2.00, 95%CI 1.76−2.27). In addition, weight perception and weight teasing were significantly associated with health risk behaviors, mainly in normal and overweight/obese groups but not in underweight groups. Weight teasing and weight self-perception play an independent and stronger role than actual body weight in the health behaviors of adolescents. This calls for more attention and intervention to reduce peer bullying and stigmas on weight among adolescents.

Prevalence and influence of depression and anxiety on dietary behaviors among adolescents in Shanghai / 中国学校卫生

Objective@#To investigate the prevalence of adolescents dietary behavior in Shanghai, and to explore emotional influence on dietary behavior.@*Methods@#A total of 7 456 students from 10 junior and 6 senior high schools in Shanghai were selected to participate in the questionnaire survey with the stratified random cluster sampling method. The survey included general information, eating behavior, PHQ-2 and GAD-7.@*Results@#During the past week, the proportion of adolescents in Shanghai reported consumption of sugar sweetened beverages, sweet desserts, frequent fried food and fast food (≥4 times/week) were 13.26%, 16.90%, 6.99 % and 13.01%, respectively. The proportion of students reported consumption of fruits, vegetables, milk and breakfast every day were 56.96%, 73.00%, 65.03% and 76.11%, respectively. There were significant differences by sex and educational stages(both P <0.05). Adolescents with depression or anxiety have a higher incidence of unhealthy eating behaviors than those without depression or anxiety( P <0.01). After adjusting for gender, school, accommodation, grades, pocket money and social class, depression and anxiety increase the risk of various unhealthy eating behaviors in adolescents( P <0.05). Compared with those without anxiety, the risks of sugar sweetened beverages consumption (≥1 time/d) among adolescents with mild and moderate to severe anxiety were 1.42 times (95% CI =1.20-1.67) and 2.51 times (95% CI =2.09-3.01), the risks of insufficient fruits consumption (<1 time/d) were 1.30 times (95% CI =1.16-1.45) and 1.28 times (95% CI =1.11-1.47), the risks of insufficient vegetable consumption (<1 time/d) were 1.35 times (95% CI =1.20-1.52) and 1.41 times(95% CI =1.21-1.65), the risks of insufficient milk consumption (<1 time/d) were 1.29 times (95% CI =1.15-1.44) and 1.20 times(95% CI =1.04-1.39), and the risks of breakfast skipping were 1.75 times (95% CI =1.54-1.99) and 2.97 times (95% CI =2.55-3.46) among adolescents with mild and moderate to severe anxiety.@*Conclusion@#The proportion of unhealthy eating behaviors among adolescents in Shanghai is still high. Early education and intervention for students eating behaviors should be carried out, and attention should be paid to the occurrence of adolescents negative emotions, so as to reduce the risk of unhealthy eating behaviors among adolescents through the promotion of mental health.

Discovery and Optimization of Pyrazole Amides as Inhibitors of ELOVL1.

Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought to underlie the pathologies observed in adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on the inhibition of elongation of very long chain fatty acid 1 enzyme (ELOVL1), we explored a series of thiazole amides that evolved into compound 27─a highly potent, central nervous system (CNS)-penetrant compound with favorable in vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts, lymphocytes, and microglia. In mouse models of ALD, compound 27 treatment reduced C26:0 VLCFA concentrations to near-wild-type levels in blood and up to 65% in the brain, a disease-relevant tissue. Preclinical safety findings in the skin, eye, and CNS precluded progression; the origin and relevance of these findings require further study. ELOVL1 inhibition is an effective approach for normalizing VLCFAs in models of ALD.

Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.

JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.

Discovery of Novel, Orally Bioavailable ß-Amino Acid Azaindole Inhibitors of Influenza PB2.

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.

Application of design of experiments (DoE) optimization to the one-pot synthesis of 4,6-dihydropteridinones.

A design of experiments (DoE) analysis of a tandem SnAr-amidation cyclization reaction between 4-chloropyrimidin-5-amine and (S)-N-methylalanine to form (S)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one is reported. Five reaction variables were optimized using DoE and conversion was improved from 26% to 74%, with a significant reduction in reaction time while retaining high optical purity. The optimized conditions were applied to the synthesis of a wide variety of analogs and the expanded reaction substrate scope included a variety of amino acids and pyrimidines. Products were obtained in isolated yields up to 95% and enantiomeric excess as high as 98%.

Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors.

VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species.

Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2.

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part 2: 4-amino-pyrido[2,3-d]pyrimidin-5(8H)-ones.

A series of 4-amino-pyrido[2,3-d]pyrimidin-5(8H)-ones were designed and synthesized as a novel class of inhibitors of NAD(+)-dependent DNA ligase that possess potency against Gram-positive bacteria.

Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part I: aminoalkoxypyrimidine carboxamides.

A series of 2,6-disubstituted aminoalkoxypyrimidine carboxamides (AAPCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligase was discovered through the use of structure-guided design. Two subsites in the NAD(+)-binding pocket were explored to modulate enzyme inhibitory potency: a hydrophobic selectivity region was explored through a series of 2-alkoxy substituents while the sugar (ribose) binding region of NAD(+) was explored via 6-alkoxy substituents.

Tubulin binding, protein-bound conformation in solution, and antimitotic cellular profiling of noscapine and its derivatives.

Noscapine and its 7-hydroxy and 7-amino derivatives were characterized for their binding to tubulin. A solution NMR structure of these compounds bound to tubulin shows that noscapine and its 7-aniline derivative do not compete for the same binding site nor does its small molecule crystal structure match its tubulin-bound conformation. These compounds were also tested for their antiproliferative effects on a panel hepatocellular carcinoma cell lines.

Synthesis of (S)-2-Boc-Amino-8-(R)-(tert-butyldimethylsilanyloxy) decanoic acid, a Precursor to the Unusual Amino Acid Residue of the Anticancer Agent Microsporin B.

(S)-2-Boc-Amino-8-(R)-(tert-butyldimethylsilanyloxy) decanoic acid, the Boc-protected precursor of an unusual amino acid residue for the synthesis of microsporin B, was synthesized. The key steps include a Suzuki coupling followed by asymmetric homogeneous hydrogenation.

Stereospecific total syntheses of proteasome inhibitors omuralide and lactacystin.

Omuralide, a transformation product of the microbial metabolite lactacystin, was the first molecule discovered as a specific inhibitor of the proteasome and is unique in that it specifically inhibits the proteolytic activity of the 20S subunit of the proteasome without inhibiting any other protease activities of the cell. The total syntheses of omuralide and (+)-lactacystin are reported. An important key intermediate is synthesized at an early stage, which allows analogues of these two natural products to be made readily.

Concise route to the chiral pyrrolidine core of selective inhibitors of neuronal nitric oxide.

2-(((3R,4R)-4-(Allyloxy)-1-benzylpyrrolidin-3-yl)methyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine (2), a key intermediate for the preparation of novel neuronal nitric oxide synthase (nNOS) inhibitors, is synthesized using diisopropyl (R)-(+)-malate as the starting material. The key steps involve a Frater-Seebach diastereoselective alkylation and a fast intramolecular cyclization.

Carbonyl- and sulfur-containing analogs of suberoylanilide hydroxamic acid: Potent inhibition of histone deacetylases.

Suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylase, is used in clinical trials for a variety of advanced cancers. Twelve new analogs of SAHA were synthesized and tested as in vitro inhibitors of isolated histone deacetylases (HDACS) and in vivo inhibitors of interferon regulated transcriptional responses (a marker for HDAC activity). The analogs containing an alpha-mercaptoketone or an alpha-thioacetoxyketone were more potent than SAHA in both assays.