ABSTRACT
This Letter to the Editor reports the findings of a study we undertook to assess the quality and content of the mental health information that is provided to children via YouTube Kids. For videos on depression and anxiety, we found that all videos were useful or neutral (neither useful nor misleading). In contrast, most videos on attention-deficit/hyperactivity disorder (ADHD) were useful or neutral, but few were deemed misleading. Many of the videos on depression, anxiety, and ADHD promoted supportive statements and help-seeking behavior. Recommendations include calling on social media platforms to continue moderating content and involving more health care professionals and/or individuals with lived experiences to create accurate but engaging videos.
ABSTRACT
BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) measure, which assesses past week status of seven domains (physical function mobility, anxiety, depressive symptoms, fatigue, peer relationships, pain interference, and pain intensity), represents a new paradigm using patient-reported outcomes. We used a data-driven approach with PROMIS to identify subgroups of youths receiving depression treatment. METHODS: Youths (n = 721) enrolled in the Texas Youth Depression and Suicide Research Network who completed the PROMIS were analyzed. Latent class analyses (LCAs) identified subgroups and compared their baseline clinical/sociodemographic features. RESULTS: Compared to population norms, our sample had worse than average physical function, anxiety, depression, fatigue, and pain interference. Using LCA, four subgroups were identified: 1) lower symptom severity and higher physical functioning (14.6 %); 2) higher symptom burden, higher pain interference/intensity, and lower physical functioning (52.7 %); 3) higher symptom burden, higher pain interference/intensity, but with higher physical functioning (9.2 %); and 4) higher symptom burden, but lower physical functioning and pain interference/intensity (23.6 %). Group 3 demonstrated higher resilience than Group 2. In contrast, Group 2 had higher anxiety than Group 4. LIMITATIONS: Individuals may have different symptom profiles due to the observational nature of the study. Replication of these subgroups may be difficult, as future samples may differ in these characteristics. Further work may demonstrate the stability of these groups. CONCLUSIONS: A data-driven analysis identified a small but significant subgroup with high physical functioning despite high symptom burden and pain, and this group reported higher resilience. Resilience-enhancing interventions may help improve functional outcomes in depressed youth.
Subject(s)
Resilience, Psychological , Suicide , Humans , Adolescent , Depression/diagnosis , Texas , Symptom Burden , Pain/epidemiology , Fatigue/epidemiologyABSTRACT
Symptoms of irritability, anxiety, panic, and insomnia are common in patients with depression, and their worsening after antidepressant treatment initiation is associated with poorer long-term outcomes. The Concise Associated Symptom Tracking (CAST) scale was developed to measure these symptoms in adults with major depressive disorder (MDD). Here, we evaluate the psychometric properties of CAST in an ongoing community-based observational study involving children, adolescents, and young adults. Individuals from the ongoing Texas Youth Depression and Suicide Research Network (TX-YDSRN; N = 952) with CAST data available were included. Fit statistics [Goodness of Fit Index (GFI), Comparative Fit Index (CFI), and Root Mean Square Error of Approximation (RMSEA)] from confirmatory factor analyses were used to evaluate the five- and four-domain structure of CAST. Item response theory (IRT) analyses were also used. Individuals were grouped based on age (in years) as youths (8-17) and young adults (18-20). Correlations with other clinical measures were used to inform construct validity. Four-domain (irritability, anxiety, panic, and insomnia) 12-item structure of CAST (CAST-12) was optimal for youths (N = 709, GFI = 0.906, CFI = 0.919, RMSEA = 0.095) and young adults (N = 243, GFI = 0.921, CFI = 0.938, RMSEA = 0.0797) with Cronbach's alpha of 0.87 and 0.88, respectively. Slope of each item exceeded 1.0 on IRT analyses suggesting adequate discrimination for each item. Scores on irritability, anxiety, panic, and insomnia were significantly correlated with similar items on other scales. Together these findings suggest that CAST-12 is a valid self-report measure of irritability, anxiety, insomnia, and panic in youths and young adults.
Subject(s)
Depressive Disorder, Major , Sleep Initiation and Maintenance Disorders , Suicide , Child , Humans , Adolescent , Young Adult , Depression/diagnosis , Depressive Disorder, Major/drug therapy , Psychometrics , Sleep Initiation and Maintenance Disorders/epidemiology , Texas/epidemiology , Reproducibility of Results , Surveys and Questionnaires , Factor Analysis, StatisticalABSTRACT
The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.
ABSTRACT
Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S. aureus GyrB and Escherichia coli ParE. X-ray co-crystal structures of select fragment hits confirmed binding and suggested a path for medicinal chemistry optimization. The identification, characterization, and elaboration of one of these fragment series to a 0.265 µM inhibitor is described herein.
Subject(s)
Anti-Bacterial Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , DNA Gyrase/chemistry , Topoisomerase II Inhibitors/chemistry , Adenosine Triphosphatases/metabolism , Anti-Bacterial Agents/metabolism , Bacterial Proteins/metabolism , Binding Sites , Crystallography, X-Ray , DNA Gyrase/metabolism , DNA Topoisomerase IV/antagonists & inhibitors , DNA Topoisomerase IV/metabolism , Drug Design , Escherichia coli/metabolism , Ligands , Magnetic Resonance Spectroscopy , Molecular Dynamics Simulation , Protein Binding , Protein Structure, Tertiary , Staphylococcus aureus/enzymology , Topoisomerase II Inhibitors/metabolismABSTRACT
Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered. Guided by structure-based drug design, indazole derivatives with excellent enzymatic and antibacterial activity as well as great animal efficacy were discovered.
ABSTRACT
The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , DNA Gyrase/metabolism , Indoles/pharmacology , Methicillin-Resistant Staphylococcus aureus/enzymology , Topoisomerase II Inhibitors/pharmacology , Urea/pharmacology , Bacterial Proteins/metabolism , Crystallography, X-Ray , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/enzymology , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/microbiology , Humans , Indoles/chemistry , Methicillin-Resistant Staphylococcus aureus/drug effects , Models, Molecular , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Topoisomerase II Inhibitors/chemistry , Urea/analogs & derivativesABSTRACT
During kidney organogenesis, tubular epithelial cells proliferate until a functional tubule is formed as sensed by cilia bending in response to fluid flow. This flow-induced ciliary mechanosensation opens the calcium (Ca(2+)) channel polycystin-2 (PC2), resulting in a calcium flux-mediated cell cycle arrest. Loss or mutation of either PC2 or its regulatory protein polycystin-1 (PC1) results in autosomal dominant polycystic kidney disease (ADPKD), characterized by cyst formation and growth and often leading to renal failure and death. Here we show that triptolide, the active diterpene in the traditional Chinese medicine Lei Gong Teng, induces Ca(2+) release by a PC2-dependent mechanism. Furthermore, in a murine model of ADPKD, triptolide arrests cellular proliferation and attenuates overall cyst formation by restoring Ca(2+) signaling in these cells. We anticipate that small molecule induction of PC2-dependent calcium release is likely to be a valid therapeutic strategy for ADPKD.
Subject(s)
Diterpenes/pharmacology , Phenanthrenes/pharmacology , Polycystic Kidney Diseases/drug therapy , TRPP Cation Channels/metabolism , Animals , Calcium/metabolism , Calcium Channels/metabolism , Epithelial Cells/cytology , Epoxy Compounds/pharmacology , Immunosuppressive Agents/pharmacology , Kidney/metabolism , Medicine, Chinese Traditional , Mice , Mice, Transgenic , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Transgenes , p21-Activated KinasesABSTRACT
The antiangiogenic agent fumagillin (Fg) and its analog TNP-470 bind to intracellular metalloprotease methionine aminopeptidase-2 (MetAP-2) and inhibit endothelial cell growth in a p53-dependent manner. To confirm the role of MetAP-2 in endothelial cell proliferation and to validate it as a physiological target for the Fg class of antiangiogenic agents, we have generated a conditional MetAP-2 knockout mouse. Ubiquitous deletion of the MetAP-2 gene (MAP2) resulted in an early gastrulation defect, which is bypassed in double MetAP-2/p53 knockout embryos. Targeted deletion of MAP2 specifically in the hemangioblast lineage resulted in abnormal vascular development, and these embryos die at the midsomite stage. In addition, knockdown of MetAP-2 using small interfering RNA or homologous recombination specifically suppresses the proliferation of cultured endothelial cells. Together, these results demonstrate an essential role for MetAP-2 in angiogenesis and indicate that MetAP-2 is responsible for the endothelial cell growth arrest induced by Fg and its derivatives.