Examining the clinical correlates of conduct disorder in youth with bipolar disorder.

BACKGROUND: Conduct Disorder (CD) is highly comorbid with Bipolar Disorder (BP) and this comorbidity is associated with high morbidity and dysfunction. We sought to better understand the clinical characteristics and familiality of comorbid BP + CD by examining children with BP with and without co-morbid CD. METHODS: 357 subjects with BP were derived from two independent datasets of youth with and without BP. All subjects were evaluated with structured diagnostic interviews, the Child Behavior Checklist (CBCL), and neuropsychological testing. We stratified the sample of subjects with BP by the presence or absence of CD and compared the two groups on measures of psychopathology, school functioning, and neurocognitive functioning. First-degree relatives of subjects with BP +/- CD were compared on rates of psychopathology in relatives. RESULTS: Subjects with BP + CD compared to BP without CD had significantly more impaired scores on the CBCL Aggressive Behavior (p < 0.001), Attention Problems (p = 0.002), Rule-Breaking Behavior (p < 0.001), Social Problems (p < 0.001), Withdrawn/Depressed clinical scales (p = 0.005), the Externalizing Problems (p < 0.001), and Total Problems composite scales(p < 0.001). Subjects with BP + CD had significantly higher rates of oppositional defiant disorder (ODD) (p = 0.002), any SUD (p < 0.001), and cigarette smoking (p = 0.001). First-degree relatives of subjects with BP + CD had significantly higher rates of CD/ODD/ASPD and cigarette smoking compared to first-degree relatives of subjects without CD. LIMITATIONS: The generalization of our findings was limited due to a largely homogeneous sample and no CD only comparison group. CONCLUSIONS: Given the deleterious outcomes associated with comorbid BP + CD, further efforts in identification and treatment are necessary.

Structural evaluation of child physical abuse in trauma: Social determinants of health at the population level.

PURPOSE: Child physical abuse (CPA) is closely linked to social factors like insurance status with limited evaluation at a structural population-level. This study evaluates the role of social determinants of health within the built environment on CPA. METHODS: A single-institution retrospective review of pediatric trauma patients was conducted between January 2016 and December 2020. Patient address was geocoded to the census-tract level. Socioeconomic metrics, including poverty rate, supermarket access and Social Vulnerability Index (SVI) were estimated from the Food Access Research Atlas. Univariate and multivariable regression analyses were conducted to compare demographics and outcomes. RESULTS: Of 3,540 patients, 317 (9.0%) had concern for physical abuse reported in the registry. CPA patients were younger (7.5 vs 9.6 years, p<0.0001) and more often Black (37.0%, N = 117 vs 23.5%, N = 753; p<0.0001). CPA had higher injury severity scores (ISS) (7.9 vs 5.8, p<0.0001) and longer length of stay (5.3 vs 2.9 days, p<0.0001). CPA had higher Medicaid (73.0%, N = 232 vs 53.8%, N = 1748, p<0.0001) and SVI (0.65 vs 0.59, p<0.0001) with lower median income ($52,100 vs $56,100, p<0.0001) and more low-food access tracts (59.6% vs 53.6%, p = 0.06). Combined low-income and low-food access populations showed widened disparities (40.0% vs 28.9%, p = 0.0002). On multivariate analysis, CPA was associated with poverty (OR 2.3, 95% CI [0.979, 3.60], p = 0.0006), low-access Black share (OR 3.3, 95% CI [1.18, 5.47], p = 0.002) and urban designation (OR 1.5, 95% CI [1.13, 1.87], p = 0.004). CONCLUSION: The built-environment and population-level social determinants of health are related to child physical abuse and should influence advocacy and prevention. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Retrospective.

Social determinants of health in pediatric scald burns: Is food access an issue?

BACKGROUND: Burn injury risk, severity, and outcomes have been associated with socioeconomic status. Limited data exist to evaluate health access-related influences at a structural population level. This study evaluated factors at the Census-tract level, specifically evaluating food access and social vulnerability in pediatric scald burns. METHODS: A single-institution retrospective review using the trauma registry and electronic medical record was conducted of pediatric burns between 2016 and 2020. Home address was coded to the Census-tract level and bulk analyzed. Socioeconomic metrics of the home environment were evaluated from publicly available databases, the United States Food and Drug Administration Food Access Research Atlas, and the Centers for Disease Control's Social Vulnerability Index. RESULTS: There were 840 patients that met inclusion criteria (49.8% scald, N = 418). The mean total body surface area for scalds was 6.6% with an age of 10.2 years; 76% (n = 317) of scalds had Medicaid, and 15% (n = 63) were due to hot noodles. Scalds occurred more in females (45.7%, N = 191 vs 28.0%, N = 118; P < .0001), non-White race (62.7%, N = 262 vs 29.1%, N = 123; P < .0001), and low-income and low-food access populations (39.8%, N = 147 vs 30.4%, N = 116; P = .007). Low-food access Black populations showed increased scald injury (18% [interquartile range 6-35] vs 10% [interquartile range 4-25]), whereas all other populations showed no association. The patients with scalds had a higher overall social vulnerability index (0.67 vs 0.62, P = .008). CONCLUSION: Often related to poverty, health access, and health equity, population-level social determinants of health like social vulnerability and food access have significant impact on health care and should influence health outreach and systems improvement.

Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinoma.

While improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis sparked us to reexamine a large kindred originally reported over 50 years ago with an autosomal dominant inheritance pattern of chronic pancreatitis, diabetes and pancreatic adenocarcinoma. Whole exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease Elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines and in CRISPR-Cas9 engineered mice indicate that this mutation causes translational upregulation of CELA3B, which upon secretion and activation by trypsin leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatitic proteases have been previously linked to hereditary pancreatitis, this is the first known instance of a mutation in CELA3B and a defect in translational control contributing to this disease.

Loss of pannexin 1 attenuates melanoma progression by reversion to a melanocytic phenotype.

Pannexin 1 (Panx1) is a channel-forming glycoprotein expressed in different cell types of mammalian skin. We examined the role of Panx1 in melanoma tumorigenesis and metastasis since qPCR and Western blots revealed that mouse melanocytes exhibited low levels of Panx1 while increased Panx1 expression was correlated with tumor cell aggressiveness in the isogenic melanoma cell lines (B16-F0, -F10, and -BL6). Panx1 shRNA knockdown (Panx1-KD) generated stable BL6 cell lines, with reduced dye uptake, that showed a marked increase in melanocyte-like cell characteristics including higher melanin production, decreased cell migration and enhanced formation of cellular projections. Western blotting and proteomic analyses using 2D-gel/mass spectroscopy identified vimentin and ß-catenin as two of the markers of malignant melanoma that were down-regulated in Panx1-KD cells. Xenograft Panx1-KD cells grown within the chorioallantoic membrane of avian embryos developed tumors that were significantly smaller than controls. Mouse-Alu qPCR of the excised avian embryonic organs revealed that tumor metastasis to the liver was significantly reduced upon Panx1 knockdown. These data suggest that while Panx1 is present in skin melanocytes it is up-regulated during melanoma tumor progression, and tumorigenesis can be inhibited by the knockdown of Panx1 raising the possibility that Panx1 may be a viable target for the treatment of melanoma.

How to design an opioid drug that causes reduced tolerance and dependence.

Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.