Digital twin mathematical models suggest individualized hemorrhagic shock resuscitation strategies.

BACKGROUND: Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting. METHODS: We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation. RESULTS: The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time. CONCLUSIONS: This workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings.

Research to improve survival in patients with severe bleeding after major trauma presents many challenges. Here, we created a computer model to simulate the effects of severe bleeding. We refined this model using data from existing animal studies to ensure our simulations were accurate. We also used patient data to further refine the simulations to accurately predict which patients would live and which would not. We studied the effects of different treatment protocols on these simulated patients and show that treatment with plasma (the fluid portion of blood that helps form blood clots) and red blood cells jointly, gave better results than treatment with intravenous fluid or plasma alone. Early treatment with plasma reduced injury severity and increased survival time. This modelling approach may improve our ability to evaluate new treatments for trauma-associated bleeding and other acute conditions.

Long-term follow-up of participants in ketamine clinical trials for mood disorders.

BACKGROUND: Participants who received ketamine at the NIMH were among the first to receive ketamine for depression in controlled clinical trials, providing a unique opportunity to assess long-term outcomes. This analysis evaluated the relationship between participating in a ketamine clinical trial and subsequent ketamine/esketamine use after leaving the research setting. METHODS: Participants seen within the NIMH Experimental Therapeutics and Pathophysiology Branch from 2002 to 2022 (n = 1000) were contacted for follow-up assessment. Participants reported whether they had used ketamine/esketamine, sought non-prescribed ketamine, attempted suicide, or been psychiatrically hospitalized since discharge. Information regarding their recent depressive symptoms, dissociative symptoms, and hallucinations was also collected. RESULTS: Of the 203 participants in follow-up assessments (55 % female, average time since leaving NIMH = 9.04 years), 52 (25.6 %) had originally received ketamine at the NIMH, and the rest had participated in non-ketamine studies. Individuals who had received ketamine at the NIMH were more likely to have received ketamine/esketamine post-discharge than those who did not receive ketamine at the NIMH (OR = 0.25, p < .001). Participants who reported using ketamine/esketamine post-discharge reported more depressive symptoms than those who had not (p < .001). Receiving ketamine at the NIMH was not associated with differences in suicide attempts, psychiatric hospitalizations, dissociation, hallucinations, or attempt to obtain non-prescribed ketamine. LIMITATIONS: Low follow-up study participation rate; varying time since discharge. CONCLUSIONS: Participants who received ketamine in an NIMH clinical trial were more likely to receive ketamine/esketamine post-discharge, but none reported symptoms indicating abuse. Results underscore the critical need for long-term follow-up of individuals receiving these and other rapid-acting antidepressants. CLINICAL TRIALS IDENTIFIER: NCT04877977.

The mental health impact of contact with COVID-19 patients on healthcare workers in the United States.

This study assessed the relationship between contact with COVID-19 patients and the mental health of healthcare workers (HCWs) in the United States (US). In a convenience sample of 957 HCWs who completed an anonymous online survey between April-May 2020, HCWs who provided direct care to confirmed or suspected COVID-19 patients reported increased depressive and posttraumatic symptoms compared to HCWs with no COVID-19 patient contact. Additionally, more frequent contact was associated with higher distress. More data drawn from diverse samples that better represent US HCWs are needed to fully assess the scope of this association.

Child and parent reports of children's depressive symptoms in relation to children's weight loss response in family-based obesity treatment.

BACKGROUND: Studies of the association between children's depressive symptoms and obesity treatment response show mixed results. Different measurement may contribute to the inconsistent findings, as children's depressive symptoms are often based on parent-report about their child rather than child self-report. OBJECTIVES: We assessed both child- and parent-report of child depressive symptoms as predictors of children's obesity treatment response. METHODS: Children with overweight/obesity (body mass index [BMI] ≥ 85th percentile; N = 181) and their parents reported on children's depressive symptoms prior to family-based behavioral weight loss treatment. RESULTS: Child percent overweight reduction from baseline to post-treatment was not predicted by child self-reported depressive symptoms or parent-report of child symptoms (P > 0.80), but was significantly predicted by the interaction between child self-report and parent-report on child (ß = 0.14, P = 0.05). In analyses using clinical cutoffs, amongst children with high self-reported symptoms, those whose parents reported low child depressive symptoms had greater reduction in percent overweight (t = 2.67, P = 0.008), whereas amongst children with low self-reported symptoms, parent ratings were not associated with treatment outcome. CONCLUSIONS: Including both child self-report and parent-report of child depressive symptoms may inform obesity care. Research is needed to examine differences amongst child and parent depressive symptom reports and strategies to address symptoms and optimize pediatric obesity treatment.

Patterns of Eating Disorder Pathology are Associated with Weight Change in Family-Based Behavioral Obesity Treatment.

OBJECTIVE: Children with overweight or obesity have elevated eating disorder (ED) pathology, which may increase their risk for clinical EDs. The current study identified patterns of ED pathology in children with overweight or obesity entering family-based behavioral weight loss treatment (FBT) and examined whether children with distinct patterns differed in their ED pathology and BMI z score (zBMI) change across FBT. METHODS: Before participating in a 16-session FBT, children (N = 241) completed surveys or interviews assessing ED pathology (emotional eating, shape/weight/eating concerns, restraint, and loss of control [LOC]). Shape and weight concerns (SWC) and LOC were also assessed post treatment. Child height and weight were measured at baseline and post treatment. Latent class analysis identified patterns of ED pathology. Repeated-measures ANOVA examined changes in zBMI and ED pathology. RESULTS: Four patterns of ED pathology were identified: low ED pathology, SWC, only loss of control, and high ED pathology. SWC decreased across treatment, with the highest decreases in patterns characterized by high SWC. All groups experienced significant decreases in zBMI; however, children with the highest ED pathology did not achieve clinically significant weight loss. CONCLUSIONS: ED pathology decreased after FBT, decreasing ED risk. While all children achieved zBMI reductions, further research is needed to enhance outcomes for children with high ED pathology.

Psychometric evaluation of the youth eating disorder examination questionnaire in children with overweight or obesity.

This study evaluated the psychometric properties of the Youth Eating Disorder Examination Questionnaire (YEDE-Q) and its utility for detecting loss of control (LOC) eating (i.e., eating episodes, regardless of size, involving a perceived inability to control what or how much one is eating) among school-age children with overweight or obesity. Identifying eating pathology, particularly LOC eating, in this population may facilitate treatment that improves weight outcomes and reduces eating disorder risk. Children with overweight or obesity (N = 241; 7-11 years) completed the YEDE-Q and abbreviated Child EDE (ChEDE) to assess LOC eating, prior to entering a weight management treatment trial. Confirmatory factor analyses (CFA) were conducted on children's YEDE-Q responses and compared to the standard adult EDE-Q factor structure and newer, alternate factor structures. CFA supported a three-factor structure, which distinguished youth with versus without LOC. The YEDE-Q showed low accuracy for detecting LOC eating as measured by the ChEDE, which served as the gold-standard benchmark (AUC = 0.69). Among children who endorsed LOC eating, more episodes per month were reported on the YEDE-Q than ChEDE (p < .001). The YEDE-Q may not have utility as a screener for identifying true cases of LOC eating among school-age children with overweight or obesity. Further evaluation of the YEDE-Q and the alternate three-factor structure is warranted.

The role of N-cadherin, MCAM and beta3 integrin in melanoma progression, proliferation, migration and invasion.

Melanoma, the most aggressive form of skin cancer, which accounts for 75% of all skin cancer-related deaths, continues to rise at an alarming rate worldwide. Despite a favorable cure rate when surgically removed at an early stage, the response rate of patients with metastatic disease to single agent chemotherapy is less than 15%, and biologic therapies are only marginally effective. Given this bleak picture, there is a great need to identify and characterize genes that play an important role in the advanced stages of melanoma and thus, may represent valuable targets for clinical therapy. The cell adhesion molecules N-cadherin, MCAM and beta3 integrin have been suggested to represent melanoma progression markers; yet, little is known as to whether they may constitute therapeutic targets for the disease. To provide information regarding this aspect, we determined by way of whole-genome and tissue microarray analysis, their level of expression concordant with melanoma progression, and via RNA interference and antisense technology, their role in melanoma cell proliferation, migration, and invasion. The results of these studies demonstrate that N-cadherin and beta3 integrin expression correlates with progression to advanced-stage melanoma, whereas expression of MCAM does not. On the other hand, MCAM and beta3 integrin are the two adhesion molecules that play a pivotal role in melanoma cell migration and invasion, and for this reason, may represent valuable targets for melanoma therapy.