Does early mentorship in child and adolescent psychiatry make a difference? The Klingenstein Third-Generation Foundation Medical Student Fellowship Program.

OBJECTIVE: There is a critical shortage of child and adolescent psychiatrists in the United States. Increased exposure, through mentorship, clinical experiences, and research opportunities, may increase the number of medical students selecting child and adolescent psychiatry (CAP) as a career choice. METHOD: Between 2008 and 2011, 241 first-year participants of a program to increase exposure to CAP, funded by the Klingenstein Third-Generation Foundation (KTGF) at 10 medical schools completed baseline surveys assessing their opinions of and experiences in CAP, and 115 second-year participants completed follow-up surveys to reflect 1 year of experience in the KTGF Program. RESULTS: Students reported significantly increased positive perception of mentorship for career and research guidance, along with perceived increased knowledge and understanding of CAP. CONCLUSIONS: Results suggest that the KTGF Program positively influenced participating medical students, although future studies are needed to determine whether these changes will translate into more medical students entering the field of CAP.

Whole blood transfusion in the treatment of acute hemorrhage, a systematic review and meta-analysis.

BACKGROUND: Whole blood (WB) transfusion received renewed interest after recent armed conflicts. The effectiveness as compared with blood component transfusion (BCT) is, however, still topic of debate. Therefore, this study investigated the effect of WB ± BCT as compared with BCT transfusion on survival in trauma patients with acute hemorrhage. METHODS: Studies published up to January 16, 2023, including patients with traumatic hemorrhage comparing WB ± BCT and BCT were included in meta-analysis. Subanalyses were performed on the effectiveness of WB in the treatment of civilian or military trauma patients, patients with massive hemorrhage and on platelet (PLT)/red blood cell (RBC), plasma/RBC and WB/RBC ratios. Methodological quality of studies was interpreted using the Cochrane risk of bias tool. The study protocol was registered in PROSPERO under number CRD42022296900. RESULTS: Random effect pooled odds ratio (OR) for 24 hours mortality in civilian and military patients treated with WB as compared with BCT was 0.72 (95% confidence interval [CI], 0.53-0.97). In subanalysis of studies conducted in civilian setting (n = 20), early (4 hours, 6 hours, and emergency department) and 24 hours mortality was lower in WB groups compared with BCT groups (OR, 0.65; 95% CI, 0.44-0.96 and OR, 0.71; 95% CI, 0.52-0.98). No difference in late mortality (28 days, 30 days, in-hospital) was found. In military settings (n = 7), there was no difference in early, 24 hours, or late mortality between groups. The WB groups received significant higher PLT/RBC ( p = 0.030) during early treatment and significant higher PLT/RBC and plasma/RBC ratios during 24 hours of treatment ( p = 0.031 and p = 0.007). The overall risk of bias in the majority of studies was judged as serious due to serious risk on confounding and selection bias, and unclear information regarding cointerventions. CONCLUSION: Civilian trauma patients with acute traumatic hemorrhage treated with WB ± BCT as compared to BCT had lower odds on early and 24-hour mortality. In addition, WB transfusion resulted in higher PLT/RBC and plasma/RBC ratios. LEVEL OF EVIDENCE: Systematic Review and Meta-Analysis; Level III.

Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis.

Adult mammals are incapable of multitissue regeneration, and augmentation of this potential may shift current therapeutic paradigms. We found that a common co-receptor of interleukin 6 (IL-6) cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) were resistant to surgically induced osteoarthritis as reflected by reduced loss of proteoglycans, reduced synovitis, and synovial fibrosis. The F814 mice also exhibited enhanced regenerative, not reparative, responses after wounding in the skin. In addition, pharmacological modulation of gp130 Y814 upstream of the SRC and MAPK circuit by a small molecule, R805, elicited a protective effect on tissues after injury. Topical administration of R805 on mouse skin wounds resulted in enhanced hair follicle neogenesis and dermal regeneration. Intra-articular administration of R805 to rats after medial meniscal tear and to canines after arthroscopic meniscal release markedly mitigated the appearance of osteoarthritis. Single-cell sequencing data demonstrated that genetic and pharmacological modulation of Y814 resulted in attenuation of inflammatory gene signature as visualized by the anti-inflammatory macrophage and nonpathological fibroblast subpopulations in the skin and joint tissue after injury. Together, our study characterized a molecular mechanism that, if manipulated, enhances the intrinsic regenerative capacity of tissues through suppression of a proinflammatory milieu and prevents pathological outcomes in injury and disease.

The haemostatic effect of deep-frozen platelets versus room temperature-stored platelets in the treatment of surgical bleeding: MAFOD-study protocol for a randomized controlled non-inferiority trial.

BACKGROUND: The Netherlands Armed Forces have been successfully using deep-frozen (- 80 °C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere environments since 2001. However, high-quality evidence for the effectiveness and safety of DTCs is currently lacking. Therefore, the MAssive transfusion of Frozen bloOD (MAFOD) trial is designed to compare the haemostatic effect of DTCs versus room temperature-stored platelets (RSP) in the treatment of surgical bleeding. METHODS: The MAFOD trial is a single-blinded, randomized controlled non-inferiority trial and will be conducted in three level 1 trauma centres in The Netherlands. Patients 12 years or older, alive at hospital presentation, requiring a massive transfusion including platelets and with signed (deferred) consent will be included. The primary outcome is the percentage of patients that have achieved haemostasis within 6 h and show signs of life. Haemostasis is defined as the time in minutes from arrival to the time of the last blood component transfusion (plasma/platelets or red blood cells), followed by a 2-h transfusion-free period. This is the first randomized controlled study investigating DTCs in trauma and vascular surgical bleeding. DISCUSSION: The hypothesis is that the percentage of patients that will achieve haemostasis in the DTC group is at least equal to the RSP group (85%). With a power of 80%, a significance level of 5% and a non-inferiority limit of 15%, a total of 71 patients in each arm are required, thus resulting in a total of 158 patients, including a 10% refusal rate. The data collected during the study could help improve the use of platelets during resuscitation management. If proven non-inferior in civilian settings, frozen platelets may be used in the future to optimize logistics and improve platelet availability in rural or remote areas for the treatment of (massive) bleeding trauma patients in civilian settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05502809. Registered on 16 August 2022.

Modulation of Hedgehog Signaling by Kappa Opioids to Attenuate Osteoarthritis.

OBJECTIVE: Inhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA. METHODS: Primary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee OA in rats was used. A novel automated 3-dimensional indentation tester (Mach-1) was used to quantify the thickness and stiffness properties of the articular cartilage. RESULTS: Inhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes (P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants (P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle-treated controls). In JT09-treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% (P = 0.005 versus vehicle-treated controls). CONCLUSION: The results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.

Integrated pharmacologic treatment of attention-deficit hyperactivity disorder (ADHD).

This article is a review of what is currently known about optimal treatments for patients with attention-deficit hyperactivity disorder (ADHD). It begins with a description of assessment techniques and the differential diagnosis, which includes learning disorders, anxiety disorders, and bipolar disorder. The high rate of comorbidity in patients with ADHD and the impact of comorbidity on treatment decisions are also discussed. Detailed descriptions of various pharmacologic treatments are provided, including a description of the role of combination pharmacotherapy and the integration of nonpharmacologic therapy. A decision-making model for selecting the most appropriate pharmacologic therapy versus combining pharmacotherapy with psychosocial interventions is described. The advantages and disadvantages of various pharmacologic agents--including long-acting stimulants and atomoxetine--are examined. Particular attention is paid to the recent Multimodal Treatment Study of Attention-Deficit Hyperactivity Disorder, sponsored by the National Institute of Mental Health, which includes a comparison of long-term pharmacotherapy, behavioral therapy, or a combination thereof, as well as an evaluation of the role of community-based therapy (i.e., treatment as usual). This article focuses on children and adolescents, because most of the research on ADHD has been conducted in this age group. However, a brief section on adults is also provided.

Future directions in air quality research: economic issues.

Our challenge was to address future directions in air quality research that involve economic issues. The paper outlines the role of economics in the evaluation of air pollution impacts on environmental systems and describes existing research. We identify studies that address economic effects in the agricultural sector, in the commercial forest sector, and in unmanaged natural systems. Effects related to ozone exposure are highlighted. The summary of available research is followed by a discussion of research recommendations. Several short-term recommendations are identified that can augment some of the new research being considered by scientists. A more ambitious, long-term research project is outlined for valuing air pollution impacts in unmanaged natural environments. Specifically, the paper describes possible advantages of an 'integrated assessment' framework that more formally brings together the complex relationships that exist in both ecological and economic systems. A final section contains thoughts on the importance of education (i.e., information transfer) in the research process, especially in relation to policy. It is further noted that education should be inclusive of all members of the research team, throughout all stages of the research process.

Diagnostic issues in childhood bipolar disorder.

The field of psychiatry has largely discounted the existence of bipolar disorder (BD) in children and viewed adolescent-onset BD as uncommon until recently. Evidence demonstrating that a significant number of adults with BD report symptom onset before age 19 has led to an explosion in the recognition of childhood BD over the past decade. Because children and adolescents, including preschoolers, are being diagnosed with BD in rapidly increasing numbers, the criteria for mania are being adjusted in children and adolescents to accommodate various presentations of emotional dysregulation into the paradigm of BD. Still, it has yet to be seen whether these presentations will develop in adulthood into what we have traditionally considered to be BD. This blurring of the diagnostic lines has led to significant controversy in the field of child and adolescent psychiatry. This article introduces current thinking about this controversial diagnosis through two case examples.

A bio-robotic leg orthosis for rehabilitation and mobility enhancement.

This paper describes a wearable powered leg orthosis that includes a high-torque actuator, electronics, sensors, and embedded firmware. The device provides multiple modes of operation including automatic assistance, manual assistance, continuous passive motion and robotic therapy. Patients affected by neurological conditions including stroke, MS, and Parkinson's disease may benefit from robotic therapy and from the improved mobility provided by this portable, lightweight device. A preliminary study of chronic stroke patients has shown retained improvement in walking speed for patients undergoing rehabilitation with the device.

FlexCVA: a continuously variable actuator for active orthotics.

Active orthotic devices require actuators with high torque, a free movement mode, high efficiency, and small size and weight. The FlexCVA is a new type of actuator that addresses these requirements in a unique way. It provides continuously varying torque through the use of two belts alternately deflected by cams. The belts alternate in supplying output torque with one belt pulling the output while the slack is removed from the other belt. The drive ratio is automatically adjusted in response to the load by varying the deflection distance of the belts. The resulting actuator prototype has been demonstrated to supply up to 34 Nm of output torque, and its free movement mode allows it to be backdriven at speeds greater than 400 deg/sec.