Characterization of PRAME immunohistochemistry reveals lower expression in pediatric melanoma compared to adult melanoma.

Pediatric melanomas are rare tumors that have clinical and histological differences from adult melanomas. In adult melanoma, the immunohistochemical marker PRAME is increasingly employed as a diagnostic adjunct. PRAME is also under investigation as a target structure for next-generation immunotherapies including T-cell engagers. Little is known about the characteristics of PRAME expression in pediatric melanoma. In this retrospective study, samples from 25 pediatric melanomas were compared with control groups of melanomas in young adults (18-30 years; n = 32), adult melanoma (>30 years, n = 30), and benign melanocytic nevi in children (0-18 years; n = 30) with regard to the immunohistochemical expression of PRAME (diffuse PRAME expression >75%/absolute expression). Pediatric melanomas show lower diffuse PRAME expression (4%) and lower absolute PRAME expression (25%) compared to young adult melanomas (15.6%/46.8%) and adult melanomas (50%/70%). A significant age-dependent expression could be observed. An analysis of event-free survival shows no prognostic role for PRAME in pediatric melanoma and young adult melanoma, but a significant association with diffuse PRAME expression in adulthood. The age dependency of PRAME expression poses a potential pitfall in the diagnostic application of melanocytic tumors in young patients and may limit therapeutic options within this age group. The immunohistochemical expression of the tumor-associated antigen PRAME is an increasingly important diagnostic marker for melanocytic tumors and is gaining attention as a possible immunotherapeutic target in melanoma. As the available data primarily stem from adult melanoma, and given the clinical and histological distinctions in pediatric melanomas, our understanding of PRAME expression in this specific patient group remains limited. The age-dependent low PRAME expression shown here constrains the use of this marker in pediatric melanoma and may also limit the use of immunotherapeutic strategies against PRAME in young patients.

Assessment of Comorbid Obsessive-Compulsive Disorder and Posttraumatic Stress Disorder.

Obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) are commonly comorbid and share prominent features (e.g., intrusions, safety behaviors, and avoidance). Excellent self-report and clinician-administered assessments exist for OCD and PTSD individually, but few assess both disorders, and even fewer provide instruction on differential diagnosis or detection of comorbid OCD and PTSD. To address this gap in the literature, the current paper aims to (1) highlight diagnostic and functional similarities and differences between OCD and PTSD to inform differential diagnosis, (2) outline assessment recommendations for individuals with suspected comorbid OCD and PTSD, OCD with a significant trauma history or posttraumatic symptoms, or PTSD with significant obsessive-compulsive symptoms, and (3) explore future directions to evaluate and improve methods for assessing co-occurring OCD and PTSD.

NUT carcinoma in pediatric patients: Characteristics, therapeutic regimens, and outcomes of 11 cases registered with the German Registry for Rare Pediatric Tumors (STEP).

BACKGROUND AND AIMS: Nuclear protein of the testis (NUT) carcinoma (NC) is a rare and highly aggressive tumor defined by the presence of a somatic NUTM1 rearrangement, occurring mainly in adolescents and young adults. We analyzed the clinical and biological features of German pediatric patients (≤18 years) with NC. METHODS: This study describes the characteristics and outcome of 11 children with NC registered in the German Registry for Rare Pediatric Tumors (STEP). RESULTS: Eleven patients with a median age of 13.2 years (range 6.6-17.8) were analyzed. Malignant misdiagnoses were made in three patients. Thoracic/mediastinal tumors were found to be the primary in six patients, head/neck in four cases; one patient had multifocal tumor with an unknown primary. All patients presented with regional lymph node involvement, eight patients (72.7%) with distant metastases. Seven patients underwent surgery, eight radiotherapy with curative intent; polychemotherapy was administered in all patients. Novel treatment strategies including immunotherapy, targeted therapies, and virotherapy were applied in three patients. Median event-free survival and overall survival were 1.5 and 6.5 months, respectively. CONCLUSIONS: Every undifferentiated or poorly differentiated carcinoma should undergo testing for the specific rearrangement of NUTM1, in order to initiate an intense therapeutic regimen as early as possible. As in adults, only few pediatric patients with NC achieve prolonged survival. Thus, novel therapeutic strategies should be included and tested in clinical trials.

UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescents.

BACKGROUND: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. METHODS: Exome sequencing of matched tumour-normal pairs from 26 paediatric patients was performed to study the mutational spectrum of melanomas. The cohort was grouped into different categories: spitzoid melanoma (SM), conventional melanoma (CM), and other melanomas (OT). FINDINGS: In all patients with CM (n = 10) germline variants associated with melanoma were found in low to moderate melanoma risk genes: in 8 patients MC1R variants, in 2 patients variants in MITF, PTEN and BRCA2. Somatic BRAF mutations were detected in 60% of CMs, homozygous deletions of CDKN2A in 20%, TERTp mutations in 30%. In the SM group (n = 12), 5 patients carried at least one MC1R variant; somatic BRAF mutations were detected in 8.3%, fusions in 25% of the cases. No SM showed a homozygous CDKN2A deletion nor a TERTp mutation. In 81.8% of the CM/SM cases the UV damage signatures SBS7 and/or DBS1 were detected. The patient with melanoma arising in giant congenital nevus (CNM) demonstrated the characteristic NRAS Q61K mutation. INTERPRETATION: UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future. FUNDING: Found in Acknowledgement.

Frontopolar multifocal transcranial direct current stimulation reduces conditioned fear reactivity during extinction training: A pilot randomized controlled trial.

Exposure-based therapies for anxiety and related disorders are believed to depend on fear extinction learning and corresponding changes in extinction circuitry. Frontopolar multifocal transcranial direct current stimulation (tDCS) has been shown to improve therapeutic safety learning during in vivo exposure and may modulate functional connectivity of networks implicated in fear processing and inhibition. A pilot randomized controlled trial was completed to determine the effects of frontopolar tDCS on extinction learning and memory. Community volunteers (n = 35) completed a 3-day fear extinction paradigm with measurement of electrodermal activity. Participants were randomized (single-blind) to 20-min of sham (n = 17, 30 s. ramp in/out) or active (n = 18) frontopolar (anode over Fpz, 10-10 EEG) multifocal tDCS (20-min, 1.5 mA) prior to extinction training. Mixed ANOVAs revealed a significant group*trial effect on skin conductance response (SCR) to the conditioned stimulus (CS + ) during extinction training (p = 0.007, Cohen's d = 0.55). The effects of frontopolar tDCS were greatest during the first two extinction trials, suggesting that tDCS may have promoted fear inhibition prior to safety learning. Return of fear to the CS + during tests were comparable across conditions (ps > 0.50). These findings suggest that frontopolar tDCS may modulate the processing of threat cues and associated circuitry or promote the inhibition of fear. This has clear implications for the treatment of anxiety and related disorders with therapeutic exposure.

Operative Trauma Courses: A Scoping Review to Inform the Development of a Trauma Surgery Course for Low-Resource Settings.

BACKGROUND: A multitude of operative trauma courses exist, most of which are designed for and conducted in high-resource settings. There are numerous barriers to adapting such courses to low- and low-middle-income countries (LMICs), including resource constraints and contextual variations in trauma care. Approaches to implementing operative trauma courses in LMICs have not been evaluated in a structured manner. METHODS: We conducted a scoping review of the literature including databases (e.g., PubMed, Web of Science, EMBASE), grey literature repositories, and structured queries of publicly available course materials to identify records that described operative trauma courses offered since 2000. RESULTS: The search identified 3,518 non-duplicative records, of which 48 relevant reports were included in analysis. These reports represented 23 named and 11 unnamed operative trauma courses offered in 12 countries. Variability existed in course format and resource requirements, ranging from USD 40 to 3,000 per participant. Courses incorporated didactic and laboratory components, which utilized simulations, cadavers, or live animals. Course content overlapped significantly but was not standardized. Data were lacking on course implementation and promulgation, credentialing of instructors, and standardized evaluation metrics. CONCLUSIONS: While many operative trauma courses have been described, most are not directly relatable to LMICs. Barriers include cost-prohibitive fees, lack of resources, limited data collection, and contextual variability that renders certain surgical care inappropriate in LMICs. Gaps exist in standardization of course content as well as transparency of credentialing and course implementation strategies. These issues can be addressed through developing an open-access operative trauma course for low-resource settings.

Latent classes of symptom trajectories during partial hospitalization for major depressive disorder and generalized anxiety disorder.

BACKGROUND: A variety of treatments have been empirically validated in the treatment of major depressive disorder and generalized anxiety disorder. Researchers commonly evaluate symptom change during treatment using single model curves, however, modeling multiple curves simultaneously allows for the identification of subgroups of patients that progress through treatment on distinct paths. METHODS: Latent growth mixture modeling was used to identify and characterize distinct classes of symptom trajectories among two samples of patients with either MDD or GAD receiving treatment in a daily partial hospital program. RESULTS: Four depression symptom trajectories were identified in the MDD sample, and three anxiety symptom trajectories were identified in the GAD sample. Both samples shared symptom trajectory classes of responders, rapid responders, and minimal responders, while the MDD sample demonstrated an additional class of early rapid responders. In both samples, low symptom severity at baseline was associated with membership in the responder class, though few other patterns emerged in baseline characteristics predicting trajectory class membership. At treatment discharge, those in the minimal responder class reported poorer outcomes on every clinical measure. Patients within each class reported similar scores at discharge as compared to each other class, indicating that class membership affects clinical measures beyond symptom severity. LIMITATIONS: Patient demographic characteristics were relatively homogeneous. Group-based trajectory modeling inherently involves some degree of uncertainty regarding the number and shape of trajectories. CONCLUSIONS: Identifying symptom trajectories can provide information regarding how patients are likely to progress through treatment, and thus inform clinicians when a patient deviates from expected progress.

Perioperative Risk Assessment in Humanitarian Settings: A Scoping Review.

BACKGROUND: No validated perioperative risk assessment models currently exist for use in humanitarian settings. To inform the development of a perioperative mortality risk assessment model applicable to humanitarian settings, we conducted a scoping review of the literature to identify reports that described perioperative risk assessment in surgical care in humanitarian settings and LMICs. METHODS: We conducted a scoping review of the literature to identify records that described perioperative risk assessment in low-resource or humanitarian settings. Searches were conducted in databases including: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Science, World Health Organization Catalog, and Google Scholar. RESULTS: Our search identified 1582 records. After title/abstract and full text screening, 50 reports remained eligible for analysis in quantitative and qualitative synthesis. These reports presented data from over 37 countries from public, NGO, and military facilities. Data reporting was highly inconsistent: fewer than half of reports presented the indication for surgery; less than 25% of reports presented data on injury severity or prehospital data. Most elements of perioperative risk models designed for high-resource settings (e.g., vital signs, laboratory data, and medical comorbidities) were unavailable. CONCLUSION: At present, no perioperative mortality risk assessment model exists for use in humanitarian settings. Limitations in consistency and quality of data reporting are a primary barrier, however, can be addressed through data-driven identification of several key variables encompassed by a minimum dataset. The development of such a score is a critical step toward improving the quality of care provided to populations affected by conflict and protracted humanitarian crises.

Disparities in detection of suspected child abuse.

BACKGROUND: Child abuse is a significant cause of injury and death among children, but accurate identification is often challenging. This study aims to assess whether racial disparities exist in the identification of child abuse. METHODS: The 2010-2014 and 2016-2017 National Trauma Data Bank was queried for trauma patients ages 1-17. Using ICD-9CM and ICD-10CM codes, children with injuries consistent with child abuse were identified and analyzed by race. RESULTS: Between 2010-2014 and 2016-2017, 798,353 patients were included in NTDB. Suspected child abuse victims (SCA) accounted for 7903 (1%) patients. Of these, 51% were White, 33% Black, 1% Asian, 0.3% Native Hawaiian/Other Pacific Islander, 2% American Indian, and 12% other race. Black patients were disproportionately overrepresented, composing 12% of the US population, but 33% of SCA patients (p < 0.001). Although White SCA patients were more severely injured (ISS 16-24: 20% vs 16%, p < 0.01) and had higher in-hospital mortality (9% vs. 6%, p = 0.01), Black SCA patients were hospitalized longer (7.2 ± 31.4 vs. 6.2 ± 9.9 days, p < 0.01) despite controlling for ISS (1-15: 4. 5.7 ± 35.7 vs. 4.2 ± 6.2 days, p < 0.01). In multivariate regression, Black children continued to have longer lengths of stay despite controlling for ISS and insurance type. CONCLUSIONS: Utilizing a nationally representative dataset, Black children were disproportionately identified as potential victims of abuse. They were also subjected to longer hospitalizations, despite milder injuries. Further studies are needed to better understand the etiology of the observed trends and whether they reflect potential underlying unconscious or conscious biases of mandated reporters. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: III.

Strengthening the emergency health response to children wounded by explosive weapons in conflict.

The 2022 war in Ukraine has highlighted the unacceptable consequences wrought on civilians and health infrastructure by conflict. Children are among the most vulnerable of those affected and constitute an increasing percentage of non-combatants injured in conflicts globally. A disproportionate number of these injuries are caused by blast mechanisms from munitions including 'conventional' landmines and indiscriminate explosive weapons such as barrel bombs and improvised explosive devices. In 21st century conflict, children are no longer only accidental casualties of war, but are increasingly targeted by parties through acts such as bombing of school buses and playgrounds, conscription as child soldiers, and use as human shields. In the present viewpoint article, we review the state of pediatric blast injury studies, synthesizing current understandings of injury epidemiology and identifying gaps in research to advance the field towards a concrete agenda to improve care for this vulnerable population.

A broadly tuned network for affective body language in the macaque brain.

Body language is a powerful tool that we use to communicate how we feel, but it is unclear whether other primates also communicate in this way. Here, we use functional magnetic resonance imaging to show that the body-selective patches in macaques are activated by affective body language. Unexpectedly, we found these regions to be tolerant of naturalistic variation in posture as well as species; the bodies of macaques, humans, and domestic cats all evoked a stronger response when they conveyed fear than when they conveyed no affect. Multivariate analyses confirmed that the neural representation of fear-related body expressions was species-invariant. Collectively, these findings demonstrate that, like humans, macaques have body-selective brain regions in the ventral visual pathway for processing affective body language. These data also indicate that representations of body stimuli in these regions are built on the basis of emergent properties, such as socio-affective meaning, and not just putative image properties.

Characterization of Humanitarian Trauma Care by US Military Facilities During Combat Operations in Afghanistan and Iraq.

OBJECTIVE: To characterize humanitarian trauma care delivered by US military treatment facilities (MTFs) in Afghanistan and Iraq during combat operations. BACKGROUND: International Humanitarian Law, which includes the Geneva Conventions, defines protections and standards of treatment to victims of armed conflicts. In 1949, these standards expanded to include injured civilians. In 2001, the Global War on Terror began in Afghanistan and expanded to Iraq in 2003. US MTFs provided care to all military forces, civilians, and enemy prisoners. A thorough understanding of the scope, epidemiology, resource requirements, and outcomes of civilian trauma in combat zones has not been previously characterized. METHODS: Retrospective cohort analysis of the Department of Defense Trauma Registry from 2005 to 2019. Inclusion criteria were civilians and Non-North Atlantic Treaty Organization (NATO) Coalition Personnel (NNCP) with traumatic injuries treated at MTFs in Afghanistan and Iraq. Patient demographics, mechanism of injury, resource requirements, procedures, and outcomes were categorized. RESULTS: A total of 29,963 casualties were eligible from the Registry. There were 16,749 (55.9%) civilians and 13,214 (44.1%) NNCP. The majority of patients were age above 13 years [26,853 (89.6%)] and male [28,000 (93.4%)]. Most injuries were battle-related: 12,740 (76.1%) civilians and 11,099 (84.0%) NNCP. Penetrating trauma was the most common cause of both battle and nonbattle injuries: 12,293 (73.4%) civilian and 10,029 (75.9%) NNCP. Median Injury Severity Score (ISS) was 9 in each cohort with ISS≥25 in 2236 (13.4%) civilians and 1398 (10.6%) NNCP. Blood products were transfused to 35% of each cohort: 5850 civilians received a transfusion with 2118 (12.6%) of them receiving ≥10 units; 4590 NNCPs received a transfusion with 1669 (12.6%) receiving ≥10 units. MTF mortality rates were civilians 1263 (7.5%) and NNCP 776 (5.9%). Interventions, both operative and nonoperative, were similar between both groups. CONCLUSIONS: In accordance with International Humanitarian Law, as well as the US military's medical rules of eligibility, civilians injured in combat zones were provided the same level of care as NNCP. Injured civilians and NNCP had similar mechanisms of injury, injury patterns, transfusion needs, and ISS. This analysis demonstrates resource equipoise in trauma care delivered to civilians and NNCP. Hospitals in combat zones must be prepared to manage large numbers of civilian casualties with significant human and material resources allocated to optimize survival. The provision of humanitarian trauma care is resource-intensive, and these data can be used to inform planning factors for current or future humanitarian care in combat zones.

Strengthening global health security by improving disease surveillance in remote rural areas of low-income and middle-income countries.

The COVID-19 pandemic has underscored the need to strengthen national surveillance systems to protect a globally connected world. In low-income and middle-income countries, zoonotic disease surveillance has advanced considerably in the past two decades. However, surveillance efforts often prioritise urban and adjacent rural communities. Communities in remote rural areas have had far less support despite having routine exposure to zoonotic diseases due to frequent contact with domestic and wild animals, and restricted access to health care. Limited disease surveillance in remote rural areas is a crucial gap in global health security. Although this point has been made in the past, practical solutions on how to implement surveillance efficiently in these resource-limited and logistically challenging settings have yet to be discussed. We highlight why investing in disease surveillance in remote rural areas of low-income and middle-income countries will benefit the global community and review current approaches. Using semi-arid regions in Kenya as a case study, we provide a practical approach by which surveillance in remote rural areas can be strengthened and integrated into existing systems. This Viewpoint represents a transition from simply highlighting the need for a more holistic approach to disease surveillance to a solid plan for how this outcome might be achieved.

Pediatric casualties in contemporary armed conflict: A systematic review to inform standardized reporting.

BACKGROUND: Children represent a significant percentage of casualties in modern conflict. Yet, the epidemiology of conflict-related injury among children is poorly understood. A comprehensive analysis of injuries sustained by children in 21st-century armed conflict is necessary to inform planning of local, military, and humanitarian health responses. METHODS: We conducted a systematic search of databases including PubMed, Embase, Web of Science, World Health Organization Catalog, and Google Scholar to identify records that described conflict-related injuries sustained by children since 2001. RESULTS: The search returned 5,264 records. 9 eligible reports without potentially duplicative data were included in analysis, representing 5,100 pediatric patients injured in 5 conflicts. Blast injury was the most frequent mechanism (57%), compared to 24.8% in adults. Mortality was only slightly higher among children (11.0% compared to 9.8% among adults; p <0.05). Non-uniform reporting prevented pooled analysis and limited the conclusions that could be drawn. CONCLUSIONS: Children sustain a higher proportion of blast injury than adults in conflict. Existing data do support the conclusion that child casualties have higher mortality than adults overall; however, this difference is slighter than has been previously reported. Specific subpopulations of children appear to have worse outcomes. Overall, non-uniform reporting renders currently available data insufficient to understand the needs of children injured in modern conflict.

Estrogen Withdrawal Increases Postpartum Anxiety via Oxytocin Plasticity in the Paraventricular Hypothalamus and Dorsal Raphe Nucleus.

BACKGROUND: Estrogen increases dramatically during pregnancy but quickly drops below prepregnancy levels at birth and remains suppressed during the postpartum period. Clinical and rodent work suggests that this postpartum drop in estrogen results in an estrogen withdrawal state that is related to changes in affect, mood, and behavior. How estrogen withdrawal affects oxytocin (OT) neurocircuitry has not been examined. METHODS: We used a hormone-simulated pseudopregnancy followed by estrogen withdrawal in Syrian hamsters, a first for this species. Ovariectomized females were given daily injections to approximate hormone levels during gestation and then withdrawn from estrogen to simulate postpartum estrogen withdrawal. These hamsters were tested for behavioral assays of anxiety and anhedonia during estrogen withdrawal. Neuroplasticity in OT-producing neurons in the paraventricular nucleus of the hypothalamus and its efferent targets was measured. RESULTS: Estrogen-withdrawn females had increased anxiety-like behaviors in the elevated plus maze and open field tests but did not differ from control females in sucrose preference. Furthermore, estrogen-withdrawn females had more OT-immunoreactive cells and OT messenger RNA in the paraventricular nucleus of the hypothalamus and an increase in OT receptor density in the dorsal raphe nucleus. Finally, blocking OT receptors in the dorsal raphe nucleus during estrogen withdrawal prevented the high-anxiety behavioral phenotype in estrogen-withdrawn females. CONCLUSIONS: Estrogen withdrawal induces OT neuroplasticity in the paraventricular nucleus of the hypothalamus and dorsal raphe nucleus to increase anxiety-like behavior during the postpartum period. More broadly, these experiments suggest Syrian hamsters as a novel organism in which to model the effects of postpartum estrogen withdrawal on the brain and anxiety-like behavior.