Slipped capital femoral epiphysis: emphasis on early recognition and potential pitfalls.

Slipped capital femoral epiphysis is a shearing injury through the growth plate of the proximal femur and is the most common hip disorder in adolescence. Delays in diagnosis persist across practice settings despite ongoing innovations in imaging. Recent insights into pathomechanics highlight the importance of femoral head surface morphology and rotational microinstability centered at the epiphyseal tubercle in causing early physeal changes, which can be detected on imaging prior to frank slip. Scrutiny of physeal morphology and comparison to the contralateral hip is critical at all stages of disease progression, and improper technique may result in undue diagnostic delay. Selective use of cross-sectional imaging can be helpful for troubleshooting equivocal early slips and can inform operative technique and adjuvant therapy candidacy in more severe cases. This review provides a comprehensive approach to imaging suspected slipped capital femoral epiphysis, with an emphasis on early detection and potential pitfalls.

Experiential Training in Psychedelic-Assisted Therapy: A Risk-Benefit Analysis.

Well-trained, competent therapists are crucial for safe and effective psychedelic-assisted therapy (PAT). The question whether PAT training programs should require aspiring therapists to undergo their own PAT-commonly referred to as "experiential training"-has received much attention within the field. In this article, we analyze the potential benefits of experiential training in PAT by applying the framework developed by Rolf Sandell et al. concerning the functions of any training therapy (the therapeutic, modeling, empathic, persuasive, and theoretical functions). We then explore six key domains in which risks could arise through mandatory experiential training: physical and psychological risks; negative impact on therapeutic skill; justice, equity, diversity, and inclusion; dual relationships; privacy and confidentiality; and undue pressure. Ultimately, we argue that experiential training in PAT should not be mandatory. Because many PAT training programs already incorporate experiential training methods, our exploration of potential harms and benefits may be used to generate comprehensive risk-mitigation strategies.

Imaging approach to pediatric calvarial bulges.

Palpable calvarial lesions in children may require multi-modality imaging for adequate characterization due to non-specific clinical features. Causative lesions range from benign incidental lesions to highly aggressive pathologies. While tissue sampling may be required for some lesions, others have a typical imaging appearance, and an informed imaging approach facilitates diagnosis. This review illustrates imaging findings of common and clinically important focal pediatric calvarial bulges to aid the radiologist in narrowing the differential diagnosis and directing appropriate referral. We focus on birth-related lesions, congenital abnormalities, and modeling disturbances (i.e., those that produce a change in calvarial contour early in development), normal variants, and neoplastic lesions with their mimics.

Palliative psychiatry: research, clinical, and educational priorities.

BACKGROUND: Palliative psychiatry has been proposed as a new clinical construct within mental health care and aims to improve quality of life (QoL) for individuals experiencing severe and persistent mental illness (SPMI). To date, explorations of palliative psychiatry have been largely theoretical, and more work is needed to develop its approaches into tangible clinical practice. METHODS: In this paper, we synthesize existing literature with discussions held at a one-day knowledge user meeting titled "A Community of Practice for Palliative Psychiatry" to generate priorities for research, clinical practice, and education that will help advance the development of palliative psychiatry. RESULTS: Palliative psychiatry will benefit from research that is co-produced by people with lived experience (PWLE) of mental illness, that clarifies contested concepts within mental health care and wider medicine, and that adapts existing interventions that have the potential to improve the QoL of individuals experiencing SPMI into the mental health care context. Specific methods and tools might be developed for use in clinical spaces taking a palliative psychiatry approach. More work must be done to understand the populations that might benefit from palliative psychiatry, and to mitigate mental health care providers' (MHCPs') anxieties about using these approaches in their work. As palliative psychiatry is developed, current MHCPs, trainees, individuals experiencing SPMI, and their loved ones will all require education about and orientation to this novel approach within mental health care. CONCLUSIONS: There are several priorities in research, clinical practice, and education that can help advance the development of palliative psychiatry. All future work must be considered through a human rights-based, anti-oppressive lens. Research projects, clinical models, and educational initiatives should all be developed in co-production with PWLE to mitigate the epistemic injustices common in mental health care.

Decidual cast: a rare cause of genital tract obstruction.

Decidual cast is a little-known entity characterized by sloughing of the endometrium in several large pieces or in one cylindrical or membranous piece retaining the shape of the uterine cavity. Accounts of the diagnosis are sporadic and have not previously appeared in the pediatric imaging literature. We describe a case of a post-menarchal adolescent girl presenting with abnormal uterine bleeding, severe dysmenorrhea, and imaging features of genital tract obstruction, the cause of which was found to be a large decidual cast during examination under anesthesia. While rare, awareness of this phenomenon should be useful to pediatric imagers as the combination of bleeding and obstructive symptoms produces a confusing picture that may lead to a protracted clinical and imaging course.

Development of a mutant aerosolized ACE2 that neutralizes SARS-CoV-2 in vivo.

The rapid evolution of SARS-CoV-2 variants highlights the need for new therapies to prevent disease spread. SARS-CoV-2, like SARS-CoV-1, uses the human cell surface protein angiotensin-converting enzyme 2 (ACE2) as its native receptor. Here, we design and characterize a mutant ACE2 that enables rapid affinity purification of a dimeric protein by altering the active site to prevent autoproteolytic digestion of a C-terminal His10 epitope tag. In cultured cells, mutant ACE2 competitively inhibits lentiviral vectors pseudotyped with spikes from multiple SARS-CoV-2 variants and infectious SARS-CoV-2. Moreover, the protein can be nebulized and retains virus-binding properties. We developed a system for the delivery of aerosolized ACE2 to K18-hACE2 mice and demonstrated protection by our modified ACE2 when delivered as a prophylactic agent. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents in vivo and suggest a new tool in the ongoing fight against SARS-CoV-2 and other ACE2-dependent viruses. IMPORTANCE: The rapid evolution of SARS-CoV-2 variants poses a challenge for immune recognition and antibody therapies. However, the virus is constrained by the requirement that it recognizes a human host receptor protein. A recombinant ACE2 could protect against SARS-CoV-2 infection by functioning as a soluble decoy receptor. We designed a mutant version of ACE2 with impaired catalytic activity to enable the purification of the protein using a single affinity purification step. This protein can be nebulized and retains the ability to bind the relevant domains from SARS-CoV-1 and SARS-CoV-2. Moreover, this protein inhibits viral infection against a panel of coronaviruses in cells. Finally, we developed an aerosolized delivery system for animal studies and show the modified ACE2 offers protection in an animal model of COVID-19. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents in vivo and suggest a new tool in the ongoing fight against SARS-CoV-2.

Checkpoint inhibitor immunotherapy induced inflammatory arthritis secondary to Nivolumab and Ipilimumab: a pediatric first.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have expanded the arsenal of cancer therapeutics over the last decade but are associated with a spectrum of immune-related adverse events (irAEs), including inflammatory arthritis. While these complications are increasingly recognized in the adult population, no cases of inflammatory arthritis irAEs have been reported in the pediatric literature. CASE PRESENTATION: A 14-year-old female with metastatic epithelioid mesothelioma was referred to the pediatric rheumatology clinic after developing progressive inflammatory joint pain in her bilateral shoulders, hips, and small joints of hands following the second cycle of Nivolumab and Ipilimumab. Initial examinations showed bilateral shoulder joint line tenderness, positive FABERs test bilaterally, tenderness over bilateral greater trochanters, and bilateral second PIP effusions. Her serological profile was notable for positive HLA-B27, positive anti-CCP, negative Rheumatoid Factor, and negative ANA. PET-CT scan performed for disease response following immunotherapy showed symmetric increased metabolic activity primarily involving the supraspinatus, gluteus medius and minimus, and semimembranosus tendon insertions. Her presentation was consistent with a grade 1 irAE that worsened to a grade 2 irAE despite NSAID therapy, prompting a short course of oral prednisolone. She achieved clinical remission of her mesothelioma following six cycles of Nivolumab and Ipilimumab and her inflammatory arthritis was controlled on Celebrex monotherapy. CONCLUSIONS: To our knowledge, this is the first pediatric case of ICI-induced inflammatory arthritis and enthesitis. This case highlights the importance of increasing awareness of diagnosis and management of irAEs in children.

Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines.

A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for Gq signaling to measure agonistic activation of the orexin receptor type 2 (OX2R). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OX2R coupled Gq signaling. Our results also indicate that agonistic activity was stereospecific at both the benzylic and homobenzylic stereogenic centra. We identified methoxyethoxy-substituted pyrido-fused dihydroimidazolimine analog 63c containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC50 of 339 nM and a maximal response (Emax) of 96 % in this assay. In vivo pharmacokinetic analysis indicated good brain exposure for several analogs. Our combined results provide important information towards a structurally novel class of orexin receptor agonists distinct from current chemotypes.

Development of a mutant aerosolized ACE2 that neutralizes SARS-CoV-2 in vivo.

The rapid evolution of SARS-CoV-2 variants highlights the need for new therapies to prevent disease spread. SARS-CoV-2, like SARS-CoV-1, uses the human cell surface protein angiotensin-converting enzyme 2 (ACE2) as its native receptor. Here, we design and characterize a mutant ACE2 that enables rapid affinity purification of a dimeric protein by altering the active site to prevent autoproteolytic digestion of a C-terminal His10 epitope tag. In cultured cells, mutant ACE2 competitively inhibits lentiviral vectors pseudotyped with spike from multiple SARS-CoV-2 variants, and infectious SARS-CoV-2. Moreover, the protein can be nebulized and retains virus-binding properties. We developed a system for delivery of aerosolized ACE2 to K18-hACE2 mice and demonstrate protection by our modified ACE2 when delivered as a prophylactic agent. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents in vivo and suggest a new tool in the ongoing fight against SARS-CoV-2 and other ACE2-dependent viruses.

Association of Redlining and Natural Environment with Depressive Symptoms in Women in the Sister Study.

BACKGROUND: Improving mental health is recognized as an important factor for achieving global development goals. Despite strong evidence that neighborhood greenery promotes better mental health, there are environmental justice concerns over the distribution of neighborhood greenery. Underlying these concerns are present-day consequences of historical discriminatory financial investment practices, such as redlining which was established by the U.S. Federal Home Owners' Loan Corporation (HOLC) in the 1930s. The impacts of redlining on environmental and health disparities have been researched extensively. However, the influences of redlining on the associations between neighborhood environment and health outcomes have not been fully assessed. OBJECTIVES: The aim of this study was to examine whether associations between residential tree cover and depressive symptoms vary across areas subject to HOLC practices. METHODS: Depressive symptoms were defined by the 10-item Center for Epidemiologic Studies Depression Scale collected during the period 2008-2012 for 3,555 women in the Sister Study cohort residing in cities subject to HOLC practices across the United States. HOLC rating maps were obtained from the Mapping Inequality Project, University of Richmond, with neighborhoods graded as A (best for financial investment, green), B (still desirable, blue), C (declining, yellow), and D (hazardous, red-known as redlined). Tree cover within 500m and 2,000m from residences was estimated using 2011 U.S. Forest Service Percent Tree Canopy Cover. Mixed model using climate zone as the random effect was applied to evaluate the associations with adjustments for potential covariates. Analyses were stratified by HOLC grade. RESULTS: Tree cover was significantly higher in neighborhoods with better HOLC grades. A 10% increase in tree cover was associated with reduced odds of depressive symptoms for the full study population, with adjusted odds ratios (AORs) of 0.93 [95% confidence interval (CI): 0.88, 0.99], and 0.91 (0.85, 0.97) for 500-m and 2,000-m buffer, respectively. Across HOLC grades, the strongest associations were observed in redlined neighborhoods, with respective AORs of 0.72 (95% CI: 0.52, 0.99) and 0.63 (95% CI: 0.45, 0.90) for 500-m and 2,000-m buffer. DISCUSSION: Findings support a remediation strategy focused on neighborhood greenery that would address multiple public health priorities, including mental health and environmental justice. https://doi.org/10.1289/EHP12212.

Commentary: Access to Psychedelics for Psychological Suffering at the End of Life - Prioritizing Our Priorities.

We agree with Kratina et al. (2023) that the problem of psychological suffering at the end of life deserves attention from a policy standpoint and that psychedelic therapies show promise in this clinical context. However, we argue the following in this rejoinder: (1) disproportionate attention to psychedelics may overstate the current evidence base, potentially diverting resources away from existing evidence-based programs; (2) a more pressing policy priority related to this public health problem is to address population-level inequities in accessing high-quality, early and holistic palliative care, including psychosocial care; and (3) discussions about expanded access to psychedelics must also foreground equity issues.

Molecular mechanism of fatty acid activation of FFAR1.

FFAR1 is a G-protein-coupled receptor (GPCR) that responds to circulating free fatty acids to enhance glucose-stimulated insulin secretion and release of incretin hormones. Due to the glucose-lowering effect of FFAR1 activation, potent agonists for this receptor have been developed for the treatment of diabetes. Previous structural and biochemical studies of FFAR1 showed multiple sites of ligand binding to the inactive state but left the mechanism of fatty acid interaction and receptor activation unknown. We used cryo-electron microscopy to elucidate structures of activated FFAR1 bound to a Gq mimetic, which were induced either by the endogenous FFA ligand docosahexaenoic acid or γ-linolenic acid and the agonist drug TAK-875. Our data identify the orthosteric pocket for fatty acids and show how both endogenous hormones and synthetic agonists induce changes in helical packing along the outside of the receptor that propagate to exposure of the G-protein-coupling site. These structures show how FFAR1 functions without the highly conserved "DRY" and "NPXXY" motifs of class A GPCRs and also illustrate how the orthosteric site of a receptor can be bypassed by membrane-embedded drugs to confer full activation of G protein signaling.

Orexin A, an amphipathic α-helical neuropeptide involved in pleiotropic functions in the nervous and immune systems: Synthetic approach and biophysical studies of the membrane-bound state.

This research reports on the membrane interactions of orexin A (OXA), an α-helical and amphipathic neuropeptide that contains 33 residues and two disulfide bonds in the N-terminal region. OXA, which activates the orexins 1 and 2 receptors in neural and immune cell membranes, has essential pleiotropic physiological effects, including at the levels of arousal, sleep/wakefulness, energy balance, neuroprotection, lipid signaling, the inflammatory response, and pain. As a result, the orexin system has become a prominent target to treat diseases such as sleep disorders, drug addiction, and inflammation. While the high-resolution structure of OXA has been investigated in water and bound to micelles, there is a lack of information about its conformation bound to phospholipid membranes and its receptors. NMR is a powerful method to investigate peptide structures in a membrane environment. To facilitate the NMR structural studies of OXA exposed to membranes, we present a novel synthetic scheme, leading to the production of isotopically-labeled material at high purity. A receptor activation assay shows that the 15N-labeled peptide is biologically active. Biophysical studies are performed using surface plasmon resonance, circular dichroism, and NMR to investigate the interactions of OXA with phospholipid bilayers. The results demonstrate a strong interaction between the peptide and phospholipids, an increase in α-helical content upon membrane binding, and an in-plane orientation of the C-terminal region critical to function. This new knowledge about structure-activity relationships in OXA could inspire the design of novel therapeutics that leverage the anti-inflammatory and neuro-protective functions of OXA, and therefore could help address neuroinflammation, a major issue associated with neurological disorders such as Alzheimer's disease.