Mental health disparities of sexual minority refugees and asylum seekers: Provider perspectives on trauma exposure, symptom presentation, and treatment approach.

Refugees and asylum seekers who identify as sexual minorities and/or who have been persecuted for same-sex acts maneuver through multiple oppressive systems at all stages of migration. Sexual minority refugees and asylum seekers (SM RAS) report experiencing a greater number of persecutory experiences and worse mental health symptoms than refugees and asylum seekers persecuted for reasons other than their sexual orientation (non-SM RAS). SM RAS are growing in numbers, report a need and desire for mental health treatment, and are often referred to therapy during the asylum process. However, little research has been conducted on the treatment needs of SM RAS in therapy or the strategies therapists use to address these needs. This study sought to identify these factors through qualitative interviews with providers at a specialty refugee mental health clinic (N = 11), who had experience treating both SM RAS and non-SM RAS. Interviews were transcribed and coded for themes of similarities and differences between SM RAS and non-SM RAS observed during treatment and factors that could be leveraged to reduce mental health disparities between SM RAS and non-SM RAS. Clinicians reported that compared to the non-SM RAS, SM RAS reported greater childhood trauma exposure, increased isolation, decreased support, identity-related shame, difficulty trusting others, and continued discrimination due to their SM identitiy. Suggested adaptations included reducing isolation, preparing for ongoing identity-based challenges, creating safe spaces to express SM identity, and a slower treatment pace. Providers reported benefits and drawbacks to centering the client's SM identity in treatment and encouraging community involvement for SM RAS, and noted additional training in cultural awareness would be beneficial. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Nontraumatic orbital hematoma secondary to labor and childbirth: a case report and review of the literature.

PURPOSE: Non-traumatic orbital hemorrhage without underlying vascular malformations or predisposing conditions is uncommon, and particularly rare in the context of maternal labor. This study combines a novel case report and retrospective review to analyze reported cases and propose insights. METHODS: This study is both a unique case report and literature review examining PubMed publications with articles traced back to original sources through citations for inclusion. Analysis included clinical presentation, visual examination, hematoma characteristics, neuroimaging, management strategies, and outcomes. RESULTS: We present a 37-year-old multigravida woman at 40 weeks gestation who developed acute right-sided proptosis, diplopia, retrobulbar pain, and periorbital edema during the second stage of labor. Computed tomography (CT) revealed a subperiosteal hemorrhage, with subsequent magnetic resonance imaging (MRI) excluding vascular anomalies. Symptoms resolved within two months. Only 14 cases of maternal orbital hematoma associated with labor have been reported. The average age was 28 with 42% (6/14) being primigravid. Including our case, forty percent (6/15) developed symptoms during the second stage of labor, 40% (6/15) immediately postpartum, and 20% (3/15) over 24 hours postpartum. Overall, 33% (5/15) had potentially contributing conditions including coagulopathies, delivery complications, or vascular malformations. Unilateral orbital hemorrhage occurred in 87% (13/15). Surgical intervention was necessary in 13% (2/15). Most (87%, 13/15) underwent observation or medical management with full recovery of symptoms. CONCLUSIONS: Non-traumatic orbital hematomas associated with maternal labor are rare and likely related to increased valsalva during delivery and heightened blood volume in pregnancy. Neuro-imaging and systemic workup are recommended to assess for vascular anomalies or underlying coagulopathies. The overall prognosis is favorable with most having full recovery.

Student High Value Care Initiative: a Longitudinal Model for Student-Led Implementation and Scholarship.

BACKGROUND: Educating medical trainees to practice high value care is a critical component to improving quality of care and should be introduced at the beginning of medical education. AIM: To create a successful educational model that provides medical students and junior faculty with experiential learning in quality improvement and mentorship opportunities, and produce effective quality initiatives. SETTING: A tertiary medical center affiliated with a medical school in New York City. PARTICIPANTS: First year medical students, junior faculty in hospital medicine, and a senior faculty course director. PROGRAM DESCRIPTION: The Student High Value Care initiative is a longitudinal initiative comprised of six core elements: (1) project development, (2) value improvement curriculum, (3) mentorship, (4), Institutional support, (5) scholarship, and (6) student leadership. PROGRAM EVALUATION: During the first 3 years, 68 medical students and ten junior faculty participated in 10 quality improvement projects. Nine projects were successful in their measured outcomes, with statistically significant improvements. Nine had an abstract accepted to a regional or national meeting, and seven produced publications in peer-reviewed literature. DISCUSSION: In the first 3 years of the initiative, we successfully engaged medical students and junior faculty to create and support the implementation of successful quality improvement initiatives. Since that time, the program continues to offer meaningful mentorship and scholarship opportunities.

Long-term efficacy of lymphovenous anastomosis for the treatment of retroperitoneal lymphangiectasia: A case report and a review of literature.

Lymphovenous anastomosis (LVA) represents an alternative treatment for retroperitoneal lymphangiectasia. In contrast to sclerotherapy or excision, which may risk lymphatic obstruction and subsequent lymphedema, LVA preserves existing lymphatic architecture and transit. This report shows long-term efficacy of LVA for functional decompression of a symptomatic pathologically dilatated retroperitoneal lymphatics. A 47-year-old female with retroperitoneal lymphangiectasia refractory to multiple percutaneous drainages and treatments with sclerosing agents underwent LVA with anastomosis of a dominant segment of retroperitoneal lymphangiectasia to the deep inferior epigastric vein. Postoperative serial magnetic resonance imaging with 3-dimensional volume calculation over the 27 months follow-up showed evidence of decompression of the lesion with patent bypass. There were no known immediate complications nor requirement of further interventions. The patient's subjective pain also decreased substantially. This report confirms long-term efficacy of LVA for retroperitoneal lymphangiectasia as an alternative to sclerotherapy and surgical excision in the setting of previously failed treatments.

Factors Associated With Radioactive Iodine Therapy-Acquired Nasolacrimal Duct Obstruction.

OBJECTIVE: To identify factors associated with radioactive iodine (RAI)-acquired nasolacrimal duct obstruction (NLDO). METHODS: Retrospective chart review and telephone surveys of patients who received RAI therapy for thyroid carcinoma at an academic institution were conducted. Telephone surveys were used to screen for post-RAI NLDO diagnoses. Databases were reviewed for documented NLDO, demographics, RAI dose, total number of RAI treatments, and sialadenitis. Routine post-RAI whole-body scintigraphy (WBS) images were analyzed for the presence or absence of 131I sodium iodide (I-131) in the nasolacrimal duct. Intranasal I-131 activity was graded as none, low, moderate, and high; those with moderate or high activity were considered to have "increased" activity. Logistic and ordinal logistic regression models were used to evaluate the associations with NLDO while adjusting for I-131 dose. RESULTS: Of the 209 patients who completed the survey, 15 (7%) had NLDO diagnoses. Increased intranasal I-131 activity on WBS, presence of nasolacrimal I-131 WBS activity, presence of documented post-RAI sialadenitis, and history of >1 RAI treatment were associated with the development of NLDO from univariate analyses (P ≤ .013). After adjusting for the administered dose of I-131, the presence of sialadenitis and nasolacrimal I-131 activity on WBS were the remaining 2 factors significantly associated with NLDO development (P < .001 and P = .01, respectively). CONCLUSIONS: The presence of sialadenitis and nasolacrimal I-131 activity on WBS are I-131 dose-independent correlative factors for RAI-associated NLDO. Patients with these characteristics should be counseled on their increased risk of NLDO after RAI therapy for thyroid carcinoma.

Blue Rubber Bleb Nevus Syndrome Manifesting as an Isolated Congenital Orbital Mass in a Neonate.

A male neonate presented with an isolated congenital right orbital vascular malformation without other mucocutaneous lesions or signs/symptoms of systemic disease. The orbital mass was progressive, causing amblyogenic ptosis by 6 months of age. Over 11 years, the patient underwent 4 orbital mass resections, 3 embolizations, and even a craniotomy with mass resection for an intraorbital meningoencephalocele secondary to orbital bony erosion. A diagnosis of blue rubber bleb nevus syndrome was made at age 7 when the patient developed a tender vascular lesion on his foot and was found to have other mucocutaneous lesions of the extremities and gastrointestinal tract. This is the first pediatric case of such an aggressive orbital vascular malformation from blue rubber bleb nevus syndrome causing neonatal amblyogenic ptosis and intraorbital meningoencephalocele in childhood. It is the second report of a patient presenting with an isolated orbital vascular malformation without other manifestations of blue rubber bleb nevus syndrome, leading to his delayed diagnosis.

A structure and function relationship study to identify the impact of the R721G mutation in the human mitochondrial lon protease.

Lon is an ATP-dependent protease belonging to the "ATPase associated with diverse cellular activities" (AAA+) protein family. In humans, Lon is translated as a precursor and imported into the mitochondria matrix through deletion of the first 114 amino acid residues. In mice, embryonic knockout of lon is lethal. In humans, some dysfunctional lon mutations are tolerated but they cause a developmental disorder known as the CODAS syndrome. To gain a better understanding on the enzymology of human mitochondrial Lon, this study compares the structure-function relationship of the WT versus one of the CODAS mutants R721G to identify the mechanistic features in Lon catalysis that are affected. To this end, steady-state kinetics were used to quantify the difference in ATPase and ATP-dependent peptidase activities between WT and R721G. The Km values for the intrinsic as well as protein-stimulated ATPase were increased whereas the kcat value for ATP-dependent peptidase activity was decreased in the R721G mutant. The mutant protease also displayed substrate inhibition kinetics. In vitro studies revealed that R721G did not degrade the endogenous mitochondrial Lon substrate pyruvate dehydrogenase kinase isoform 4 (PDK4) effectively like WT hLon. Furthermore, the pyruvate dehydrogenase complex (PDH) protected PDK4 from hLon degradation. Using hydrogen deuterium exchange/mass spectrometry and negative stain electron microscopy, structural perturbations associated with the R721G mutation were identified. To validate the in vitro findings under a physiologically relevant condition, the intrinsic stability as well as proteolytic activity of WT versus R721G mutant towards PDK 4 were compared in cell lysates prepared from immortalized B lymphocytes expressing the respective protease. The lifetime of PDK4 is longer in the mutant cells, but the lifetime of Lon protein is longer in the WT cells, which corroborate the in vitro structure-functional relationship findings.

A Selective Fluorogenic Peptide Substrate for the Human Mitochondrial ATP-Dependent Protease Complex ClpXP.

The goal of this work is to identify differences in the substrate determinants of two human mitochondrial matrix ATP-dependent proteases, human ClpXP (hClpXP) and human Lon (hLon). This information allows the generation of protease-specific peptide substrates that can be used as chemical biology tools to investigate the physiological functions of hClpXP. These enzymes play a role in protein quality control, but currently the physiological functions of human ClpXP are not well defined. In this study, the degradation profile of casein, an alanine positional scanning decapeptide library, and a specific peptide sequence found in an endogenous substrate of bacterial ClpXP by hClpXP as well as hLon were examined. Based on our findings, we generated a specific fluorogenic peptide substrate, FR-Cleptide, for hClpXP with a kcat of 2.44±0.15 s-1 and Km =262±43 µM, respectively. The FR-Cleptide substrate was successfully used to identify a leucine methyl ketone as a potent lead inhibitor, and to detect endogenous hClpXP activity in HeLa cell lysate. We propose that the fluorogenic peptide substrate is a valuable tool for quantitatively monitoring the activity of hClpXP in cell lysate, as well as mechanistic characterization of hClpXP. The peptide-based chemical tools developed in this study will complement the substrates developed for human Lon in aiding the investigation of the physiological functions of the respective protease.

A Proteolytic Site-Directed Affinity Label to Inhibit the Human ATP-Dependent Protease Caseinolytic Complex XP.

Human caseinolytic protease component X and P (hClpXP) is a heterooligomeric ATP-dependent protease. The hClpX subunit catalyzes ATP hydrolysis whereas the hClpP subunit catalyzes peptide bond cleavage. In this study, we generated a peptidyl chloromethyl ketone (dansyl-FAPAL-CMK) that inhibited the hClpP subunit through alkylation of the catalytic His122, which was detected by LC-MS. This inhibitor is composed of a peptide sequence derived from a hydrolyzed peptide product of a substrate cleaved by hClpXP. Binding of FAPAL positions the electrophilic chloromethyl ketone moiety near His122 where alkylation occurs. Dansyl FAPAL-CMK exhibits selectivity for hClpXP over other ATP-dependent proteases such as hLon and the 26S proteasome and abolishes hClpXP activity in HeLa cell lysate. Using the fluorogenic peptide substrate FR-Cleptide as reporter, we detected biphasic inhibition time courses; this supports a slow-binding, time-dependent, covalent inhibition mechanism that is often found in active-site directed affinity labels. Because this inhibitor reacts only with hClpXP but not hLon or the proteasome, it has the potential to serve as a chemical tool to help validate endogenous protein substrates of hClpXP in cell lysate, thereby benefiting investigation of the physiological functions of hClpXP in different cell types or tissue samples.

Synaptic, transcriptional and chromatin genes disrupted in autism.

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration.

Oxidative and endoplasmic reticulum (ER) stresses are hallmarks of the pathophysiology of ALS and other neurodegenerative diseases. In these stresses, different kinases phosphorylate eukaryotic initiation factor eIF2α, enabling the translation of stress response genes; among these is GADD34, the protein product of which recruits the α-isoform of protein phosphatase 1 catalytic subunit (PP1α) and eIF2α to assemble a phosphatase complex catalyzing eIF2α dephosphorylation and resumption of protein synthesis. Aberrations in this pathway underlie the aforementioned disorders. Previous observations indicating that GADD34 is induced by arsenite, a thiol-directed oxidative stressor, in the absence of eIF2α phosphorylation suggest other roles for GADD34. Here, we report that arsenite-induced oxidative stress differs from thapsigargin- or tunicamycin-induced ER stress in promoting GADD34 transcription and the preferential translation of its mRNA in the absence of eIF2α phosphorylation. Arsenite also stabilized GADD34 protein, slowing its degradation. In response to oxidative stress, but not ER stress, GADD34 recruited TDP-43, and enhanced cytoplasmic distribution and cysteine modifications of TDP-43 promoted its binding to GADD34. Arsenite also recruited a TDP-43 kinase, casein kinase-1ϵ (CK1ϵ), to GADD34. Concomitant with TDP-43 aggregation and proteolysis after prolonged arsenite exposure, GADD34-bound CK1ϵ catalyzed TDP-43 phosphorylations at serines 409/410, which were diminished or absent in GADD34-/- cells. Our findings highlight that the phosphatase regulator, GADD34, also functions as a kinase scaffold in response to chronic oxidative stress and recruits CK1ϵ and oxidized TDP-43 to facilitate its phosphorylation, as seen in TDP-43 proteinopathies.

Fovea-sparing rhegmatogenous retinal detachments: impact of clinical factors including time to surgery on visual and anatomic outcomes.

PURPOSE: Evaluate the impact of time to surgery and other clinical factors on visual and anatomic outcomes following surgical repair of fovea-sparing rhegmatogenous retinal detachments (RRD). METHODS: Visual and anatomic outcomes were analyzed for their association with clinical factors, including lens status, preoperative visual acuity (VA), contralateral RRD, RRD symptom duration, time to surgery, single-operation anatomic success, number of quadrants involved, posterior RRD extent, RRD extent closest to the fovea, number of retinal breaks, quadrants with retinal breaks, and surgery performed Saturday or Sunday versus Monday-Friday. RESULTS: Medical records of 423 eyes with fovea-sparing RRD repaired with pneumatic retinopexy (PR), scleral buckle (SB), pars plana vitrectomy (PPV), and PPV with SB (PPV/SB) were included. Sixty-seven percent and 89% were operated within 24 and 72 h of RRD presentation, respectively. Single-operation anatomic success rates were 59%, 89%, 84%, and 92% for PR, SB, PPV, and PPV/SB interventions, respectively. Final anatomic success was 100%. Three clinical factors correlated with faster time to surgery: shorter symptom duration (p < 0.02), RRD superior location (p = 0.001), and posterior extension into the macula (p = 0.01). The time to surgery did not correlate with visual or anatomic outcomes. Two clinical factors positively correlated with postoperative vision: preoperative VA (r > 0.25, p < 0.04) and single-operation anatomic success (p < 0.04). Surgeries performed on Monday through Friday (n = 411) were associated with better anatomic outcomes compared with the limited number performed on Saturday or Sunday (n = 12) (p = 0.005), although a greater proportion of operated cases over the weekend were PR. CONCLUSIONS: In the context of the current series, time to surgery did not correlate with visual or anatomic outcomes following the surgical repair of fovea-sparing RRDs. Preoperative VA and single-operation anatomic success correlated with improved visual outcome.

Regulation of Pyruvate Dehydrogenase Kinase 4 in the Heart through Degradation by the Lon Protease in Response to Mitochondrial Substrate Availability.

Cardiac metabolic inflexibility is driven by robust up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) and phosphorylation-dependent inhibition of pyruvate dehydrogenase (PDH) within a single day of feeding mice a high fat diet. In the current study, we have discovered that PDK4 is a short lived protein (t½ ∼ 1 h) and is specifically degraded by the mitochondrial protease Lon. Lon does not rapidly degrade PDK1 and -2, indicating specificity toward the PDK isoform that is a potent modulator of metabolic flexibility. Moreover, PDK4 degradation appears regulated by dissociation from the PDH complex dependent on the respiratory state and energetic substrate availability of mouse heart mitochondria. Finally, we demonstrate that pharmacologic inhibition of PDK4 promotes PDK4 degradation in vitro and in vivo These findings reveal a novel strategy to manipulate PDH activity by selectively targeting PDK4 content through dissociation and proteolysis.

CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease.

CODAS syndrome is a multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. Using whole-exome and Sanger sequencing, we identified four LONP1 mutations inherited as homozygous or compound-heterozygous combinations among ten individuals with CODAS syndrome. The individuals come from three different ancestral backgrounds (Amish-Swiss from United States, n = 8; Mennonite-German from Canada, n = 1; mixed European from Canada, n = 1). LONP1 encodes Lon protease, a homohexameric enzyme that mediates protein quality control, respiratory-complex assembly, gene expression, and stress responses in mitochondria. All four pathogenic amino acid substitutions cluster within the AAA(+) domain at residues near the ATP-binding pocket. In biochemical assays, pathogenic Lon proteins show substrate-specific defects in ATP-dependent proteolysis. When expressed recombinantly in cells, all altered Lon proteins localize to mitochondria. The Old Order Amish Lon variant (LONP1 c.2161C>G[p.Arg721Gly]) homo-oligomerizes poorly in vitro. Lymphoblastoid cell lines generated from affected children have (1) swollen mitochondria with electron-dense inclusions and abnormal inner-membrane morphology; (2) aggregated MT-CO2, the mtDNA-encoded subunit II of cytochrome c oxidase; and (3) reduced spare respiratory capacity, leading to impaired mitochondrial proteostasis and function. CODAS syndrome is a distinct, autosomal-recessive, developmental disorder associated with dysfunction of the mitochondrial Lon protease.

Physiological enzymology: The next frontier in understanding protein structure and function at the cellular level.

Historically, the study of proteins has relied heavily on characterizing the activity of a single purified protein isolated from other cellular components. This classic approach allowed scientists to unambiguously define the intrinsic kinetic and chemical properties of that protein. The ultimate hope was to extrapolate this information toward understanding how the enzyme or receptor behaves within its native cellular context. These types of detailed in vitro analyses were necessary to reduce the innate complexities of measuring the singular activity and biochemical properties of a specific enzyme without interference from other enzymes and potential competing substrates. However, recent developments in fields encompassing cell biology, molecular imaging, and chemical biology now provide the unique chemical tools and instrumentation to study protein structure, function, and regulation in their native cellular environment. These advancements provide the foundation for a new field, coined physiological enzymology, which quantifies the function and regulation of enzymes and proteins at the cellular level. In this Special Edition, we explore the area of Physiological Enzymology and Protein Function through a series of review articles that focus on the tools and techniques used to measure the cellular activity of proteins inside living cells. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions.

Translating protein phosphatase research into treatments for neurodegenerative diseases.

Many of the major neurodegenerative disorders are characterized by the accumulation of intracellular protein aggregates in neurons and other cells in brain, suggesting that errors in protein quality control mechanisms associated with the aging process play a critical role in the onset and progression of disease. The increased understanding of the unfolded protein response (UPR) signaling network and, more specifically, the structure and function of eIF2α phosphatases has enabled the development or discovery of small molecule inhibitors that show great promise in restoring protein homeostasis and ameliorating neuronal damage and death. While this review focuses attention on one or more eIF2α phosphatases, the wide range of UPR proteins that are currently being explored as potential drug targets bodes well for the successful future development of therapies to preserve neuronal function and treat neurodegenerative disease.

Evaluating social (pragmatic) communication disorder.

BACKGROUND: Social (pragmatic) communication disorder (SPCD) is a new diagnosis introduced by DSM-5, characterised by problems with verbal and nonverbal social communication. It is currently unclear whether SPCD is a valid diagnostic category, because little is known about the characteristics of those who meet its criteria. We sought to identify and describe cases of SPCD, to contribute to debates about its validity. We investigated whether the symptoms of SPCD cluster together to form a coherent syndrome that is distinct from autism spectrum disorder (ASD) in terms of its core and associated features. METHODS: Participants were young people (N = 1,081, age range = 4-18 years) who had attended a specialist social communication disorders clinic for children with fluent language and normal-range intelligence. Standardised parent-report data were collected using the Developmental, Dimensional and Diagnostic Interview (3Di), Child Communication Checklist (CCC) and Strengths and Difficulties Questionnaire (SDQ). An algorithm was designed using 3Di and CCC items to implement DSM-5 SPCD criteria. RESULTS: Eighty-eight young people met our criteria for SPCD, with 801 meeting DSM-5 ASD criteria and the remaining 192 having neither SPCD nor ASD ('clinical comparison group'). The core symptoms of SPCD co-occurred to a moderate degree (average interitem correlation = .22). SPCD cases had autistic social difficulties that were intermediate between ASD and the clinical comparison group. SPCD was associated with high rates of nonautistic psychopathology, with 63.5% scoring in the abnormal range of the SDQ's Total Problems scale. CONCLUSIONS: We did not find evidence that SPCD is qualitatively distinct from ASD. Rather, it appears to lie on the borderlands of the autism spectrum, describing those with autistic traits that fall just below the threshold for an ASD diagnosis. SPCD may have clinical utility for identifying people with autistic traits that are insufficiently severe for ASD diagnosis, but who nevertheless require support.