Competition for DNA binding between paralogous transcription factors determines their genomic occupancy and regulatory functions.

Most eukaryotic transcription factors (TFs) are part of large protein families, with members of the same family (i.e., paralogous TFs) recognizing similar DNA-binding motifs but performing different regulatory functions. Many TF paralogs are coexpressed in the cell and thus can compete for target sites across the genome. However, this competition is rarely taken into account when studying the in vivo binding patterns of eukaryotic TFs. Here, we show that direct competition for DNA binding between TF paralogs is a major determinant of their genomic binding patterns. Using yeast proteins Cbf1 and Pho4 as our model system, we designed a high-throughput quantitative assay to capture the genomic binding profiles of competing TFs in a cell-free system. Our data show that Cbf1 and Pho4 greatly influence each other's occupancy by competing for their common putative genomic binding sites. The competition is different at different genomic sites, as dictated by the TFs' expression levels and their divergence in DNA-binding specificity and affinity. Analyses of ChIP-seq data show that the biophysical rules that dictate the competitive TF binding patterns in vitro are also followed in vivo, in the complex cellular environment. Furthermore, the Cbf1-Pho4 competition for genomic sites, as characterized in vitro using our new assay, plays a critical role in the specific activation of their target genes in the cell. Overall, our study highlights the importance of direct TF-TF competition for genomic binding and gene regulation by TF paralogs, and proposes an approach for studying this competition in a quantitative and high-throughput manner.

Transcutaneous retrobulbar amphotericin B for rhino-orbital-cerebral mucormycosis: a multi-center retrospective comparative study.

PURPOSE: To assess whether transcutaneous retrobulbar amphotericin B injections (TRAMB) reduce exenteration rate without increasing mortality in rhino-orbital-cerebral mucormycosis (ROCM). METHODS: In this retrospective case-control study, 46 patients (51 eyes) with biopsy-proven ROCM were evaluated at 9 tertiary care institutions from 1998 to 2021. Patients were stratified by radiographic evidence of local orbital versus extensive involvement at presentation. Extensive involvement was defined by MRI or CT evidence of abnormal or loss of contrast enhancement of the orbital apex with or without cavernous sinus, bilateral orbital, or intracranial extension. Cases (+TRAMB) received TRAMB as adjunctive therapy while controls (-TRAMB) did not. Patient survival, globe survival, and vision/motility loss were compared between +TRAMB and -TRAMB groups. A generalized linear mixed effects model including demographic and clinical covariates was used to evaluate the impact of TRAMB on orbital exenteration and disease-specific mortality. RESULTS: Among eyes with local orbital involvement, exenteration was significantly lower in the +TRAMB group (1/8) versus -TRAMB (8/14) (p = 0.04). No significant difference in mortality was observed between the ±TRAMB groups. Among eyes with extensive involvement, there was no significant difference in exenteration or mortality rates between the ±TRAMB groups. Across all eyes, the number of TRAMB injections correlated with a statistically significant decreased rate of exenteration (p = 0.048); there was no correlation with mortality. CONCLUSIONS: Patients with ROCM with local orbital involvement treated with adjunctive TRAMB demonstrated a lower exenteration rate and no increased risk of mortality. For extensive involvement, adjunctive TRAMB does not improve or worsen these outcomes.

Breast cancer survivorship and sexual dysfunction: a population-based cohort study.

BACKGROUND: Breast cancer is the most common non-skin cancer in women and an increasing number of people are living as breast cancer survivors. While the prognosis of breast cancer continues to improve, the rates of sexual dysfunction and the risk related to cancer treatments have not been well characterized in a population-based study. METHODS: We identified a cohort of 19,709 breast cancer survivors diagnosed between 1997 and 2017 from the Utah Cancer Registry, and 93,389 cancer-free women who were matched by age and birth state from the Utah Population Database. Sexual dysfunction diagnoses were identified through ICD-9 and ICD-10 codes from electronic medical records and statewide healthcare facilities data. Cox proportional hazard models were used to estimate hazard ratios for risk of sexual dysfunction. RESULTS: Breast cancer survivors were at higher risk of sexual dysfunction diagnosis (9.1% versus 6.9%, HR 1.60, 95% CI 1.51-1.70) compared to the general population. This risk increased 2.05-fold within 1 to 5 years after cancer diagnosis (95% CI 1.89-2.22) and 3.05-fold in individuals diagnosed with cancer at < 50 years of age (95% CI 2.65-3.51). Cancer treatments including endocrine therapy, chemotherapy and radiation therapy were associated with an increased risk of sexual dysfunction among breast cancer survivors. CONCLUSIONS: Risk of sexual dysfunction in breast cancer survivors is higher than in the general population, but may be underdiagnosed in the clinical setting. Health care professionals should be encouraged to address the topic of sexual health early on in the treatment of breast cancer, and routinely screen patients for symptoms of sexual dysfunction.

Social threat, fronto-cingulate-limbic morphometry, and symptom course in depressed adolescents: a longitudinal investigation.

BACKGROUND: Psychosocial stressors characterized by social threat, such as interpersonal loss and social rejection, are associated with depression in adolescents. Few studies, however, have examined whether social threat affects fronto-cingulate-limbic systems implicated in adolescent depression. METHODS: We assessed lifetime stressor severity across several domains using the Stress and Adversity Inventory (STRAIN) in 57 depressed adolescents (16.15 ± 1.32 years, 34 females), and examined whether the severity of social threat and non-social threat stressors was associated with gray matter volumes (GMVs) in the anterior cingulate cortex (ACC), amygdala, hippocampus, and nucleus accumbens (NAcc). We also examined how lifetime social threat severity and GMVs in these regions related to depressive symptoms at baseline and over 9 months. RESULTS: General stressor severity was related to greater depression severity at baseline and over 9 months. Moreover, greater severity of social threat (but not non-social threat) stressors was associated with smaller bilateral amygdala and NAcc GMVs, and smaller bilateral surface areas of caudal and rostral ACC (all pFDR ⩽ 0.048). However, neither social threat nor non-social threat stressor severity was related to hippocampal GMVs (all pFDR ⩾ 0.318). All fronto-cingulate-limbic structures that were associated with the severity of social threat were negatively associated with greater depression severity over 9 months (all pFDR ⩽ 0.014). Post-hoc analyses suggested that gray matter morphometry of bilateral amygdala, NAcc, and rostral and caudal ACC mediated the association between social threat and depression severity in adolescents over 9 months (all pFDR < 0.048). CONCLUSIONS: Social threat specifically affects fronto-cingulate-limbic pathways that contribute to the maintenance of depression in adolescents.

Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of the role of puberty.

Suicide is the second leading cause of death among adolescents. While clinicians and researchers have begun to recognize the importance of considering multidimensional factors in understanding risk for suicidal thoughts and behaviors (STBs) during this developmental period, the role of puberty has been largely ignored. In this review, we contend that the hormonal events that occur during puberty have significant effects on the organization and development of brain systems implicated in the regulation of social stressors, including amygdala, hippocampus, striatum, medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex. Guided by previous experimental work in adults, we also propose that the influence of pubertal hormones and social stressors on neural systems related to risk for STBs is especially critical to consider in adolescents with a neurobiological sensitivity to hormonal changes. Furthermore, facets of the pubertal transition, such as pubertal timing, warrant deeper investigation and may help us gain a more comprehensive understanding of sex differences in the neurobiological and psychosocial mechanisms underlying adolescent STBs. Ultimately, advancing our understanding of the pubertal processes that contribute to suicide risk will improve early detection and facilitate the development of more effective, sex-specific, psychiatric interventions for adolescents.

Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

A Systematic Review of Warfarin Use in Post-Bariatric Surgery Patients: Cases Compiled From a Literature Review.

OBJECTIVE: The objective of this review was to provide dosing recommendations for percentage change in weekly warfarin dose and rates of thrombotic and bleeding events in patients requiring long-term warfarin therapy after bariatric surgery. DATA SOURCES: A comprehensive literature search of PubMed (through April 5, 2021), Cochrane Library, and Google Scholar (through April 5, 2021) databases was completed using the keywords warfarin OR vitamin k antagonist AND bariatric surgery. STUDY SELECTION AND DATA EXTRACTION: Retrospective studies and matched-cohort studies evaluating preoperative and postoperative use of warfarin after bariatric surgery for obesity were considered. Weekly dose defined as sum of daily doses of warfarin for 7 consecutive days was a required outcome to be considered in this review. Patients were excluded from review if post-operative dosage change was not reported. DATA SYNTHESIS: Six studies were included with a total of 160 patients who met the criteria. A decrease in average warfarin dose was seen in all studies, with the largest decrease occurring at 1 month postsurgery followed by an upward trend toward baseline about 90 days postsurgery. While thrombotic events were observed in none of the patients, there was an increased risk of bleeding in patients, particularly in those who underwent roux-en-y gastric bypass (RYGB) surgery. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The study provides a specific warfarin dosing titration regimen, as well as embolic and bleed risk in post-bariatric surgery population. CONCLUSIONS: Clinicians may consider lowering warfarin weekly dose by about 25% immediately postsurgery, with doses approaching closer to baseline about 90 days postsurgery.

We Cannot Put This Genie Back in the Bottle: Qualitative Interview Study Among Family Medicine Providers About Their Experiences With Virtual Visits During the COVID-19 Pandemic.

BACKGROUND: When a genie is freed from its bottle, things cannot be restored to the way they were before. At the beginning of the global COVID-19 pandemic, health care systems adjusted how they delivered care overnight. Primary care practices switched from seeing patients in person to virtual care applications, including video and phone visits, e-visits, e-consults, and messaging with clinicians. Prior to the pandemic, these applications were not as widely used, but discussions around their advantages and disadvantages in some settings were being explored. Emergency regulatory changes spurred by the pandemic freed this virtual care "genie" from its bottle. Wide-scale adoption of virtual care in family medicine has much potential, as primary care services are often a patient's first point of contact with the health care system. OBJECTIVE: This study aims to analyze family medicine providers' experiences using virtual visits during the pandemic, perceived outcomes of the shift to virtual visits, and discusses its implications for the future of family medicine. METHODS: This qualitative study took place at 3 academic primary care clinics between June and December 2020. Data were collected through one-on-one Zoom (version 5.2.1) interviews with family medicine clinical faculty who experienced the rapid transition of in-person visits to mostly "virtual" visits. The interviews were recorded, deidentified, and transcribed. We adopted a constructivist approach to qualitative content analysis to evaluate the results. RESULTS: In total, 25 participants were eligible, and 20 individuals participated in this study (80% participation rate). The mean age was 43.4 years, and 85% (17/20) of the participants were female. We identified 3 main themes: the care process, patient engagement, and team-based care. CONCLUSIONS: This study highlights the transition from in-person to virtual visits during the pandemic from the perspective of family medicine providers. Generally, family medicine providers' perceptions of the shift to virtual visits were positive, especially regarding team-based care. Challenges involved virtual inhibition, particularly for providers. Providers described ways they integrated virtual care with aspects of in-person care, creating a hybrid environment. The genie is out of the bottle-things will not be the same-but family medicine now has the opportunity to evolve.

Longitudinal Change in Adolescent Depression and Anxiety Symptoms from before to during the COVID-19 Pandemic.

This study aimed to examine changes in depression and anxiety symptoms from before to during the first 6 months of the COVID-19 pandemic in a sample of 1,339 adolescents (9-18 years old, 59% female) from three countries. We also examined if age, race/ethnicity, disease burden, or strictness of government restrictions moderated change in symptoms. Data from 12 longitudinal studies (10 U.S., 1 Netherlands, 1 Peru) were combined. Linear mixed effect models showed that depression, but not anxiety, symptoms increased significantly (median increase = 28%). The most negative mental health impacts were reported by multiracial adolescents and those under 'lockdown' restrictions. Policy makers need to consider these impacts by investing in ways to support adolescents' mental health during the pandemic.

Disorders of the Angular Vein.

PURPOSE: The angular vein extends between the supraorbital and supratrochlear veins superiorly and the facial vein inferiorly. Rarely, this vessel can be involved by infections, vascular malformations, or benign tumors. In this study, we report both our experience and the published literature on angular vein disorders. METHODS: A retrospective study was performed on patients seen between 2008 and 2022. The medical literature was searched for reports of conditions affecting the angular vein. RESULTS: During the study period, we encountered 5 patients with angular vein disorders. Information from these patients was combined with 18 published cases. Among the 23 patients, the diagnosis was confused with lacrimal drainage abnormalities in 52%, and 57% underwent imaging. "Swelling" or a palpable, moveable mass were frequent findings. Pain or tenderness was experienced by 43.5% of patients. Five patients were observed, and 2 infections were treated with antibiotics. The remaining 16 lesions were successfully treated with excision (n = 15) or cauterization (n = 1), without complications. Final diagnosis included 14 vascular malformations (isolated varix: 7, thrombosis: 6, cavernous venous malformation: 1), 7 vascular tumors (intravenous pyogenic granulomas: 6, intravascular papillary endothelial hyperplasia: 1) and thrombophlebitis (n = 2). CONCLUSIONS: Disorders of the angular vein are uncommon and frequently misdiagnosed as lacrimal abnormalities. While these lesions can frequently be identified on clinical findings, imaging can be helpful in some cases. Patients with suspected thrombophlebitis require urgent antibiotic therapy. Minimally symptomatic angular vein lesions can be observed. Surgical excision is effective in treating the different vascular malformations and tumors affecting this structure.

Outcomes of Patients With Thyroid Eye Disease Partially Treated With Teprotumumab.

PURPOSE: In response to the coronavirus (COVID-19) pandemic, teprotumumab production was temporarily halted with resources diverted toward vaccine production. Many patients who initiated treatment with teprotumumab for thyroid eye disease were forced to deviate from the standard protocol. This study investigates the response of teprotumumab when patients receive fewer than the standard 8-dose regimen. METHODS: This observational cross-sectional cohort study included patients from 15 institutions with active or minimal to no clinical activity thyroid eye disease treated with the standard teprotumumab infusion protocol. Patients were included if they had completed at least 1 teprotumumab infusion and had not yet completed all 8 planned infusions. Data were collected before teprotumumab initiation, within 3 weeks of last dose before interruption, and at the visit before teprotumumab reinitiation. The primary outcome measure was reduction in proptosis more than 2 mm. Secondary outcome measures included change in clinical activity score (CAS), extraocular motility restriction, margin reflex distance-1 (MRD1), and reported adverse events. RESULTS: The study included 74 patients. Mean age was 57.8 years, and 77% were female. There were 62 active and 12 minimal to no clinical activity patients. Patients completed an average of 4.2 teprotumumab infusions before interruption. A significant mean reduction in proptosis (-2.9 mm in active and -2.8 mm in minimal to no clinical activity patients, P < 0.01) was noted and maintained during interruption. For active patients, a 3.4-point reduction in CAS ( P < 0.01) and reduction in ocular motility restriction ( P < 0.01) were maintained during interruption. CONCLUSIONS: Patients partially treated with teprotumumab achieve significant reduction in proptosis, CAS, and extraocular muscle restriction and maintain these improvements through the period of interruption.

Racial and Ethnic Bias in Letters of Recommendation and Personal Statements for Application to Otolaryngology Residency.

INTRODUCTION: The persistent lack of racial and ethnic diversity within the field of otolaryngology calls for an analysis of potential bias within the residency application system. Letters of recommendation (LORs) and personal statements (PSs) are the most important subjective application constituents. This subjectivity predisposes these components to implicit bias. In applications to various surgical subspecialties, prior linguistic studies assessing bias in reviews of LOR show race-based differences. Thus far, racial and ethnic linguistic differences in LORs for otolaryngology applicants have not been analyzed in the literature. METHODS: LORs and PSs were abstracted from otolaryngology - head and neck surgery applications in the Electronic Residency Application Service for the 2019-20 and 2020-21 application cycles. Linguistic Inquiry and Word Count 2015 was used for quantitative analysis of emotional, cognitive, and structural components of written text. RESULTS: Race-pair analysis of the 2019-2021 application cycles revealed higher mean "teaching" scores for LORs for Asian, black, Hispanic, and white applicants when compared to applicants who self-identified as Other. White applicants had lower scores for the terms "research" and "analytic" when compared to Asian and black applicants, respectively. Analysis of PSs revealed greater scores for an "authentic" writing style for white versus Asian applicants. White applicants were found to have higher scores for "tone" compared to black applicants. CONCLUSION: Minor racial and ethnic language differences exist in both LORs and PSs. A statistically significant difference was observed among LORs, with the "teaching" term used more frequently for Asian, black, Hispanic, and white applicants compared to self-identified Other individuals. For PSs, statistically significant differences were observed among white applicants, who wrote about themselves using more "authentic" language when compared with Asian applicants and who also had higher scores for "tone" compared to black applicants. Although these differences were statistically significant, the practical impact of the variances is likely small.

Lateral orbital wall anomaly in a patient with thyroid eye disease.

An isolated defect in the lateral orbital wall is an uncommon occurrence, although cases of orbital floor, roof, and medial wall spontaneous dehiscence have been described in the literature. Here, we describe a lateral orbital wall defect in a patient with thyroid eye disease - which may be related to bony remodeling or may represent a rare congenital anomaly. Computed tomography (CT) prior to decompression surgery revealed a defect in the left lateral orbital wall. At the time of orbital decompression, prolapse of buccal fat into the orbit was noted once the subperiosteal plane was entered along the lateral orbital wall in the area of this bony defect. Literature review revealed only a few previous reports of lateral wall abnormalities, including two involving the inferior orbital fissure; one other case was associated with Down syndrome, and other reports consist of sphenoid hypoplasia associated with neurofibromatosis.

Lower eyelid margin reconstruction: results of five different techniques.

PURPOSE: This retrospective study was performed to examine surgical results of five different techniques for lower eyelid margin reconstruction after Mohs surgery: primary closure, semicircular flap, dermal matrix graft, sliding tarsal flap, and tarsoconjunctival flap. METHODS: Medical records were reviewed in 178 patients undergoing surgery between 2005 and 2020. Outcomes were evaluated (photographic review) by three oculoplastic observers masked to procedure type, both with and without knowledge of the eyelid defect. RESULTS: All patients achieved a good-excellent functional result and 90.4% were asymptomatic after surgery. Tarsoconjunctival flaps were associated with greater need for subsequent interventions (p < .001) and anterior lamellar deformities (p < .001). Semicircular flaps had a higher incidence of lateral canthal deformity (p < .001), but less eyelash disruption than other flap/graft techniques (p < .001). Mean cosmetic ratings (defect masked) were similar for dermal matrix grafts, semicircular, and sliding tarsal flaps; with each grading higher than tarsoconjunctival flaps (p ≤ .05). Among patients with 9-15 mm wide defects, results were better for semicircular and sliding tarsalflaps, than dermal matrix grafts (p ≤ .005) and tarsoconjunctival flaps (p ≤ .02). CONCLUSIONS: All patients achieved a good-excellent functional result and 87.1% a good-excellent cosmetic result. The semicircular flap was effective for repairing medium sized wounds that could not be closed primarily, creating a continuous lash line, although with a higher incidence of lateral canthal deformities. The sliding tarsal flap was effective for shallow wounds of varying widths. The single-staged dermal matrix graft provided similar results as the tarsoconjunctival flap. Subsequent interventions were more frequent after the tarsoconjunctival flap than other methods.

Novel Strategy to Drive the Intracellular Uptake of Lipid Nanoparticles for Photodynamic Therapy.

Nanoparticles' uptake by cancer cells upon reaching the tumor microenvironment is often the rate-limiting step in cancer nanomedicine. Herein, we report that the inclusion of aminopolycarboxylic acid conjugated lipids, such as EDTA- or DTPA-hexadecylamide lipids in liposome-like porphyrin nanoparticles (PS) enhanced their intracellular uptake by 25-fold, which was attributed to these lipids' ability to fluidize the cell membrane in a detergent-like manner rather than by metal chelation of EDTA or DTPA. EDTA-lipid-incorporated-PS (ePS) take advantage of its unique active uptake mechanism to achieve >95 % photodynamic therapy (PDT) cell killing compared to <5 % cell killing by PS. In multiple tumor models, ePS demonstrated fast fluorescence-enabled tumor delineation within minutes post-injection and increased PDT potency (100 % survival rate) compared to PS (60 %). This study offers a new nanoparticle cellular uptake strategy to overcome challenges associated with conventional drug delivery.

Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group.

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = -0.164 to -0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = -0.173 to -0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.

The effect of obstructed action efficacy on reward-based decision-making in healthy adolescents: a novel functional MRI task to assay frustration.

Frustration is common in adolescence and often interferes with executive functioning, particularly reward-based decision-making, and yet very little is known about how incidental frustrating events (independent of task-based feedback) disrupt the neural circuitry of reward processing in this important age group. While undergoing functional magnetic resonance imaging (fMRI), 45 healthy adolescents played a card game in which they had to guess between two options to earn points, in low- and high-stake conditions. Functioning of button presses through which they made decisions was intermittently blocked, thereby increasing frustration potential. Neural deactivation of the precuneus, a Default Mode Network region, was observed during obstructed action blocks across stake conditions, but less so on high- relative to low-stake trials. Moreover, less deactivation in goal-directed reward processing regions (i.e., caudate), frontoparietal "task control" regions, and interoceptive processing regions (i.e., somatosensory cortex, thalamus) were observed on high-stake relative to low-stake trials. These findings are consistent with less disruption of goal-directed reward seeking during blocked action efficacy in high-stake conditions among healthy adolescents. These results provide a roadmap of neural systems critical to the processing of frustrating events during reward-based decision-making in youths and could help to characterize how frustration regulation is altered in a range of pediatric psychopathologies.

Prolonged Circulating Lipid Nanoparticles Enabled by High-Density Gd-DTPA-Bis(stearylamide) for Long-Lasting Enhanced Tumor Magnetic Resonance Imaging.

Porphysomes (PS) were explored to incorporate different types of diethylenetriaminepentaacetic-acid-gadolinium-(III) (Gd-DTPA)-lipids into their bilayer membrane to assess PS potential as an MRI contrast agent. The Gd-dPS-BSA by integration of over 30% Gd-DTPA-bis(stearylamide) (Gd-DTPA-BSA)-lipids in PS construction resulted in exceptional serum stability and T1 and T2 relaxivity measurements of 13 mM-1 s-1 and 19 mM-1 s-1, respectively. The Gd-dPS-BSA demonstrated significantly enhanced retention in blood circulation with a half-life of 13.6 h and high tumor accumulation up to 19.5%ID/g at 72 h post-injection in select cancer mouse models. Additionally, Gd-dPS-BSA displayed excellent MRI tumor enhancement over 24, 48, and 72 h with contrast enhancements from the baseline of 35.8%, 38.2%, and 38.3%, respectively. Results reported here highlight a high-density incorporation of Gd-DTPA-BSA-lipids within PS, and other liposome formulations can enhance circulatory longevity, independently of particles' concentration, suggesting effective MRI contrast agent potential for Gd-dPS-BSA and potential utility of Gd-DTPA-BSA-lipids to enhance other liposomal-influenced diagnostic and therapeutic functions.

White Matter Microstructural Properties of the Cerebellar Peduncles Predict Change in Symptoms of Psychopathology in Adolescent Girls.

Internalizing symptoms typically emerge in adolescence and are more prevalent in females than in males; in contrast, externalizing symptoms typically emerge in childhood and are more commonly observed in males. Previous research has implicated aspects of white matter organization, including fractional anisotropy (FA), of cerebral tracts in both internalizing and externalizing symptoms. Although the cerebellum has been posited to integrate limbic and cortical regions, its role in psychopathology is not well understood. In this longitudinal study, we investigated whether FA of the superior (SCP), middle (MCP), and inferior cerebellar peduncles (ICP) predict change in symptoms and whether sex moderates this association. One hundred eleven adolescents completed the Youth Self-Report, assessing symptoms at baseline (ages 9-13 years) and again 2 years later. Participants also underwent diffusion-weighted imaging at baseline. We used deterministic tractography to segment and compute mean FA of the cerebellar peduncles. Lower FA of the right SCP at baseline predicted increases in internalizing symptoms in females only. Lower FA in the right SCP and ICP also predicted increases in externalizing symptoms in females, but these associations did not survive multiple comparison correction. There was no association between FA of the cerebellar peduncles and change in symptoms in males or between MCP FA and symptom changes in males or females. Organizational properties of the SCP may be a sex-specific marker of internalizing symptom changes in adolescence. The cerebellar peduncles should be explored further in future studies to elucidate sex differences in symptoms.

Early life stress, systemic inflammation, and neural correlates of implicit emotion regulation in adolescents.

Exposure to early life stress (ELS) increases the risk for developing psychopathology; however, the mechanisms underlying this association are not clear. In this study we examined systemic inflammation as a pathway that may link exposure to stress to altered neural correlates of implicit emotion regulation in adolescents with varying levels of exposure to ELS (n = 83; 52 females, 31 males; 15.63 ± 1.10 years). We measured ventrolateral prefrontal cortex (vlPFC) activation and functional connectivity (FC) between the bilateral amygdala and the vlPFC as adolescents completed an affect labeling task in the scanner and assessed concentrations of C-reactive protein (CRP) using a dried blood spot protocol. We found that CRP levels were negatively associated with vlPFC activation during implicit regulation of negatively-valenced stimuli, and that cumulative severity of ELS exposure moderated this neuroimmune association. Severity of ELS also significantly moderated the association between CRP levels and FC between the bilateral amygdala and l-vlPFC during implicit emotion regulation: in adolescents who had been exposed to more severe ELS, higher CRP was associated with more negative frontoamygdala FC during implicit regulation of negatively-valenced stimuli. Thus, ELS may disrupt the normative association between the immune system and the neural processes that underlie socioemotional functioning potentially increasing adolescents' risk for maladaptive outcomes.