Domain-specific associations between psychopathology and neurocognitive functioning.

BACKGROUND: Neurocognitive dysfunction is a transdiagnostic finding in psychopathology, but relationships among cognitive domains and general and specific psychopathology dimensions remain unclear. This study aimed to examine associations between cognition and psychopathology dimensions in a large youth cohort. METHOD: The sample (N = 9350; age 8-21 years) was drawn from the Philadelphia Neurodevelopmental Cohort. Data from structured clinical interviews were modeled using bifactor confirmatory factor analysis (CFA), resulting in an overall psychopathology ('p') factor score and six orthogonal psychopathology dimensions: dysphoria/distress, obsessive-compulsive, behavioral/externalizing, attention-deficit/hyperactivity, phobias, and psychosis. Neurocognitive data were aggregated using correlated-traits CFA into five factors: executive functioning, memory, complex cognition, social cognition, and sensorimotor speed. We examined relationships among specific and general psychopathology dimensions and neurocognitive factors. RESULTS: The final model showed both overall and specific associations between cognitive functioning and psychopathology, with acceptable fit (CFI = 0.91; TLI = 0.90; RMSEA = 0.024; SRMR = 0.054). Overall psychopathology and most psychopathology dimensions were negatively associated with neurocognitive functioning (phobias [p < 0.0005], behavioral/externalizing [p < 0.0005], attention-deficit/hyperactivity [p < 0.0005], psychosis [p < 0.0005 to p < 0.05]), except for dysphoria/distress and obsessive-compulsive symptoms, which were positively associated with complex cognition (p < 0.05 and p < 0.01, respectively). CONCLUSION: By modeling a broad range of cognitive and psychopathology domains in a large, diverse sample of youth, we found aspects of neurocognitive functioning shared across clinical phenotypes, as well as domain-specific patterns. Findings support transdiagnostic examination of cognitive performance to parse variability in the link between neurocognitive functioning and clinical phenotypes.

Enhanced antimicrobial efficacy and energy efficiency of low irradiance 405-nm light for bacterial decontamination.

Due to its increased safety over ultraviolet light, there is interest in the development of antimicrobial violet-blue light technologies for infection control applications. To ensure compatibility with exposed materials and tissue, the light irradiances and dose regimes used must be suitable for the target application. This study investigates the antimicrobial dose responses and germicidal efficiency of 405 nm violet-blue light when applied at a range of irradiance levels, for inactivation of surface-seeded and suspended bacteria. Bacteria were seeded onto agar surfaces (101-108 CFUplate-1) or suspended in PBS (103-109 CFUmL-1) and exposed to increasing doses of 405-nm light (≤ 288 Jcm-2) using various irradiances (0.5-150 mWcm-2), with susceptibility at equivalent light doses compared. Bacterial reductions ≥ 96% were demonstrated in all cases for lower irradiance (≤ 5 mWcm-2) exposures. Comparisons indicated, on a per unit dose basis, that significantly lower doses were required for significant reductions of all species when exposed at lower irradiances: 3-30 Jcm-2/0.5 mWcm-2 compared to 9-75 Jcm-2/50 mWcm-2 for low cell density (102 CFUplate-1) surface exposures and 22.5 Jcm-2/5 mWcm-2 compared to 67.5 Jcm-2/150 mWcm-2 for low density (103 CFUmL-1) liquid exposures (P ≤ 0.05). Similar patterns were observed at higher densities, excluding S. aureus exposed at 109 CFUmL-1, suggesting bacterial density at predictable levels has minimal influence on decontamination efficacy. This study provides fundamental evidence of the greater energy efficacy of 405-nm light for inactivation of clinically-significant pathogens when lower irradiances are employed, further supporting its relevance for practical decontamination applications.

Early single-center experience with middle meningeal artery embolization using Zoom™ 45 Catheter.

BACKGROUND: Middle meningeal artery (MMA) embolization for subdural hematomas (SDH) and dural arteriovenous fistulas (dAVFs) has gained momentum in the neuroendovascular space. However, there is variability in the technique for safe and effective embolization. The aim of this report is to describe the technical feasibility and clinical performance of using Zoom™ 45 catheter for MMA access to facilitate embolization. METHODS: We analyzed all cases of MMA embolization in which the Zoom™ 45 catheter was used and performed in our institution from February 2021 to March 2023 for SDH and dAVFs. RESULTS: A total of 32 patients were included. Mean age was 64.0 ± 18.0 years, 75.0% (4/32) were male, and 56.7% (17/30), were black. The technical success was achieved in 93.8% (30/32) of cases, with selective embolization utilizing microcatheter directly into frontal and parietal branches for most patients (96.9%, 31/32). Identification of dangerous collaterals, such as lacrimal and petrous branches, prior to embolization, was achieved in most patients (96.9%, 31/32). Bilateral MMA embolization was done in 50.0% (16/32) of patients. The transradial approach and transfemoral approach were used in 53.1% (17/32) and 46.9% (15/32) of patients, respectively. The most common embolization material was n-butyl cyanoacrylate (84.4%, 27/32). There were no access site complications or complications related to the MMA embolization procedures and used devices. CONCLUSIONS: The use of Zoom™ 45 Catheter seems to be technically feasible, safe, and effective for facilitating MMA access for embolization in the context of SDH and dAVFs.

Development of a ground-based sensorimotor disorientation analog to replicate astronaut postflight experience.

The perceptual and motor coordination problems experienced following return from spaceflight reflect the sensory adaptation to altered gravity. The purpose of this study was to develop a ground-based analog that replicates similar sensorimotor impairment using a standard measures test battery and subjective feedback from experienced crewmembers. This Sensorimotor Disorientation Analog (SDA) included varying levels of sensorimotor disorientation through combined vestibular, visual, and proprioceptive disruptions. The SDA was evaluated on five previously flown astronauts to compare with their postflight experience and functional motor performance immediately (Return (R)+0 days) and +24 h (R+1) after landing. The SDA consisted of galvanic vestibular stimulation (GVS), visual disruption goggles, and a weighted suit to alter proprioceptive feedback and replicate perceived heaviness postflight. Astronauts reported that GVS alone replicated ∼50-90% of their postflight performance with the weighted suit fine-tuning the experience to replicate an additional 10%-40% of their experience. Astronauts did not report feeling that the disruption goggles represented either the visual disruptions or illusory sensations that they experienced, nor did they impact motor performance in postflight tasks similarly. Based on these results, we recommend an SDA including the GVS and the weighted suit. These results provide a more realistic and portable SDA framework to provide transient spaceflight-relevant sensorimotor disruptions for use in countermeasure testing and as a pre-flight training tool.

Diabetic Kidney Disease Prevention Care Model Development.

More than one-third of people with diabetes develop diabetic kidney disease (DKD), which substantially increases risks of kidney failure, cardiovascular disease (CVD), hypoglycemia, death, and other adverse health outcomes. A multifaceted approach incorporating self-management education, lifestyle optimization, pharmacological intervention, CVD prevention, and psychosocial support is crucial to mitigate the onset and progression of DKD. The American Diabetes Association convened an expert panel to develop the DKD Prevention Model presented herein. This model addresses prevention and treatment, including screening guidelines, diagnostic tools, and management approaches; comprehensive, holistic interventions; well-defined roles for interdisciplinary health care professionals; community engagement; and future directions for research and policy.

Development and Characterization of Heparin-Containing Hydrogel/3D-Printed Scaffold Composites for Craniofacial Reconstruction.

Regeneration of cartilage and bone tissues remains challenging in tissue engineering due to their complex structures, and the need for both mechanical support and delivery of biological repair stimuli. Therefore, the goal of this study was to develop a composite scaffold platform for anatomic chondral and osteochondral repair using heparin-based hydrogels to deliver small molecules within 3D-printed porous scaffolds that provide structure, stiffness, and controlled biologic delivery. We designed a mold-injection system to combine hydrolytically degradable hydrogels and 3D-printed scaffolds that could be employed rapidly (< 30 min) in operating room settings (~23 °C). Micro-CT analysis demonstrated the effectiveness of our injection system through homogeneously distributed hydrogel within the pores of the scaffolds. Hydrogels and composite scaffolds exhibited efficient loading (~94%) of a small positively charged heparin-binding molecule (crystal violet) with sustained release over 14 days and showed high viability of encapsulated porcine chondrocytes over 7 days. Compression testing demonstrated nonlinear viscoelastic behavior where tangent stiffness decreased with scaffold porosity (porous scaffold tangent stiffness: 70%: 4.9 MPa, 80%: 1.5 MPa, and 90%: 0.20 MPa) but relaxation was not affected. Lower-porosity scaffolds (70%) showed stiffness similar to lower ranges of trabecular bone (4-8 MPa) while higher-porosity scaffolds (80% and 90%) showed stiffness similar to auricular cartilage (0.16-2 MPa). Ultimately, this rapid composite scaffold fabrication method may be employed in the operating room and utilized to control biologic delivery within load-bearing scaffolds.

Translating proof-of-concept for platelet slip into improved antithrombotic therapeutic regimens.

Platelets are central to thrombosis. Research at the intersection of biological and physical sciences provides proof-of-concept for shear rate-dependent platelet slip at vascular stenosis and near device surfaces. Platelet slip extends the observed biological "slip-bonds" to the boundary of functional gliding without contact. As a result, there is diminished engagement of the coagulation cascade by platelets at these surfaces. Comprehending platelet slip would more precisely direct antithrombotic regimens for different shear environments, including for percutaneous coronary intervention (PCI). In this brief report we promote translation of the proof-of-concept for platelet slip into improved antithrombotic regimens by: (1) reviewing new supporting basic biological science and clinical research for platelet slip; (2) hypothesizing the principal variables that affect platelet slip; (3) applying the consequent construct model in support of-and in some cases to challenge-relevant contemporary guidelines and their foundations (including for urgent, higher-risk PCI); and (4) suggesting future research pathways (both basic and clinical). Should future research demonstrate, explain and control platelet slip, then a paradigm shift for choosing and recommending antithrombotic regimens based on predicted shear rate should follow. Improved clinical outcomes with decreased complications accompanying this paradigm shift for higher-risk PCI would also result in substantive cost savings.

Serum cytokine and inflammatory markers in individuals with heroin use disorder: potential biomarkers for diagnosis and disease severity.

Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially as a multi-target biomarker. We used a validated proximity extension assay for relative quantification of 92 cytokines and inflammatory proteins in serum of iHUD on medication assisted therapy (MAT; n=21), versus HC (n=24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison correction (p=0.05). This included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, and PC1 scores were iHUD>HC (p<0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC=91.7% (p<0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, which included demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, and provides a multi-target "cytokine biomarker score" for potential diagnostic purposes, and examination of disease severity.

Postoperative Cosmetic Scores and Revision Rates After Nasal Mohs Reconstructive Surgery.

OBJECTIVE: Few studies have examined the impact of preoperative and surgical factors on the change in cosmetic survey scores after nasal Mohs reconstruction using a subset of the 10-item Standardized Cosmesis and Health Nasal Outcomes Survey-Cosmesis (SCHNOS-C). We aim to determine preoperative and surgical factors that impact cosmetic outcomes following Mohs nasal reconstruction. STUDY DESIGN: Retrospective analysis. SETTING: Nasal Mohs reconstruction patients at a tertiary medical center. METHODS: All patients receiving Mohs reconstruction of any nasal subunit at a tertiary medical center were analyzed. Variables collected included demographic and Mohs defect/reconstruction characteristics. Primary outcomes were changes in cosmetic (SCHNOS-C) scores and revision rates. Multivariable analysis was used to identify independent predictors of cosmetic scores/revision. RESULTS: We included 296 patients for analysis. On multivariable logistic regression, factors contributing to better final cosmetic scores were receiving a skin/composite graft (odds ratio [OR]: 0.22, 95% confidence interval: 0.06-0.68, P = .014) compared to a local flaps. Women were more likely to have worsening cosmetic scores (OR: 2.27, 1.06-4.99, P = .037). Only initial cosmetic scores independently predicted receiving any revision (OR: 1.11, 1.03-1.20, P = .006). CONCLUSION: Average SCHNOS-C scores after nasal reconstruction of Mohs defects are low. Only worse patient reported SCHNOS-C scores predicted revision. It is important to understand preoperative and surgical factors that affect cosmetic outcomes to optimize patient counseling and reconstructive planning. Patient perception is a key factor in predicting revisions.

Influence of Isolated Talonavicular and Subtalar Joint Arthrodesis on Hindfoot Kinematics and Range of Motion During Cadaveric Gait Simulation.

BACKGROUND: Isolated subtalar and talonavicular joint arthrodeses have been associated with adjacent joint arthritis and altered hindfoot kinematics during simplified loading scenarios. However, the effect on kinematics during dynamic activity is unknown. This study assessed changes in subtalar and talonavicular kinematics after isolated talonavicular (TNiso) and subtalar (STiso) arthrodesis, respectively, during stance simulations. METHODS: Fourteen midtibia specimens received either a TNiso or STiso arthrodesis, with 7 randomized to each group. A 6-degree-of-freedom robot sequentially simulated the stance phase for the intact and arthrodesis conditions. Bootstrapped bias-corrected 95% CIs of the talonavicular and subtalar joint kinematics were calculated and compared between conditions. RESULTS: The TNiso decreased subtalar inversion, adduction, and plantarflexion in late stance (P < .05). The subtalar range of motion in the sagittal and coronal planes decreased by 40% (P = .009) and 46% (P = .002), respectively. No significant changes in talonavicular joint kinematics were observed after isolated subtalar arthrodesis; however, the range of motion was reduced by 61% (P = .007) and 50% (P = .003) in the coronal and axial planes, respectively. CONCLUSION: In this model for arthrodesis, changes in subtalar kinematics and motion restriction were observed after isolated talonavicular arthrodesis, and motion restriction was observed after isolated subtalar arthrodesis. Surprisingly, talonavicular kinematics did not appear to change after isolated subtalar arthrodesis. CLINICAL RELEVANCE: Both joint fusions substantially decrease the motion of the reciprocal adjacent joint. Surgeons should be aware that the collateral costs with talonavicular fusion appear higher, and it has a significant effect on subtalar kinematics during the toe-off phase of gait.

A Hitchhiker's guide to high-dimensional tissue imaging with multiplexed ion beam imaging.

Advancements in multiplexed tissue imaging technologies are vital in shaping our understanding of tissue microenvironmental influences in disease contexts. These technologies now allow us to relate the phenotype of individual cells to their higher-order roles in tissue organization and function. Multiplexed Ion Beam Imaging (MIBI) is one of such technologies, which uses metal isotope-labeled antibodies and secondary ion mass spectrometry (SIMS) to image more than 40 protein markers simultaneously within a single tissue section. Here, we describe an optimized MIBI workflow for high-plex analysis of Formalin-Fixed Paraffin-Embedded (FFPE) tissues following antigen retrieval, metal isotope-conjugated antibody staining, imaging using the MIBI instrument, and subsequent data processing and analysis. While this workflow is focused on imaging human FFPE samples using the MIBI, this workflow can be easily extended to model systems, biological questions, and multiplexed imaging modalities.

Distances from ligands as main predictive features for pathogenicity and functional effect of variants in NMDA receptors.

Genetic variants in genes GRIN1 , GRIN2A , GRIN2B , and GRIN2D , which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic diseases. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects are therefore crucial for accurate diagnosis and therapeutic applications. We assembled missense variants: 201 from patients, 631 from general population, and 159 characterized by electrophysiological readouts showing whether they can enhance or reduce the receptor function. This includes new functional data from 47 variants reported here, for the first time. We found that pathogenic/benign variants and variants that increase/decrease the channel function were distributed unevenly on the protein structure, with spatial proximity to ligands bound to the agonist and antagonist binding sites being key predictive features. Leveraging distances from ligands, we developed two independent machine learning-based predictors for NMDAR missense variants: a pathogenicity predictor which outperforms currently available predictors (AUC=0.945, MCC=0.726), and the first binary predictor of molecular function (increase or decrease) (AUC=0.809, MCC=0.523). Using these, we reclassified variants of uncertain significance in the ClinVar database and refined a previous genome-informed epidemiological model to estimate the birth incidence of molecular mechanism-defined GRIN disorders. Our findings demonstrate that distance from ligands is an important feature in NMDARs that can enhance variant pathogenicity prediction and enable functional prediction. Further studies with larger numbers of phenotypically and functionally characterized variants will enhance the potential clinical utility of this method.

Mitf, with Yki and STRIPAK-PP2A, is a key determinant of form and fate in the progenitor epithelium of the Drosophila eye.

The Microphthalmia-associated Transcription Factor (MITF) governs numerous cellular and developmental processes. In mice, it promotes specification and differentiation of the retinal pigmented epithelium (RPE), and in humans, some mutations in MITF induce congenital eye malformations. Herein, we explore the function and regulation of Mitf in Drosophila eye development and uncover two roles. We find that knockdown of Mitf results in retinal displacement (RDis), a phenotype associated with abnormal eye formation. Mitf functions in the peripodial epithelium (PE), a retinal support tissue akin to the RPE, to suppress RDis, via the Hippo pathway effector Yorkie (Yki). Yki physically interacts with Mitf and can modify its transcriptional activity in vitro. Severe loss of Mitf, instead, results in the de-repression of retinogenesis in the PE, precluding its development. This activity of Mitf requires the protein phosphatase 2 A holoenzyme STRIPAK-PP2A, but not Yki; Mitf transcriptional activity is potentiated by STRIPAK-PP2A in vitro and in vivo. Knockdown of STRIPAK-PP2A results in cytoplasmic retention of Mitf in vivo and in its decreased stability in vitro, highlighting two potential mechanisms for the control of Mitf function by STRIPAK-PP2A. Thus, Mitf functions in a context-dependent manner as a key determinant of form and fate in the Drosophila eye progenitor epithelium.

Comparative efficacy of low-volume retrobulbar anesthesia using three commercial local anesthetics in adult horses.

OBJECTIVE: To compare the efficacy of low-volume (5-mL) locoregional retrobulbar anesthesia ("retrobulbar block") by use of 3 commercial local anesthetic formulations. ANIMALS: 8 healthy adult mares. METHODS: A block-randomized, masked, controlled design was used. A single ultrasound-guided retrobulbar block was performed with 2% lidocaine, 2% mepivacaine, or 0.5% bupivacaine (n = 5 eyes/group). Contralateral eyes served as untreated controls. End points performed at baseline and time intervals up to 24 hours postblock included the following: assessment of neurophthalmic reflexes/responses, intraocular pressure, and vertical pupil diameter measurement, corneal and periocular esthesiometry, and observation for adverse effects. RESULTS: Low-volume block did not result in increased intraocular pressure or other adverse effects at any time point in any treatment group. Statistically significant corneal anesthesia (P < .001) was observed 1 minute after block in all groups, persisting through 4 hours after lidocaine or mepivacaine block and through 24 hours after bupivacaine block. Clinically significant periocular anesthesia was not observed in any group. Significant vertical pupil diameter increase (P < .05) was observed for up to 4 hours after lidocaine or mepivacaine block and 6 hours after bupivacaine block. CLINICAL RELEVANCE: Low-volume retrobulbar block with any of the 3 local anesthetic drugs evaluated was not associated with adverse effects. In terms of efficacy, mepivacaine block showed no clinical advantage over lidocaine block. However, bupivacaine block induced comparatively rapid and sustained corneal anesthesia. In comparison to published findings using a larger injection volume, low-volume retrobulbar block with lidocaine produced clinically comparable corneal anesthesia. However, periocular soft tissue anesthesia was not achieved with any local anesthetic drug at low volume.

Ankle fracture open reduction and internal fixation in patients with cerebral palsy.

AIM: To examine patients with cerebral palsy (CP) undergoing open reduction and internal fixation (ORIF) for ankle fractures. METHOD: This was a retrospective study of adult patients undergoing ankle fracture ORIF for closed, isolated ankle fractures identified in between 2010 and 2021 in the Q1 PearlDiver M151 database. Patients with CP were identified with International Classification of Diseases (ICD)-9 and ICD-10 codes, and were matched to those without 1:10 on age, sex, and Elixhauser comorbidity index (ECI). Ninety-day adverse events were assessed with multivariable logistic regression. RESULTS: A total of 148 993 patients with isolated ankle fracture ORIF were identified, of whom 407 (0.27%) had CP. After matching, 3863 without CP were compared to 389 with CP. Patients with CP were at increased odds of: 90-day urinary tract infection (odds ratios [OR] 6.26), pneumonia (OR 3.50), minor adverse events (OR 3.46), sepsis (OR 3.30), any adverse events (OR 3.04), emergency department visits (OR 2.28), serious adverse events (OR 1.77), and prolonged length of stay more than 4 days (OR 22.44) (p < 0.001 for all). INTERPRETATION: Patients with CP undergoing ORIF for isolated, closed ankle fractures are at increased odds of several 90-day adverse events and prolonged length of stay compared to matched patients without CP.