Myocardial Blood Flow Quantification Using Stress Cardiac Magnetic Resonance Improves Detection of Coronary Artery Disease.

BACKGROUND: Myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) using stress cardiovascular magnetic resonance (CMR) have been shown to identify epicardial coronary artery disease. However, comparative analysis between quantitative perfusion and conventional qualitative assessment (QA) remains limited. OBJECTIVES: The aim of this multicenter study was to test the hypothesis that quantitative stress MBF (sMBF) and MPR analysis can identify obstructive coronary artery disease (obCAD) with comparable performance as QA of stress CMR performed by experienced physicians in interpretation. METHODS: The analysis included 127 individuals (mean age 62 ± 16 years, 84 men [67%]) who underwent stress CMR. obCAD was defined as the presence of stenosis ≥50% in the left main coronary artery or ≥70% in a major vessel. Each patient, coronary territory, and myocardial segment was categorized as having either obCAD or no obCAD (noCAD). Global, per coronary territory, and segmental MBF and MPR values were calculated. QA was performed by 4 CMR experts. RESULTS: At the patient level, global sMBF and MPR were significantly lower in subjects with obCAD than in those with noCAD, with median values of sMBF of 1.5 mL/g/min (Q1-Q3: 1.2-1.8 mL/g/min) vs 2.4 mL/g/min (Q1-Q3: 2.1-2.7 mL/g/min) (P < 0.001) and median values of MPR of 1.3 (Q1-Q3: 1.0-1.6) vs 2.1 (Q1-Q3: 1.6-2.7) (P < 0.001). At the coronary artery level, sMBF and MPR were also significantly lower in vessels with obCAD compared with those with noCAD. Global sMBF and MPR had areas under the curve (AUCs) of 0.90 (95% CI: 0.84-0.96) and 0.86 (95% CI: 0.80-0.93). The AUCs for QA by 4 physicians ranged between 0.69 and 0.88. The AUC for global sMBF and MPR was significantly better than the average AUC for QA. CONCLUSIONS: This study demonstrates that sMBF and MPR using dual-sequence stress CMR can identify obCAD more accurately than qualitative analysis by experienced CMR readers.

Genetic regulation of microRNAs in the older adult brain and their contribution to neuropsychiatric conditions.

MicroRNAs are essential post-transcriptional regulators of gene expression and involved in many biological processes; however, our understanding of their genetic regulation and role in brain illnesses is limited. Here, we mapped brain microRNA expression quantitative trait loci (miR-QTLs) using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex (dlPFC) samples of 604 older adult donors of European ancestry. miR-QTLs were identified for 224 miRNAs (48% of 470 tested miRNAs) at false discovery rate < 1%. We found that miR-QTLs were enriched in brain promoters and enhancers, and that intragenic miRNAs often did not share QTLs with their host gene. Additionally, we integrated the brain miR-QTLs with results from 16 GWAS of psychiatric and neurodegenerative diseases using multiple independent integration approaches and identified four miRNAs that contribute to the pathogenesis of bipolar disorder, major depression, post-traumatic stress disorder, schizophrenia, and Parkinson's disease. This study provides novel insights into the contribution of miRNAs to the complex biological networks that link genetic variation to disease.

Cardiopulmonary exercise testing prior to radical cystectomy: a systematic review and meta-analysis.

OBJECTIVE: To identify the association between cardiopulmonary exercise testing (CPET) and outcomes of radical cystectomy (RC), as RC is historically associated with high rates of short- and long-term morbidity and mortality. METHODS: This quantitative systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. An electronic literature search was conducted to identify all relevant studies evaluating the relationship between CPET parameters and RC outcomes. The primary outcome was short-term mortality. Secondary outcomes included hospital length of stay (LOS) and rate of serious adverse events as defined by the Clavien-Dindo classification. RESULTS: The search identified six studies for inclusion. A total of 546 patients underwent CPET prior to RC. There were significantly more deaths following RC observed in patients with poorer cardiopulmonary function (risk ratio RR 5.80, 95% confidence interval 4.96-6.78). There was no significant association between CPET parameters and adverse events or hospital LOS. CONCLUSIONS: The present systematic review and meta-analysis identified a greater risk of 90-day mortality in patients with poorer cardiorespiratory function, as measured by CPET. However, there remains a paucity of robust clinical data and further high-quality studies are required to verify these results.

Chronic innate immune impairment and ZIKV persistence in the gastrointestinal tract during SIV infection in pigtail macaques.

Mosquito borne flaviviruses, including dengue (DENV) and Zika (ZIKV) viruses, have caused global epidemics in areas with high HIV prevalence due to the expanded geographic range of arthropod vectors. Despite the occurrence of large flavivirus outbreaks in countries with high HIV prevalence, there is little knowledge regarding the effects of flavivirus infection in people living with HIV (PLWH). Here, we use a pigtail macaque model of HIV/AIDS to investigate the impact of simian immunodeficiency virus (SIV)-induced immunosuppression on ZIKV replication and pathogenesis. Early acute SIV infection induced expansion of peripheral ZIKV cellular targets and increased innate immune activation and peripheral blood mononuclear cells (PBMC) from SIV infected macaques were less permissive to ZIKV infection in vitro. In SIV-ZIKV co-infected animals, we found increased persistence of ZIKV in the periphery and tissues corresponding to alterations in innate cellular (monocytes, neutrophils) recruitment to the blood and tissues, decreased anti-ZIKV immunity, and chronic peripheral inflammatory and innate immune gene expression. Collectively, these findings suggest that untreated SIV infection may impair cellular innate responses and create an environment of chronic immune activation that promotes prolonged ZIKV viremia and persistence in the gastrointestinal tract. These results suggest that PLWH or other immunocompromised individuals could be at a higher risk for chronic ZIKV replication, which in turn could increase the timeframe of ZIKV transmission. Thus, PLWH are important populations to target during the deployment of vaccine and treatment strategies against ZIKV.

Innovation in prevention of poison oak contact dermatitis.

Poison oak-induced contact dermatitis poses a significant challenge due to its urushiol oil-induced allergic reactions. Conventional preventive measures like avoidance and post-exposure cleansing are often impractical, necessitating innovative strategies. This comprehensive review explores emerging technologies and formulations for preventing poison oak dermatitis. Literature search via PubMed and Covidence identified 13 relevant studies, with six discussing preventive measures. Barrier methods, including occlusive creams and protective clothing, showed promise in reducing dermatitis risk. Immunotherapy, although investigated, requires further development. Complete avoidance, while effective, is often impractical. The complexity of poison oak management underscores the need for ongoing research to develop more effective preventive measures. This review highlights the current landscape, identifies gaps in knowledge, and emphasizes the importance of continued research for improved prevention and management of poison oak-induced dermatitis.

Comparison of dual-bolus versus dual-sequence techniques for determining myocardial blood flow and myocardial perfusion reserve by cardiac magnetic resonance stress perfusion: From the Automated Quantitative analysis of myocardial perfusion cardiac Magnetic Resonance Consortium.

BACKGROUND: Quantitative stress cardiac magnetic resonance (CMR) can be performed using the dual-sequence (DS) technique or dual-bolus (DB) method. It is unknown if DS and DB produce similar results for myocardial blood flow (MBF) and myocardial perfusion reserve (MPR). The study objective is to investigate if there are any differences between DB- and DS-derived MBF and MPR. METHODS: Retrospective observational study with 168 patients who underwent stress CMR. DB and DS methods were simultaneously performed on each patient on the same day. Global and segmental stress MBF and rest MBF values were collected. RESULTS: Using Bland-Altman analysis, segmental and global stress MBF values were higher in DB than DS (0.22 ± 0.60 mL/g/min, p < 0.001 and 0.20 ± 0.48 mL/g/min, p = 0.005, respectively) with strong correlation (r = 0.81, p < 0.001 for segmental and r = 0.82, p < 0.001 for global). In rest MBF, segmental and global DB values were higher than by DS (0.15 ± 0.51 mL/g/min, p < 0.001 and 0.14 ± 0.36 mL/g/min, p = 0.011, respectively) with strong correlation (r = 0.81, p < 0.001 and r = 0.77, p < 0.001). Mean difference between MPR by DB and DS was -0.02 ± 0.68 mL/g/min (p = 0.758) for segmental values and -0.01 ± 0.49 mL/g/min (p = 0.773) for global values. MPR values correlated strongly as well in both segmental and global, both (r = 0.74, p < 0.001) and (r = 0.75, p < 0.001), respectively. CONCLUSION: There is a very good correlation between DB- and DS-derived MBF and MPR values. However, there are significant differences between DB- and DS-derived global stress and rest MBF. While MPR values did not show statistically significant differences between DB and DS methods.

Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial.

BACKGROUND: The rate of antibiotic resistance continues to grow, outpacing small-molecule-drug development efforts. Novel therapies are needed to combat this growing threat, particularly for the treatment of urinary tract infections (UTIs), which are one of the largest contributors to antibiotic use and associated antibiotic resistance. LBP-EC01 is a novel, genetically enhanced, six-bacteriophage cocktail developed by Locus Biosciences (Morrisville, NC, USA) to address UTIs caused by Escherichia coli, regardless of antibiotic resistance status. In this first part of the two-part phase 2 ELIMINATE trial, we aimed to define a dosing regimen of LBP-EC01 for the treatment of uncomplicated UTIs that could advance to the second, randomised, controlled, double-blinded portion of the study. METHODS: This first part of ELIMINATE is a randomised, uncontrolled, open-label, phase 2 trial that took place in six private clinical sites in the USA. Eligible participants were female by self-identification, aged between 18 years and 70 years, and had an uncomplicated UTI at the time of enrolment, as well as a history of at least one drug-resistant UTI caused by E coli within the 12 months before enrolment. Participants were initially randomised in a 1:1:1 ratio into three treatment groups, but this part of the trial was terminated on the recommendation of the safety review committee after a non-serious tolerability signal was observed based on systemic drug exposure. A protocol update was then implemented, comprised of three new treatment groups. Groups A to C were dosed with intraurethral 2 × 1012 plaque-forming units (PFU) of LBP-EC01 on days 1 and 2 by catheter, plus one of three intravenous doses daily on days 1-3 of LBP-EC01 (1 mL of 1 × 1010 PFU intravenous bolus in group A, 1 mL of 1 × 109 PFU intravenous bolus in group B, and a 2 h 1 × 1011 PFU intravenous infusion in 100 mL of sodium lactate solution in group C). In all groups, oral trimethoprim-sulfamethoxazole (TMP-SMX; 160 mg and 800 mg) was given twice daily on days 1-3. The primary outcome was the level of LBP-EC01 in urine and blood across the treatment period and over 48 h after the last dose and was assessed in patients in the intention-to-treat (ITT) population who received at least one dose of LBP-EC01 and had concentration-time data available throughout the days 1-3 dosing period (pharmacokinetic population). Safety, a secondary endpoint, was assessed in enrolled patients who received at least one dose of study drug (safety population). As exploratory pharmacodynamic endpoints, we assessed E coli levels in urine and clinical symptoms of UTI in patients with at least 1·0 × 105 colony-forming units per mL E coli in urine at baseline who took at least one dose of study drug and completed their day 10 test-of-cure assessment (pharmacodynamic-evaluable population). This trial is registered with ClinicalTrials.gov, NCT05488340, and is ongoing. FINDINGS: Between Aug 22, 2022, and Aug 28, 2023, 44 patients were screened for eligibility, and 39 were randomly assigned (ITT population). Initially, eight participants were assigned to the first three groups. After the protocol was updated, 31 participants were allocated into groups A (11 patients), B (ten patients), and C (ten patients). One patient in group C withdrew consent on day 2 for personal reasons, but as she had received the first dose of the study drug was included in the modified ITT population. Maximum urine drug concentrations were consistent across intraurethral dosing, with a maximum mean concentration of 6·3 × 108 PFU per mL (geometric mean 8·8 log10 PFU per mL and geometric SD [gSD] 0·3). Blood plasma level of bacteriophages was intravenous dose-dependent, with maximum mean concentrations of 4·0 × 103 (geometric mean 3·6 log10 PFU per mL [gSD 1·5]) in group A, 2·5 × 103 (3·4 log10 PFU per mL [1·7]) in group B, and 8·0 × 105 (5·9 log10 PFU per mL [1·4]) in group C. No serious adverse events were observed. 44 adverse events were reported across 18 (46%) of the 39 participants in the safety population, with more adverse events seen with higher intravenous doses. Three patients in groups 1 to 3 and one patient in group C, all of whom received 1 × 1011 LBP-EC01 intravenously, had non-serious tachycardia and afebrile chills after the second intravenous dose. A rapid reduction of E coli in urine was observed by 4 h after the first treatment and maintained at day 10 in all 16 evaluable patients; these individuals had complete resolution of UTI symptoms by day 10. INTERPRETATION: A regimen consisting of 2 days of intraurethral LBP-EC01 and 3 days of concurrent intravenous LBP-EC01 (1 × 1010 PFU) and oral TMP-SMX twice a day was well tolerated, with consistent pharmacokinetic profiles in urine and blood. LBP-EC01 and TMP-SMX dosing resulted in a rapid and durable reduction of E coli, with corresponding elimination of clinical symptoms in evaluable patients. LBP-EC01 holds promise in providing an alternative therapy for uncomplicated UTIs, with further testing of the group A dosing regimen planned in the controlled, double-blind, second part of ELIMINATE. FUNDING: Federal funds from the US Department of Health and Human Services, Administration for Strategic Preparedness and Response, and Biomedical Advanced Research and Development Authority (BARDA).

The Effects of Burnout, Team Support, and Perceived Leader Effectiveness on Career Intentions Among JAG Corps Personnel.

INTRODUCTION: Destructive interpersonal relationships at work may result in negative feelings among employees that hinder personal and organizational productivity, which may also result in high levels of job disengagement and subsequent career turnover intentions. Leaders play a key role in creating work environments conducive to optimizing employee performance, organizational culture, and workplace well-being. Social support, which may include support from one's supervisor, colleagues, and loved ones, has been shown to reduce strains and perceived stressors at work. In the Army, the Judge Advocate General's Corps (JAGC) personnel have a unique position as lawyers and legal staff and have been shown to have high rates of burnout. To promote soldier health, well-being, and career longevity, it is important to understand the impact interpersonal relationships have on career intentions. The current study assesses the relationship between perceived leadership effectiveness and career intentions as moderated by burnout measured by job disengagement and team care activities in JAGC personnel. MATERIALS AND METHODS: The Walter Reed Army Institute of Research conducted a survey to understand factors affecting the well-being of the JAGC's soldier and civilian personnel as requested by the JAGC. JAGC personnel were administered several questionnaires covering a range of work and mental health topics. Job disengagement, career intentions, team care activities, and general leadership were assessed. A total of 831 JAGC personnel completed the survey, the majority (92%) of which were soldiers. Among soldiers, first lieutenants and captains (∼49%) were the majority. The sample largely consisted of men (∼63%), White individuals (∼76%), married individuals, (70%), and individuals with graduate degrees (∼81%). RESULTS: One in four participants (∼29%) experienced high levels of disengagement, with their work. Over two-thirds of participants agreed that their immediate supervisor is an effective leader. When asked about career intentions, the majority of JAGC participants (54%) indicated that they would probably or definitely stay in the JAGC until retirement. Ordinal logistic regressions were conducted to assess the relationship between perceived leader effectiveness and career intentions, assessing the main effects of job disengagement and team care activities, and the interactions between those variables. No interaction effects were found to be significant, but main effects for perceived leader effectiveness were significant. CONCLUSIONS: JAGC personnel reported higher levels of job disengagement for those with career intentions that were undecided or definitely leaving the JAGC after their current obligation. Those who were engaged in more team care activities had lower levels of disengagement. While the majority of the JAGC participants indicated career intentions to stay in the JAGC until retirement, increasing perceived effectiveness of leaders could help increase attrition and career intentions to stay in the JAGC beyond one's current obligation.

Epidemiology of odontogenic tumours and selected cysts diagnosed at a single New Zealand oral pathology centre- A 15-year retrospective study.

PURPOSE: This research aimed to investigate the relative frequency of odontogenic tumours (OT) and selected odontogenic cysts in a single oral pathology center in New Zealand from 2008 to 2023. METHODS: Histopathological records from the Oral Pathology Centre, University of Otago (2008-2023) were examined to identify OT. Odontogenic keratocyst (OKC) and calcifying odontogenic cyst (COC), previously classified as OT were also included. Patient demographics, clinical details and histopathologic diagnoses were recorded. Data were analyzed using SPSS. RESULTS: Of the 34,225 biopsies over the 15-year period, 1.8% were identified as OTs, COC and OKCs and accounted for 47%, 1.5% and 51.5% respectively. The most prevalent OT types were odontoma (43.7%), ameloblastoma (27%) and cemento-ossifying fibroma (7.5%). Malignant OT, ameloblastic carcinoma, constituted 1.4% of OT. The average age at diagnosis for OKC, COC and OT patients were 48.2 ± 20.9, 33.7 ± 23.3 and 28.9 ± 19.3 years. Overall, male and mandibular site predilections were observed. Recurrence of OKC and ameloblastoma occurred in 15.2% and 13.7% of patients. The time for recurrence for OKC and Ameloblastoma were 61.7 ± 56.5 months and 122 ± 152 months respectively. CONCLUSION: The demographic features and range of OT, COC and OKC in New Zealand align with those of other western countries. The study also confirms need for long term follow up for patient with OKC and ameloblastoma.

Open Versus Percutaneous Stabilization of Thoracolumbar Fractures: A Large Retrospective Analysis of Safety and Reoperation Rates.

BACKGROUND: Thoracolumbar fractures (TLF) requiring surgical intervention can be treated with either open or percutaneous stabilization, each with some distinct risks and benefits. There is insufficient evidence available to support one approach as superior. METHODS: Patients who underwent spinal fixation for TLF between 2008 and 2020 were reviewed. Patients with one or two levels of fracture treated with either open or percutaneous stabilization were included. Exclusion criteria were more than two levels of fracture, patients requiring corpectomy, stabilization constructs that crossed the cervicothoracic or lumbosacral junction, history of previous thoracolumbar fusion at the same level, spinal neoplasm, anterior or lateral fixation, and spinal infection. Demographic, operative, and clinical data were collected for all patients. RESULTS: 691 patients (377 open, 314 percutaneous) met the inclusion criteria. Patients in the percutaneous cohort sustained lower estimated blood loss (73 vs 334 ml; p< 0.001) and shorter length of surgery (114 vs. 151 minutes; p< 0.001). No differences were observed in the length of hospital stay or overall reoperation rates. Asymptomatic (7.0% vs 0.8%) and symptomatic (3.5% vs 0.5%) hardware removal was more common with the percutaneous cohort, while the incidence of revision surgery due to hardware failure requiring the extension of the construct (1.9% vs 5.8%) and infection (1.9% vs 6.4%) was greater in the open group. CONCLUSION: Percutaneous stabilization for TLF was associated with shorter operative time, less blood loss, lower infection rate, higher rates of elective hardware removal, and lower rates of hardware failure requiring extension of the construct compared to open stabilization.

Concordance of clinician, Chat-GPT4, and ORAD diagnoses against histopathology in Odontogenic Keratocysts and tumours: a 15-Year New Zealand retrospective study.

BACKGROUND: This research aimed to investigate the concordance between clinical impressions and histopathologic diagnoses made by clinicians and artificial intelligence tools for odontogenic keratocyst (OKC) and Odontogenic tumours (OT) in a New Zealand population from 2008 to 2023. METHODS: Histopathological records from the Oral Pathology Centre, University of Otago (2008-2023) were examined to identify OKCs and OT. Specimen referral details, histopathologic reports, and clinician differential diagnoses, as well as those provided by ORAD and Chat-GPT4, were documented. Data were analyzed using SPSS, and concordance between provisional and histopathologic diagnoses was ascertained. RESULTS: Of the 34,225 biopsies, 302 and 321 samples were identified as OTs and OKCs. Concordance rates were 43.2% for clinicians, 45.6% for ORAD, and 41.4% for Chat-GPT4. Corresponding Kappa value against histological diagnosis were 0.23, 0.13 and 0.14. Surgeons achieved a higher concordance rate (47.7%) compared to non-surgeons (29.82%). Odds ratio of having concordant diagnosis using Chat-GPT4 and ORAD were between 1.4 and 2.8 (p < 0.05). ROC-AUC and PR-AUC were similar between the groups (Clinician 0.62/0.42, ORAD 0.58/0.28, Char-GPT4 0.63/0.37) for ameloblastoma and for OKC (Clinician 0.64/0.78, ORAD 0.66/0.77, Char-GPT4 0.60/0.71). CONCLUSION: Clinicians with surgical training achieved higher concordance rate when it comes to OT and OKC. Chat-GPT4 and Bayesian approach (ORAD) have shown potential in enhancing diagnostic capabilities.

Reconstitution of human tissue barrier function for precision and personalized medicine.

Tissue barriers in a body, well known as tissue-to-tissue interfaces represented by endothelium of the blood vessels or epithelium of organs, are essential for maintaining physiological homeostasis by regulating molecular and cellular transports. It is crucial for predicting drug response to understand physiology of tissue barriers through which drugs are absorbed, distributed, metabolized and excreted. Since the FDA Modernization Act 2.0, which prompts the inception of alternative technologies for animal models, tissue barrier chips, one of the applications of organ-on-a-chip or microphysiological system (MPS), have only recently been utilized in the context of drug development. Recent advancements in stem cell technology have brightened the prospects for the application of tissue barrier chips in personalized medicine. In past decade, designing and engineering these microfluidic devices, and demonstrating the ability to reconstitute tissue functions were main focus of this field. However, the field is now advancing to the next level of challenges: validating their utility in drug evaluation and creating personalized models using patient-derived cells. In this review, we briefly introduce key design parameters to develop functional tissue barrier chip, explore the remarkable recent progress in the field of tissue barrier chips and discuss future perspectives on realizing personalized medicine through the utilization of tissue barrier chips.

Motion robust coronary MR angiography using zigzag centric ky-kz trajectory and high-resolution deep learning reconstruction.

PURPOSE: To develop a new MR coronary angiography (MRCA) technique by employing a zigzag fan-shaped centric ky-kz k-space trajectory combined with high-resolution deep learning reconstruction (HR-DLR). METHODS: All imaging data were acquired from 12 healthy subjects and 2 patients using two clinical 3-T MR imagers, with institutional review board approval. Ten healthy subjects underwent both standard 3D fast gradient echo (sFGE) and centric ky-kz k-space trajectory FGE (cFGE) acquisitions to compare the scan time and image quality. Quantitative measures were also performed for signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) as well as sharpness of the vessel. Furthermore, the feasibility of the proposed cFGE sequence was assessed in two patients. For assessing the feasibility of the centric ky-kz trajectory, the navigator-echo window of a 30-mm threshold was applied in cFGE, whereas sFGE was applied using a standard 5-mm threshold. Image quality of MRCA using cFGE with HR-DLR and sFGE without HR-DLR was scored in a 5-point scale (non-diagnostic = 1, fair = 2, moderate = 3, good = 4, and excellent = 5). Image evaluation of cFGE, applying HR-DLR, was compared with sFGE without HR-DLR. Friedman test, Wilcoxon signed-rank test, or paired t tests were performed for the comparison of related variables. RESULTS: The actual MRCA scan time of cFGE with a 30-mm threshold was acquired in less than 5 min, achieving nearly 100% efficiency, showcasing its expeditious and robustness. In contrast, sFGE was acquired with a 5-mm threshold and had an average scan time of approximately 15 min. Overall image quality for MRCA was scored 3.3 for sFGE and 2.7 for cFGE without HR-DLR but increased to 3.6 for cFGE with HR-DLR and (p < 0.05). The clinical result of patients obtained within 5 min showed good quality images in both patients, even with a stent, without artifacts. Quantitative measures of SNR, CNR, and sharpness of vessel presented higher in cFGE with HR-DLR. CONCLUSION: Our findings demonstrate a robust, time-efficient solution for high-quality MRCA, enhancing patient comfort and increasing clinical throughput.

Familial and religious ethnic-racial socialization in promoting activism among Asian American Christians.

The adversity faced by Asian Americans (AAs) due to discrimination is a testament to the ongoing fight for human rights. At the crux of social activism, familial and religious ethnic-racial socialization (ERS) instills cultural values, ethnic identity, belonging to one's racial group, and a meaningful outlook, navigating generations through these challenges. This study examined the role of family and religion in amplifying social advocacy among AAs by assessing the relationship between race-related stress and social activism, as well as the mediating role of familial and religious ERS via a parallel mediation. Our research, utilizing a cross-sectional, nonexperimental design, involved 254 AA emerging adults identifying as Christian (Mage = 29.06, SDage = 7.55), sourced from Prolific (n = 203) and community sampling (n = 51). Linear regression findings revealed significant positive associations between familial ERS and social action (ß = .226, p < .001), as well as religious ERS and social action (ß = .085, p = .033). Nevertheless, parallel mediation analysis through bootstrapping demonstrated that neither familial nor religious ERS fully mediated the effects of race-related stress on social activism. These results underscore the significance of applying culturally imbued insights from different contexts to address discrimination within the AA Christian community. Scrutinizing these pathways can safeguard AA Christians, while promoting the amalgamation of Christian theology and psychological science. Future research should address the spectrum of beliefs and practices within Christianity that intersect with AA families and culture, unraveling the foundations of the call for social action. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Intranasal Delivery of Cell-Penetrating Therapeutic Peptide Enhances Brain Delivery, Reduces Inflammation, and Improves Neurologic Function in Moderate Traumatic Brain Injury.

Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood-brain barrier (BBB), which prevents the passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal (IN) administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of proinflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance after TBI in KAFAK-treated mice. This study demonstrates KAFAK's ability to cross the blood-brain barrier, to lower proinflammatory cytokines in vivo, and to restore function after a moderate TBI.

Progerin forms an abnormal meshwork and has a dominant-negative effect on the nuclear lamina.

Progerin, the protein that causes Hutchinson-Gilford progeria syndrome, triggers nuclear membrane (NM) ruptures and blebs, but the mechanisms are unclear. We suspected that the expression of progerin changes the overall structure of the nuclear lamina. High-resolution microscopy of smooth muscle cells (SMCs) revealed that lamin A and lamin B1 form independent meshworks with uniformly spaced openings (~0.085 µm2). The expression of progerin in SMCs resulted in the formation of an irregular meshwork with clusters of large openings (up to 1.4 µm2). The expression of progerin acted in a dominant-negative fashion to disrupt the morphology of the endogenous lamin B1 meshwork, triggering irregularities and large openings that closely resembled the irregularities and openings in the progerin meshwork. These abnormal meshworks were strongly associated with NM ruptures and blebs. Of note, the progerin meshwork was markedly abnormal in nuclear blebs that were deficient in lamin B1 (~50% of all blebs). That observation suggested that higher levels of lamin B1 expression might normalize the progerin meshwork and prevent NM ruptures and blebs. Indeed, increased lamin B1 expression reversed the morphological abnormalities in the progerin meshwork and markedly reduced the frequency of NM ruptures and blebs. Thus, progerin expression disrupts the overall structure of the nuclear lamina, but that effect-along with NM ruptures and blebs-can be abrogated by increased lamin B1 expression.

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis.

Protein kinase C (PKC) plays a key role in modulating the activities of the innate immune cells of the central nervous system (CNS). A delicate balance between pro-inflammatory and regenerative activities by microglia and CNS-associated macrophages is necessary for the proper functioning of the CNS. Thus, a maladaptive activation of these CNS innate immune cells results in neurodegeneration and demyelination associated with various neurologic disorders, such as multiple sclerosis (MS) and Alzheimer's disease. Prior studies have demonstrated that modulation of PKC activity by bryostatin-1 (bryo-1) and its analogs (bryologs) attenuates the pro-inflammatory processes by microglia/CNS macrophages and alleviates the neurologic symptoms in experimental autoimmune encephalomyelitis (EAE), an MS animal model. Here, we demonstrate that (2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB), a structurally distinct PKC modulator, has a similar effect to bryo-1 on CNS innate immune cells both in vitro and in vivo, attenuating neuroinflammation and resulting in CNS regeneration and repair. This study identifies a new structural class of PKC modulators, which can therapeutically target CNS innate immunity as a strategy to treat neuroinflammatory and neurodegenerative disorders.

4D intravital imaging studies identify platelets as the predominant cellular procoagulant surface in a mouse hemostasis model.

ABSTRACT: Interplay between platelets, coagulation factors, endothelial cells (ECs), and fibrinolytic factors is necessary for effective hemostatic plug formation. This study describes a 4-dimensional (4D) imaging platform to visualize and quantify hemostatic plug components in mice with high spatiotemporal resolution. Fibrin accumulation after laser-induced vascular injury was observed at the platelet plug-EC interface, controlled by the antagonistic balance between fibrin generation and breakdown. We observed less fibrin accumulation in mice expressing low levels of tissue factor or F12-/-mice compared with controls, whereas increased fibrin accumulation, including on the vasculature adjacent to the platelet plug, was observed in plasminogen-deficient mice or wild-type mice treated with tranexamic acid. Phosphatidylserine (PS), a membrane lipid critical for the assembly of coagulation factors, was first detected at the platelet plug-EC interface, followed by exposure across the endothelium. Impaired PS exposure resulted in a significant reduction in fibrin accumulation in cyclophilin D-/-mice. Adoptive transfer studies demonstrated a key role for PS exposure on platelets, and to a lesser degree on ECs, in fibrin accumulation during hemostatic plug formation. Together, these studies suggest that (1) platelets are the functionally dominant procoagulant cellular surface, and (2) plasmin is critical for limiting fibrin accumulation at the site of a forming hemostatic plug.

Comparison of transforaminal and posterior lumbar interbody fusion outcomes in patients receiving a novel allograft versus rhBMP-2: a radiographic and patient-reported outcomes analysis.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been demonstrated to achieve the highest rates of arthrodesis in multilevel lumbar fusion but is also associated with possible perioperative morbidity. A novel allograft (OSTEOAMP) is a differentiated allograft that retains growth factors supporting bone healing. The authors sought to compare the clinical and radiographic outcomes of rhBMP-2 and the novel allograft in lumbar interbody arthrodesis to determine if the latter may be a safer and equally effective alternative to rhBMP-2 for single- and multilevel posterior or transforaminal lumbar interbody fusion (PLIF or TLIF). METHODS: Patients who underwent single- or multilevel TLIF or PLIF using either OSTEOAMP or rhBMP-2 at the authors' institution over a 2-year period were prospectively followed for 12 months. Healthcare utilization, safety measures, patient satisfaction, physical disability (measured on the Oswestry Disability Index [ODI]), back and leg pain (on the numeric rating scale [NRS]), quality of life (on the EQ-5D scale), and return to work (RTW) were prospectively recorded. For purposes of this study, this consecutive series was retrospectively analyzed and pseudarthrosis rates were assessed at 2 years of follow-up. All patients (100%) had both 12-month patient-reported outcome follow-up and 24-month clinical and radiographic follow-up. RESULTS: One thousand one hundred fifty-four patients (654 treated with OSTEOAMP, 500 with rhBMP-2) were prospectively enrolled in the institutional registry. After propensity score matching, there were no significant baseline differences between 330 novel allograft and 330 rhBMP-2 cases. Perioperative morbidity and 90-day hospital readmission (3.3% vs 2.4%, p = 0.485) did not significantly differ between the novel allograft and the rhBMP-2 cases. At the 2-year follow-up, symptomatic pseudarthrosis requiring revision surgery occurred in 8 patients (2.4%) with OSTEOAMP and 6 patients (1.8%) with rhBMP-2 (p = 0.589). The overall fusion rate at 2 years was similar between groups (p = 0.213). Both groups showed significant and equivalent improvement in patient-reported outcome measures (PROMs) from baseline to 12-month follow-up, with no significant difference in 1-year mean NRS leg pain score (2.5 vs 2.7), ODI (25 vs 26), quality-adjusted life years (0.73 vs 0.73), satisfaction (83% vs 80%), or RTW (6.6 vs 7 weeks). CONCLUSIONS: In the authors' institutional experience, OSTEOAMP is a clinically viable substitute for rhBMP-2 for single- and multilevel lumbar fusion. This novel allograft provides clinically effective arthrodesis and improvements in PROMs comparable to rhBMP-2 with a similar safety profile. Additional indications and outcome assessment in longitudinal studies are needed to further characterize this allogeneic graft.