HEXIM1 is correlated with Alzheimer's disease pathology and regulates immediate early gene dynamics in neurons.

Impaired memory formation and recall is a distinguishing feature of Alzheimer's disease, and memory requires de novo gene transcription in neurons. Rapid and robust transcription of many genes is facilitated by the formation of a poised basal state, in which RNA polymerase II (RNAP2) has initiated transcription, but is paused just downstream of the gene promoter. Neuronal depolarization releases the paused RNAP2 to complete the synthesis of messenger RNA (mRNA) transcripts. Paused RNAP2 release is controlled by positive transcription elongation factor b (P-TEFb), which is sequestered into a larger inactive complex containing Hexamethylene bisacetamide inducible protein 1 (HEXIM1) under basal conditions. In this work, we find that neuronal expression of HEXIM1 mRNA is highly correlated with human Alzheimer's disease pathologies. Furthermore, P-TEFb regulation by HEXIM1 has a significant impact on the rapid induction of neuronal gene transcription, particularly in response to repeated depolarization. These data indicate that HEXIM1/P-TEFb has an important role in inducible gene transcription in neurons, and for setting and resetting the poised state that allows for the robust activation of genes necessary for synaptic plasticity.

BMP antagonist Gremlin 2 regulates hippocampal neurogenesis and is associated with seizure susceptibility and anxiety.

The Bone Morphogenic Protein (BMP) signaling pathway is vital in neural progenitor cell proliferation, specification, and differentiation. The BMP signaling antagonist Gremlin2 (Grem2) is the most potent natural inhibitor of BMP expressed in the adult brain, however its function remains unknown. To address this knowledge gap, we have analyzed mice lacking Grem2 via homologous recombination (Grem2-/- ). Histological analysis of brain sections revealed significant scattering of CA3 pyramidal cells within the dentate hilus in the hippocampus of Grem2-/- mice. Furthermore, the number of proliferating neural stem cells (NSCs) and neuroblasts was significantly decreased in the subgranular zone (SGZ) of Grem2-/- mice compared to wild-type (WT) controls. Due to the role of hippocampal neurogenesis in neurological disorders, we tested mice on a battery of neurobehavioral tests. Grem2-/- mice exhibited increased anxiety on the elevated zero maze (EZM) in response to acute and chronic stress. Specifically, male Grem2-/- mice showed increased anxiogenesis following chronic stress, and this was corelated with higher levels of BMP signaling and decreased proliferation in the dentate gyrus (DG). Additionally, when chemically challenged with Kainic Acid (KA), Grem2-/- mice displayed a higher susceptibility to and increased severity of seizures compared to WTs. Together, our data indicate that Grem2 regulates BMP signaling and is vital in maintaining homeostasis in adult hippocampal neurogenesis and structure. Furthermore, lack of Grem2 contributes to the development and progression of neurogenesis-related disorders such as anxiety and epilepsy.Significance statement Regulation of adult neurogenesis via BMP signaling is important in various neurological disorders. Grem2 is a secreted protein regulator of BMP signaling with strong inhibitory potential due to its unique formation of daisy chain polymers with BMP ligands. However, despite being highly expressed in the hippocampus, the role of the BMP inhibitor Grem2 in hippocampal structure and function is unknown. This paper provides the first evidence that Grem2 is necessary for proper BMP signaling and hippocampal morphology and neurogenesis. Furthermore, we found increased stress-induced anxiety and seizure susceptibility phenotypes in mice lacking Grem2. Together, our data introduce a novel molecular mechanism of hippocampal homeostasis and putative therapeutic target of neurological disorders.

Delayed neurological deficit due to a medially misplaced thoracic pedicle screw during adolescent idiopathic scoliosis correction: a complication 6 years in the making.

PURPOSE: Neurological deficits developing years after pedicle screw misplacement is a rare phenomenon. Here, we report level IV evidence of a previously asymptomatic medial thoracic pedicle screw resulting in paraparesis after a motor vehicle accident. METHODS: A 21-year-old male presented with acute onset of paraparesis following a motor vehicle collision. Six years prior this incident, the patient underwent a thoracolumbar fusion T4-L4 for AIS performed by an outside orthopedic surgeon. CT scan and CT myelogram illustrated decreased spinal canal diameter and cord compression from a medial T8 pedicle screw. RESULTS: Surgical removal of the misplaced pedicle screw resulted in a gradual complete recovery sustained over a period of 2 years. This case is compared to those reported in the literature review between 1981 and 2019 concerning delayed neurological deterioration related to misplaced pedicle screw. CONCLUSION: This case reports a delayed neurological deficit implicating a misplaced pedicle screw. This phenomenon remains rare since 5 cases were reported in the literature over the last 4 decades. It calls into focus the need for confirmation of safe instrumentation during the intraoperative period. It also illustrates the potential difficult decision-making in regard to asymptomatic misplaced instrumentation. LEVEL OF EVIDENCE: IV.

Assessing core outcome set uptake in randomized controlled trials for chronic kidney disease: Cross-sectional analysis.

Main problem: Chronic kidney disease (CKD) is a progressive condition that affects millions of people worldwide. A standardized core outcome set (COS) was developed for CKD by the International Consortium for Health Outcomes and Measurements in 2019. This study aims to evaluate the frequency of measurement for these outcomes before and after the publication of the COS. Methods: A literature search was done to gather the phase III/IV clinical trials evaluating chronic kidney disease through ClinicalTrials.gov. Data extraction of included studies was completed in a masked, duplicate fashion. The included studies were evaluated for characteristics such as survival, burden of disease, patient-reported health-related quality of life, and treatment modality-specific outcomes. Results: Our results showed that the majority of all COS domains were inadequately measured in CKD clinical trials before and after publication of the COS. Despite the increase in COS measurements following publication, the average percent of COS outcomes measured was less than 40 % per year even after four years. Conclusion: There is a notable deficiency in the complete measurement of COS among all domains both before and after COS publication. We suggest efforts be made to improve the adoption of consistent outcome measures that would benefit the growing population of patients affected by CKD.

Simultaneous Optical Imaging of Gastric Slow Waves and Contractions in the In Vivo Porcine Stomach.

Gastric peristalsis is governed by electrical "slow waves" generally assumed to travel from proximal to distal stomach (antegrade propagation) in symmetric rings. While alternative slow wave patterns have been correlated with gastric disorders, their mechanisms and how they alter contractions remain understudied. Optical electromechanical mapping, a developing field in cardiac electrophysiology, images electrical and mechanical physiology simultaneously. Here, we translate this technology to the in-vivo porcine stomach. Stomachs were surgically exposed and a fluorescent dye (di-4-ANEQ(F)PTEA) that transduces the membrane potential (Vm) was injected through the right gastroepiploic artery. Fluorescence was excited by LEDs and imaged with one or two 256x256 pixel cameras. Motion artifact was corrected using a marker-based motion tracking method and excitation ratiometry, which cancels common-mode artifact. Tracking marker displacement also enabled gastric deformation to be measured. We validated detection of electrical activation and Vm morphology against alternative non-optical technologies. Non-antegrade slow waves and propagation direction differences between the anterior and posterior stomach were commonly present in our data. However, sham experiments suggest they were a feature of the animal preparation and not an artifact of optical mapping. In experiments to demonstrate the method's capabilities, we found that repolarization did not always follow at a fixed time behind activation "wavefronts," which could be a factor in dysrhythmia. Contraction strength and the latency between electrical activation and contraction differed between antegrade and non-antegrade propagation. In conclusion, optical electromechanical mapping, which simultaneously images electrical and mechanical activity, enables novel questions regarding normal and abnormal gastric physiology to be explored.

Evaluating academic productivity and match outcomes in neurosurgery residents from medical schools without a neurosurgery residency program: a 2016-2022 bibliometric analysis.

OBJECTIVE: Transition of the United States Medical Licensing Examination Step 1 to a pass/fail structure has focused attention on medical student research in residency application. Previous studies have explored how various factors affect the neurosurgery match success, but none have focused on applicants from schools without a neurosurgery residency program. METHODS: The authors compiled a list of neurosurgery residents matched from 2016 to 2022 from schools lacking a neurosurgery program. They gathered demographic and bibliometric data, focusing on academic productivity before residency. The distinction between the top 40 and non-top 40 programs used the 5-year institutional h-index (ih[5]-index) of departments. RESULTS: Between 2016 and 2022, the gross number of students entering neurosurgery from schools without a home program rose from 15 to 26 in 2021, declining to 23 in 2022. The range of matched applicants per school was 0 to 10. The median number of publications per resident increased from 2 in 2016 to 5 in 2022 (p < 0.001). The lowest and highest numbers of publications by applicants were 0 and 40, respectively, with 22.5% reporting no publications. The lowest and highest h-indices by applicants were 0 and 11, respectively, with nearly one-third (31.2%) possessing an h-index of 0. Applicants from schools lacking a neurosurgery residency program who matched into top 40 programs had a publication range of 0-11, with a higher median of 3 compared with those who did not (median 2, range 0-8). While no significant differences were found in publication numbers (p = 0.084), a difference in h-index was observed (p = 0.024) between the two groups. Publications significantly correlated with the h-index, with each additional publication increasing the h-index by 0.19 (p < 0.001, adjusted R2 = 0.3348). CONCLUSIONS: Median publication counts have increased in this cohort, but they do not distinguish top 40 program matches. Conversely, the h-index, correlating with publication quantity and journal impact factor, does.

A strategy for the controllable generation of organic superbases from benchtop-stable salts.

Organic superbases are a distinct class of strong base that enable numerous modern reaction applications. Despite their great synthetic potential, widespread use and study of superbases are limited by their air sensitivity and difficult preparation. To address this, we report air-stable carboxylate salts of BTPP and P2-t-Bu phosphazene superbases that, when added to solution with an epoxide, spontaneously generate freebase. These systems function as effective precatalysts and stoichiometric prereagents for superbase-promoted addition, substitution and polymerization reactions. In addition to improving the synthesis, shelf stability, handling and recycling of phosphazenes, this approach enables precise regulation of the rate of base generation in situ. The activation strategy effectively mimics manual slow addition techniques, allowing for control over a reaction's rate or induction period and improvement of reactions that require strong base but are also sensitive to its presence, such as Pd-catalyzed coupling reactions.

Incidents and patterns of commotio cordis among athletes in the USA from 1982 to 2023.

INTRODUCTION: Commotio cordis is a rare event that occurs following blunt, non-penetrating trauma to the chest, precipitating a ventricular arrhythmia. Commotio cordis requires immediate medical attention through cardiopulmonary resuscitation and defibrillation, often resulting in death. Commotio cordis is most common condition among young male athletes. The purpose of this study was to describe the incidents and patterns of commotio cordis among young athletes participating in organised sports in the USA from academic years 1982-1983 through 2022-2023. METHODS: This was a retrospective, descriptive epidemiology study using surveillance data from the National Center for Catastrophic Sport Injury Research. The study included all commotio cordis incidents captured in the database. We calculated descriptive statistics (counts and proportions) overall and stratified by outcome and athlete sport. RESULTS: Over the study period, 64 incidents of commotio cordis were captured. The majority occurred among males (n=60) and were caused by contact with an object/apparatus (n=39) or contact with another player (n=20). The most common sports were baseball (n=20), lacrosse (n=17) and football (n=13). Over half of these incidents resulted in death (n=34), although survival from commotio cordis increased over the study period. A higher proportion of fatal incidents occurred among football athletes and were caused by contact with another player. CONCLUSIONS: Commotio cordis remains most common among young male athletes who participate in organised baseball, lacrosse and football. Although survival has improved over time, greater awareness and emergency preparedness for commotio cordis in an organised sport are needed to facilitate prompt recognition and intervention.

Association Between Co-occurring Anxiety and Depressive Symptoms at Baseline and Risk for Sports-Related Concussion in Collegiate Athletes.

Background: There is limited research examining whether mental health problems increase the risk for future concussions, even though these problems are highly prevalent in college-aged populations-including student-athletes. Purpose/Hypothesis: To examine whether affective disturbance (ie, depressive and anxiety symptoms) at baseline increases the risk for prospective concussion. It was hypothesized that athletes with co-occurring depressive/anxiety symptoms would incur the greatest risk for injury. Methods: A total of 878 collegiate athletes completed baseline neuropsychological testing. Athletes were separated into the following 4 groups based on self-reported anxiety and depressive symptoms at baseline: healthy controls; depressive symptoms alone; anxiety symptoms alone; and co-occurring depressive and anxiety symptoms. Of the 878 athletes, 88 sustained future concussions. Logistic regression was conducted with prospective concussion (yes/no) as the outcome and the affective group as the predictor. Sport was included as a covariate. Results: After controlling for sport, athletes in the co-occurring depressive/anxiety symptoms group were more than twice as likely to be diagnosed with a future concussion compared with healthy controls (odds ratio, 2.72 [95% CI, 1.33-5.57]; P = .01). The co-occurring depressive/anxiety symptoms group also showed an increased risk for prospective concussion compared with the depressive symptoms alone and anxiety symptoms alone groups, respectively. However, the results were not statistically significant. Athletes in the depressive symptoms alone and anxiety symptoms alone groups did not show a significantly increased risk for prospective concussion compared with healthy controls. Conclusion: Athletes with co-occurring depressive/anxiety symptoms at baseline showed a notably increased risk of being diagnosed with a future concussion, even after controlling for sport. This suggests that co-occurring depressive/anxiety symptoms infer a unique risk that is associated with a greater susceptibility to concussion diagnosis.

Thoracic Stent Grafts Induce Persistent Aortic Remodeling in Aortic Coarctation.

BACKGROUND: This study's objective is to describe outcomes of adult patients who underwent thoracic stent graft placement treatment for primary or recurrent aortic coarctation. METHODS: This is a retrospective study of 30 adult patients who underwent thoracic stent graft placement for aortic coarctation at our institution. Average age was 46.5 years, with 53.3% of patients presented with no prior treatment or repair for coarctation. Indications for repair included gradient ≥20 mm Hg with anatomic evidence of coarctation on imaging with left ventricular hypertrophy, pseudoaneurysm, aneurysm, refractory hypertension, or claudication. Stent grafts used for repair included MDT (Medtronic, Santa Rosa, CA) and GORE TAG (W. L. Gore & Associates, Flagstaff, AZ). RESULTS: Patients were observed for a median of 979 days, with one death during the study. All patients had complete resolution of symptoms with no recurrences. Thoracic endovascular aortic repair significantly reduced the gradient across the coarctation (P < 0.0001). Aortic coarctation diameter significantly increased at 30 days postoperatively and continued to increase up to 5 years posttreatment. At 3+ years, aortic remodeling was observed at the coarctation site and surrounding regions. At 30 days, systolic, diastolic, and mean arterial pressure were all reduced. Systolic and diastolic blood pressure and mean arterial pressure continued to significantly improve 1-year posttreatment. CONCLUSIONS: Stent grafts are a safe and effective treatment for aortic coarctation. We observed a clinically significant improvement in blood pressure and longitudinal aortic remodeling of the coarctation segment and the entire aorta that persisted more than more than 3 years.

Examining the role of depression on the relationship between performance-based and self-reported cognitive functioning after sport-related concussion.

OBJECTIVE: Little is known about the relationship between neuropsychological test performance, cognitive symptom reporting, and depressive symptoms after sport-related concussion. Accordingly, this cross-sectional study examined these relationships in collegiate athletes. It was hypothesized that depressive symptoms would moderate and mediate the relationship between performance-based and self-reported cognitive functioning after concussion. METHODS: After sustaining a sport-related concussion, 110 collegiate athletes completed a neuropsychological battery, the Post-Concussion Symptoms Scale, and the Beck Depression Inventory-Fast Screen. Neuropsychological test performance, depressive symptoms, and their interactions were entered into distinct hierarchical linear regression analyses with self-reported cognition as the dependent variable to assess moderation. Mediation was analyzed using the PROCESS macro with 5000 bootstrap samples and a 95% confidence interval. RESULTS: There was a significant interaction between the mean memory composite and depressive symptoms when predicting cognitive symptom reporting, p = 0.047. Simple effects tests revealed that for athletes who had a lower memory composite score, an increase in depressive symptoms led to an increase in self-reported cognitive dysfunction, p < 0.001, ηp2 = 0.11. Depressive symptoms partially mediated the relationship between the memory composite and cognitive symptom reporting, indirect effect = -0.26, 95%CI[-0.58,0.001], but this relationship was not found for any other neurocognitive domain. CONCLUSIONS: For tests of memory, depressive symptoms moderated and partially mediated the relationship between performance-based and self-reported cognitive functioning after sport-related concussion. Athletes reporting high depressive symptoms and cognitive dysfunction may need more comprehensive evaluations to inform return-to-play decisions, and depression could be a treatment target for athletes who report high levels of cognitive dysfunction after concussion.

Chemokine receptor hetero-oligomers regulate monocyte chemotaxis.

It is known that stress influences immune cell function. The underlying molecular mechanisms are unclear. We recently reported that many chemokine receptors (CRs) heteromerize with α1-adrenoceptors (α1-ARs) through which CRs are regulated. Here, we show that arginine vasopressin receptor 1A (AVPR1A) heteromerizes with all human CRs, except chemokine (C-X-C motif) receptor (CXCR)1, in recombinant systems and that such heteromers are detectable in THP-1 cells and human monocytes. We demonstrate that ligand-free AVPR1A differentially regulates the efficacy of CR partners to mediate chemotaxis and that AVPR1A ligands disrupt AVPR1A:CR heteromers, which enhances chemokine (C-C motif) receptor (CCR)1-mediated chemotaxis and inhibits CCR2-, CCR8-, and CXCR4-mediated chemotaxis. Using bioluminescence resonance energy transfer to monitor G protein activation and CRISPR/Cas9 gene-edited THP-1 cells lacking AVPR1A or α1B-AR, we show that CRs that share the propensity to heteromerize with α1B/D-ARs and AVPR1A exist and function within interdependent hetero-oligomeric complexes through which the efficacy of CRs to mediate chemotaxis is controlled. Our findings suggest that hetero-oligomers composed of CRs, α1B/D-ARs, and AVPR1A may enable stress hormones to regulate immune cell trafficking.

New Approaches to Assessment and Management of Tricuspid Regurgitation Before Intervention.

Severe tricuspid regurgitation (TR) is a progressive condition associated with substantial morbidity, poor quality of life, and increased mortality. Patients with TR commonly have coexisting conditions including congestive heart failure, pulmonary hypertension, chronic lung disease, atrial fibrillation, and cardiovascular implantable electronic devices, which can increase the complexity of medical and surgical TR management. As such, the optimal timing of referral for isolated tricuspid valve (TV) intervention is undefined, and TV surgery has been associated with elevated risk of morbidity and mortality. More recently, an unprecedented growth in TR treatment options, namely the development of a wide range of transcatheter TV interventions (TTVI) is stimulating increased interest and referral for TV intervention across the entire medical community. However, there are no stepwise algorithms for the optimal management of symptomatic severe TR before TTVI. This article reviews the contemporary assessment and management of TR with addition of a medical framework to optimize TR before referral for TTVI.

Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution.

Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.