NMR Spectroscopy and Multiscale Modeling Shed Light on Ion-Solvent Interactions and Ion Pairing in Aqueous NaF Solutions.

The balance between ion solvation and ion pairing in aqueous solutions modulates chemical and physical processes from catalysis to protein folding. Yet, despite more than a century of investigation, experimental determination of the distribution of ion-solvation and ion-pairing states remains elusive, even for archetypal systems like aqueous alkali halides. Here, we combine nuclear magnetic resonance (NMR) spectroscopy and multiscale modeling to disentangle ion-solvent interactions from ion pairing in aqueous sodium fluoride solutions. We have developed a high-accuracy method to collect experimental NMR resonance frequencies for both ions as functions of temperature and concentration. Comparison of these data with resonance frequencies for nonassociating salts allows us to differentiate the influence of solvation and ion pairing on NMR spectra. These high-quality experimental NMR data are used to validate our modeling framework comprising polarizable force field molecular dynamics (MD) simulations and quantum chemical calculations of NMR resonance frequencies. Our experimental and theoretical resonance frequency shifts agree over a wide range of temperatures and concentrations. Structural analysis reveals how both trends are dominated by interactions with water molecules. For the more sensitive 19F nucleus, the NMR resonance frequency decreases as hydrogen bonds between fluoride and water molecules are reduced in number with increased temperature and molality. Through a detailed analysis of the theoretical NMR resonance frequencies for both ions, we show that NMR spectroscopy can distinguish both contact ion pairs and single-solvent-separated ion pairs from free ions. This quantitative framework can be applied directly to other systems.

A longitudinal health promotion program for autistic children and their caregivers: Impact of an urban community-based program.

Autistic children, as well as their primary caregivers (e.g., parents), experience greater health disparities when compared with the general population. Despite this reality, there has been relatively little priority placed on promoting positive trajectories of health in either of these underserved populations. The primary purpose of this study was to examine the impact of participation in a 12-month, longitudinal health promotion program designed for both autistic children and their parent. A total of 27 families participated in the intervention, including 29 autistic children (83% male, M = 8.28 ± 3.60 years) and 27 parents (93% female, M = 40.04 ± 7.95). Families attended in-person health promotion programming for 90 min per week. Children and parents were evaluated at four time points across the program, including baseline (0-months), 4-months, 8-months, and 12-months. Children were measured on fundamental motor competence, physical fitness, body composition, and proxy-reported physical activity. Parents were measured on body composition, physical fitness, and self-reported physical activity. Significant improvements were observed for autistic children in motor competence (p < 0.001) and grip strength (p = 0.006), and for parents in body mass index (p = 0.004) and aerobic capacity (p = 0.003) across the 12-month intervention. Differing trajectories of improvement were noted between urban- and suburban-dwelling families on multiple outcomes. The knowledge acquired from this research may offer initial support for the need to bolster opportunities for accessible and ongoing health promotion programs for both autistic children and their parents.

Mutual Relationships of Nanoconfined Hexoses: Impacts on Hydrodynamic Radius and Anomeric Ratios.

Although all hexose sugars share the same chemical formula, C6H12O6, subtle differences in their stereochemical structures lead to their various biological roles. Due to their prominent role in metabolism, hexose sugars are commonly found in nanoconfined environments. The complexity of authentic nanoconfined biological environments makes it challenging to study how confinement affects their behavior. Here, we present a study using a common model system, AOT reverse micelles, to study hexose sugars in nanoconfinement. We examine how reverse micelles affect the hexoses, how the hexoses affect reverse micelle formation, and the differences between specific hexoses: glucose, mannose, and galactose. We find that addition of glucose, mannose or galactose to reverse micelles that already contain water leaves their size smaller or nearly unchanged. Introducing aqueous hexose solution yields reverse micelles smaller than those prepared with the same volume of water. We use 1H NMR to show how the nanoconfined environment impacts hexose sugars' anomeric ratios. Nanoconfined mannose and galactose display smaller changes in their anomeric ratios compared to glucose. These conclusions may provide insights about the biological roles of each hexose when studied under a more authentic nanoconfined system.

Efficient synthesis for each of the eight stereoisomers of the iminosugars lentiginosine and 1,4-dideoxy-1,4-imino-D-arabinitol (DAB).

Herein, we describe the efficient, diastereoselective syntheses of the iminosugars 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) 1b, lentiginosine 3a, and the seven stereoisomers of each of these iminosugars starting from 4-benzoyl-6-deoxy-6-iodoglycopyranosides 47 with yields ranging from 38 % to 68 % for the DAB and isomers 1a-1h and from 44 % to 89 % for the lentiginosine and isomers 3a-3h. We also report the syntheses of the eight stereoisomers of the 4-benzoyl-6-deoxy-6-iodoglycopyranosides 47 from commercially available sugars. Key to the iminosugar syntheses is a single multistep reaction that converts the 4-benzoyl-6-deoxy-6-iodoglycopyranosides 47 to a vinyl pyrrolidine through a one-pot zinc mediated reductive elimination, followed by a reductive amination and finally an intramolecular nucleophilic substitution. Strategic selection of the amine utilized in the reductive amination and the functionalization of the intermediate carbon-carbon double bond provides access to a vast array of iminosugars.

Systematic mapping review of player safety, sport science and clinical care in lacrosse.

OBJECTIVE: The objective is to comprehensively classify the types, topics and populations represented in the published lacrosse literature. DESIGN: Mapping review. Protocol registration at Open Science Framework (https://osf.io/kz4e6). DATA SOURCES: 10 electronic databases were searched from inception to 31 March 2023. ELIGIBILITY CRITERIA: Peer-reviewed studies in English that included lacrosse were eligible. Publications without participant demographic or lacrosse-specific data were excluded. RESULTS: We identified 498 articles pertaining to lacrosse, with 270 (54.2%) focused on player safety, 128 (25.7%) on sport science and 74 (14.9%) on clinical care. Musculoskeletal injury was the focus of 179 studies (35.9%), and the most common study design was cross-sectional (n=162, 32.5%). Most (n=423, 84.9%) originated in the USA. Over half (n=254, 51.0%) were published since 2017. 216 articles (43.4%) included female and male athletes, while 112 (22.5%) and 142 (28.5%) focused solely on female and male athletes, respectively. Collegiate athletes were the most frequent study population (n=277, 55.6%), and traditional field lacrosse was the focus of 298 (59.8%) articles. We observed that 77.1% (27/35) of quasiexperimental, 91.3% (21/23) of randomised controlled trials and 62.1% (18/29) of systematic reviews had a high or moderate risk of bias. CONCLUSION: The vast majority of lacrosse research originates from the USA, is in collegiate athletes, with a focus on player safety, and has a high risk of bias. With the sport's inclusion in the 2028 Olympics and growing global participation, higher quality research studies that are more inclusive and adaptable to diverse athletic groups and changing gameplay parameters are needed.

Adverse childhood experiences, brain efficiency, and the development of pain symptoms in youth.

BACKGROUND: Adverse childhood experiences (ACEs) are often reported by youths with chronic pain, and both ACEs and chronic pain disrupt how information is processed. However, it is unknown whether changes to shared neural networks underlie the relationship between ACEs and the development of pain symptoms. This study explored the relationships between ACEs, brain efficiency, and pain symptomology in youth. METHODS: A community sample of youths aged 14-18 years underwent MRIs, answered trauma and pain questionnaires, and underwent pain sensory testing, twice, 3 months apart (Nbaseline = 44; Nfollow-up = 42). Sensory testing determined thresholds for mechanical and thermal stimuli. Global and local network efficiencies were evaluated using graph theory. Generalized estimating equations were applied to examine whether brain efficiency moderated the relationships between ACEs, pain intensity, and pain sensitivity (i.e., mechanical detection, heat pain, and temperature change thresholds). RESULTS: There was a significant interaction between ACEs and global brain efficiency in association with pain intensity (ß = -0.31, p = 0.02) and heat pain (ß = -0.29, p = 0.004). Lower global brain efficiency exacerbated the relationship between ACEs and pain intensity (θX → Y|W = -1.16 = 0.37, p = 0.05), and heat pain sensitivity (θX → Y|W = -1.30 = 0.44, p = 0.05). Higher global brain efficiency ameliorated the relationship between ACEs and pain intensity (θX → Y|W = 1.75 = -0.53, p = 0.05). CONCLUSIONS: The relationship between ACEs and pain symptomology was comparable to chronic pain phenotypes (i.e., higher pain intensity and pain thresholds) and may vary as a function of brain efficiency in youth. This stresses the importance of assessing for pain symptoms in trauma-exposed youth, as earlier identification and intervention are critical in preventing the chronification of pain. SIGNIFICANCE: This article explores the relationship between ACEs, pain symptomology, and brain efficiency in youth. ACEs may affect how the brain processes information, including pain. Youths with lower brain efficiencies that were exposed to more ACEs have pain symptomology comparable to youths with chronic pain. Understanding this relationship is important for the earlier identification of pain symptoms, particularly in vulnerable populations such as youths exposed to trauma, and is critical for preventing the chronification of pain.

Peptide and Peptidomimetic Inhibitors Targeting the Interaction of Collapsin Response Mediator Protein 2 with the N-Type Calcium Channel for Pain Relief.

Ion channels serve pleiotropic functions. Often found in complexes, their activities and functions are sculpted by auxiliary proteins. We discovered that collapsin response mediator protein 2 (CRMP2) is a binding partner and regulator of the N-type voltage-gated calcium channel (CaV2.2), a genetically validated contributor to chronic pain. Herein, we trace the discovery of a new peptidomimetic modulator of this interaction, starting from the identification and development of CBD3, a CRMP2-derived CaV binding domain peptide. CBD3 uncouples CRMP2-CaV2.2 binding to decrease CaV2.2 surface localization and calcium currents. These changes occur at presynaptic sites of nociceptive neurons and indeed, CBD3 ameliorates chronic pain in preclinical models. In pursuit of a CBD3 peptidomimetic, we exploited a unique approach to identify a dipeptide with low conformational flexibility and high solvent accessibility that anchors binding to CaV2.2. From a pharmacophore screen, we obtained CBD3063, a small-molecule that recapitulated CBD3's activity, reversing nociceptive behaviors in rodents of both sexes without sensory, affective, or cognitive effects. By disrupting the CRMP2-CaV2.2 interaction, CBD3063 exerts these effects indirectly through modulating CaV2.2 trafficking, supporting CRMP2 as an auxiliary subunit of CaV2.2. The parent peptide CBD3 was also found by us and others to have neuroprotective properties at postsynaptic sites, through N-methyl-d-aspartate receptor and plasmalemmal Na+/Ca2+ exchanger 3, potentially acting as an auxiliary subunit for these pathways as well. Our new compound is poised to address several open questions regarding CRMP2's role in regulating the CaV2.2 pathways to treat pain with the potential added benefit of neuroprotection.

Regulating neuronal excitability: The role of S-palmitoylation in NaV1.7 activity and voltage sensitivity.

S-palmitoylation, a reversible lipid post-translational modification, regulates the functions of numerous proteins. Voltage-gated sodium channels (NaVs), pivotal in action potential generation and propagation within cardiac cells and sensory neurons, can be directly or indirectly modulated by S-palmitoylation, impacting channel trafficking and function. However, the role of S-palmitoylation in modulating NaV1.7, a significant contributor to pain pathophysiology, has remained unexplored. Here, we addressed this knowledge gap by investigating if S-palmitoylation influences NaV1.7 channel function. Acyl-biotin exchange assays demonstrated that heterologously expressed NaV1.7 channels are modified by S-palmitoylation. Blocking S-palmitoylation with 2-bromopalmitate resulted in reduced NaV1.7 current density and hyperpolarized steady-state inactivation. We identified two S-palmitoylation sites within NaV1.7, both located in the second intracellular loop, which regulated different properties of the channel. Specifically, S-palmitoylation of cysteine 1126 enhanced NaV1.7 current density, while S-palmitoylation of cysteine 1152 modulated voltage-dependent inactivation. Blocking S-palmitoylation altered excitability of rat dorsal root ganglion neurons. Lastly, in human sensory neurons, NaV1.7 undergoes S-palmitoylation, and the attenuation of this post-translational modification results in alterations in the voltage-dependence of activation, leading to decreased neuronal excitability. Our data show, for the first time, that S-palmitoylation affects NaV1.7 channels, exerting regulatory control over their activity and, consequently, impacting rodent and human sensory neuron excitability. These findings provide a foundation for future pharmacological studies, potentially uncovering novel therapeutic avenues in the modulation of S-palmitoylation for NaV1.7 channels.

National Athletic Trainers' Association Position Statement: Emergency Action Plan Development and Implementation in Sport.

OBJECTIVE: An emergency action plan (EAP) is a written document detailing the preparations and on-site emergency response of health care professionals and other stakeholders to medical emergencies in the prehospital setting. The EAP is developed to address any type of catastrophic injury response and should not be condition specific. The objective of this National Athletic Trainers' Association position statement is to provide evidence-based and consensus-based recommendations for developing and implementing an EAP for sports settings. METHODS: These recommendations were developed by a multidisciplinary expert panel that performed (1) a comprehensive review of existing EAP evidence, (2) a modified Delphi process to define consensus recommendations, and (3) a strength of recommendation taxonomy determination for each recommendation. RESULTS: An EAP is an essential tool designed to facilitate emergency preparedness and an efficient, coordinated emergency response during an athletic event. A comprehensive EAP should consider modes to optimize patient outcomes, the various stakeholders needed to develop the plan, the factors influencing effective implementation of the EAP, and the roles and responsibilities to ensure a structured response to a catastrophic injury. CONCLUSIONS: These evidence-informed recommendations outline the necessary steps for emergency planning and provide considerations for the immediate management of patients with catastrophic injuries. Increasing knowledge and implementation of the EAP to manage patients with catastrophic injuries improves the overall response and decreases errors during an emergency.

Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.

Rescue Therapy for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: A Pooled Analysis of the Society of Vascular and Interventional Neurology Registry.

OBJECTIVE: We aimed to evaluate the association between rescue therapy (RT) and functional outcomes compared to medical management (MM) in patients presenting after failed mechanical thrombectomy (MT). METHODS: This cross-sectional study utilized prospectively collected and maintained data from the Society of Vascular and Interventional Neurology Registry, spanning from 2011 to 2021. The cohort comprised patients with large vessel occlusions (LVOs) with failed MT. The primary outcome was the shift in the degree of disability, as gauged by the modified Rankin Scale (mRS) at 90 days. Additional outcomes included functional independence (90-day mRS score of 0-2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality. RESULTS: Of a total of 7,018 patients, 958 presented failed MT and were included in the analysis. The RT group comprised 407 (42.4%) patients, and the MM group consisted of 551 (57.5%) patients. After adjusting for confounders, the RT group showed a favorable shift in the overall 90-day mRS distribution (adjusted common odds ratio = 1.79, 95% confidence interval [CI] = 1.32-2.45, p < 0.001) and higher rates of functional independence (RT: 28.8% vs MM: 15.7%, adjusted odds ratio [aOR] = 1.93, 95% CI = 1.21-3.07, p = 0.005) compared to the MM group. RT also showed lower rates of sICH (RT: 3.8% vs MM: 9.1%, aOR = 0.52, 95% CI = 0.28-0.97, p = 0.039) and 90-day mortality (RT: 33.4% vs MM: 45.5%, aOR = 0.61, 95% CI = 0.42-0.89, p = 0.009). INTERPRETATION: Our findings advocate for the utilization of RT as a potential treatment strategy for cases of LVO resistant to first-line MT techniques. Prospective studies are warranted to validate these observations and optimize the endovascular approach for failed MT patients. ANN NEUROL 2024;96:343-355.

Secondary School State Athletic Association Health and Safety Policy Development Processes.

BACKGROUND: The National Federation of State High School Associations provides recommendations regarding health and safety policies; however, policy development is governed at the state level. Given interstate differences in governance, the primary purpose was to describe processes that State High School Athletic Associations (SHSAAs) utilize to develop a new policy. The secondary objective was to determine what methods associations use to implement new policies. METHODS: A cross-sectional survey requested SHSAA (n = 51) representatives to report how athlete health and safety policies are introduced, revised, approved, and implemented within their state. The 22-question survey was developed to gather variables for the aims of the study. Descriptive statistics were calculated for each survey item. RESULTS: Of states who responded (n = 33), most reported a 2-committee (n = 24, 72.7%) process for developing and vetting policies, with initiation from the Sports Medicine Advisory Committee (n = 27, 81.8%), followed by an executive-level committee (n = 18, 66.7%). States reported total time from policy initiation to final approval ranged from 2 weeks to over 12 months. When a new policy was approved, most states indicated implementation began with an e-mail (n = 24, 72.7%) sent to Athletic Directors (n = 26, 78.8%). School principal or district superintendent were reported as the position in charge of compliance (36.4%, n = 12). CONCLUSIONS: Most SHSAAs use a 2-step process to write and review an athlete health and safety policy before approval. SHSAAs that require a longer policy development time could delay the implementation of important health measures. SHSAAs could consider additional communication methods to ensure information reaches all stakeholders.

Fubuki XF Long Sheath guide catheter use in neuroendovascular procedures: Institutional experience in 60 cases.

BACKGROUND: Endovascular treatment devices require compatible guide catheters to navigate complex vessels and anatomy. The Fubuki XF Long Sheath guide catheter (Fubuki XF) was developed with a 0.090-inch internal diameter with hydrophilic coating, an atraumatic rounded tip, and enhanced trackability and support with gradual shaft transition zones. METHODS: We retrospectively analyzed a prospectively maintained database of neuroendovascular patients treated using Fubuki XF at our center (July 2022─May 2023). Baseline/procedural characteristics were collected. Outcomes of interest included technical success (procedure completion with Fubuki XF without alternative guide catheter use) and peri-procedural complications. RESULTS: This study included 60 patients (43.3% [26/60] female; mean age: 69.6 ± 9.7) presenting with stenosis (45.0% [27/60]), unruptured aneurysms (31.7% [19/60]), ruptured aneurysm (1.7% [1/60]), arteriovenous fistula (5.0% [3/60]), arteriovenous malformation (3.3% [2/60]), chronic subdural hematoma (3.3% [2/60]), stroke/emboli (6.7% [4/60]), vasospasm (1.7% [1/60]), or carotid web (5.0% [1/60]). Fubuki XF was used to deliver endovascular treatment devices for stenting (43.3% [26/60]), flow diversion (23.3% [14/60]), embolization (11.7% [7/60]), coiling (10.0% [6/60]), balloon angioplasty (10.0% [6/60]), and mechanical thrombectomy (1.7% [1/60]). The Fubuki XF tip was placed in the internal carotid artery in 38.3% (23/60) of cases. Technical success was achieved in all cases. One V1 non-flow-limiting dissection (not related to Fubuki XF) and one failed closure occurred (1.7% [1/60] each). No iatrogenic strokes or intraprocedural ruptures occurred. CONCLUSION: We used Fubuki XF to safely and effectively deliver a variety of compatible neuroendovascular devices. Fubuki XF was stable in all cases and locations, and there were no device-related complications or dissections.

Exertional Heatstroke Survivors' Knowledge and Beliefs about Exertional Heatstroke Diagnosis, Treatment, and Return to Play.

CONTEXT: Little information exists regarding what exertional heatstroke (EHS) survivors know and believe about EHS best practices. Understanding this would help clinicians focus educational efforts to ensure survival and safe return-to-play following EHS. OBJECTIVE: We sought to better understand what EHS survivors knew about EHS seriousness (e.g., lethality, short- and long-term effects), diagnosis and treatment procedures, and recovery. Design: Multi-year, cross-sectional, descriptive design. SETTING: An 11.3-km road race located in the Northeastern United States in August 2022 and 2023. PATIENTS OR OTHER PARTICIPANTS: Forty-two of 62 runners with EHS (15 women, 27 men; age: 33±15 y; pre-treatment rectal temperature [TREC]: 41.5±0.9°C). INTERVENTIONS: Medical professionals evaluated runners requiring medical attention at the finish line. If they observed TREC ≥40°C with concomitant central nervous system dysfunction (CNS) EHS was diagnosed and patients were immersed in a 189.3-L tub filled with ice-water. Before medical discharge, we asked EHS survivors 15 questions about their experience and knowledge of select EHS best practices. Survey items were piloted and validated by experts and laypersons a priori (content validity index ≥0.88 for items and scale). MAIN OUTCOME MEASURES: Survey responses. RESULTS: Sixty-seven percent (28/42) of patients identified EHS as potentially fatal and 76% (32/42) indicated it negatively affected health. Seventy-nine percent (33/42) correctly identified TREC as the best temperature site to diagnose EHS. Most patients (74%, 31/42) anticipated returning to normal exercise within 1 week post-EHS; 69% (29/42) stated EHS would not impact future race participation. Patients (69%, 29/42) indicated it was important to tell their primary care physician about their EHS. CONCLUSIONS: Our patients were knowledgeable on the potential seriousness and adverse health effects of EHS and the necessity of TREC for diagnosis. However, educational efforts should be directed towards helping patients understand safe recovery and return-to-play timelines following EHS.

The resolute Onyx in TIA management (ROTIA).

BACKGROUND: First-line treatment for symptomatic intracranial atherosclerotic disease (ICAD) is medical management; however, interventional approaches are increasingly considered for refractory disease. The Resolute Onyx in TIA management (ROTIA) study is a post-market evaluation of the Resolute Onyx (R-Onyx) drug-eluting stent in the treatment of recurrent transient ischemic attacks (TIAs) due to refractory ICAD (off-label use). METHODS: This is a single-center, retrospective case series of consecutive patients who underwent angioplasty and stenting with R-Onyx for treatment of recurrent TIAs due to refractory ICAD from October 2019 to November 2022. Included patients were ages 22-80, had a baseline modified Rankin Scale of ≤2, and had recurrent TIAs attributed to intracranial artery stenosis >70% despite maximal medical therapy. Primary outcomes of interest were peri-procedural complications (TIA, stroke, intracranial hemorrhage, mortality) up to 72 h post-stenting and ischemic stroke up to 18 months post-stenting. RESULTS: Twenty patients (mean age 66.84 ± 14; 25% female; 80% Hispanic) were included. A total of 21 stents were successfully deployed with no peri-procedural complications. There were no recurrent ischemic events at 30 days post-stenting. At 18 months post-stenting, there were no ischemic events and no patient exhibited in-stent restenosis. CONCLUSION: ROTIA demonstrates the feasibility of using the Resolute Onyx drug-eluting stent for the management of TIAs due to refractory ICAD, with high technical success and low peri-procedural complications. Limitations include the retrospective and single-center nature of this study. Future prospective, multi-center, randomized trials with extended observation periods are needed.

Epidural anesthesia causes outbreak of mycotic aneurysms: complications of Fusarium solani meningitis.

BACKGROUND: A health advisory was issued in response to a fungal meningitis outbreak linked to epidural anesthesia exposure in two plastic surgery clinics in Mexico, from January 1 to May 13, 2023. This descriptive analysis describes the neuroendovascular and neurosurgical observations and management of patients treated at a single stroke center located along the US-Mexico Border. METHODS: We conducted a retrospective chart review of fungal meningitis patients presenting between April and July 2023. RESULTS: Among the patients diagnosed with fungal meningitis (n=12), the majority (n=11) were afflicted with angio-invasive Fusarium solani. 83% received dual antifungal therapy, with 40% initiated on alternate-day intrathecal amphotericin B. Diagnostic cerebral angiography was performed on all patients, revealing aneurysms in 58% of cases, predominantly within the posterior circulation, notably the basilar artery, with a median size of 4.2 mm (IQR 3.3-4.8). Treatment strategies included flow diversion (70%) and primary coiling (14%) for aneurysms. Ventriculostomy placement was undertaken in 67% of patients, with 37.5% of these requiring conversion to ventriculoperitoneal shunts. Subarachnoid hemorrhage development was uniformly associated with 100% mortality. CONCLUSIONS: In patients presenting with Fusarium solani meningitis, weekly angiographic surveillance proved instrumental for monitoring aneurysm and vasospasm development. Conventional angiography outperformed CT angiography due to its enhanced ability to detect small aneurysms. A proactive approach to aneurysm treatment is advocated, given their elevated rupture risk. While our findings suggest the potential reversibility of angiographic vasospasm with effective antifungal treatment, we acknowledge the challenge of drawing definitive conclusions based on a limited sample size.

Targeted transcriptional upregulation of SENP1 by CRISPR activation enhances deSUMOylation pathways to elicit antinociception in the spinal nerve ligation model of neuropathic pain.

ABSTRACT: The voltage-gated sodium channel Na V 1.7 is an essential component of human pain signaling. Changes in Na V 1.7 trafficking are considered critical in the development of neuropathic pain. SUMOylation of collapsin response mediator protein 2 (CRMP2) regulates the membrane trafficking and function of Na V 1.7. Enhanced CRMP2 SUMOylation in neuropathic pain correlates with increased Na V 1.7 activity. Pharmacological and genetic interventions that interfere with CRMP2 SUMOylation in rodents with neuropathic pain have been shown to reverse mechanical allodynia. Sentrin or SUMO-specific proteases (SENPs) are vital for balancing SUMOylation and deSUMOylation of substrates. Overexpression of SENP1 and/or SENP2 in CRMP2-expressing cells results in increased deSUMOylation and decreased membrane expression and currents of Na V 1.7. Although SENP1 is present in the spinal cord and dorsal root ganglia, its role in regulating Na V 1.7 function and pain is not known. We hypothesized that favoring SENP1 expression can enhance CRMP2 deSUMOylation to modulate Na V 1.7 channels. In this study, we used a clustered regularly interspaced short palindromic repeats activation (CRISPRa) SENP1 lentivirus to overexpress SENP1 in dorsal root ganglia neurons. We found that SENP1 lentivirus reduced CRMP2 SUMOylation, Na V 1.7-CRMP2 interaction, and Na V 1.7 membrane expression. SENP1 overexpression decreased Na V 1.7 currents through clathrin-mediated endocytosis, directly linked to CRMP2 deSUMOylation. Moreover, enhancing SENP1 expression did not affect the activity of TRPV1 channels or voltage-gated calcium and potassium channels. Intrathecal injection of CRISPRa SENP1 lentivirus reversed mechanical allodynia in male and female rats with spinal nerve injury. These results provide evidence that the pain-regulating effects of SENP1 overexpression involve, in part, the modulation of Na V 1.7 channels through the indirect mechanism of CRMP2 deSUMOylation.

Prevalence of Branch Pulmonary Artery Reintervention Following the Arterial Switch Operation.

BACKGROUND: The arterial switch operation (ASO) is the preferred surgical procedure used to correct dextro-transposition of the great arteries. A known complication of the ASO is branch pulmonary arteries (PAs) stenosis, which may require reintervention. Our goal is to determine the frequency of reintervention after the ASO and any factors associated with reintervention. METHODS: This was a single center, retrospective study of infants who underwent the ASO from June 6, 2011 to February 21, 2021. The primary outcome was the prevalence of reintervention on the PAs following the ASO. RESULTS: Sixty-eight infants were analyzed; 9 (13%) patients had 10 reinterventions. The mean age at time of the ASO was 6.52 ± 6.63 days; weight was 3.34 ± 0.57 kg. Those with a reintervention had a longer bypass time (P = .047). Mean age at reintervention was 0.80 ± 0.72 years; mean time from the ASO to reintervention was 0.799 ± 0.717 years. Six surgical procedures, two stent placements, and four balloon angioplasties were performed on a total of 13 branch PAs. There was no increased risk for reintervention on the right versus left PA. After reintervention, there was an improvement in the minimal PA diameter and echo gradient. There were no adverse events or mortality related to the reintervention. Mean follow-up was 6.17 ± 2.94 years. CONCLUSION: The prevalence of branch PA reintervention following the ASO in our cohort was 13%. There is an association between longer cardiopulmonary bypass time and reintervention. After reintervention, there was an increase in PA diameter and a decrease in echo gradient.