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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.
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AVC Isquêmico , Sistema de Registros , Trombectomia , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Trombectomia/métodos , AVC Isquêmico/cirurgia , AVC Isquêmico/terapia , Estudos Transversais , Idoso de 80 Anos ou mais , Falha de Tratamento , Trombólise Mecânica/métodos , Resultado do Tratamento , Procedimentos Endovasculares/métodosRESUMO
BACKGROUND: On June 1, 2021, Vermont repealed all criminal penalties for possessing 224 milligrams or less of buprenorphine. We examined the potential impact of decriminalization with a survey of Vermont clinicians who prescribed buprenorphine within the past year. METHODS: All 638 Vermont clinicians with a waiver to prescribe buprenorphine were emailed the survey by Vermont Department of Health; 117 responded. We estimated the prevalence of the following four outcomes, for all responding clinicians and stratified by clinician demographics and practice characteristics: awareness of decriminalization, beliefs about the effects of decriminalization, support for decriminalization, and changes in practice resulting from decriminalization. RESULTS: 72 (62%) prescribers correctly stated that Vermont does not have criminal penalties for buprenorphine possession. 107 (91%) support decriminalization. 56 (48%) believe that, because buprenorphine is decriminalized, their patients are more likely to give, sell, or trade the buprenorphine that is prescribed to them to someone else. However, only 5 providers (4%) said they now prescribe to fewer patients. CONCLUSION: The great majority of Vermont clinicians who prescribe buprenorphine support its decriminalization and have not changed their prescribing practices because of decriminalization.
In 2021, Vermont repealed criminal penalties for buprenorphine possession.We surveyed Vermont (n = 117) buprenorphine prescribers about decriminalization.91% of providers support decriminalization.48% of providers believe decriminalization will increase diversion of medications.Only 4% of providers prescribe to fewer patients because of decriminalization.
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Buprenorfina , Transtornos Relacionados ao Uso de Opioides , Humanos , Buprenorfina/uso terapêutico , Vermont , Inquéritos e Questionários , Padrões de Prática Médica , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Tratamento de Substituição de OpiáceosRESUMO
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 2022âMay 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.
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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.
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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 72â 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.
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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 â Y|W = -1.16 = 0.37, p = 0.05), and heat pain sensitivity (θX â Y|W = -1.30 = 0.44, p = 0.05). Higher global brain efficiency ameliorated the relationship between ACEs and pain intensity (θX â 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.
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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.
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Política de Saúde , Formulação de Políticas , Instituições Acadêmicas , Esportes , Humanos , Estudos Transversais , Instituições Acadêmicas/organização & administração , Estados Unidos , Adolescente , Inquéritos e QuestionáriosRESUMO
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.
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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.
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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.
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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.
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Traumatismos em Atletas , Humanos , Traumatismos em Atletas/terapia , Serviços Médicos de Emergência/normas , Medicina Esportiva/normas , Consenso , Técnica Delphi , EsportesRESUMO
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.