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.

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.

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.

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.

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.

Exertional Heat Illness: Adoption of Policies and Influencing Contextual Factors as Reported by Athletic Administrators.

BACKGROUND: Little is known about the adoption by athletic administrators (AAs) of exertional heat illness (EHI) policies, and the corresponding facilitators and barriers of such policies within high school athletics. This study describes the adoption of comprehensive EHI policies by high school AAs and explores factors influencing EHI policy adoption. HYPOTHESIS: We hypothesized that <50% of AAs would report adoption of an EHI policy, and that the most common facilitator would be access to an athletic trainer (AT), whereas the most common barrier would be financial limitations. STUDY DESIGN: Cross-sectional. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 466 AAs (82.4% male; age, 48 ± 9 years) completed a validated online survey to assess EHI prevention and treatment policy adoption (11 components), as well as facilitators and barriers to policy implementation. Access to athletic training services was ascertained by matching the participants' zip codes with the Athletic Training Locations and Services Project. Policy adoption, facilitators, and barriers data are presented as summary statistics (proportions, interquartile range (IQR)). A Welch t test evaluated the association between access to athletic training services and EHI policy adoption. RESULTS: Of the AAs surveyed, 77.9% (n = 363) reported adopting a written EHI policy. The median of EHI policy components adopted was 5 (IQR = 1,7), with only 5.6% (n = 26) of AAs reporting adoption of all policy components. AAs who had access to an AT (P = 0.04) were more likely to adopt a greater number of EHI-related policies, compared with those without access to an AT. An AT employed at the school was the most frequently reported facilitator (36.9%). CONCLUSION: Most AAs reported having written EHI policy components, and access to an AT resulted in a more comprehensive policy. CLINICAL RELEVANCE: Employment of an AT within high school athletics may serve as a vital component in facilitating the adoption of comprehensive EHI policies.

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.

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.

Beliefs and Attitudes about Vermont's Buprenorphine Decriminalization Law among Clinicians Who Prescribe Buprenorphine.

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.

Breast cancer therapies reduce risk of Alzheimer's disease and promote estrogenic pathways and action in brain.

Worldwide, an ever-increasing number of women are prescribed estrogen-modulating therapies (EMTs) for the treatment of breast cancer. In parallel, aging of the global population of women will contribute to risk of both breast cancer and Alzheimer's disease. To address the impact of anti-estrogen therapies on risk of Alzheimer's and neural function, we conducted medical informatic and molecular pharmacology analyses to determine the impact of EMTs on risk of Alzheimer's followed by determination of EMT estrogenic mechanisms of action in neurons. Collectively, these data provide both clinical and mechanistic data indicating that select EMTs exert estrogenic agonist action in neural tissue that are associated with reduced risk of Alzheimer's disease while simultaneously acting as effective estrogen receptor antagonists in breast.

A peptidomimetic modulator of the CaV2.2 N-type calcium channel for chronic pain.

Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Cav2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A1R2 dipeptide in CBD3 as the anchoring Cav2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Cav2.2 from CRMP2, reduced membrane Cav2.2 expression and Ca2+ currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Cav2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.

Application of the Theory of Planned Behaviour to inform development of a Dissemination and Implementation science training for nutrition practitioners.

OBJECTIVE: To determine nutrition practitioners' attitudes, behavioural control and normative beliefs to best inform the development and formulation of a nutrition-specific Dissemination and Implementation (D&I) science training. DESIGN: A cross-sectional survey aimed to assess Theory of Planned Behaviour (TPB) constructs and intention to use D&I science. A validated TPB questionnaire assessed constructs including perceived behavioural control, subjective, injunctive and descriptive normative beliefs, attitudes and intention to use D&I science. For analysis, Spearman's ρ, Kruskal-Wallis and Steel-Dwass tests were conducted for quantitative variables. SETTING: Online, 26-item Qualtrics survey. PARTICIPANTS: Cross-sectional sample of members (n 70) affiliated with the Society for Nutrition Education and Behaviour listserv. RESULTS: The major finding from this study was a significant positive correlation between perceived behavioural control score and intention (r = 0·315, P = 0·0119). CONCLUSIONS: D&I training interventions could formulate learning and teaching strategies to target perceived behavioural control (self-efficacy, knowledge and ability) to enhance intention. For example, application and experience-based learning techniques trainings could be strategies to increase knowledge and abilities.

A new polymodal gating model of the proton-activated chloride channel.

The proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we investigated the gating of PAC channels using its novel bifunctional modulator C77304. C77304 acted as a weak activator of the PAC channel, causing moderate activation by acting on its proton gating. However, at higher concentrations, C77304 acted as a weak inhibitor, suppressing channel activity. This dual function was achieved by interacting with 2 modulatory sites of the channel, each with different affinities and dependencies on the channel's state. Moreover, we discovered a protonation-independent voltage activation of the PAC channel that appears to operate through an ion-flux gating mechanism. Through scanning-mutagenesis and molecular dynamics simulation, we confirmed that E181, E257, and E261 in the human PAC channel serve as primary proton sensors, as their alanine mutations eliminated the channel's proton gating while sparing the voltage-dependent gating. This proton-sensing mechanism was conserved among orthologous PAC channels from different species. Collectively, our data unveils the polymodal gating and proton-sensing mechanisms in the PAC channel that may inspire potential drug development.

Identification and targeting of a unique NaV1.7 domain driving chronic pain.

Small molecules directly targeting the voltage-gated sodium channel (VGSC) NaV1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other NaV isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased NaV1.7 currents. A cell-penetrant decoy peptide corresponding to the NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the NaV1.7-CRS peptide did not produce motor impairment, nor did it alter physiological pain sensation, which is essential for survival. As a proof-of-concept for a NaV1.7 -targeted gene therapy, we packaged a plasmid encoding the NaV1.7-CRS in an AAV virus. Treatment with this virus reduced NaV1.7 function in both rodent and rhesus macaque sensory neurons. This gene therapy reversed and prevented mechanical allodynia in a model of nerve injury and reversed mechanical and cold allodynia in a model of chemotherapy-induced peripheral neuropathy. These findings support the conclusion that the CRS domain is a targetable region for the treatment of chronic neuropathic pain.

Attitudes and beliefs about Vermont's 2021 buprenorphine decriminalization law among residents who use illicit opioids.

BACKGROUND: In July 2021, Vermont removed all criminal penalties for possessing 224mg or less of buprenorphine. METHODS: Vermont residents (N=474) who used illicit opioid drugs or received treatment for opioid use disorder in the past 90 days were recruited for a mixed-methods survey on the health and criminal legal effects of decriminalization. Topics assessed included: motivations for using non-prescribed buprenorphine, awareness of and support for decriminalization, and criminal legal system experiences involving buprenorphine. We examined the frequencies of quantitative measures and qualitatively summarized themes from free-response questions. RESULTS: Three-quarters of respondents (76%) reported lifetime use of non-prescribed buprenorphine. 80% supported decriminalization, but only 28% were aware buprenorphine was decriminalized in Vermont. Respondents described using non-prescribed buprenorphine to alleviate withdrawal symptoms and avoid use of other illicit drugs. 18% had been arrested while in buprenorphine, with non-White respondents significantly more likely to report such arrests (15% v 33%, p<0.001). CONCLUSION: Decriminalization of buprenorphine may reduce unnecessary criminal legal system involvement, but its health impact was limited by low awareness at the time of our study.

Evolving Thrombolytics: from Alteplase to Tenecteplase.

Alteplase has been the primary thrombolytic used in the treatment of acute ischemic stroke since thrombolysis was first established as an effective treatment of acute ischemic stroke in 1995. Tenecteplase, a genetically modified tissue plasminogen activator, has gained attention as an attractive alternative to alteplase given its practical workflow advantages and possible superior efficacy in large vessel recanalization. As more data is analyzed both from randomized trials and non-randomized patient registries, there is mounting support that tenecteplase appears to be at least equally, if not more, safe and potentially more effective than alteplase in the treatment of acute ischemic stroke. Randomized trials investigating tenecteplase in the delayed treatment window and with thrombectomy are ongoing, and their results are eagerly awaited. This paper provides an overview of completed and ongoing randomized trials and nonrandomized studies analyzing tenecteplase in the treatment of acute ischemic stroke. Results reviewed support the safe use of tenecteplase in clinical practice.

Argentatin C Analogues with Potential Antinociceptive Activity and Other Triterpenoid Constituents from the Aerial Parts of Parthenium incanum.

Four new triterpenes, 25-dehydroxy-25-methoxyargentatin C (1), 20S-hydroxyargentatin C (2), 20S-hydroxyisoargentatin C (3), and 24-epi-argentatin C (4), together with 10 known triterpenes (5-14) were isolated from the aerial parts of Parthenium incanum. The structures of 1-4 were elucidated by detailed analysis of their spectroscopic data, and the known compounds 5-14 were identified by comparison of their spectroscopic data with those reported. Since argentatin C (11) was found to exhibit antinociceptive activity by decreasing the excitability of rat and macaque dorsal root ganglia (DRG) neurons, 11 and its new analogues 1-4 were evaluated for their ability to decrease the excitability of rat DRG neurons. Of the argentatin C analogues tested, 25-dehydroxy-25-methoxyargentatin C (1) and 24-epi-argentatin C (4) decreased neuronal excitability in a manner comparable to 11. Preliminary structure-activity relationships for the action potential-reducing effects of argentatin C (11) and its analogues 1-4, and their predicted binding sites in pain-relevant voltage-gated sodium and calcium channels (VGSCs and VGCCs) in DRG neurons are presented.