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BACKGROUND: Mechanical thrombectomy (MT) has revolutionized the treatment of acute ischemic stroke (AIS) due to large vessel occlusion (LVO), but its efficacy and safety in medium vessel occlusion (MeVO) remain less explored. This multicenter, retrospective study aims to investigate the incidence and clinical outcomes of vessel perforations (confirmed by extravasation during an angiographic series) during MT for AIS caused by MeVO. METHODS: Data were collected from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. A total of 1373 AIS patients with MeVO underwent MT. Baseline characteristics, procedural details, and clinical outcomes were analyzed. RESULTS: The incidence of vessel perforation was 4.8% (66/1373). Notably, our analysis indicates variations in perforation rates across different arterial segments: 8.9% in M3 segments, 4.3% in M2 segments, and 8.3% in A2 segments (p = 0.612). Patients with perforation had significantly worse outcomes, with lower rates of favorable angiographic outcomes (TICI 2c-3: 23% vs 58.9%, p

Pretreatment CT Perfusion (CTP) parameter rCBV < 42% lesion volume has recently been shown to predict 90-day mRS. In this study, we aim to assess the relationship between rCBV < 42% and a radiographic follow-up infarct volume delineated on FLAIR images. In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 9 January 2017 and 10 January 2023. Follow-up FLAIR imaging was used to determine the final infarct volume. Student t, Mann-Whitney-U, and Chi-Square tests were used to assess differences. Spearmans rank correlation and linear regression analysis were used to assess associations between rCBV < 42% and follow-up infarct volume on FLAIR. In total, 158 patients (median age: 68 years, 52.5% female) met our inclusion criteria. rCBV < 42% (ρ = 0.56, p < 0.001) significantly correlated with follow-up-FLAIR infarct volume. On multivariable linear regression analysis, rCBV < 42% lesion volume (beta = 0.60, p < 0.001), ASPECTS (beta = -0.214, p < 0.01), mTICI (beta = -0.277, p < 0.001), and diabetes (beta = 0.16, p < 0.05) were independently associated with follow-up infarct volume. The rCBV < 42% lesion volume is independently associated with FLAIR follow-up infarct volume.

Background: The pretreatment CT perfusion (CTP) marker the relative cerebral blood volume (rCBV) < 42% lesion volume has recently been shown to predict 90-day functional outcomes; however, studies assessing correlations of the rCBV < 42% lesion volume with other outcomes remain sparse. Here, we aim to assess the relationship between the rCBV < 42% lesion volume and the reference standard digital subtraction angiography (DSA)-derived American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN) collateral score, hereby referred as the DSA CS. Methods: In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 1 September 2017 and 1 October 2023. Group differences were assessed using the Students t test, Mann-Whitney U test and Chi-Square test. Spearmans rank correlation and logistic regression analyses were used to assess associations between rCBV < 42% and DSA CS. Results: In total, 222 patients (median age: 69 years, 56.3% female) met our inclusion criteria. In the multivariable logistic regression analysis, taking into account age, sex, race, hypertension, hyperlipidemia, diabetes, atrial fibrillation, prior stroke or transient ischemic attack, the admission National Institute of Health stroke scale, the premorbid modified Rankin score, the Alberta stroke program early CT score (ASPECTS), and segment occlusion, the rCBV < 42% lesion volume (adjusted OR: 0.98, p < 0.05) was independently associated with the DSA CS. Conclusion: The rCBV < 42% lesion volume is independently associated with the DSA CS.

INTRODUCTION: First pass effect (FPE), achievement of complete recanalization (mTICI 2c/3) with a single pass, is a significant predictor of favorable outcomes for endovascular treatment (EVT) in large vessel occlusion stroke (LVO). However, data concerning the impact on functional outcomes and predictors of FPE in medium vessel occlusions (MeVO) are scarce. PATIENTS AND METHODS: We conducted an international retrospective study on MeVO cases. Multivariable logistic modeling was used to establish independent predictors of FPE. Clinical and safety outcomes were compared between the two study groups (FPE vs non-FPE) using logistic regression models. Good outcome was defined as modified Rankin Scale 0-2 at 3 months. RESULTS: Eight hundred thirty-six patients with a final mTICI ⩾ 2b were included in this analysis. FPE was observed in 302 patients (36.1%). In multivariable analysis, hypertension (aOR 1.55, 95% CI 1.10-2.20) and lower baseline NIHSS score (aOR 0.95, 95% CI 0.93-0.97) were independently associated with an FPE. Good outcomes were more common in the FPE versus non-FPE group (72.8% vs 52.8%), and FPE was independently associated with favorable outcome (aOR 2.20, 95% CI 1.59-3.05). 90-day mortality and intracranial hemorrhage (ICH) were significantly lower in the FPE group, 0.43 (95% CI, 0.25-0.72) and 0.55 (95% CI, 0.39-0.77), respectively. CONCLUSION: Over 2/3 of patients with MeVOs and FPE in our cohort had a favorable outcome at 90 days. FPE is independently associated with favorable outcomes, it may reduce the risk of any intracranial hemorrhage, and 3-month mortality.

Background and Purpose The management of acute ischemic stroke (AIS) due to distal medium vessel occlusion (DMVO) remains uncertain, particularly in comparing the effectiveness of intravenous thrombolysis (IVT) plus mechanical thrombectomy (MT) versus IVT alone. This study aimed to evaluate the safety and efficacy in DMVO patients treated with either MT-IVT or IVT alone. Methods This multinational study analyzed data from 37 centers across North America, Asia, and Europe. Patients with AIS due to DMVO were included, with data collected from September 2017 to July 2023. The primary outcome was functional independence, with secondary outcomes including mortality and safety measures such as types of intracerebral hemorrhage. Results The study involved 1,057 patients before matching, and 640 patients post-matching. Functional outcomes at 90 days showed no significant difference between groups in achieving good functional recovery (modified Rankin Scale 0–1 and 0–2), with adjusted odds ratios (OR) of 1.21 (95% confidence interval [CI] 0.81 to 1.79; P=0.35) and 1.00 (95% CI 0.66 to 1.51; P>0.99), respectively. Mortality rates at 90 days were similar between the two groups (OR 0.75, 95% CI 0.44 to 1.29; P=0.30). The incidence of symptomatic intracerebral hemorrhage was comparable, but any type of intracranial hemorrhage was significantly higher in the MT-IVT group (OR 0.43, 95% CI 0.29 to 0.63; P

John Hatheway,1 Alexander Perry Hersel,2 Jonathan Song,3 Mitchell P Engle,4 Genaro Gutierrez,5 Vishal Khemlani,6 Leonardo Kapural,7 Gregory Moore,8 Reginald Chinaedu Ajakwe,9 Drew M Trainor,10 Jennifer M Hah,11 Peter Staats,12 Paul Lynch,13 James Makous,14 Gary Heit15 ,† Shilpa Kottalgi,16 Mehul J Desai17 1Pain Management, Northwest Pain Care, Spokane, WA, USA; 2Pain Management, Pain Management and Injury Relief, Thousand Oaks, CA, USA; 3Pain Management, Arizona Pain Specialists, Scottsdale, AZ, USA; 4Pain Management, Institute of Precision Pain Medicine, Corpus Christi, TX, USA; 5Pain Management, Pain Specialists of America, Austin, TX, USA; 6Pain Management, Columbia Pain Management, Portland, OR, USA; 7Pain Management, Center for Clinical Research, Carolinas Pain Institute, Winston-Salem, NC, USA; 8Pain Management, Pacific Sports and Spine, Eugene, OR, USA; 9Pain Management, Comprehensive Spine & Pain, Burbank, CA, USA; 10Pain Management, Denver Spine and Pain Institute, Denver, CO, USA; 11Pain Management, Division of Pain Medicine, Stanford University, Palo Alto, CA, USA; 12Pain Management, Premier Pain Centers, Shrewsbury, NJ, USA; 13Pain Management, US Pain Care, Scottsdale, AZ, USA; 14Pain Management, Makous Research, LLC, Carlsbad, CA, USA; 15Department of Neurosurgery, Hue University of Medicine and Pharmacy, Hue, Vietnam; 16Clinical Affairs, Nalu Medical, Inc., Carlsbad, CA, USA; 17Pain Management, International Spine Pain & Performance Center, Washington, DC, USA†Gary Heit passed away in February 2023Correspondence: Shilpa Kottalgi, Nalu Medical, Inc., 2320 Faraday Ave, Carlsbad, CA, 92008, USA, Tel +1 858 344 1591, Fax +1 760 448 2379, Email skottalgi@nalumed.comBackground: Peripheral Nerve Stimulation (PNS) is an established therapy for chronic neuropathic pain of peripheral origin, typically following nerve injury. However, there is a paucity of Randomized Controlled Trials (RCTs) demonstrating the therapeutic benefits of PNS. The goals of the current study (COMFORT Study) are to document the safety and efficacy of the Nalu Neurostimulation in a PNS RCT, compared to conventional medical management (CMM).Methods/Design: This is a prospective, multicenter, RCT evaluating the treatment of neuropathic pain with PNS therapy. One of the following four regions will be targeted for treatment: low back, shoulder, knee or foot/ankle. Consented subjects will undergo a baseline evaluation, after which they are randomized 2:1 (PNS+CMM arm to CMM arm). Subjects randomized to PNS+CMM arm will undergo a trial implant period using best clinical practices. Subjects who pass the trial phase, by showing a ≥ 50% reduction in pain relative to baseline, will receive the permanent implant. All subjects receiving a permanent implant will be followed for a total of 36 months. At the 3-month primary end point, subjects in CMM arm will be given the option to crossover into PNS+CMM arm, beginning with a trial implant. The study duration is expected to be 5.5 years from first enrollment to last follow-up of last subject and subsequent study closure. Adverse events will be captured throughout the study.Discussion: The COMFORT study, described here, has the potential to demonstrate the efficacy and safety of the Nalu Neurostimulation System in the treatment of peripheral neuropathy. Results of this study will be the first Level-I evidence, out to 36 months, validating the use of this PNS system in the treatment of chronic pain. This study is designed to enroll the largest cohort, to date, of subjects comparing PNS+CMM vs CMM alone.Plain Language Summary: Peripheral nerve stimulation (PNS) has been used for decades to treat neuropathic pain of peripheral origin. This therapy typically involves the placement small (~1 mm diameter) cylindrical electrodes (leads) near the nerve(s) in question, which is then followed by the delivery mild electrical pulses to the target, thereby blocking the pain signal from reaching the central nervous system. Despite the clinical success of this approach, there are few randomized controlled trials (RCTs) demonstrating PNS efficacy in the treatment of peripheral neuralgia/neuropathy. This may be, in large part, due to a paucity of PNS devices that are small enough to deliver this therapy at multiple locations in the extremities and the torso. For example, most implantable pulse generators (IPGs) range in size from 14 to 40 cm3 in volume. The purpose of this RCT is to demonstrate the safety and efficacy of an externally powered micro-IPG (< 1.5 cm3 in volume), in the delivery of PNS to treat peripheral neuropathic pain. Active Arm subjects will receive therapy with the micro-IPG and continue to use conventional medical management (CMM); Control Arm subjects will be treated with CMM only. The primary endpoint is the responder rate at 3-months, in both arms, defined as the percentage of subjects with ≥ 50% pain reduction from baseline following implantation of the micro-IPG. Control Arm subjects will be given the option to crossover to the Active Arm at 3-months. Study subjects in both arms are followed out to 36 months.Keywords: peripheral nerve stimulation, PNS, chronic pain, neuropathy, neuralgia, micro-IPG, battery-free

Abstract Our group previously showed that genetic or pharmacological inhibition of the cystine/glutamate antiporter, system xc−, mitigates excitotoxicity after anoxia by increasing latency to anoxic depolarization, thus attenuating the ischaemic core. Hypoxia, however, which prevails in the ischaemic penumbra, is a condition where neurotransmission is altered, but excitotoxicity is not triggered. The present study employed mild hypoxia to further probe ischaemia‐induced changes in neuronal responsiveness from wild‐type and xCT KO (xCT−/−) mice. Synaptic transmission was monitored in hippocampal slices from both genotypes before, during and after a hypoxic episode. Although wild‐type and xCT−/− slices showed equal suppression of synaptic transmission during hypoxia, mutant slices exhibited a persistent potentiation upon re‐oxygenation, an effect we termed ‘post‐hypoxic long‐term potentiation (LTP)’. Blocking synaptic suppression during hypoxia by antagonizing adenosine A1 receptors did not preclude post‐hypoxic LTP. Further examination of the induction and expression mechanisms of this plasticity revealed that post‐hypoxic LTP was driven by NMDA receptor activation, as well as increased calcium influx, with no change in paired‐pulse facilitation. Hence, the observed phenomenon engaged similar mechanisms as classical LTP. This was a remarkable finding as theta‐burst stimulation‐induced LTP was equivalent between genotypes. Importantly, post‐hypoxic LTP was generated in wild‐type slices pretreated with system xc− inhibitor, S‐4‐carboxyphenylglycine, thereby confirming the antiporter's role in this phenomenon. Collectively, these data indicate that system xc− interference enables neuroplasticity in response to mild hypoxia, and, together with its regulation of cellular damage in the ischaemic core, suggest a role for the antiporter in post‐ischaemic recovery of the penumbra.

BACKGROUND: Pretreatment CT Perfusion (CTP) parameters serve as reliable surrogates of collateral status (CS). In this study, we aim to assess the relationship between the novel compensation index (CI, Tmax > 4 s/Tmax > 6 s) and already established CTP collateral markers, namely cerebral blood volume (CBV) index and Hypoperfusion Intensity Ratio (HIR), with the reference standard American Society of Interventional and Therapeutic Neuroradiology (ASITN) collateral score (CS) on DSA. METHODS: In this retrospective study, inclusion criteria were the following: (a) CT angiography confirmed anterior circulation large vessel occlusion from 9 January 2017 to 10 January 2023; (b) diagnostic CT perfusion; and (c) underwent mechanical thrombectomy with documented DSA-CS. Student t-test, Mann-Whitney-U-test and Chi-square test were used to assess differences. Spearmans rank correlation and logistic regression analysis were used to assess associations. p ≤ 0.05 was considered significant. RESULTS: In total, 223 patients (mean age: 67.8 ± 15.8, 56% female) met our inclusion criteria. The CI (ρ = 0.37, p < 0.001) and HIR (ρ = -0.29, p < 0.001) significantly correlated with DSA-CS. Whereas the CBV Index (ρ = 0.1, p > 0.05) did not correlate with DSA-CS. On multivariate logistic regression analysis taking into account age, sex, ASPECTS, tPA, premorbid mRS, NIH stroke scale, prior history of TIA, stroke, atrial fibrillation, diabetes mellitus, hyperlipidemia, heart disease and hypertension, only CI was not found to be independently associated with DSA-CS (adjusted OR = 1.387, 95% CI: 1.09-1.77, p < 0.01). CONCLUSION: CI demonstrates a stronger correlation with DSA-CS compared to both the HIR and CBV Index where it may show promise as an additional quantitative pretreatment CS biomarker.

Atherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation. Characterization of the morphology and vulnerability of the lesion is essential for effective clinical management. Here, near-infrared auto-photoacoustic (NIRAPA) imaging is shown to detect plaque components and, when combined with ultrasound imaging, to differentiate stable and vulnerable plaque. In an ex vivo study of photoacoustic imaging of excised plaque from 25 patients, 88.2% sensitivity and 71.4% specificity were achieved using a clinically-relevant protocol. In order to determine the origin of the NIRAPA signal, immunohistochemistry, spatial transcriptomics and spatial proteomics were co-registered with imaging and applied to adjacent plaque sections. The highest NIRAPA signal was spatially correlated with bilirubin and associated blood-based residue and with the cytoplasmic contents of inflammatory macrophages bearing CD74, HLA-DR, CD14 and CD163 markers. In summary, we establish the potential to apply the NIRAPA-ultrasound imaging combination to detect vulnerable carotid plaque and a methodology for fusing molecular imaging with spatial transcriptomic and proteomic methods.

Background Acute ischemic stroke arising from medium vessel occlusions (MeVO) poses substantial challenges in treatment and management. This study aims to elucidate the outcomes and factors contributing to achieving excellent recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] 2c–3) versus successful recanalization (mTICI 2b) in patients with MeVO stroke undergoing mechanical thrombectomy (MT). Methods We conducted a multinational study analyzing data from the MAD‐MT (Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy) registry, encompassing 37 centers across North America, Asia, and Europe, collected between September 2017 and July 2023. The study included acute ischemic stroke patients with MeVO treated with MT, with or without intravenous thrombolysis, who achieved mTICI 2b–3 post‐MT. Results Among 1463 patients with successful recanalization (mTICI 2b–3), 523 achieved mTICI 2b recanalization, and 940 achieved mTICI 2c–3. Distal occlusions exhibited higher odds of excellent recanalization compared with proximal MeVO vessel occlusions (odds ratio, 1.58; 95% CI, 1.17–2.15; P = 0.003). Cardioembolic stroke pathogenesis was associated with a higher likelihood of excellent recanalization (1.67; 95% CI, 1.07–2.59; P = 0.018). Patients achieving mTICI 2c–3 recanalization demonstrated lower initial National Institutes of Health Stroke Scale scores, significant improvements in postprocedural National Institutes of Health Stroke Scale shift, and a higher percentage of favorable 90‐day outcomes compared with those with mTICI 2b. However, no significant difference in 90‐day mortality rates was observed. Conclusion This study underscores that among patients with MeVO stroke with successful recanalization (mTICI 2b–3) there is higher likelihood of achieving excellent recanalization (mTICI 2c–3) in distal occlusions and cardioembolic pathogenesis. mTICI 2c–3 scores post‐MT correlate with improved clinical outcomes compared with mTICI 2b, affirming the superiority of excellent recanalization over successful recanalization in patients with MeVO stroke. Further prospective studies and randomized controlled trials are warranted for validation.

Summary: The serine-/arginine-rich splicing factor 2 (SRSF2) plays pivotal roles in pre-mRNA processing and gene transcription. Recurrent mutations, particularly a proline-to-histidine substitution at position 95 (P95H), are common in neoplastic diseases. Here, we assess SRSF2’s diverse functions in squamous cell carcinoma. We show that SRSF2 deletion or homozygous P95H mutation both cause extensive DNA damage leading to cell-cycle arrest. Mechanistically, SRSF2 regulates efficient bi-directional transcription of DNA replication and repair genes, independent from its function in splicing. Further, SRSF2 haploinsufficiency induces DNA damage without halting the cell cycle. Exposing mouse skin to tumor-promoting carcinogens enhances the clonal expansion of heterozygous Srsf2 P95H epidermal cells but unexpectedly inhibits tumor formation. To survive carcinogen treatment, Srsf2 P95H+/− cells undergo substantial transcriptional rewiring and restore bi-directional gene expression. Thus, our study underscores SRSF2’s importance in regulating transcription to orchestrate the cell cycle and the DNA damage response.

Background Unfavorable clinical outcomes in patients with acute ischemic stroke caused by large‐vessel occlusions despite successful reperfusion have been associated with poor venous outflow. The objective of this study is to assess the relationship between prolonged venous transit (PVT), a novel perfusion imaging surrogate for poor venous outflow, and likelihood of favorable clinical recovery. Methods In this retrospective review of prospectively collected data of consecutive patients (2017–2022) with successfully reperfused, anterior circulation acute ischemic stroke caused by large‐vessel occlusions, we assessed the association between PVT+, defined as time to maximum ≧10‐second timing delays within either the posterior superior sagittal sinus, torcula, or both regions on pretreatment perfusion imaging, and favorable clinical outcomes defined as 90‐day modified Rankin Scale score of 0 to 2. Patients were dichotomized into PVT+ and PVT− for analysis. Multivariable logistic regression analyses for favorable recovery were performed with demographic variables and stroke characteristics. Results A total of 127 consecutive patients (median age, 71 [interquartile range 61—77] years; 59.1% women) were included, and 40 of 127 (31.5%) were PVT+. PVT+ (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07–0.81]; P = 0.02) and advanced age (aOR, 0.92 [95% CI, 0.88–0.97]; P = 0.01) were significantly associated with the primary outcome. Conclusion PVT+ was associated with a lower likelihood of achieving favorable clinical recovery in successfully reperfused patients with acute ischemic stroke caused by large vessel occlusion. PVT may serve as a clinically useful adjunctive imaging parameter.

Seismic methods are emerging as efficient tools for imaging the subsurface to investigate the weathering zone. The structure of the weathering zone can be identified by differing shear wave velocities as various weathering processes will alter the properties of rocks. Currently, 3D subsurface modelling of the weathering zone is gaining increasing importance as results allow the identification of the weathering imprint in the subsurface not only from top to bottom but also in three dimensions. We investigated the 3D weathering structure of monzogranite bedrock near the Pan de Azúcar National Park (Atacama Desert, northern Chile), where the weathering is weak due to the arid climate conditions. We set up an array measurement that records seismic ambient noise, which we used to extract the horizontal-to-vertical spectral ratio (HVSR) curves. The curves were then used to invert for 1D shear wave velocity (Vs) models, which we then used to compile a pseudo-3D model of the subsurface structure in our study area. To invert the 1D Vs model, we applied a transdimensional hierarchical Bayesian inversion scheme, allowing us to invert the HVSR curve with minimal prior information. The resulting 3D model allowed us to image the granite gradient from the surface down to ca. 50 m depth and confirmed the presence of dikes of mafic composition intruding the granite. We identified three main zones of fractured granite, altered granite, and the granite bedrock in addition to the mafic dikes with relatively higher Vs. The fractured granite layer was identified with Vs of 1.4 km s−1 at 30–40 m depth, while the granite bedrock was delineated with Vs of 2.5 km s−1 and a depth range between 10 and 50 m depth. We compared the resulting subsurface structure to other sites in the Chilean coastal cordillera located in various climatic conditions and found that the weathering depth and structure at a given location depend on a complex interaction between surface processes such as precipitation rate, tectonic uplift and fracturing, and erosion. Moreover, these local geological features such as the intrusion of mafic dikes can create significant spatial variations to the weathering structure and therefore emphasize the importance of 3D imaging of the weathering structure. The imaged structure of the subsurface in Pan de Azúcar provides the unique opportunity to image the heterogeneities of a rock preconditioned for weathering but one that has never experienced extensive weathering given the absence of precipitation.

Summary: Background: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE). Methods: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls). Findings: Sixteen genes showed an association with PDAC risk (FDR

Abstract Generalized linear models (GLMs) are an integral tool in ecology. Like general linear models, GLMs assume linearity, which entails a linear relationship between independent and dependent variables. However, because this assumption acts on the link rather than the natural scale in GLMs, it is more easily overlooked. We reviewed recent ecological literature to quantify the use of linearity. We then used two case studies to confront the linearity assumption via two GLMs fit to empirical data. In the first case study we compared GLMs to generalized additive models (GAMs) fit to mammal relative abundance data. In the second case study we tested for linearity in occupancy models using passerine point‐count data. We reviewed 162 studies published in the last 5 years in five leading ecology journals and found less than 15% reported testing for linearity. These studies used transformations and GAMs more often than they reported a linearity test. In the first case study, GAMs strongly out‐performed GLMs as measured by AIC in modeling relative abundance, and GAMs helped uncover nonlinear responses of carnivore species to landscape development. In the second case study, 14% of species‐specific models failed a formal statistical test for linearity. We also found that differences between linear and nonlinear (i.e., those with a transformed independent variable) model predictions were similar for some species but not for others, with implications for inference and conservation decision‐making. Our review suggests that reporting tests for linearity are rare in recent studies employing GLMs. Our case studies show how formally comparing models that allow for nonlinear relationships between the dependent and independent variables has the potential to impact inference, generate new hypotheses, and alter conservation implications. We conclude by suggesting that ecological studies report tests for linearity and use formal methods to address linearity assumption violations in GLMs.

Unmanned Aerial Vehicles (UAVs) are increasingly utilized across various industries, necessitating high reliability to ensure safety and reduce operational costs. This paper introduces a systematic methodology for physics-based reliability modeling tailored for UAV control applications, focusing on adaptive control allocation to optimize reliability. The study addresses the limitations of conventional degradation-independent behavior factor-based models, which often rely on inaccurate degradation models due to the lack of parameterization data sources and methods. By replacing time with stress-derived variables in the reliability function, this approach enables the combination of any time-dependent reliability functions with any stress-life relationships, allowing for real-time physics-based reliability assessments. The approach is demonstrated through the development and application of models for electronic speed controllers within a hexarotor UAV, using a virtual prototype for flight simulation. Simulation results reveal that physics-based models improve reliability prediction accuracy compared to conventional proportional hazard models, particularly due to their reliance on published and manufacturer’s data for parameterization. The paper concludes by highlighting the need for future research to simplify the integration of stress factor online measurements, addressing the complexity and data requirements inherent in physics-based models.

John Salmon,1 Daniel Bates,2 Neels Du Toit,2 Paul Verrills,2 James Yu,3 Murray G Taverner,4 Vahid Mohabbati,5 Matthew Green,6 Gary Heit7 ,† Robert Levy,8 Peter Staats,9 Shilpa Kottalgi,10 James Makous,11 Bruce Mitchell2 1Pain Management, Pain Care Perth, Perth Cottesloe, WA, Australia; 2Pain Management, Metro Pain Group, Melbourne, VIC, Australia; 3Pain Management, Sydney Spine and Pain, Sydney, NSW, Australia; 4Pain Management, Frankston Pain Management, Frankston, VIC, Australia; 5Pain Management, Sydney Pain Management Centre, Sydney, NSW, Australia; 6Pain Management, Pain Medicine of South Australia, Adelaide, SA, Australia; 7Department of Neurosurgery, Hue University of Medicine and Pharmacy, Hue, Vietnam; 8Neurosurgery, Institute for Neuromodulation, Boca Raton, FL, USA; 9Premier Pain Centers, Shrewsbury, NJ, USA; 10Clinical Department, Nalu Medical, Inc, Carlsbad, CA, USA; 11Makous Research, LLC, Carlsbad, CA, USA†Gary Heit passed away in February 2023Correspondence: John Salmon, Pain Management, Pain Care Perth, 2/89 Forrest Street, Perth Cottesloe, WA, 6011, Australia, Tel +61 428 246 846, Fax +61 8 92845759, Email Salmon8@bigpond.comPurpose: Spinal cord stimulation (SCS) is a highly effective treatment for chronic neuropathic pain. Despite recent advances in technology, treatment gaps remain. A small SCS system with a miniaturized implantable pulse generator (micro-IPG; < 1.5 cm3 in volume) and an externally worn power source may be preferred by patients who do not want a large, implanted battery. We report here the long-term outcomes from the first-in-human study evaluating the safety and performance of a new neurostimulation system.Patients and Methods: This was a prospective, multi-center, open-label, single-arm study to evaluate this SCS system, in the treatment of chronic, intractable leg and low-back pain. Consented subjects who passed screening continued on to the long-term phase of the study. One-year, patient-reported outcomes (PRO’s) such as pain (Numeric Rating Scale, NRS), functional disability, quality of life, and mood were captured.Results: Twenty-six (26) evaluable subjects with permanent implants were included in this analysis. The average leg pain NRS score decreased from 6.8 ± 1.2 at baseline to 1.1 ± 1.2 at the end of the study (p < 0.001), while the average low-back pain NRS score decreased from 6.8 ± 1.2 to 1.5 ± 1.2 (p < 0.001). The responder rate (proportion with ≥ 50% pain relief) was 91% in the leg(s) and 82% in the low back. There were significant improvements in functional disability (Oswestry Disability Index) and in mood (Beck Depression Inventory), demonstrating a 46% and 62% improvement, respectively (p < 0.001). Eleven-point Likert scales demonstrated the wearable to be very comfortable and very easy to use.Conclusion: There were considerable challenges conducting a clinical study during the COVID-19 pandemic, such as missed study programming visits. Nevertheless, subjects had significant PRO improvements through 1-year. The small size of the implanted device, along with a proprietary waveform, may allow for improved SCS outcomes and a drop in incidence of IPG-pocket pain.Plain Language Summary: Chronic neuropathic pain of the low back and legs is a common affliction. Unfortunately, many of these cases are medically intractable and require more invasive treatments. One such treatment is spinal cord stimulation, in which very small, cylindrical electrodes (leads) are percutaneously introduced into the epidural space where they deliver mild electrical pulses to the spinal cord thereby blocking the pain signals from reaching the brain. Among the shortcomings of this general approach is the bulkiness of the implanted battery and electronics that power the electrodes, which can be as large as 44 cm3 in volume. We report here the results of a study employing a very small spinal cord stimulator implant (< 1.5 cm3 in volume) that is externally powered by a wearable device. The results of this multi-center, prospective, open-label, single-arm study are reported here. Following 1 year of spinal cord stimulation therapy, the average pain reduction was 79% in the legs and 81% in the back, both of which were statistically significant at the p< 0.001 level. At the same study endpoint, patient-reported outcomes demonstrated significant improvements in functional disability (p < 0.001) and mood (p < 0.05). These outcomes are comparable to many of the other larger, fully implantable systems.Keywords: implantable pulse generator, IPG, battery free, neuropathic pain, pulsed stimulation pattern, micro-IPG, persistent spinal pain syndrome, failed back surgery syndrome, FBSS

BackgroundThe present study evaluated the therapeutic efficacy and tolerability of 10 transcranial direct current stimulation (tDCS) sessions in treatment-resistance obsessive-compulsive disorder (OCD) patients using a multisite double-blind sham-controlled design.MethodsEighty treatment-resistance outpatients suffering from obsessive-compulsive disorder were randomized to receive either active or sham transcranial direct current stimulation. The cathode was positioned over the supplementary motor area and the anode over the right supraorbital area. Patients were evaluated at baseline, end of treatment (day 14), one-month follow-up (day 45), and three-month follow-up (day 105) on the Yale-Brown Obsessive Compulsive Scale.ResultsAlthough a significant interaction between time and treatment was observed, the primary endpoint—measuring the change in Yale-Brown obsessive compulsive scale scores after two weeks—was not achieved. Conversely, the secondary endpoint, which concerned the change in Yale-Brown obsessive compulsive scale scores after three months, was successfully met. It is important to note, however, that there were no significant differences in the percentage of responders and remitters at any of the post-treatment assessments. This suggests that the treatment may not have had a clinically relevant impact. Patients well received the transcranial direct current stimulation treatment, indicating its good tolerability.ConclusionThis is the largest controlled trial using transcranial direct current stimulation in treatment-resistance obsessive-compulsive disorder patients. Our results indicate the importance of studying the placebo effect in transcranial direct current stimulation and the necessity to consider a long follow-up time to best evaluate the effects of the intervention.Clinical trial registrationClinicalTrials.gov, identifier NCT03304600.

Background Hemorrhagic transformation (HT) is a major complication in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy. However, HT in patients with AIS due to medium‐vessel occlusions has still not been well researched. In large‐vessel occlusions, collateral status is an important determinant of postprocedural HT, and the cerebral blood volume (CBV) index is a reliable surrogate of collateral status. The aim of our study is to identify an optimal CBV index threshold associated with HT in patients with AIS due to medium‐vessel occlusion and evaluate additional parameters that are independently associated with HT in this group. Methods This retrospective analysis of our prospectively collected database from 2 comprehensive stroke centers consisted of patients presenting with AIS due to medium‐vessel occlusion from 2019 to 2023. The primary outcome was the presence of HT on follow‐up imaging. Optimal CBV index cutoff for HT was derived from a univariate logistic regression analysis. Multivariable logistic regression analysis for HT was derived from the dichotomized CBV index and other covariates. The receiver operator characteristic curve yielded area under the curve. Statistical significance was P≤$ \le $0.05. Results Of 111 patients (median age, 70 years; 43.2% women) included, 26 (23.4%) patients had HT. The optimal CBV index cutoff was 0.7. From multivariable regression analysis, significant variables included prior stroke (adjusted odds ratio [aOR], 7.18 [95% CI, 1.60–32.16]; P = 0.01), endovascular thrombectomy attempt (aOR, 7.86 [95% CI, 1.78–34.68]; P = 0.01), and CBV index (≤$ \le $ 0.7; aOR, 4.23 [95% CI, 1.02–17.59]; P = 0.04). The area under the curve was 0.82 (95% CI, 0.69–0.91). Conclusion A CBV index ≤$ \le $ 0.7 was independently associated with HT in patients with AIS due to medium‐vessel occlusion. Endovascular thrombectomy attempt and prior stroke history were also independently associated with HT in this population.

Abstract We determined if a convolutional neural network (CNN) deep learning model can accurately segment acute ischemic changes on non-contrast CT compared to neuroradiologists. Non-contrast CT (NCCT) examinations from 232 acute ischemic stroke patients who were enrolled in the DEFUSE 3 trial were included in this study. Three experienced neuroradiologists independently segmented hypodensity that reflected the ischemic core on each scan. The neuroradiologist with the most experience (expert A) served as the ground truth for deep learning model training. Two additional neuroradiologists’ (experts B and C) segmentations were used for data testing. The 232 studies were randomly split into training and test sets. The training set was further randomly divided into 5 folds with training and validation sets. A 3-dimensional CNN architecture was trained and optimized to predict the segmentations of expert A from NCCT. The performance of the model was assessed using a set of volume, overlap, and distance metrics using non-inferiority thresholds of 20%, 3 ml, and 3 mm, respectively. The optimized model trained on expert A was compared to test experts B and C. We used a one-sided Wilcoxon signed-rank test to test for the non-inferiority of the model-expert compared to the inter-expert agreement. The final model performance for the ischemic core segmentation task reached a performance of 0.46 ± 0.09 Surface Dice at Tolerance 5mm and 0.47 ± 0.13 Dice when trained on expert A. Compared to the two test neuroradiologists the model-expert agreement was non-inferior to the inter-expert agreement, $$p < 0.05$$ p < 0.05 . The before, CNN accurately delineates the hypodense ischemic core on NCCT in acute ischemic stroke patients with an accuracy comparable to neuroradiologists.

Aneurysmal subarachnoid hemorrhage (aSAH) results in significant mortality and disability. Delayed Cerebral Ischemia (DCI) is the leading cause of poor outcome after aSAH among those who survive the initial hemorrhage event. Significant effort is expended to identify patients at risk of DCI, but existing tests, such as trans-cranial Doppler, suffer from relatively poor sensitivity. Tests to identify patients with DCI prospectively are of high interest.

Background In patients with acute ischemic stroke secondary to large vessel occlusion, achieving modified Thrombolysis in Cerebral Infarction (mTICI) 2c/3 (excellent recanalization) over mTICI 2b is associated with improved functional outcomes. We aimed to determine pretreatment and interventional parameters that are independently associated with mTICI 2c/3 over 2b reperfusion in patients who underwent technically successful mechanical thrombectomy. Methods In this retrospective study, consecutive patients with acute ischemic stroke with anterior circulation large vessel occlusion achieving mTICI 2b/2c/3 recanalization after mechanical thrombectomy were included. We evaluated the association between pretreatment clinical, imaging, and interventional parameters in patients who achieved mTICI 2c/3 versus 2b using multivariate logistic regressions. Results From May 11, 2019 to October 9, 2022, 149 consecutive patients met our inclusion criteria (median 70 years old [interquartile range 65–78.5], 57.7% female). Adjusted multivariate regression analyses showed that patients with excellent recanalization had lower admission National Institutes of Health Stroke Scale scores (adjusted odds ratio [aOR], 0.93; P=0.036), were less likely to have a history of diabetes (aOR, 0.42; P=0.050) and prior stroke (aOR, 0.27; P=0.007), had a cerebral blood volume index ≥0.7 (aOR, 3.75; P=0.007), and were more likely to achieve excellent recanalization with aspiration alone (aOR, 2.89; P=0.012). A multivariate logistic regression model comprising these independent factors predicted mTICI 2c/3 with an area under the curve 0.79 (95% CI, 0.68–0.86; P

Objective: To assess pretreatment and interventional parameters as predictors of favorable Activity Measure for Post-Acute Care (AM-PAC) scores for optimal discharge planning. Design: In this prospectively collected, retrospectively reviewed multicenter study from 9/1/2017 to 9/22/2022, patients were dichotomized into favorable and unfavorable AM-PAC. Multivariate logistic regression and receiver operator characteristics analyses were performed for the identified significant variables. A P value of ≤.05 was significant. Setting: Hospitalized care. Participants: In total, 229 patients (mean ±SD 70.65 ±15.2 [55.9% women]) met our inclusion criteria. Inclusion criteria were (a) computed tomography (CT) angiography confirmed LVO from 9/1/2017 to 9/22/2022; (b) diagnostic CT perfusion; and (c) available AM-PAC scores. Interventions: None. Main Outcome Measures: Favorable AM-PAC, defined as a daily activity score ≥19 and basic mobility score of ≥17. Results: Patients with favorable AM-PAC were younger (61.3 vs 70.7, P

Summary: The lymph node (LN) is a critical biological site for immune maturation after vaccination as it includes several cell populations critical for priming the antibody response. Here, we present a protocol for sampling the LN and isolating cell populations to evaluate immunogens targeting germline cells. We describe steps for media and tube preparation and sample collection using an ultrasound-guided LN fine-needle aspiration procedure. This protocol is safe, quick, low-cost, and less invasive than excisional biopsy.For complete details on the use and execution of this protocol, please refer to Leggat et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

C-term magnetic circular dichroism (MCD) spectroscopy is a powerful method for probing d-d and f-f transitions in paramagnetic metal complexes. However, this technique remains underdeveloped both experimentally and theoretically for studies of U(v) complexes of Oh symmetry, which have been of longstanding interest for probing electronic structure, bonding, and covalency in 5f systems. In this study, C-term NIR MCD of the Laporte forbidden f-f transitions of [UCl6]- and [UF6]- are reported, demonstrating the significant fine structure resolution possible with this technique including for the low energy Γ7 → Γ8 transitions in [UF6]-. The experimental NIR MCD studies were further extended to [U(OC6F5)6]-, [U(CH2SiMe3)6]-, and [U(NC(tBu)(Ph))6]- to evaluate the effects of ligand-type on the f-f MCD fine structure features. Theoretical calculations were conducted to determine the Laporte forbidden f-f transitions and their MCD intensity experimentally observed in the NIR spectra of the U(v) hexahalide complexes, via the inclusion of vibronic coupling, to better understand the underlying spectral fine structure features for these complexes. These spectra and simulations provide an important platform for the application of MCD spectroscopy to this widely studied class of U(v) complexes and identify areas for continued theoretical development.

Pretreatment CT Perfusion (CTP) parameter rCBV < 42% lesion volume has recently been shown to predict 90-day mRS. In this study, we aim to assess the relationship between rCBV < 42% and a radiographic follow-up infarct volume delineated on FLAIR images. In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 9 January 2017 and 10 January 2023. Follow-up FLAIR imaging was used to determine the final infarct volume. Student t, Mann-Whitney-U, and Chi-Square tests were used to assess differences. Spearman’s rank correlation and linear regression analysis were used to assess associations between rCBV < 42% and follow-up infarct volume on FLAIR. In total, 158 patients (median age: 68 years, 52.5% female) met our inclusion criteria. rCBV < 42% (ρ = 0.56, p < 0.001) significantly correlated with follow-up-FLAIR infarct volume. On multivariable linear regression analysis, rCBV < 42% lesion volume (beta = 0.60, p < 0.001), ASPECTS (beta = −0.214, p < 0.01), mTICI (beta = −0.277, p < 0.001), and diabetes (beta = 0.16, p < 0.05) were independently associated with follow-up infarct volume. The rCBV < 42% lesion volume is independently associated with FLAIR follow-up infarct volume.