Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

OBJECTIVE: We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. METHODS: The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). RESULTS: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. INTERPRETATION: Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024.

Headpulse measurement can reliably identify large-vessel occlusion stroke in prehospital suspected stroke patients: Results from the EPISODE-PS-COVID study.

BACKGROUND: Large-vessel occlusion (LVO) stroke represents one-third of acute ischemic stroke (AIS) in the United States but causes two-thirds of poststroke dependence and >90% of poststroke mortality. Prehospital LVO stroke detection permits efficient emergency medical systems (EMS) transport to an endovascular thrombectomy (EVT)-capable center. Our primary objective was to determine the feasibility of using a cranial accelerometry (CA) headset device for prehospital LVO stroke detection. Our secondary objective was development of an algorithm capable of distinguishing LVO stroke from other conditions. METHODS: We prospectively enrolled consecutive adult patients suspected of acute stroke from 11 study hospitals in four different U.S. geographical regions over a 21-month period. Patients received device placement by prehospital EMS personnel. Headset data were matched with clinical data following informed consent. LVO stroke diagnosis was determined by medical chart review. The device was trained using device data and Los Angeles Motor Scale (LAMS) examination components. A binary threshold was selected for comparison of device performance to LAMS scores. RESULTS: A total of 594 subjects were enrolled, including 183 subjects who received the second-generation device. Usable data were captured in 158 patients (86.3%). Study subjects were 53% female and 56% Black/African American, with median age 69 years. Twenty-six (16.4%) patients had LVO and 132 (83.6%) were not LVO (not-LVO AIS, 33; intracerebral hemorrhage, nine; stroke mimics, 90). COVID-19 testing and positivity rates (10.6%) were not different between groups. We found a sensitivity of 38.5% and specificity of 82.7% for LAMS ≥ 4 in detecting LVO stroke versus a sensitivity of 84.6% (p < 0.0015 for superiority) and specificity of 82.6% (p = 0.81 for superiority) for the device algorithm (CA + LAMS). CONCLUSIONS: Obtaining adequate recordings with a CA headset is highly feasible in the prehospital environment. Use of the device algorithm incorporating both CA and LAMS data for LVO detection resulted in significantly higher sensitivity without reduced specificity when compared to the use of LAMS alone.

Alpha-7 Nicotinic Acetylcholine Receptor Activation Inhibits Trauma Induced Pronociceptive Autoimmune Responses.

Both autonomic nervous system dysfunction and immune system activation are characteristic of chronic pain after limb injuries. Cholinergic agonists reduce immune system activation in many settings. We hypothesized, therefore, that alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist administration would reduce nociceptive and immune changes after tibia fracture and cast immobilization in mice. Fracture mice were treated with either vehicle, a low (.2 mg/kg) dose, or a high (1 mg/kg) dose of the selective α7nAChR agonist PNU-282987 for 4 weeks. We assessed hindpaw allodynia and weight bearing as behavioral outcomes. The assessment of adaptive immune responses included regional lymph node hypertrophy, germinal center formation, α7nAChR expression, and IgM deposition. Assessment of innate immune system activation focused on IL-1ß and IL-6 generation in fractured hindlimb skin. We observed that mechanical allodynia and unweighting were alleviated by PNU-282987 treatment. Drug treatment also reduced popliteal lymph node hypertrophy and germinal center formation. Immunohistochemical studies localized α7nAChR to germinal center B lymphocytes, and this expression increased after fracture. Analysis of fracture limb hindpaw skin demonstrated increased inflammatory mediator (IL-1ß and IL-6) levels and IgM deposition, which were abrogated by PNU-282987. Serum analyses demonstrated fracture-induced IgM reactivity against keratin 16, histone 3.2, GFAP, and NMDAR-2B. Administration of PNU-282987 reduced the enhancement of IgM reactivity. Collectively, these data suggest that the α7nAChR is involved in regulating posttraumatic innate and adaptive immune responses and the associated nociceptive sensitization. PERSPECTIVE: These studies evaluate the effects of a selective α7nAChR agonist in a tibial fracture/cast immobilization model of limb pain. Administration of the drug reduced nociceptive and functional changes 4 weeks after injury. These novel findings suggest that well-tolerated α7nAChR agonists may be viable analgesics for chronic pain after limb injuries.

Large vessel occlusion prediction scale thresholds that are sensitive for DAWN Trial patients.

BACKGROUND: Large vessel occlusion (LVO) prediction scales are used to triage prehospital suspected stroke patients with a high probability of LVO stroke to endovascular therapy centers. The sensitivities of these scales in the 6-to-24-h time window are unknown. Higher scale score thresholds are typically less sensitive and more specific. Knowing the highest scale score thresholds that remain sensitive could inform threshold selection for clinical use. Sensitivities may also vary between left and right-sided LVOs. METHODS: LVO prediction scale scores were retrospectively calculated using the National Institutes of Health Stroke Scale (NIHSS) scores of patients enrolled in the DAWN Trial. All patients had last known well times between 6 and 24 h, NIHSS scores ≥ 10, intracranial internal carotid artery or proximal middle cerebral artery occlusions, and mismatches between their clinical severities and infarct core volumes. Scale thresholds with sensitivities ≥ 85% were identified, along with scores ≥ 5% more sensitive for left or right-sided LVOs. Specificities could not be calculated because all patients had LVOs. RESULTS: A total of 201 out of 206 patients had the required NIHSS subitem scores. CPSS = 3, C-STAT ≥ 2, FAST-ED ≥ 4, G-FAST ≥ 3, RACE ≥ 5, and SAVE ≥ 3 were the highest thresholds that were still 85% sensitive for DAWN Trial LVO stroke patients. RACE ≥ 5 was the only typically used score threshold more sensitive for right-sided LVOs, though similar small differences were seen for other scales at higher thresholds. CONCLUSIONS: Our findings likely represent the maximum sensitivities of the LVO prediction scales tested for ideal thrombectomy candidates in the 6-to-24-h time window because NIHSS scores were documented in hospitals during a clinical trial rather than in the prehospital setting. Patients with NIHSS scores < 10 or more distal LVOs would lower sensitivities further. Selecting even higher scale thresholds for LVO triage would lead to many missed LVO strokes.

Headpulse Biometric Measures Following Concussion in Young Adult Athletes.

Importance: Concussions are common in sports. Return-to-play protocols can be enhanced by objective biometrics. Objective: To characterize temporal changes of headpulse, a digital biometric, in athletes with sports-related concussion; to explore the association of unstructured physical activity with headpulse changes. Design, Setting, and Participants: This cohort study included headpulse measurements from players in the highest level of amateur Australian Rules Football in South Australia. Analysis included feasibility and validation phases, with the feasibility cohort recruited between August 5, 2021, and September 10, 2021, and the validation cohort recruited between May 5, 2022, and September 3, 2022. Data were analyzed October 2022 through January 2023. Interventions: Cranial accelerometry detected micromovements of the head following cardiac contraction (what we have described as "headpulse"). Headpulse was serially recorded for 1 month in concussed individuals. Main Outcomes and Measures: Headpulse waveforms underwent frequency transformation analysis per prespecified algorithm. Result Z scores were calculated. Headpulse Z scores exceeding 2 (2 SDs from control means) met an abnormality threshold. Headpulse sensitivity, timing, and duration of change were determined. Results: A total of 59 control and 43 concussed individuals (44 total concussions; 1 control also concussed, 1 concussed individual injured twice) provided headpulse measurements. The feasibility cohort (all male) included 17 control (median [IQR] age, 23 [19-28] years) and 15 concussed individuals (median [IQR] age, 21 [19-23] years). The validation cohort included 25 female (median [IQR] age, 21 [20-22] years) and 17 male (median [IQR] age, 26 [23-29] years) control individuals, and 8 female (median [IQR] age, 28 [20-31] years) and 20 male (median [IQR] age, 21 [19-23] years) concussed individuals. Headpulse reached abnormality threshold in 26 of 32 concussed individuals (81%; 9% on day 0, 50% by day 2, 90% by day 14). Headpulse alterations lasted 14 days longer than symptoms and were exacerbated by return-to-play or unsupervised physical activity. Conclusions and Relevance: In this study of 101 amateur Australian Rules Football athletes, the digital headpulse biometric was evaluated in 44 sports-related concussions. Compared with controls, new headpulse changes occurred after concussion; this objective metric may complement return-to-play protocols.

Microbiologically influenced corrosion-more than just microorganisms.

Microbiologically influenced corrosion (MIC) is a phenomenon of increasing concern that affects various materials and sectors of society. MIC describes the effects, often negative, that a material can experience due to the presence of microorganisms. Unfortunately, although several research groups and industrial actors worldwide have already addressed MIC, discussions are fragmented, while information sharing and willingness to reach out to other disciplines are limited. A truly interdisciplinary approach, which would be logical for this material/biology/chemistry-related challenge, is rarely taken. In this review, we highlight critical non-biological aspects of MIC that can sometimes be overlooked by microbiologists working on MIC but are highly relevant for an overall understanding of this phenomenon. Here, we identify gaps, methods, and approaches to help solve MIC-related challenges, with an emphasis on the MIC of metals. We also discuss the application of existing tools and approaches for managing MIC and propose ideas to promote an improved understanding of MIC. Furthermore, we highlight areas where the insights and expertise of microbiologists are needed to help progress this field.

A pharmacist-led penicillin allergy de-labelling project within a preoperative assessment clinic: the low-hanging fruit is within reach.

BACKGROUND: Having a false penicillin-allergy label is linked to longer hospital stays and to an increased risk of Clostridioides difficile and meticillin-resistant Staphylococcus aureus infection. AIM: To assess a penicillin-allergy de-labelling tool designed for use by the non-allergist. METHODS: Patients attending the surgical preoperative assessment clinic (POAC) at a large UK teaching hospital, who reported a penicillin allergy, were directly de-labelled by nursing or pharmacy staff, where appropriate. A penicillin-allergy de-labelling tool designed for use by the non-allergist was adapted and applied; nursing staff were provided with supporting information and education to enable removal of spurious labels. Antimicrobial pharmacists (AMPs) provided follow-up, cross-checked prophylactic antibiotics administered, interrogated clinical notes, and telephoned patients following their surgery, for details of any adverse reactions suffered. FINDINGS: A total of 163 patients reporting a penicillin allergy were identified for intervention. Twenty-nine (17.8%) patients reported a penicillin-allergy history appropriate for direct de-labelling, of whom eight (27.6%) declined to consent. The remaining 21 patients (12.8%) were directly de-labelled, with 12 (7.4%) patients consenting during their POAC appointment; the remaining nine (5.5%) patients were consented and de-labelled after their surgery by an AMP. CONCLUSION: The POAC was identified as an appropriate location and time-point in the patient pathway to enable the direct removal of spurious penicillin-allergy labels prior to surgery. Results suggest that this could be undertaken by nursing staff, although support from AMPs enabled a greater number of patients to be de-labelled.

A Survey on Monitoring and Management of Cerebral Vasospasm and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: The Mantra Study.

INTRODUCTION: Cerebral infarction from delayed cerebral ischemia (DCI) is a leading cause of poor neurological outcome after aneurysmal subarachnoid hemorrhage (aSAH). We performed an international clinical practice survey to identify monitoring and management strategies for cerebral vasospasm associated with DCI in aSAH patients requiring intensive care unit admission. METHODS: The survey questionnaire was available on the European Society of Intensive Care Medicine (May 2021-June 2022) and Neurocritical Care Society (April - June 2022) websites following endorsement by these societies. RESULTS: There were 292 respondents from 240 centers in 38 countries. In conscious aSAH patients or those able to tolerate an interruption of sedation, neurological examination was the most frequently used diagnostic modality to detect delayed neurological deficits related to DCI caused by cerebral vasospasm (278 respondents, 95.2%), while in unconscious patients transcranial Doppler/cerebral ultrasound was most frequently used modality (200, 68.5%). Computed tomography angiography was mostly used to confirm the presence of vasospasm as a cause of DCI. Nimodipine was administered for DCI prophylaxis by the majority of the respondents (257, 88%), mostly by an enteral route (206, 71.3%). If there was a significant reduction in arterial blood pressure after nimodipine administration, a vasopressor was added and nimodipine dosage unchanged (131, 45.6%) or reduced (122, 42.5%). Induced hypertension was used by 244 (85%) respondents as first-line management of DCI related to vasospasm; 168 (59.6%) respondents used an intra-arterial procedure as second-line therapy. CONCLUSIONS: This survey demonstrated variability in monitoring and management strategies for DCI related to vasospasm after aSAH. These findings may be helpful in promoting educational programs and future research.

Bayesian cluster analysis.

Bayesian cluster analysis offers substantial benefits over algorithmic approaches by providing not only point estimates but also uncertainty in the clustering structure and patterns within each cluster. An overview of Bayesian cluster analysis is provided, including both model-based and loss-based approaches, along with a discussion on the importance of the kernel or loss selected and prior specification. Advantages are demonstrated in an application to cluster cells and discover latent cell types in single-cell RNA sequencing data to study embryonic cellular development. Lastly, we focus on the ongoing debate between finite and infinite mixtures in a model-based approach and robustness to model misspecification. While much of the debate and asymptotic theory focuses on the marginal posterior of the number of clusters, we empirically show that quite a different behaviour is obtained when estimating the full clustering structure. This article is part of the theme issue 'Bayesian inference: challenges, perspectives, and prospects'.

End-Of-Life Care in the Potential Donor after Circulatory Death: A Systematic Review.

Background: Donation after circulatory death (DCD) is becoming increasingly common, yet little is known about the way potential donors receive end-of-life care. Purpose: The aims of this systematic review are to describe the current practice in end-of-life care for potential donors and identify metrics that are being used to assess discomfort among these patients. Research design and Study Sample: This review encompasses published literature between June 1, 2000 and June 31, 2020 of end-of-life care received by potential DCD patients. The population of interest was defined as patients eligible for Maastracht classification III donation after circulatory death for a solid organ transplantation. Outcomes examined included: analgesic or palliative protocols, and surrogates of discomfort (eg dyspnea, agitation). Results: Among 141 unique articles, 27 studies were included for full review. The primary reason for exclusion was lack of protocol description, or lack of reporting on analgesic medications. No primary research studies specifically examined distress in the DCD eligible population. Numerous professional guidelines were identified. Surveys of critical care practitioners identified concerns regarding the impact of symptom management on hastening the dying process in the DCD population as a potential barrier to end-of-life palliative treatment. Conclusions: There is a paucity of empirical evidence for end-of-life symptom assessment and management for DCD patients. Key evidence gaps identified for DCD include the need for: i) a multidisciplinary structure of treatment teams and preferred environment for DCD, ii) objective tools for monitoring of distress in this patient population, and iii) evidence guiding the administration of analgesic medications following withdrawal of life sustaining therapy.

Pronociceptive autoantibodies in the spinal cord mediate nociceptive sensitization, loss of function, and spontaneous pain in the lumbar disk puncture model of chronic back pain.

ABSTRACT: Previously, we observed that B cells and autoantibodies mediated chronic nociceptive sensitization in the mouse tibia fracture model of complex regional pain syndrome and that complex regional pain syndrome patient antibodies were pronociceptive in fracture mice lacking mature B cells and antibodies (muMT). The current study used a lumbar spinal disk puncture (DP) model of low back pain in wild-type (WT) and muMT mice to evaluate pronociceptive adaptive immune responses. Spinal disks and cords were collected 3 weeks after DP for polymerase chain reaction and immunohistochemistry analyses. Wild-type DP mice developed 24 weeks of hindpaw mechanical allodynia and hyperalgesia, grip weakness, and a conditioned place preference response indicative of spontaneous pain, but pain responses were attenuated or absent in muMT DP mice. Spinal cord expression of inflammatory cytokines, immune cell markers, and complement components were increased in WT DP mice and in muMT DP mice. Dorsal horn immunostaining in WT DP mice demonstrated glial activation and increased complement 5a receptor expressionin spinal neurons. Serum collected from WT DP mice and injected into muMT DP mice caused nociceptive sensitization, as did intrathecal injection of IgM collected from WT DP mice, and IgM immune complexes were observed in lumbar spinal disks and cord of WT DP mice. Serum from WT tibia fracture mice was not pronociceptive in muMT DP mice and vice versa, evidence that each type of tissue trauma chronically generates its own unique antibodies and targeted antigens. These data further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain state.

Large vessel occlusion prediction scales provide high negative but low positive predictive values in prehospital suspected stroke patients.

Introduction: We studied a registry of Emergency Medical Systems (EMS) identified prehospital suspected stroke patients brought to an academic endovascular capable hospital over 1 year to assess the prevalence of disease and externally validate large vessel occlusion (LVO) stroke prediction scales with a focus on predictive values. Methods: All patients had last known well times within 6 hours and a positive prehospital Cincinnati Prehospital Stroke Scale. LVO prediction scale scores were retrospectively calculated from emergency department arrival National Institutes of Health Stroke Scale scores. Final diagnoses were determined by chart review. Prevalence and diagnostic performance statistics were calculated. We prespecified analyses to identify scale thresholds with positive predictive values (PPVs) ≥80% and negative predictive values (NPVs) ≥95%. A secondary analysis identified thresholds with PPVs ≥50%. Results: Of 220 EMS transported patients, 13.6% had LVO stroke, 15.9% had intracranial haemorrhage, 20.5% had non-LVO stroke and 50% had stroke mimic diagnoses. LVO stroke prevalence was 15.8% among the 184 diagnostic performance study eligible patients. Only Field Assessment Stroke Triage for Emergency Destination (FAST-ED) ≥7 had a PPV ≥80%, but this threshold missed 83% of LVO strokes. FAST-ED ≥6, Prehospital Acute Severity Scale =3 and Rapid Arterial oCclusion Evaluation ≥7 had PPVs ≥50% but sensitivities were <50%. Several standard and lower alternative scale thresholds achieved NPVs ≥95%, but false positives were common. Conclusions: Diagnostic performance tradeoffs of LVO prediction scales limited their ability to achieve high PPVs without missing most LVO strokes. Multiple scales provided high NPV thresholds, but these were associated with many false positives.

HIV envelope antibodies and TLR7 agonist partially prevent viral rebound in chronically SHIV-infected monkeys.

A key challenge for the development of a cure to HIV-1 infection is the persistent viral reservoir established during early infection. Previous studies using Toll-like receptor 7 (TLR7) agonists and broadly neutralizing antibodies (bNAbs) have shown delay or prevention of viral rebound following antiretroviral therapy (ART) discontinuation in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques. In these prior studies, ART was initiated early during acute infection, which limited the size and diversity of the viral reservoir. Here we evaluated in SHIV-infected rhesus macaques that did not initiate ART until 1 year into chronic infection whether the TLR7 agonist vesatolimod in combination with the bNAb PGT121, formatted either as a human IgG1, an effector enhanced IgG1, or an anti-CD3 bispecific antibody, would delay or prevent viral rebound following ART discontinuation. We found that all 3 antibody formats in combination with vesatolimod were able to prevent viral rebound following ART discontinuation in a subset of animals. These data indicate that a TLR7 agonist combined with antibodies may be a promising strategy to achieve long-term ART-free HIV remission in humans.

From laboratory tests to field trials: a review of cathodic protection and microbially influenced corrosion.

Cathodic protection (CP), an electrochemical method for managing corrosion, is widely used in many industries in both marine and buried environments. However, literature surrounding cathodic protection and its ability to prevent microbially influenced corrosion (MIC) is mixed. This review describes the mechanics of CP, how CP may influence MIC, and collates and summarises tests on CP and MIC reported in literature. The aim of the review is to identify any trends and knowledge gaps requiring further study. While the outcomes of CP testing are generally mixed, some trends can be seen and, overall, MIC is detrimental to the protective effects of CP, with CP being less effective when used according to current international standards. Tests conducted in the field or with mix communities of microbes showed that CP could be effective at preventing MIC, while tests with sulfate-reducing bacteria generally proved CP to be highly ineffective. It was commonly seen that the effectiveness of CP can be improved by increasing polarization, to potentials as low as -1000 mV (Ag/AgCl). However, a balance does need to be met via careful monitoring to ensure negative side effects of over protection do not become a major problem.

The spectrum of hemophagocytic lymphohistiocytosis: a retrospective study comparing adult macrophage activation syndrome to malignancy-associated hemophagocytic lymphohistiocytosis.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening inflammatory syndrome that can be triggered by autoimmune diseases, malignancy, or infection. In rheumatologic patients, sHLH is referred to as macrophage activation syndrome (MAS). Differentiating between triggers is important for prompt treatment and prognosis. Data comparing subsets of sHLH are limited due to the rarity of this disease. We aim to explore differences in clinical features that may differentiate MAS from malignancy-associated HLH (mHLH) patients. We conducted a single-center retrospective study assessing clinical characteristics, laboratory parameters, treatment regimens and outcomes in 34 patients with sHLH over a 16 year period. We compared patients with MAS to those with mHLH. Hepatomegaly was not present in the MAS group but was present in the mHLH group (0 vs. 25%, p = 0.024). MAS patients had on average nearly double the concentration of platelets at 50.0 (IQR: 31.0-78.0 Kµ/L) vs. 29.0 Kµ/L (IQR: 14.0-37.5 Kµ/L), p = 0.003. Soluble IL-2R concentrations were four times lower in the MAS group with a median soluble IL-2R concentration of 6814.5 kU/L (IQR: 2101-2610 kU/L) vs. 27972.0 kU/L (IQR: 12,820-151,650 kU/L), p = 0.010. The MAS group fared better overall than the mHLH group but was not statistically significant (mortality 22 vs. 44%, p = 0.18). MAS and mHLH patients exhibited different laboratory parameters and clinical features, most notably differences in platelet counts, soluble IL-2R concentration and hepatomegaly, which may help differentiate these conditions early in their course.

Autonomic Regulation of Nociceptive and Immunologic Changes in a Mouse Model of Complex Regional Pain Syndrome.

Chronic pain frequently develops after limb injuries, and its pathogenesis is poorly understood. We explored the hypothesis that the autonomic nervous system regulates adaptive immune system activation and nociceptive sensitization in a mouse model of chronic post-traumatic pain with features of complex regional pain syndrome (CRPS). In studies sympathetic signaling was reduced using 6-hydroxydopamine (6-OHDA) or lofexidine, while parasympathetic signaling was augmented by nicotine administration. Hindpaw allodynia, unweighting, skin temperature, and edema were measured at 3 and 7 weeks after fracture. Hypertrophy of regional lymph nodes and IgM deposition in the skin of injured limbs were followed as indices of adaptive immune system activation. Passive transfer of serum from fracture mice to recipient B cell deficient (muMT) mice was used to assess the formation of pain-related autoantibodies. We observed that 6-OHDA or lofexidine reduced fracture-induced hindpaw nociceptive sensitization and unweighting. Nicotine had similar effects. These treatments also prevented IgM deposition, hypertrophy of popliteal lymph nodes, and the development of pronociceptive serum transfer effects. We conclude that inhibiting sympathetic or augmenting parasympathetic signaling inhibits pro-nociceptive immunological changes accompanying limb fracture. These translational results support the use of similar approaches in trials potentially alleviating persistent post-traumatic pain and, possibly, CRPS. PERSPECTIVE: Selective treatments aimed at autonomic nervous system modulation reduce fracture-related nociceptive and functional sequelae. The same treatment strategies limit pain-supporting immune system activation and the production of pro-nociceptive antibodies. Thus, the therapeutic regulation of autonomic activity after limb injury may reduce the incidence of chronic pain.

Collateral Circulation in Thrombectomy for Stroke After 6 to 24 Hours in the DAWN Trial.

BACKGROUND AND PURPOSE: Collaterals govern the pace and severity of cerebral ischemia, distinguishing fast or slow progressors and corresponding therapeutic opportunities. The fate of sustained collateral perfusion or collateral failure is poorly characterized. We evaluated the nature and impact of collaterals on outcomes in the late time window DAWN trial (Diffusion-Weighted Imaging or Computed Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo). METHODS: The DAWN Imaging Core Lab prospectively scored collateral grade on baseline computed tomography angiography (CTA; endovascular and control arms) and digital subtraction angiography (DSA; endovascular arm only), blinded to all other data. CTA collaterals were graded with the Tan scale and DSA collaterals were scored by ASITN grade (American Society of Interventional and Therapeutic Neuroradiology collateral score). Descriptive statistics characterized CTA collateral grade in all DAWN subjects and DSA collaterals in the endovascular arm. The relationship between collateral grade and day 90 outcomes were separately analyzed for each treatment arm. RESULTS: Collateral circulation to the ischemic territory was evaluated on CTA (n=144; median 2, 0-3) and DSA (n=57; median 2, 1-4) before thrombectomy in 161 DAWN subjects (mean age 69.8±13.6 years; 55.3% women; 91 endovascular therapy, 70 control). CTA revealed a broad range of collaterals (Tan grade 3, n=64 [44%]; 2, n=45 [31%]; 1, n=31 [22%]; 0, n=4 [3%]). DSA also showed a diverse range of collateral grades (ASITN grade 4, n=4; 3, n=22; 2, n=27; 1, n=4). Across treatment arms, baseline demographics, clinical variables except atrial fibrillation (41.6% endovascular versus 25.0% controls, P=0.04), and CTA collateral grades were balanced. Differences were seen across the 3 levels of collateral flow (good, fair, poor) for baseline National Institutes of Health Stroke Scale, blood glucose <150, diabetes, previous ischemic stroke, baseline and 24-hour core infarct volume, baseline and 24-hour Alberta Stroke Program Early CT Score, dramatic infarct progression, final Thrombolysis in Cerebral Infarction 2b+, and death. Collateral flow was a significant predictor of 90-day modified Rankin Scale score of 0 to 2 in the endovascular arm, with 43.7% (31/71) of subjects with good collaterals, 30.8% (16/52) of subjects with fair collaterals, and 17.7% (6/34) of subjects with poor collaterals reaching modified Rankin Scale score of 0 to 2 at 90 days (P=0.026). CONCLUSIONS: DAWN subjects enrolled at 6 to 24 hours after onset with limited infarct cores had a wide range of collateral grades on both CTA and DSA. Even in this late time window, better collaterals lead to slower stroke progression and better functional outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02142283.

High Taxonomic Diversity in Ship Bilges Presents Challenges for Monitoring Microbial Corrosion and Opportunity To Utilize Community Functional Profiling.

One of the key areas in which microbially influenced corrosion (MIC) has been found to be a problem is in the bilges of maritime vessels. To establish effective biological monitoring protocols, baseline knowledge of the temporal and spatial biological variation within bilges, as well as the effectiveness of different sampling methodologies, is critical. We used 16S rRNA gene metabarcoding of pelagic and sessile bacterial communities from ship bilges to assess the variation in bilge bacterial communities to determine how the inherent bilge diversity could guide or constrain biological monitoring. Bilge communities exhibited high levels of spatial and temporal variation, with >80% of the community able to be turned over in the space of 3 months, likely due to disturbance events such as cleaning and maintenance. Sessile and pelagic communities within a given bilge were also inherently distinct, with dominant exact sequence variants (ESVs) rarely shared between the two. Taxa containing KEGG orthologies (KOs) associated with dissimilatory sulfate reduction and biofilm production, functions typically associated with MIC, were generally more prevalent in sessile communities. Collectively, our findings indicate that neither bilge water nor an unaffected bilge from within the same vessel would constitute an appropriate reference community for MIC diagnosis. Optimal sampling locations and strategies that could be incorporated into a standardized method for monitoring bilge biology in relation to MIC were identified. Finally, taxonomic and functional comparisons of bilge diversity highlight the potential of functional approaches in future biological monitoring of MIC and MIC mitigation strategies in general. IMPORTANCE Microbially influenced corrosion (MIC) has been estimated to contribute 20 to 50% of the costs associated with corrosion globally. Diagnosis and monitoring of MIC are complex problems requiring knowledge of corrosion rates, corrosion morphology, and the associated microbiology to distinguish MIC from abiotic corrosion processes. Historically, biological monitoring of MIC utilized a priori knowledge to monitor sulfate-reducing bacteria; however, it is becoming widely accepted that a holistic or community-level understanding of corrosion-associated microbiology is needed for MIC diagnosis and monitoring. Before biology associated with MIC attack can be identified, standardized protocols for sampling and monitoring must be developed. The significance of our research is in contributing to the development of robust and repeatable sampling strategies of bilges, which are required for the development of standardized biological monitoring methods for MIC. We achieve this via a biodiversity survey of bilge communities and by comparing taxonomic and functional variation.

Serial ASPECTS in the DAWN Trial: Infarct Evolution and Clinical Impact.

Background and Purpose: The impact of baseline ischemia on Alberta Stroke Program Early CT Score (ASPECTS) and evolution over 24 hours may be distinct in late thrombectomy. We analyzed predictors of serial ASPECTS and clinical outcomes in the DAWN trial (Diffusion-Weighted Imaging or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo). Methods: The DAWN Imaging Core Laboratory independently scored ASPECTS at baseline and 24 hours. Descriptive statistics characterized ASPECTS on computed tomography/magnetic resonance imaging at baseline and 24 hours, delineating ASPECTS change over 24 hours. Results: 206 subjects (mean age 70.0±13.7 years; 54.9% (n=113) female; baseline National Institutes of Health Stroke Scale median (interquartile range) 17 (13, 21) were included. Baseline ASPECTS was median (interquartile range) 8.0 (7­8), with 92/205 (44.9%) between 0 and 7 and 113/205 (55.1%) 8 and 10. 24-hour ASPECTS was median 6.0 (4­8), with ASPECTS change or infarct evolution having median −1, ranging from −8 to +2. Multivariable logistic regression showed older age (odds ratio [OR] for 10-year interval, 1.26 [95% CI, 1.02­1.55], P=0.030) and dyslipidemia (OR, 1.84 [95% CI, 1.06­3.19], P=0.031) were independently associated with higher baseline ASPECTS. Higher 24-hour ASPECTS was predicted by endovascular treatment (OR, 2.76 [95% CI, 1.58­4.81], P=0.0004), baseline glucose <150 mg/dL (OR, 2.86 [95% CI, 1.50­5.46], P=0.001), lower baseline National Institutes of Health Stroke Scale (OR, 0.93 [95% CI, 0.89­0.98], P=0.010), and older age (OR for 10-year interval, 1.25 [95% CI, 1.01­1.55], P=0.041). Internal carotid artery lesion location (OR, 0.47 [95% CI, 0.24­0.89], P=0.021) was inversely related to 24-hour ASPECTS. Good clinical outcome (day 90 modified Rankin Scale score 0­2) was predicted by 24-hour ASPECTS (OR, 1.46 [95% CI, 1.08­1.96], P=0.014). Extensive infarct evolution (ASPECTS decrease ≥6) occurred in 14/201 (7.0%). Elevated baseline serum glucose ≥150 mg/dL was a predictor of ASPECTS decrease of ≥4 points (OR, 2.78 [95% CI, 1.21­6.35] P=0.016) as was internal carotid artery occlusion (OR, 2.49 [95% CI, 1.05­5.88]; P=0.038). ASPECTS change was influenced by treatment arm (P=0.001 by Wilcoxon), including 0 ASPECTS change in 42/105 (40.0%) of the endovascular arm and only 20/96 (20.8%) of the medical arm. Conclusions: DAWN subjects enrolled with small infarct cores had a broad range of baseline ASPECTS. Twenty-four-hour ASPECTS, strikingly influenced by endovascular therapy, predicted good clinical outcomes. Registration: https://www.clinicaltrials.gov; Unique identifier: NCT02142283.