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Pain is one of the many debilitating side effects of cancer. Now, Rohini Kuner and her colleagues show that blocking hematopoietic colony-stimulating factor signaling on neurons can inhibit pain caused by bone cancer. Pain is one of the most severe and debilitating symptoms associated with several forms of cancer 1 , 2 . Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves 2 . Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood 2 . Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells 3 and tumor cells 4 . Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) 3 are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo , potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve–specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.

Post-stroke infections may cause sepsis, which is associated with poor clinical outcome. Sepsis is defined by life-threatening organ dysfunction that can be identified using the Sequential Organ Failure Assessment (SOFA) score. The applicability of the SOFA score for patients not treated on an intensive care unit (ICU) is limited. The aim of this study was to develop and validate an easier-to-use modification of the SOFA score for stroke patients. Using a registry-based cohort of 212 patients with large vessel occlusion stroke and infection, potential predictors of a poor outcome indicating sepsis were assessed by logistic regression. The derived score was validated on a separate cohort of 391 patients with ischemic stroke and infection admitted to our hospital over a period of 1.5 years. The derived Stroke-SOFA (S-SOFA) score included the following predictors: National Institutes of Health stroke scale ≥ 14, peripheral oxygen saturation < 90%, mean arterial pressure < 70 mmHg, thrombocyte count < 150 10 /l and creatinine ≥ 1.2 mg/dl. The area under the receiver operating curve for the prediction of a poor outcome indicating sepsis was 0.713 [95% confidence interval: 0.665-0.762] for the S-SOFA score, which was comparable to the standard SOFA score (0.750 [0.703-0.798]), but the prespecified criteria for non-inferiority were not met (p = 0.115). However, the S-SOFA score was non-inferior compared to the SOFA score in non-ICU patients (p = 0.013). The derived S-SOFA score may be useful to identify non-ICU patients with stroke-associated sepsis who have a high risk of a poor outcome.

A variety of cancers are accompanied by debilitating pain, which constitutes the primary reason for poor quality of life in cancer patients. There is an urgent demand for the development of specific mechanism-based therapies against cancer pain. Recently, important advances have been made in mechanisms contributing to cancer pain. A notable finding was that the tumor-derived hematopoietic growth factors, granulocyte- and granulocyte-macrophage-colony-stimulating factors (G-CSF/GM-CSF), subserve important functions in the generation of pain hypersensitivity in tumor-affected regions. In this context, their receptors were unexpectedly found on pain-sensing nerves and were observed to be functionally linked to nociceptive sensitization and tumor-induced pain. Here, we review evidence supporting a role for G-/GM-CSF in sensitization of pain-sensing nerves, the underlying signaling pathways and the cross-talk with other pronociceptive cytokines, peptides and modulators derived from immune cells, osteoclasts and tumor cells. These findings hold implications in the therapy of pain in disease states, such as cancer and rheumatoid arthritis.

Objective Predicting long‐term functional outcomes shortly after a stroke is challenging, even for experienced neurologists. Therefore, we aimed to evaluate multiple machine learning models and the importance of clinical/radiological parameters to develop a model that balances minimal input data with reliable predictions of long‐term functional independency. Methods Our study utilized data from the German Stroke Registry on patients with large anterior vessel occlusion who underwent endovascular treatment. We trained seven machine learning models using 30 parameters from the first day postadmission to predict a modified Ranking Scale of 0–2 at 90 days poststroke. Model performance was assessed using a 20‐fold cross‐validation and one‐sided Wilcoxon rank‐sum tests. Key features were identified through backward feature selection. Results We included 7485 individuals with a median age of 75 years and a median NIHSS score at admission of 14 in our analysis. Our Deep Neural Network model demonstrated the best performance among all models including data from 24 h postadmission. Backward feature selection identified the seven most important features to be NIHSS after 24 h, age, modified Ranking Scale after 24 h, premorbid modified Ranking Scale, intracranial hemorrhage within 24 h, intravenous thrombolysis, and NIHSS at admission. Narrowing the Deep Neural Network model's input data to these features preserved the high performance with an AUC of 0.9 (CI: 0.89–0.91). Interpretation Our Deep Neural Network model, trained on over 7000 patients, predicts 90‐day functional independence using only seven clinical/radiological features from the first day postadmission, demonstrating both high accuracy and practicality for clinical implementation on stroke units.

Background: On-going pain is one of the most debilitating symptoms associated with a variety of chronic pain disorders. An understanding of mechanisms underlying on-going pain, i.e. stimulus-independent pain has been hampered so far by a lack of behavioural parameters which enable studying it in experimental animals. Ultrasound vocalizations (USVs) have been proposed to correlate with pain evoked by an acute activation of nociceptors. However, literature on the utility of USVs as an indicator of chronic pain is very controversial. A majority of these inconsistencies arise from parameters confounding behavioural experiments, which include novelty, fear and stress due to restrain, amongst others. Results: We have developed an improved assay which overcomes these confounding factors and enables studying USVs in freely moving mice repetitively over several weeks. Using this improved assay, we report here that USVs increase significantly in mice with bone metastases-induced cancer pain or neuropathic pain for several weeks, in comparison to sham-treated mice. Importantly, analgesic drugs which are known to alleviate tumour pain or neuropathic pain in human patients significantly reduce USVs as well as mechanical allodynia in corresponding mouse models. Conclusions: We show that studying USVs and mechanical allodynia in the same cohort of mice enables comparing the temporal progression of on-going pain (i.e. stimulus-independent pain) and stimulus-evoked pain in these clinically highly-relevant forms of chronic pain.

Purpose Endovascular treatment (ET) in patients with large vessel occlusion stroke (LVOS) with unknown onset or an extended time window can be safe and effective if patients are selected by defined clinical and imaging criteria; however, it is unclear if these criteria should also be applied to patients with unknown onset and unknown time last known well. In this study, we aimed to assess whether absent information on the time patients were last known to be well impacts outcome in patients with unknown onset LVOS. Methods We analyzed patients who were enrolled in the German Stroke Registry-Endovascular Treatment between 2015 and 2019. Patients with unknown onset and unknown time last known well (LKWu) were compared to patients with known onset (KO) and to patients with unknown onset but known time last known well (LKWk) regarding clinical and imaging baseline characteristics and outcome. Results Out of 5909 patients, 561 presented with LKWu (9.5%), 1849 with LKWk (31.3%) and 3499 with KO (59.2%). At 90 days, functional independency was less frequent in LKWu (27.0%) compared to KO (42.6%) and LKWk patients (31.8%). These differences were not significant after adjusting for confounders. A main confounder was the initial Alberta stroke program early CT score. Conclusion The LKWu patients had a similar outcome after ET as KO and LKWk patients after adjusting for confounders. Thus, ET should not be withheld if the time last known well is unknown. Instead, LKWu patients may be selected for ET using the same criteria as in LKWk patients.

Oral anticoagulation (OAC) is the mainstay of secondary prevention in ischemic stroke patients with atrial fibrillation (AF). However, in AF patients with large vessel occlusion stroke treated by endovascular therapy (ET) and acute carotid artery stenting (CAS), the optimal antithrombotic medication remains unclear. This is a subgroup analysis of the German Stroke Registry-Endovascular Treatment (GSR-ET), a prospective multicenter cohort of patients with large vessel occlusion stroke undergoing ET. Patients with AF and CAS during ET were included. We analyzed baseline and periprocedural characteristics, antithrombotic strategies and functional outcome at 90 days. Among 6635 patients in the registry, a total of 82 patients (1.2%, age 77.9 ± 8.0 years, 39% female) with AF and extracranial CAS during ET were included. Antithrombotic medication at admission, during ET, postprocedural and at discharge was highly variable and overall mortality in hospital (21%) and at 90 days (39%) was high. Among discharged patients (n = 65), most frequent antithrombotic regimes were dual antiplatelet therapy (DAPT, 37%), single APT + OAC (25%) and DAPT + OAC (20%). Comparing DAPT to single or dual APT + OAC, clinical characteristics at discharge were similar (median NIHSS 7.5 [interquartile range, 3-10.5] vs 7 [4-11], p = 0.73, mRS 4 [IQR 3-4] vs. 4 [IQR 3-5], p = 0.79), but 90-day mortality was higher without OAC (32 vs 4%, p = 0.02). In AF patients who underwent ET and CAS, 90-day mortality was higher in patients not receiving OAC. https://www. gov ; Unique identifier: NCT03356392.

Background and objectiveSmall vessel cerebrovascular disease (SVCD) can manifest with epileptic seizures and transient ischemic attacks (TIA). This study was designed to test if the extent and spatial distribution of SVCD differs in patients with focal impaired awareness seizures (FIAS) from patients with TIA.MethodsThis is a retrospective single-center case–control study of elderly patients at a high cardiovascular risk. 118 patients with FIAS (cases) were compared to a matched control group of 118 patients with TIA. The extent and spatial distribution of white matter hyperintensities (WMH) characteristic for SVCD and medial temporal lobe atrophy were analyzed on magnetic resonance imaging (MRI) obtained at admission. The Fazekas, Wahlund, and Scheltens scales were used for grading. Juxtacortical small lesions were analyzed separately.ResultsFIAS patients were observed to have more extensive WMH (p < 0.001) and more pronounced medial temporal lobe atrophy (p < 0.001) than TIA patients. WMH in FIAS patients were predominantly localized in supratentorial white matter compared to TIA patients (p < 0.001). Juxtacortical hyperintensities were far more common in FIAS patients than in TIA patients (80.5% vs. 22.0%; p < 0.001). Multivariate analysis revealed juxtacortical small lesions as strong independent predictor (OR, 95% CI 12.8, 6.7–24.3) and medial temporal lobe atrophy as further independent predictor of FIAS (3.1, 1.3–7.1).ConclusionsJuxtacortical small lesions and to a smaller extent medial temporal lobe atrophy are associated with epileptic seizures in elderly patients at a high cardiovascular risk. This observation may provide a structural explanation for epilepsy in SVCD. Juxtacortical small lesions in SVCD should be considered a structural cause for epilepsy and promote anticonvulsive therapy after a first seizure.

Patients suffering from strokes are at increased risk of developing post-stroke dementia. Serum anti-NMDA receptor autoantibodies (NMDAR1-abs) have been associated with unfavorable post-stroke outcomes. However, their effect on specific cognitive domains remains unclear. We used data from the prospective multicenter DZNE—mechanisms after stroke (DEMDAS) cohort, and measured NMDAR1-abs in serum at baseline. Cognitive function was assessed with a comprehensive neuropsychological test battery at 6- and 12-months follow-up. We employed crude and stepwise confounder adjusted linear and logistic regression models as well as generalized estimating equation models (GEE) to determine the relevance of NMDAR1-abs seropositivity on cognitive function after stroke. 10.2% (58/569) DEMDAS patients were NMDAR1-abs seropositive (IgM:n = 44/IgA:n = 21/IgG:n = 2). Seropositivity was not associated with global cognitive impairment after stroke. However, NMDAR1-abs seropositive patients performed lower in the memory domain (β adjusted  = −0.11; 95%CI = −0.57 to −0.03) and were at increased risk for memory impairment (OR adjusted  = 3.8; 95%CI = 1.33–10.82) compared to seronegative patients, 12 months after stroke. Further, NMDAR1-abs were linked to memory impairment over time in GEE from 6- to 12-months follow-up (OR adjusted  = 2.41; 95%CI = 1.05–5.49). Our data suggests that NMDAR1-abs contribute to memory dysfunction 1 year after stroke while not affecting other cognitive subdomains. Hence, antineuronal autoimmunity may be involved in distinct mechanisms of post-stroke memory impairment. Clinical trial name and registration number : The Determinants of Dementia After Stroke (DEMDAS; study identifier on clinical trials.gov: NCT01334749)

INTRODUCTION While incident ischemic lesions (IILs) are not unusual on follow‐up magnetic resonance imaging (MRI) following stroke, their risk factors and prognostic significance remain unknown. METHODS In a prospective multicenter study of 503 acute stroke patients, we assessed IILs on registered MRI images at baseline and 6 months, analyzing risk factors and clinical outcomes across 36 months. RESULTS At 6 months, 78 patients (15.5%) had IILs, mostly diffusion‐weighted imaging‐positive (72%) and clinically covert (91%). Older age and small vessel disease (SVD) lesions were baseline risk factors for IILs. IILs were associated with worse cognitive (beta for global cognition: −0.31, 95% confidence interval [CI]: −0.48 to −0.14) and functional outcomes (beta for modified Rankin scale [mRS]: 0.36, 95% CI: 0.14 to 0.58), and higher recurrent stroke risk (hazard ratio: 3.81, 95% CI: 1.35 to 10.69). IILs partially explained the relationship between SVD and poor cognition. DISCUSSION IILs are common and are associated with worse cognitive and functional outcomes and stroke recurrence risk. Assessing IILs following stroke might aid prognostication. Highlights Incident ischemic lesions (IILs) were assessed with registered baseline and 6‐month magnetic resonance imaging (MRI) scans in a stroke cohort. IILs 6 months after stroke are present in one‐sixth of patients and are mostly clinically silent. Small vessel disease burden is the main baseline risk factor for IILs. IILs are associated with cognitive and functional impairment and stroke recurrence. Assessing IILs by follow‐up MRI aids long‐term prognostication for stroke patients.