Decompressive craniectomy plus best medical treatment versus best medical treatment alone for spontaneous severe deep supratentorial intracerebral haemorrhage: a randomised controlled clinical trial.

BACKGROUND: It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. METHODS: In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. FINDINGS: SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. INTERPRETATION: SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.

Decision-Making for Preventive Interventions in Asymptomatic Patients.

The decision to treat an incidental finding in an asymptomatic patient results from careful risk-benefit consideration and is often challenging. One of the main aspects is after how many years the group who underwent the intervention and faced the immediate treatment complications will gain a treatment benefit over the conservatively managed group, which maintains a lower but ongoing risk. We identify a common error in decision-making. We illustrate how a risk-based approach using the classical break-even point at the Kaplan-Meier curves can be misleading and advocate for using an outcome-based approach, counting the cumulative number of lost quality-adjusted life years instead. In clinical practice, we often add together the yearly risk of the natural course up to the time point where the number equals the risk of the intervention and assume that the patient will benefit from an intervention beyond this point in time. It corresponds to the crossing of the Kaplan-Meier curves. However, because treatment-related poor outcome occurs at the time of the intervention, while the poor outcome in the conservative group occurs over a given time period, the true benefit of retaining more quality-adjusted life years in the interventional group emerges at a much later time. To avoid overtreatment of patients with asymptomatic diseases, decision-making should be outcome-based with counting the cumulative loss of quality-adjusted life years, rather than risk-based, comparing the interventional risk with the ongoing yearly risk of the natural course.

Relaxing the restricted structural dynamics in the human hepatitis B virus RNA encapsidation signal enables replication initiation in vitro.

Hepadnaviruses, including hepatitis B virus (HBV) as a major human pathogen, replicate their tiny 3 kb DNA genomes by capsid-internal protein-primed reverse transcription of a pregenomic (pg) RNA. Initiation requires productive binding of the viral polymerase, P protein, to a 5´ proximal bipartite stem-loop, the RNA encapsidation signal ε. Then a residue in the central ε bulge directs the covalent linkage of a complementary dNMP to a Tyr sidechain in P protein´s Terminal Protein (TP) domain. After elongation by two or three nucleotides (nt) the TP-linked DNA oligo is transferred to a 3´ proximal acceptor, enabling full-length minus-strand DNA synthesis. No direct structural data are available on hepadnaviral initiation complexes but their cell-free reconstitution with P protein and ε RNA (Dε) from duck HBV (DHBV) provided crucial mechanistic insights, including on a major conformational rearrangement in the apical Dε part. Analogous cell-free systems for human HBV led at most to P-ε binding but no detectable priming. Here we demonstrate that local relaxation of the highly basepaired ε upper stem, by mutation or via synthetic split RNAs, enables ε-dependent in vitro priming with full-length P protein from eukaryotic translation extract yet also, and without additional macromolecules, with truncated HBV miniP proteins expressed in bacteria. Using selective 2-hydroxyl acylation analyzed by primer extension (SHAPE) we confirm that upper stem destabilization correlates with in vitro priming competence and show that the supposed bulge-closing basepairs are largely unpaired even in wild-type ε. We define the two 3´ proximal nt of this extended bulge as main initiation sites and provide evidence for a Dε-like opening of the apical ε part upon P protein binding. Beyond new HBV-specific basic aspects our novel in vitro priming systems should facilitate the development of high-throughput screens for priming inhibitors targeting this highly virus-specific process.

Treatment outcome of IDH1/2 wildtype CNS WHO grade 4 glioma histologically diagnosed as WHO grade II or III astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH)1/2 wildtype (wt) astrocytomas formerly classified as WHO grade II or III have significantly shorter PFS and OS than IDH mutated WHO grade 2 and 3 gliomas leading to a classification as CNS WHO grade 4. It is the aim of this study to evaluate differences in the treatment-related clinical course of these tumors as they are largely unknown. METHODS: Patients undergoing surgery (between 2016-2019 in six neurosurgical departments) for a histologically diagnosed WHO grade 2-3 IDH1/2-wt astrocytoma were retrospectively reviewed to assess progression free survival (PFS), overall survival (OS), and prognostic factors. RESULTS: This multi-center study included 157 patients (mean age 58 years (20-87 years); with 36.9% females). The predominant histology was anaplastic astrocytoma WHO grade 3 (78.3%), followed by diffuse astrocytoma WHO grade 2 (21.7%). Gross total resection (GTR) was achieved in 37.6%, subtotal resection (STR) in 28.7%, and biopsy was performed in 33.8%. The median PFS (12.5 months) and OS (27.0 months) did not differ between WHO grades. Both, GTR and STR significantly increased PFS (P < 0.01) and OS (P < 0.001) compared to biopsy. Treatment according to Stupp protocol was not associated with longer OS or PFS compared to chemotherapy or radiotherapy alone. EGFR amplification (P = 0.014) and TERT-promotor mutation (P = 0.042) were associated with shortened OS. MGMT-promoter methylation had no influence on treatment response. CONCLUSIONS: WHO grade 2 and 3 IDH1/2 wt astrocytomas, treated according to the same treatment protocols, have a similar OS. Age, extent of resection, and strong EGFR expression were the most important treatment related prognostic factors.

Surgical closure of spinal cerebrospinal fluid leaks improves symptoms in patients with superficial siderosis.

BACKGROUND AND PURPOSE: Spinal cerebrospinal fluid (CSF) leaks may cause a myriad of symptoms, most common being orthostatic headache. In addition, ventral spinal CSF leaks are a possible etiology of superficial siderosis (SS), a rare condition characterized by hemosiderin deposits in the central nervous system (CNS). The classical presentation of SS involves ataxia, bilateral hearing loss, and myelopathy. Unfortunately, treatment options are scarce. This study was undertaken to evaluate whether microsurgical closure of CSF leaks can prevent further clinical deterioration or improve symptoms of SS. METHODS: This cohort study was conducted using data from a prospectively maintained database in two large spontaneous intracranial hypotension (SIH) referral centers in Germany and Switzerland of patients who meet the modified International Classification of Headache Disorders, 3rd edition criteria for SIH. Patients with spinal CSF leaks were screened for the presence of idiopathic infratentorial symmetric SS of the CNS. RESULTS: Twelve patients were included. The median latency between the onset of orthostatic headaches and symptoms attributed to SS was 9.5 years. After surgical closure of the underlying spinal CSF leak, symptoms attributed to SS improved in seven patients and remained stable in three. Patients who presented within 1 year after the onset of SS symptoms improved, but those who presented in 8-12 years did not improve. We could show a significant association between patients with spinal longitudinal extrathecal collections and SS. CONCLUSIONS: Long-standing untreated ventral spinal CSF leaks can lead to SS of the CNS, and microsurgical sealing of spinal CSF leaks might stop progression and improve symptoms in patients with SS in a time-dependent manner.

Diagnostic and therapeutic insights in individuals with persistent post-dural puncture headache: A cross-sectional study.

BACKGROUND: Post-dural puncture headache (PDPH) is a frequent complication following lumbar puncture, epidural analgesia, or neuraxial anesthesia. The International Classification of Headache Disorders, third edition categorizes PDPH as a self-limiting condition; however, emerging evidence, including our findings, suggests that PDPH can have a prolonged course, challenging this traditional view. OBJECTIVES: To elucidate the diagnostic characteristics and treatment outcomes of persistent PDPH (pPDPH), offering insights into its demographic profiles and diagnostic features. METHODS: We executed an anonymous, web-based survey targeting individuals aged ≥18 years diagnosed with or suspected of having pPDPH. Recruitment occurred through self-help groups on Facebook. The survey comprised questions regarding diagnostic procedures, treatment regimens, outcomes, and healthcare consultation. RESULTS: The survey achieved a response rate of 179/347 (51.6%) individuals completing the questionnaire. Cerebrospinal fluid (CSF) leaks were confirmed in nine of 179 (5.0%) cases. Signs of intracranial hypotension without a CSF leak were observed in 70/179 (39.1%) individuals. All participants underwent magnetic resonance imaging scans of the brain and spine, with computed tomography myelography performed in 113/179 (63.1%) cases. Medications, including analgesics, theophylline, and gabapentin, provided minimal short-term relief. Epidural blood patch treatments resulted in slight-to-moderate short-term improvement in 136/179 (76.0%), significant improvement in 22/179 (12.3%), and complete effectiveness in eight of 179 (4.5%) individuals. For long-term outcomes, slight-to-moderate improvement was reported by 118/179 (66.0%) individuals. Surgical interventions were carried out in 42/179 (23.5%) patients, revealing pseudomeningoceles intraoperatively in 20/42 (47.6%) individuals. After surgery, 21/42 (50.0%) of the participants experienced slight-to-moderate improvement, 12/42 (28.6%) showed more pronounced improvement, and five of the 42 (11.9%) achieved complete effectiveness. CONCLUSION: This study underscores the complexities of managing pPDPH. The delay in diagnosis can impact the effectiveness of treatments, including epidural blood patch and surgical interventions, resulting in ongoing symptoms. This underscores the importance of tailored and adaptable treatment strategies. The findings advocate for additional research to deepen the understanding of pPDPH and improve long-term patient outcomes.

Clinical severity of aneurysmal subarachnoid hemorrhage over time: systematic review.

The incidence of aneurysmal subarachnoid hemorrhage (aSAH) is well studied. Yet, little is known about the trend of aSAH severity. This systematic review aims to analyze the distribution of aSAH severity over time. We performed a systematic review of the literature according to the PRISMA-P guidelines. We included studies from January 1968 up to December 2022. Studies were included if they either reported the severity of aSAH as single increments of the corresponding 5-point scale or as a binary measure (good grade 1-3, poor grade 4-5) on the Hunt and Hess (HH) or World Federation of Neurosurgical Societies (WFNS) scale. Studies with fewer than 50 patients, (systematic) reviews, and studies including non-aSAH patients were excluded. A total of 2465 publications were identified, of which 214 met the inclusion and exclusion criteria. In total, 102,845 patients with an aSAH were included. Over the last five decades the number of good-grade HH (0.741 fold, p = 0.004) and WFNS (0.749 fold, p < 0.001) has decreased. Vice versa, an increase in number of poor grade HH (2.427 fold, p = 0.004), WFNS (2.289 fold, p < 0.001), as well as HH grade 5 (6.737 fold, p = 0.010), WFNS grade 4 (1.235 fold, p = 0.008) and WFNS grade 5 (8.322 fold, p = 0.031) was observed. This systematic review shows a worldwide 2-3 fold increase of poor grade aSAH patients and an 6-8 fold increase of grade 5 patients, over the last 50 years. Whether this evolution is due to more severe hemorrhage, improvements in neuro-intensive care and prehospital management, or to a change in grading behavior is unknown. This study strongly emphasizes the necessity for an improved grading system to differentiate grade 4 and grade 5 patients for meaningful clinical decision- making.

Quantification of cervical spinal stenosis by automated 3D MRI segmentation of spinal cord and cerebrospinal fluid space.

DESIGN: Prospective diagnostic study. OBJECTIVES: Anatomical evaluation and graduation of the severity of spinal stenosis is essential in degenerative cervical spine disease. In clinical practice, this is subjectively categorized on cervical MRI lacking an objective and reliable classification. We implemented a fully-automated quantification of spinal canal compromise through 3D T2-weighted MRI segmentation. SETTING: Medical Center - University of Freiburg, Germany. METHODS: Evaluation of 202 participants receiving 3D T2-weighted MRI of the cervical spine. Segments C2/3 to C6/7 were analyzed for spinal cord and cerebrospinal fluid space volume through a fully-automated segmentation based on a trained deep convolutional neural network. Spinal canal narrowing was characterized by relative values, across sever segments as adapted Maximal Canal Compromise (aMCC), and within the index segment as adapted Spinal Cord Occupation Ratio (aSCOR). Additionally, all segments were subjectively categorized by three observers as "no", "relative" or "absolute" stenosis. Computed scores were applied on the subjective categorization. RESULTS: 798 (79.0%) segments were subjectively categorized as "no" stenosis, 85 (8.4%) as "relative" stenosis, and 127 (12.6%) as "absolute" stenosis. The calculated scores revealed significant differences between each category (p ≤ 0.001). Youden's Index analysis of ROC curves revealed optimal cut-offs to distinguish between "no" and "relative" stenosis for aMCC = 1.18 and aSCOR = 36.9%, and between "relative" and "absolute" stenosis for aMCC = 1.54 and aSCOR = 49.3%. CONCLUSION: The presented fully-automated segmentation algorithm provides high diagnostic accuracy and objective classification of cervical spinal stenosis. The calculated cut-offs can be used for convenient radiological quantification of the severity of spinal canal compromise in clinical routine.

Conservation of the HBV RNA element epsilon in nackednaviruses reveals ancient origin of protein-primed reverse transcription.

Hepadnaviruses, with the human hepatitis B virus as prototype, are small, enveloped hepatotropic DNA viruses which replicate by reverse transcription of an RNA intermediate. Replication is initiated by a unique protein-priming mechanism whereby a hydroxy amino acid side chain of the terminal protein (TP) domain of the viral polymerase (P) is extended into a short DNA oligonucleotide, which subsequently serves as primer for first-strand synthesis. A key component in the priming of reverse transcription is the viral RNA element epsilon, which contains the replication origin and serves as a template for DNA primer synthesis. Here, we show that recently discovered non-enveloped fish viruses, termed nackednaviruses [C. Lauber et al., Cell Host Microbe 22, 387-399 (2017)], employ a fundamentally similar replication mechanism despite their huge phylogenetic distance and major differences in genome organization and viral lifestyle. In vitro cross-priming studies revealed that few strategic nucleotide substitutions in epsilon enable site-specific protein priming by heterologous P proteins, demonstrating that epsilon is functionally conserved since the two virus families diverged more than 400 Mya. In addition, other cis elements crucial for the hepadnavirus-typical replication of pregenomic RNA into relaxed circular double-stranded DNA were identified at conserved positions in the nackednavirus genomes. Hence, the replication mode of both hepadnaviruses and nackednaviruses was already established in their Paleozoic common ancestor, making it a truly ancient and evolutionary robust principle of genome replication that is more widespread than previously thought.

Complex intracranial aneurysms: a DELPHI study to define associated characteristics.

PURPOSE: Intracranial aneurysms present significant health risks, as their rupture leads to subarachnoid haemorrhage, which in turn has high morbidity and mortality rates. There are several elements affecting the complexity of an intracranial aneurysm. However, criteria for defining a complex intracranial aneurysm (CIA) in open surgery and endovascular treatment could differ, and actually there is no consensus on the definition of a "complex" aneurysm. This DELPHI study aims to assess consensus on variables defining a CIA. METHODS: An international panel of 50 members, representing various specialties, was recruited to define CIAs through a three-round Delphi process. The panelists participated in surveys with Likert scale responses and open-ended questions. Consensus criteria were established to determine CIA variables, and statistical analysis evaluated consensus and stability. RESULTS: In open surgery, CIAs were defined by fusiform or blister-like shape, dissecting aetiology, giant size (≥ 25 mm), broad neck encasing parent arteries, extensive neck surface, wall calcification, intraluminal thrombus, collateral branch from the sac, location (AICA, SCA, basilar), vasospasm context, and planned bypass (EC-IC or IC-IC). For endovascular treatment, CIAs included giant size, very wide neck (dome/neck ratio ≤ 1:1), and collateral branch from the sac. CONCLUSIONS: The definition of aneurysm complexity varies by treatment modality. Since elements related to complexity differ between open surgery and endovascular treatment, these consensus criteria of CIAs could even guide in selecting the best treatment approach.

Health-related quality of life, work ability and disability among individuals with persistent post-dural puncture headache.

BACKGROUND AND OBJECTIVES: Postdural puncture headache (PDPH) is an acknowledged consequence of procedures like lumbar punctures, epidural analgesia, and neurosurgical interventions. Persistence over more than three months, however has been poorly studied. In particular, little is known about the impact of persistent PDPH (pPDPH) on health related quality of life (HRQoL), disability and ability to work. The study aimed to provide a holistic understanding of pPDPH, encompassing medical, physical and psychological aspects. METHODS: We conducted a cross-sectional anonymous online survey in individuals aged 18 or older, diagnosed with, or suspected to have pPDPH via self-help groups on Facebook. Participants completed a structured questionnaire covering diagnosis, symptoms, and the ability to work. For assessing headache related disability, and mental health, they filled in the Henry Ford Hospital Headache Disability Inventory (HDI) and the Depression Anxiety Stress Scale-21 (DASS-21). RESULTS: A total of 179 participants (83.2% female, mean age 39.7 years) completed the survey. PPDPH had been present for one year or more in 74.3%, and 44.1% were unable to be in an upright position for more than one hour per day without having to lie down or sit down. Headaches were extremely severe or severe in 18% and 34%, respectively. According to the HDI, 31.8% of participants had mild, 25.7% moderate, and 42.5% severe disability. DASS-21 revealed substantial mental health challenges with depression, anxiety and stress experienced by 83%, 98%, and 88% of the respondents. The ability to work was limited considerably: 27.9% were unable to work, 59.8% worked part-time, 1.1% changed their job because of pPDPH, and only 11.2% were able to work full-time in their previous job. Despite treatment, the patients' condition had deteriorated in 32.4% and remained unchanged in 27.9%. CONCLUSION: This study stresses the burden of pPDPH in terms of substantial disability, limited quality of life, mental health concerns, and significant impact on the ability to work. The study highlights the long-term impact of pPDPH on individuals, emphasizing the need for timely diagnosis and effective treatment. It underscores the complexity of managing pPDPH and calls for further research into its long-term effects on patient health and HRQoL.

Multidisciplinary consensus guideline for the diagnosis and management of spontaneous intracranial hypotension.

BACKGROUND: We aimed to create a multidisciplinary consensus clinical guideline for best practice in the diagnosis, investigation and management of spontaneous intracranial hypotension (SIH) due to cerebrospinal fluid leak based on current evidence and consensus from a multidisciplinary specialist interest group (SIG). METHODS: A 29-member SIG was established, with members from neurology, neuroradiology, anaesthetics, neurosurgery and patient representatives. The scope and purpose of the guideline were agreed by the SIG by consensus. The SIG then developed guideline statements for a series of question topics using a modified Delphi process. This process was supported by a systematic literature review, surveys of patients and healthcare professionals and review by several international experts on SIH. RESULTS: SIH and its differential diagnoses should be considered in any patient presenting with orthostatic headache. First-line imaging should be MRI of the brain with contrast and the whole spine. First-line treatment is non-targeted epidural blood patch (EBP), which should be performed as early as possible. We provide criteria for performing myelography depending on the spine MRI result and response to EBP, and we outline principles of treatments. Recommendations for conservative management, symptomatic treatment of headache and management of complications of SIH are also provided. CONCLUSIONS: This multidisciplinary consensus clinical guideline has the potential to increase awareness of SIH among healthcare professionals, produce greater consistency in care, improve diagnostic accuracy, promote effective investigations and treatments and reduce disability attributable to SIH.

Recovery and long-term outcome after neurosurgical closure of spinal CSF leaks in patients with spontaneous intracranial hypotension.

INTRODUCTION: Spontaneous intracranial hypotension due to a spinal cerebrospinal fluid leak causes orthostatic headaches and impacts quality of life. Successful closure rates are often reported, whereas data on long-term outcome are still scarce. METHODS: Between April 2020 and December 2022 surgically treated patients completed the Headache Impact Test-6 prior to surgery and at 14 days, three months, six months, and 12 months postoperatively. In addition to the Headache Impact Test-6 score, we extracted data related to orthostatic symptoms. RESULTS: Eighty patients were included. Median Headache Impact Test-6 score preoperatively was 65 (IQR 61-69), indicating severe and disabling impact of headaches. At three months headache impact significantly improved to 49 (IQR 44-58) (p < 0.001) and remained stable up to 12 months (48, IQR 40-56), indicating little to no impact of headaches on quality of life. The need to lie down "always" or "very often" was reduced from 79% to 23% three months postoperatively (p < 0.001). CONCLUSIONS: Surgical closure of spinal CSF leaks significantly improves the impact of headaches in the long term. At least three months should be expected for recovery. Despite permanent closure of the CSF-leak, a quarter of patients still have relevant long-term impairment, indicating the need for further research on its cause and possible treatment.

Calcium modeling of spine apparatus-containing human dendritic spines demonstrates an "all-or-nothing" communication switch between the spine head and dendrite.

Dendritic spines are highly dynamic neuronal compartments that control the synaptic transmission between neurons. Spines form ultrastructural units, coupling synaptic contact sites to the dendritic shaft and often harbor a spine apparatus organelle, composed of smooth endoplasmic reticulum, which is responsible for calcium sequestration and release into the spine head and neck. The spine apparatus has recently been linked to synaptic plasticity in adult human cortical neurons. While the morphological heterogeneity of spines and their intracellular organization has been extensively demonstrated in animal models, the influence of spine apparatus organelles on critical signaling pathways, such as calcium-mediated dynamics, is less well known in human dendritic spines. In this study we used serial transmission electron microscopy to anatomically reconstruct nine human cortical spines in detail as a basis for modeling and simulation of the calcium dynamics between spine and dendrite. The anatomical study of reconstructed human dendritic spines revealed that the size of the postsynaptic density correlates with spine head volume and that the spine apparatus volume is proportional to the spine volume. Using a newly developed simulation pipeline, we have linked these findings to spine-to-dendrite calcium communication. While the absence of a spine apparatus, or the presence of a purely passive spine apparatus did not enable any of the reconstructed spines to relay a calcium signal to the dendritic shaft, the calcium-induced calcium release from this intracellular organelle allowed for finely tuned "all-or-nothing" spine-to-dendrite calcium coupling; controlled by spine morphology, neck plasticity, and ryanodine receptors. Our results suggest that spine apparatus organelles are strategically positioned in the neck of human dendritic spines and demonstrate their potential relevance to the maintenance and regulation of spine-to-dendrite calcium communication.

Photon-Counting Computed Tomography (PC-CT) of the spine: impact on diagnostic confidence and radiation dose.

OBJECTIVES: Computed tomography (CT) is employed to evaluate surgical outcome after spinal interventions. Here, we investigate the potential of multispectral photon-counting computed tomography (PC-CT) on image quality, diagnostic confidence, and radiation dose compared to an energy-integrating CT (EID-CT). METHODS: In this prospective study, 32 patients underwent PC-CT of the spine. Data was reconstructed in two ways: (1) standard bone kernel with 65-keV (PC-CTstd) and (2) 130-keV monoenergetic images (PC-CT130 keV). Prior EID-CT was available for 17 patients; for the remaining 15, an age-, sex-, and body mass index-matched EID-CT cohort was identified. Image quality (5-point Likert scales on overall, sharpness, artifacts, noise, diagnostic confidence) of PC-CTstd and EID-CT was assessed by four radiologists independently. If metallic implants were present (n = 10), PC-CTstd and PC-CT130 keV images were again assessed by 5-point Likert scales by the same radiologists. Hounsfield units (HU) were measured within metallic artifact and compared between PC-CTstd and PC-CT130 keV. Finally, the radiation dose (CTDIvol) was evaluated. RESULTS: Sharpness was rated significantly higher (p = 0.009) and noise significantly lower (p < 0.001) in PC-CTstd vs. EID-CT. In the subset of patients with metallic implants, reading scores for PC-CT130 keV revealed superior ratings vs. PC-CTstd for image quality, artifacts, noise, and diagnostic confidence (all p < 0.001) accompanied by a significant increase of HU values within the artifact (p < 0.001). Radiation dose was significantly lower for PC-CT vs. EID-CT (mean CTDIvol: 8.83 vs. 15.7 mGy; p < 0.001). CONCLUSIONS: PC-CT of the spine with high-kiloelectronvolt reconstructions provides sharper images, higher diagnostic confidence, and lower radiation dose in patients with metallic implants. KEY POINTS: • Compared to energy-integrating CT, photon-counting CT of the spine had significantly higher sharpness and lower image noise while radiation dose was reduced by 45%. • In patients with metallic implants, virtual monochromatic photon-counting images at 130 keV were superior to standard reconstruction at 65 keV in terms of image quality, artifacts, noise, and diagnostic confidence.

Cerebrospinal fluid biomarkers of superficial siderosis in patients with spontaneous intracranial hypotension.

BACKGROUND AND PURPOSE: Spontaneous intracranial hypotension (SIH) is an important etiology of infratentorial superficial siderosis (iSS) of the central nervous system. However, the prevalence of iSS amongst patients with SIH is unknown and the imaging findings of iSS might represent a late stage of disease. The aim was to identify cerebrospinal fluid (CSF) biomarkers of iSS in patients with SIH. METHODS: Consecutive patients evaluated for SIH at our institution between May 2017 and January 2019 were included. Lumbar CSF samples were analyzed for the presence of ferritin and bilirubin. Magnetic resonance imaging was assessed for the presence of iSS. RESULTS: Twenty-four patients with SIH were included. CSF samples were positive for bilirubin in 2/19 (10.5%). CSF ferritin was elevated in 7/23 (30.4%). Signs of iSS on imaging were present in four patients (16.7%). All patients with imaging signs of iSS demonstrated elevated CSF ferritin. Ferritin level was significantly higher amongst patients demonstrating iSS compared to those without (median 45.0 vs. 11.0 µg/l; p = 0.003). Symptom duration was longer in patients with iSS than in patients without iSS (median 40 months vs. 9 months, p = 0.018). CONCLUSION: Cerebrospinal fluid alterations indicative of iSS are prevalent amongst patients with SIH. It is speculated that a preclinical phase without symptoms or imaging signs but during which elevated biomarkers of the disease are apparent from CSF analysis might exist. It is suggested that measurement of CSF ferritin is incorporated in the work-up of patients with SIH to identify those at risk of developing iSS.

Automated signal intensity analysis of the spinal cord for detection of degenerative cervical myelopathy - a matched-pair MRI study.

PURPOSE: Detection of T2 hyperintensities in suspected degenerative cervical myelopathy (DCM) is done subjectively in clinical practice. To gain objective quantification for dedicated treatment, signal intensity analysis of the spinal cord is purposeful. We investigated fully automated quantification of the T2 signal intensity (T2-SI) of the spinal cord using a high-resolution MRI segmentation. METHODS: Matched-pair analysis of prospective acquired cervical 3D T2-weighted sequences of 114 symptomatic patients and 88 healthy volunteers. Cervical spinal cord was segmented automatically through a trained convolutional neuronal network with subsequent T2-SI registration slice-by-slice. Received T2-SI curves were subdivided for each cervical level from C2 to C7. Additionally, all levels were subjectively classified concerning a present T2 hyperintensity. For T2-positive levels, corresponding T2-SI curves were compared to curves of age-matched volunteers at the identical level. RESULTS: Forty-nine patients showed subjective T2 hyperintensities at any level. The corresponding T2-SI curves showed higher signal variabilities reflected by standard deviation (18.51 vs. 7.47 a.u.; p < 0.001) and range (56.09 vs. 24.34 a.u.; p < 0.001) compared to matched controls. Percentage of the range from the mean absolute T2-SI per cervical level, introduced as "T2 myelopathy index" (T2-MI), was correspondingly significantly higher in T2-positive segments (23.99% vs. 10.85%; p < 0.001). ROC analysis indicated excellent differentiation for all three parameters (AUC 0.865-0.920). CONCLUSION: This fully automated T2-SI quantification of the spinal cord revealed significantly increased signal variability for DCM patients compared to healthy volunteers. This innovative procedure and the applied parameters showed sufficient diagnostic accuracy, potentially diagnosing radiological DCM more objective to optimize treatment recommendation. TRIAL REGISTRATION: DRKS00012962 (17.01.2018) and DRKS00017351 (28.05.2019).

Desorption of plasmid DNA from anion exchangers: Salt concentration at elution is independent of plasmid size and load.

Detailed studies on the sorption behavior of plasmids on anion exchangers are rare compared to proteins. In this study, we systematically compare the elution behavior of plasmid DNA on three common anion exchange resins using linear gradient and isocratic elution experiments. Two plasmids of different lengths, 8 and 20 kbp, were studied and their elution characteristics were compared to a green fluorescent protein. Using established methods for determining retention characteristics of biomolecules in ion exchange chromatography lead to remarkable results. In contrast to the green fluorescent protein, plasmid DNA consistently elutes at one characteristic salt concentration in linear gradient elution. This salt concentration was the same independent of plasmid size but differed slightly for different resins. The behavior is consistent also at preparative loadings of plasmid DNA. Thus, only a single linear gradient elution experiment is sufficient to design elution in a process scale capture step. At isocratic elution conditions, plasmid DNA elutes only above this characteristic concentration. Even at slightly lower concentrations most plasmids remain tightly bound. We hypothesize, that the desorption is accompanied by a conformational change leading to a reduced number of available negative charges for binding. This explanation is supported by structural analysis before and after elution.

Defining activities in neurovascular microsurgery training: entrustable professional activities for vascular neurosurgery.

BACKGROUND: Entrustable professional activities (EPAs) represent an assessment framework with an increased focus on competency-based assessment. Originally developed and adopted for undergraduate medical education, concerns over resident ability to practice effectively after graduation have led to its implementation in residency training but yet not in vascular neurosurgery. Subjective assessment of resident or fellow performance can be problematic, and thus, we aim to define core EPAs for neurosurgical vascular training. METHODS: We used a nominal group technique in a multistep interaction between a team of experienced neurovascular specialists and a medical educator to identify relevant EPAs. Panel members provided feedback on the EPAs until they reached consent. RESULTS: The process produced seven core procedural EPAs for vascular residency and fellowship training, non-complex aneurysm surgery, complex aneurysm surgery, bypass surgery, arteriovenous malformation resection, spinal dural fistula surgery, perioperative management, and clinical decision-making. CONCLUSION: These seven EPAs for vascular neurosurgical training may support and guide the neurosurgical society in the development and implementation of EPAs as an evaluation tool and incorporate entrustment decisions in their training programs.

Stimulated Raman histology for histological evaluation of oral squamous cell carcinoma.

OBJECTIVES: To investigate whether in patients undergoing surgery for oral squamous cell carcinoma, stimulated Raman histology (SRH), in comparison with H&E-stained frozen sections, can provide accurate diagnoses regarding neoplastic tissue and sub-classification of non-neoplastic tissues. MATERIALS AND METHODS: SRH, a technology based on Raman scattering, was applied to generate digital histopathologic images of 80 tissue samples obtained from 8 oral squamous cell carcinoma (OSCC) patients. Conventional H&E-stained frozen sections were then obtained from all 80 samples. All images/sections (SRH and H&E) were analyzed for squamous cell carcinoma, normal mucosa, connective tissue, muscle tissue, adipose tissue, salivary gland tissue, lymphatic tissue, and inflammatory cells. Agreement between SRH and H&E was evaluated by calculating Cohen's kappa. Accuracy of SRH compared to H&E was quantified by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) as well as area under the receiver operating characteristic curve (AUC). RESULTS: Thirty-six of 80 samples were classified as OSCC by H&E-based diagnosis. Regarding the differentiation between neoplastic and non-neoplastic tissue, high agreement between H&E and SRH (kappa: 0.880) and high accuracy of SRH (sensitivity: 100%; specificity: 90.91%; PPV: 90.00%, NPV: 100%; AUC: 0.954) were demonstrated. For sub-classification of non-neoplastic tissues, SRH performance was dependent on the type of tissue, with high agreement and accuracy for normal mucosa, muscle tissue, and salivary glands. CONCLUSION: SRH provides high accuracy in discriminating neoplastic and non-neoplastic tissues. Regarding sub-classification of non-neoplastic tissues in OSCC patients, accuracy varies depending on the type of tissue examined. CLINICAL RELEVANCE: This study demonstrates the potential of SRH for intraoperative imaging of fresh, unprocessed tissue specimens from OSCC patients without the need for sectioning or staining.