Correlative multiphoton-STED microscopy of podocyte calcium levels and slit diaphragm ultrastructure in the renal glomerulus.

In recent years functional multiphoton (MP) imaging of vital mouse tissues and stimulation emission depletion (STED) imaging of optically cleared tissues allowed new insights into kidney biology. Here, we present a novel workflow where MP imaging of calcium signals can be combined with super-resolved STED imaging for morphological analysis of the slit diaphragm (SD) within the same glomerulus. Mice expressing the calcium indicator GCaMP3 in podocytes served as healthy controls or were challenged with two different doses of nephrotoxic serum (NTS). NTS induced glomerular damage in a dose dependent manner measured by shortening of SD length. In acute kidney slices (AKS) intracellular calcium levels increased upon disease but showed a high variation between glomeruli. We could not find a clear correlation between intracellular calcium levels and SD length in the same glomerulus. Remarkably, analysis of the SD morphology of glomeruli selected during MP calcium imaging revealed a higher percentage of completely disrupted SD architecture than estimated by STED imaging alone. Our novel co-imaging protocol is applicable to a broad range of research questions. It can be used with different tissues and is compatible with diverse reporters and target proteins.

Aversive contexts enhance defensive responses to conditioned threat.

The ability to flexibly transition between defensive states is crucial for adaptive responding in life-threatening situations. Potentially threatening situations typically induce a sustained feeling of apprehension in association with hypervigilance, while acute threat is usually characterized by an intense and transient response to cope with the imminent danger. While potential and acute threat states have traditionally been viewed as mutually exclusive, this distinction is being challenged by a growing body of evidence suggesting a more complex interplay during simultaneous activation of these states. However, the interaction between potential and acute threat on a psychophysiological level remains elusive. To fill this gap, 94 healthy individuals participated in one of two contextual fear-conditioning paradigms. In both paradigms, a differential fear-learning phase was conducted, followed by a test phase in which the conditioned stimuli were presented in front of either conditioned or inherently aversive contextual images compared to neutral contexts. To capture defensive responses, we recorded subjective (threat and expectancy ratings) and physiological (electrodermal and cardiovascular) activity to the conditioned stimuli as a function of contextual threat. Besides indices of successful fear conditioning, our results revealed stronger threat and unconditioned stimulus expectancy ratings, cardiac deceleration, and skin conductance responses for threat and safety cues presented in inherently aversive compared to neutral contexts. Conditioned contexts had less impact on physiological responses to threat and safety cues than inherently aversive contexts. These findings provide new insights into the additive nature of defensive responses to fear cues and situations of contextual threat.

A fully synthetic three-dimensional human cerebrovascular model based on histological characteristics to investigate the hemodynamic fingerprint of the layer BOLD fMRI signal formation.

Recent advances in functional magnetic resonance imaging (fMRI) at ultra-high field (≥7 tesla), novel hardware, and data analysis methods have enabled detailed research on neurovascular function, such as cortical layer-specific activity, in both human and nonhuman species. A widely used fMRI technique relies on the blood oxygen level-dependent (BOLD) signal. BOLD fMRI offers insights into brain function by measuring local changes in cerebral blood volume, cerebral blood flow, and oxygen metabolism induced by increased neuronal activity. Despite its potential, interpreting BOLD fMRI data is challenging as it is only an indirect measurement of neuronal activity. Computational modeling can help interpret BOLD data by simulating the BOLD signal formation. Current developments have focused on realistic 3D vascular models based on rodent data to understand the spatial and temporal BOLD characteristics. While such rodent-based vascular models highlight the impact of the angioarchitecture on the BOLD signal amplitude, anatomical differences between the rodent and human vasculature necessitate the development of human-specific models. Therefore, a computational framework integrating human cortical vasculature, hemodynamic changes, and biophysical properties is essential. Here, we present a novel computational approach: a three-dimensional VAscular MOdel based on Statistics (3D VAMOS), enabling the investigation of the hemodynamic fingerprint of the BOLD signal within a model encompassing a fully synthetic human 3D cortical vasculature and hemodynamics. Our algorithm generates microvascular and macrovascular architectures based on morphological and topological features from the literature on human cortical vasculature. By simulating specific oxygen saturation states and biophysical interactions, our framework characterizes the intravascular and extravascular signal contributions across cortical depth and voxel-wise levels for gradient-echo and spin-echo readouts. Thereby, the 3D VAMOS computational framework demonstrates that using human characteristics significantly affects the BOLD fingerprint, making it an essential step in understanding the fundamental underpinnings of layer-specific fMRI experiments.

Complete genome sequence of a Pseudomonas fluorescens bacteriophage UNO-G1W1 isolated from freshwater ice in Nebraska.

We provide the complete genome sequence for a novel Pseudomonas fluorescens bacteriophage named UNO-G1W1. This phage was isolated from a single ice cover sampling. The genome was sequenced on the Nanopore MinION, generated with the direct terminal repeat-phage-pipeline and polished with Illumina short reads. Sequence identity classifies the phage as an otagovirus.

Uncertainty quantification in computed tomography pulmonary angiography.

Computed tomography (CT) imaging of the thorax is widely used for the detection and monitoring of pulmonary embolism (PE). However, CT images can contain artifacts due to the acquisition or the processes involved in image reconstruction. Radiologists often have to distinguish between such artifacts and actual PEs. We provide a proof of concept in the form of a scalable hypothesis testing method for CT, to enable quantifying uncertainty of possible PEs. In particular, we introduce a Bayesian Framework to quantify the uncertainty of an observed compact structure that can be identified as a PE. We assess the ability of the method to operate under high-noise environments and with insufficient data.

Interrater Agreement of Height Assessment by Rigid Proctoscopy/ Rectoscopy for Rectal Carcinoma.

BACKGROUND: Some guidelines for rectal carcinoma consider 12 cm, measured by rigid endoscopy to be the cutoff tumor height for optional neoadjuvant chemoradiation. Measuring differences of only a few centimeters may therefore predetermine choice of further therapy. However, rigid endoscopy may exhibit similar operator dependence as do most other clinical examination methods. OBJECTIVES: Evaluation of concordance of rigid rectoscopic tumor height measurements performed by 4 experienced examiners, 2 in lithotomy and 2 in left lateral position. Assessment of tumor palpability and distance of the anal verge to the anocutaneous line were also evaluated. DESIGN: Prospective observational study. SETTING: Academic teaching hospital, referral center for colorectal surgery. PATIENTS: There were 50 patients, of whom were 35 males (70%). The median age was 72.5 years (53-88 years). MAIN OUTCOME MEASURES: Interrater agreement of tumor height assessment and tumor allocation beneath or beyond the 12-cm height limit. RESULTS: With an intraclass correlation coefficient of 0.947 (95% CI: 0.918-0.967, p < 0.001), interrater reliability of tumor height assessment was statistically rated "excellent." Despite this, in 26% of patients, there was no agreement regarding the allocation of the tumor beneath or beyond the 12-cm height limit. Furthermore there was also considerable disagreement concerning tumor palpability and the distance of the anal verge to the anocutaneous line. Patient positioning was not found to influence results. LIMITATIONS: Single center study. CONCLUSIONS: Rigid rectal endoscopy may not be a sound pivotal basis for the consideration of optional chemoradiation in rectal carcinoma. Application of a universally valid height limit obviously ignores biological variability in body frame, gender, and acquired pelvic descent. Eligibility for neoadjuvant therapy should not rely on height measurements alone. Uniform MRI or CT imaging protocols, based on agreed terminology, including factors such as tumor height relative to pelvic frame and peritoneal reflection, may be an important diagnostic addition for such decision. See Video Abstract . CLINICAL TRIAL REGISTRATION: DRKS00012758 (German National Study Registry), ST-D 406 (German Cancer Society).

Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies.

The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

Pathophysiology, Diagnosis, Prognosis, and Prevention of Poststroke Epilepsy: Clinical and Research Implications.

Poststroke epilepsy (PSE) is associated with higher mortality and poor functional and cognitive outcomes in patients with stroke. With the remarkable development of acute stroke treatment, there is a growing number of survivors with PSE. Although approximately 10% of patients with stroke develop PSE, given the significant burden of stroke worldwide, PSE is a significant problem in stroke survivors. Therefore, the attention of health policymakers and significant funding are required to promote PSE prevention research. The current PSE definition includes unprovoked seizures occurring more than 7 days after stroke onset, given the high recurrence risks of seizures. However, the pathologic cascade of stroke is not uniform, indicating the need for a tissue-based approach rather than a time-based one to distinguish early seizures from late seizures. EEG is a commonly used tool in the diagnostic work-up of PSE. EEG findings during the acute phase of stroke can potentially stratify the risk of subsequent seizures and predict the development of poststroke epileptogenesis. Recent reports suggest that cortical superficial siderosis, which may be involved in epileptogenesis, is a promising marker for PSE. By incorporating such markers, future risk-scoring models could guide treatment strategies, particularly for the primary prophylaxis of PSE. To date, drugs that prevent poststroke epileptogenesis are lacking. The primary challenge involves the substantial cost burden due to the difficulty of reliably enrolling patients who develop PSE. There is, therefore, a critical need to determine reliable biomarkers for PSE. The goal is to be able to use them for trial enrichment and as a surrogate outcome measure for epileptogenesis. Moreover, seizure prophylaxis is essential to prevent functional and cognitive decline in stroke survivors. Further elucidation of factors that contribute to poststroke epileptogenesis is eagerly awaited. Meanwhile, the regimen of antiseizure medications should be based on individual cardiovascular risk, psychosomatic comorbidities, and concomitant medications. This review summarizes the current understanding of poststroke epileptogenesis, its risks, prognostic models, prophylaxis, and strategies for secondary prevention of seizures and suggests strategies to advance research on PSE.

Development of the entrustable professional activity 'medication reconciliation' for clinical pharmacy.

BACKGROUND: Entrustable professional activities (EPAs) are observable process descriptions of clinical work units. EPAs support learners and tutors in assessment within healthcare settings. For use amongst our pharmacy students as well as pre-registration pharmacists we wanted to develop and validate an EPA for use in a clinical pharmacy setting at LMU University Hospital. METHODS: The development of the clinical pharmacy EPA followed a set pathway. A rapid literature review informed the first draft, an interprofessional consensus group consisting of pharmacists, nurses, and medical doctors refined this draft. The refined version was then validated via online survey utilising clinical pharmacists from Germany. RESULTS: We designed, refined and validated an EPA regarding medication reconciliation for assessment of pharmacy students and trainees within the pharmacy department at LMU University Hospital in Munich. Along with the EPA description an associated checklist to support the entrustment decision was created. For validation an online survey with 27 clinical pharmacists from all over Germany was conducted. Quality testing with the EQual rubric showed a good EPA quality. CONCLUSIONS: We developed the first clinical pharmacy EPA for use in a German context. Medication reconciliation is a suitable EPA candidate as it describes a clinical activity performed by pharmacists in many clinical settings. The newly developed and validated EPA 'Medication Reconciliation' will be used to assess pharmacy students and trainees.

Biomechanical Performance of Transtibial Pull-Out Posterior Horn Medial Meniscus Root Repair Is Improved With Knotless Adjustable Suture Anchor-Based Fixation.

Background: While posterior medial meniscus root (PMMR) techniques have evolved, there remains a need to both optimize repair strength and improve resistance to cyclic loading. Hypothesis: Adjustable tensioning would lead to higher initial repair strength and reduce displacement with cyclic loading compared with previously described transtibial pull-out repair (TPOR) fixation techniques. Study Design: Controlled laboratory study. Methods: A total of 56 porcine medial menisci were used. Eight intact specimens served as a control for the native meniscus. For the others, PMMR tears were created and repaired with 6 different TPOR techniques (8 in each group). Fixed PMMR repairs were executed using 4 different suture techniques (two No. 2 cinch sutures, two cinch tapes, two No. 2 simple sutures, and two No. 2 sutures in a Mason-Allen configuration) all tied over a cortical button. Adjustable PMMR repairs using Mason-Allen sutures were fixed with an adjustable soft tissue anchor fixation tensioned at either 80 N or 120 N. The initial force, stiffness, and relief displacement of the repairs were measured after fixation. Repair constructs were then cyclically loaded, with cyclic displacement and stiffness measured after 1000 cycles. Finally, the specimens were pulled to failure. Results: The PMMR repaired with the 2 cinch sutures fixed technique afforded the lowest (P < .001) initial repair load, stiffness, and relief displacement. The adjustable PMMR repairs achieved a higher initial repair load (P < .001) and relief displacement (P < .001) than all fixed repairs. The 2 cinch sutures fixed technique showed an overall higher cyclic displacement (P < .028) and was completely loose compared with the native meniscus functional zone. Repairs with adjustable intratunnel fixation showed displacement with cyclic loading similar to the native meniscus. With cyclic loading, the Mason-Allen adjustable repair with 120 N of tension showed less displacement (P < .016) than all fixed repairs and a stiffness comparable to the fixed Mason-Allen repair. The fixed Mason-Allen technique demonstrated a higher ultimate load (P < .007) than the adjustable Mason-Allen techniques. All repairs were less stiff, with lower ultimate failure loads, than the native meniscus root attachment (P < .0001). Conclusion: Adjustable TPOR led to considerably higher initial repair load and relief displacement than other conventional fixed repairs and restricted cyclic displacement to match the native meniscus function. However, the ultimate failure load of the adjustable devices was lower than that of a Mason-Allen construct tied over a cortical button. All repair techniques had a significantly lower load to failure than the native meniscus root. Clinical Relevance: Knotless adjustable PMMR repair based on soft anchor fixation results in higher tissue compression and less displacement, but the overall clinical significance on healing rates remains unclear.

Riboswitch-controlled IL-12 gene therapy reduces hepatocellular cancer in mice.

Hepatocellular carcinoma (HCC) and solid cancers with liver metastases are indications with high unmet medical need. Interleukin-12 (IL-12) is a proinflammatory cytokine with substantial anti-tumor properties, but its therapeutic potential has not been realized due to severe toxicity. Here, we show that orthotopic liver tumors in mice can be treated by targeting hepatocytes via systemic delivery of adeno-associated virus (AAV) vectors carrying the murine IL-12 gene. Controlled cytokine production was achieved in vivo by using the tetracycline-inducible K19 riboswitch. AAV-mediated expression of IL-12 led to STAT4 phosphorylation, interferon-γ (IFNγ) production, infiltration of T cells and, ultimately, tumor regression. By detailed analyses of efficacy and tolerability in healthy and tumor-bearing animals, we could define a safe and efficacious vector dose. As a potential clinical candidate, we characterized vectors carrying the human IL-12 (huIL-12) gene. In mice, bioactive human IL-12 was expressed in a vector dose-dependent manner and could be induced by tetracycline, suggesting tissue-specific AAV vectors with riboswitch-controlled expression of highly potent proinflammatory cytokines as an attractive approach for vector-based cancer immunotherapy.

Human brain clearance imaging: Pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood.

Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the "EU Joint Programme - Neurodegenerative Disease Research (JPND)" consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration-time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF.

Naming fMRI-guided white matter language tract volumes influence naming decline after temporal lobe resection.

OBJECTIVE: The aim of this study was to explore the relation of language functional MRI (fMRI)-guided tractography with postsurgical naming decline in people with temporal lobe epilepsy (TLE). METHODS: Twenty patients with unilateral TLE (9 left) were studied with auditory and picture naming functional MRI tasks. Activation maxima in the left posterobasal temporal lobe were used as seed regions for whole-brain fibre tractography. Clinical naming performance was assessed preoperatively, 4 months, and 12 months following temporal lobe resection. Volumes of white matter language tracts in both hemispheres as well as tract volume laterality indices were explored as moderators of postoperative naming decline using Pearson correlations and multiple linear regression with other clinical variables. RESULTS: Larger volumes of white matter language tracts derived from auditory and picture naming maxima in the hemisphere of subsequent surgery as well as stronger lateralization of picture naming tract volumes to the side of surgery correlated with greater language decline, which was independent of fMRI lateralization status. Multiple regression for picture naming tract volumes was associated with a significant decline of naming function with 100% sensitivity and 93% specificity at both short-term and long-term follow-up. INTERPRETATION: Naming fMRI-guided white matter language tract volumes relate to postoperative naming decline after temporal lobe resection in people with TLE. This can assist stratification of surgical outcome and minimize risk of postoperative language deficits in TLE.

Influence of arterial transit time delays on the differentiation between tumor progression and pseudoprogression in glioblastoma by arterial spin labeling magnetic resonance imaging.

Arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) have shown potential for differentiating tumor progression from pseudoprogression. For pseudocontinuous ASL with a single postlabeling delay, the presence of delayed arterial transit times (ATTs) could affect the evaluation of ASL-MRI perfusion data. In this study, the influence of ATT artifacts on the perfusion assessment and differentiation between tumor progression and pseudoprogression were studied. This study comprised 66 adult patients (mean age 60 ± 13 years; 40 males) with a histologically confirmed glioblastoma who received postoperative radio (chemo)therapy. ASL-MRI and DSC-MRI scans were acquired at 3 months postradiotherapy as part of the standard clinical routine. These scans were visually scored regarding (i) the severity of ATT artifacts (%) on the ASL-MRI scans only, scored by two neuroradiologists; (ii) perfusion of the enhancing tumor lesion; and (iii) radiological evaluation of tumor progression versus pseudoprogression by one neuroradiologist. The final outcome was based on combined clinical and radiological follow-up until 9 months postradiotherapy. ATT artifacts were identified in all patients based on the mean scores of two raters. A significant difference between the radiological evaluation of ASL-MRI and DSC-MRI was observed only for ASL images with moderate ATT severity (30%-65%). The perfusion assessment showed ASL-MRI tending more towards hyperperfusion than DSC-MRI in the case of moderate ATT artifacts. In addition, there was a significant difference between the prediction of tumor progression with ASL-MRI and the final outcome in the case of severe ATT artifacts (McNemar test, p = 0.041). Despite using ASL imaging parameters close to the recommended settings, ATT artifacts frequently occur in patients with treated brain tumors. Those artifacts could hinder the radiological evaluation of ASL-MRI data and the detection of true disease progression, potentially affecting treatment decisions for patients with glioblastoma.

Serum and cerebrospinal fluid neurofilament light chain and glial fibrillary acid protein levels in early and advanced stages of cerebral amyloid Angiopathy.

BACKGROUND: Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking. We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA. METHODS: For this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aß40 and Aß42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups. RESULTS: We included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years). In presymptomatic D-CAA, only GFAP in CSF (7.7*103pg/mL vs. 4.4*103pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*102pg/mL vs. 7.8*102pg/mL; P=0.01 and GFAP:11.4*103pg/mL vs. 7.5*103pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*102pg/mL vs 7.8*102pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aß42 levels (P=0.01/0.02). CONCLUSIONS: GFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA.

40-Year Outcome of Old-School, Non-Surgical Endodontic Treatment: Practice-Based Retrospective Evaluation.

(1) Background: Non-surgical endodontic treatment has been shown to be clinically successful; however, clinical long-term data are scarce. This practice-based retrospective clinical investigation evaluated endodontic outcomes over 40 years and identified relevant clinical co-factors. (2) Methods: Two experienced dental practitioners in two different private dental practices treated 174 patients with 245 teeth from 1969 to 1993. After root canal obturation, either a new direct restoration (amalgam, resin composite, or glass-ionomer cement) or the re-cementation of a pre-existing prosthetic restoration or renewal of prosthetic restoration followed. Metal posts (operator A) or metal screws (operator B) were inserted when coronal substance loss was significant. The primary outcome (i.e., tooth survival) was achieved when the endodontically treated tooth was, in situ, painless and had full function at the end of the observation period. A secondary outcome, the impact of different prognostic factors on survival rate, was evaluated. (3) Results: The overall mean survival was 56.1% of all treated teeth after 40 years of clinical service, resulting in an annual failure rate of 1.1%. Most investigated clinical co-factors (jaw, tooth position, intracanal dressings, post/screw placement, and gender) showed no significant influence on survival. (4) Conclusions: Even with materials and techniques from the 1970s and 1980s, successful root canal treatment was achievable. Except for post-endodontic restorations, most of the evaluated factors had no significant influence on the clinical long-term survival of root canal-treated teeth.

COVID-19 response in a long-term care facility for people with epilepsy.

OBJECTIVE: To assess asymptomatic rates and severity of SARS-CoV-2 infection in people with epilepsy and their healthcare workers in a long-term care facility which had implemented weekly surveillance testing between April 2020 and June 2022. METHODS: Questionnaires focused on objective and subjective COVID-19 symptoms for people with epilepsy residing in and their healthcare workers at the Chalfont Centre for Epilepsy in June 2022. Demographic information, comorbidities, and seizure frequency were gathered from medical records. We also collected responses on objective and subjective COVID-19 symptoms from healthcare workers who participated in a prospective study assessing the reaction to COVID-19 vaccinations (SAFER). RESULTS: Fifty-five out of 89 (62%) residents tested positive at least once on weekly PCR testing for SARS-CoV-2 during the period of interest; 20 of those (37%) were asymptomatic. In comparison, of those 63 healthcare workers who tested positive at least once on weekly testing during the same period, only four (6%) were asymptomatic. Of the 159 healthcare workers who also participated in the SAFER study, 41 tested positive at least once, and seven (17%) were completely asymptomatic during infection with SARS-CoV-2. SIGNIFICANCE: People with epilepsy living in a long-term care facility were more likely to present with asymptomatic SARS-CoV-2 infections than healthcare workers at the same facility. Despite possible bias in the reporting of subjective symptoms due to management-by-proxy, there is no evidence that vulnerable people living in an epilepsy long-term care facility showed reduced resilience towards infections. PLAIN LANGUAGE SUMMARY: People with epilepsy living in care home facilities had a surprisingly high degree of asymptomatic infections with SARS-CoV-2. Very few residents had severe or fatal outcomes. This is in stark contrast to the widely reported bad outcomes for people without epilepsy in other care homes. People with epilepsy reported significantly less symptoms than their healthcare workers. No changes in seizure frequency during or after infection were observed.

Recommendations for quantitative cerebral perfusion MRI using multi-timepoint arterial spin labeling: Acquisition, quantification, and clinical applications.

Accurate assessment of cerebral perfusion is vital for understanding the hemodynamic processes involved in various neurological disorders and guiding clinical decision-making. This guidelines article provides a comprehensive overview of quantitative perfusion imaging of the brain using multi-timepoint arterial spin labeling (ASL), along with recommendations for its acquisition and quantification. A major benefit of acquiring ASL data with multiple label durations and/or post-labeling delays (PLDs) is being able to account for the effect of variable arterial transit time (ATT) on quantitative perfusion values and additionally visualize the spatial pattern of ATT itself, providing valuable clinical insights. Although multi-timepoint data can be acquired in the same scan time as single-PLD data with comparable perfusion measurement precision, its acquisition and postprocessing presents challenges beyond single-PLD ASL, impeding widespread adoption. Building upon the 2015 ASL consensus article, this work highlights the protocol distinctions specific to multi-timepoint ASL and provides robust recommendations for acquiring high-quality data. Additionally, we propose an extended quantification model based on the 2015 consensus model and discuss relevant postprocessing options to enhance the analysis of multi-timepoint ASL data. Furthermore, we review the potential clinical applications where multi-timepoint ASL is expected to offer significant benefits. This article is part of a series published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group, aiming to guide and inspire the advancement and utilization of ASL beyond the scope of the 2015 consensus article.