Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability.

BACKGROUND: Cellular prion protein (PrPC) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrPC in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrPC is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrPC, with some functions recently shown to be misattributed to PrPC due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrPC in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp0/0 mouse model (PrnpZH3/ZH3). RESULTS: We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in PrnpZH3/ZH3 animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of PrnpZH3/ZH3 vs wildtype mice. PrPC absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the PrnpZH3/ZH3 hippocampus. In addition, we observed a delay in neuronal maturation and network formation in PrnpZH3/ZH3 cultures. CONCLUSION: Our results demonstrate that PrPC promotes neuronal network formation and connectivity. PrPC mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

Optical and thermal performance of a toroidal compound parabolic concentrator.

The design, construction, and ray simulation of a new compound parabolic concentrator based on a toroidal shape (toroidal compound parabolic concentrator, TCPC) are addressed. Such analysis indicates that the amount of concentrated radiation is independent of the Sun trajectory. Thus, the TCPC has the advantage of concentrating Sun rays in a spot, and if positioned with an inclination corresponding to the latitude, a solar tracker would not be needed. Experimental measurements with a prototype model are shown to be in good agreement with the simulation results. The possibility of a variety of applications, as natural illumination for this TCPC device, is also pointed out. The simple design, fabrication, and implementation of the TCPC make it an excellent alternative for low concentration in a spot. We present the analysis of the TCPC in natural illumination as one of these applications.

The Adult Cardiac Anesthesiology Section of STS Adult Cardiac Surgery Database: 2020 Update on Quality and Outcomes.

The Society of Cardiovascular Anesthesiologists, in partnership with The Society of Thoracic Surgeons, has developed the Adult Cardiac Anesthesiology Section of the Adult Cardiac Surgery Database. The goal of this landmark collaboration is to advance clinical care, quality, and knowledge, and to demonstrate the value of cardiac anesthesiology in the perioperative care of cardiac surgical patients. Participation in the Adult Cardiac Anesthesiology Section has been optional since its inception in 2014 but has progressively increased. Opportunities for further growth and improvement remain. In this first update report on quality and outcomes of the Adult Cardiac Anesthesiology Section, we present an overview of the clinically significant anesthesia and surgical variables submitted between 2015 and 2018. Our review provides a summary of quality measures and outcomes related to the current practice of cardiothoracic anesthesiology. We also emphasize the potential for addressing high-impact research questions as data accumulate, with the overall goal of elucidating the influence of cardiac anesthesiology contributions to patient outcomes within the framework of the cardiac surgical team.

Optical coherence tomography measures correlate with brain and spinal cord atrophy and multiple sclerosis disease-related disability.

BACKGROUND AND PURPOSE: Both optical coherence tomography (OCT) and magnetic resonance imaging (MRI) volumetric measures have been postulated as potential biomarkers of multiple sclerosis (MS)-related disability. The aim of the study was to investigate the association between OCT and brain volume and spinal cord area (SCA) parameters in patients with relapsing MS and to assess their independent associations with disability. METHODS: This was a cross-sectional analysis of 90 patients with MS who underwent OCT and MRI examination. Values of peripapillary retinal nerve fibre layer (pRNFL), ganglion cell/inner plexiform layer (GCIPL) and inner nuclear layer of eyes without previous optic neuritis were obtained. SCA and brain parenchymal fraction (BPF), grey and white matter fractions were obtained. Multivariable regression analyses were conducted with disability as dependent variable. RESULTS: Lower pRNFL thickness and lower GCIPL volume as well as lower BPF, grey matter fraction and SCA were associated with a longer disease duration and a higher Expanded Disability Status Scale score. Lower pRNFL thickness and GCIPL volumes were associated with lower BPF and SCA. In the multivariable logistic regression analyses, pRNFL thickness and GCIPL volume outperformed MRI in predicting disability. CONCLUSIONS: The OCT measures correlate with brain and spinal cord atrophy and appear more closely associated with disability than MRI volumetric measures.

Anesthetic management of lung transplantation: Results from a multicenter, cross-sectional survey by the society for advancement of transplant anesthesia.

BACKGROUND: Current protocols for the perioperative care of lung transplant (LTX) recipients lack rigorous evidence and are often empiric, based upon institutional preferences. We surveyed LTX anesthesiologists to determine the most common practices. METHODS: We developed a survey of 40 questions regarding perioperative care of LTX recipients using Qualtrics software. The survey was sent out to members of the Society of Cardiovascular Anesthesiologists performing LTX at geographically diverse sites to facilitate data collection for as many practices as possible. RESULTS: The responses were center-weighed (127 responses, 85% from academic settings). The clamshell approach was commonly used (70%). Cardiopulmonary bypass was preferred by 56%, ex vivo lung perfusion utilized by 43%, and 49.4% indicated they use lungs from donation after circulatory determination of death. Most (69%) used oximetric pulmonary artery catheters, 60% used tissue oximetry, and 89.3% utilized transesophageal echocardiography. Inhaled nitric oxide was preferred by 48%, restrictive fluid management by 48%, and systemic analgesia advocated by 49% of participants. Inspired oxygen concentration <30% was applied to the new lung on reperfusion by 28% of the respondents. CONCLUSION: Variations in healthcare delivery and utilization for LTX recipients indicate gaps in knowledge and potential opportunities to improve the quality of care.

[Frailty of the elderly and physical activity in general practice: A prospective study]. / Étude de la fragilité de la personne âgée et de l'activité physique en médecine générale : à propos d'une étude prospective.

INTRODUCTION: Frailty is a transient and reversible condition that can lead to significant morbidity and mortality and to the loss of autonomy. It is one of the key issues in public health and the prevention of addiction. Physical activity is often described as a protective factor against addiction and as a factor in limiting frailty. Our goal is to analyze the relationship between physical activity and frailty among the elderly METHODS: A cross-sectional observational study was carried out in three general practice clinics located in the French department of Eure. Patients aged 65 and over were included during a consultation with their GP. Dependent patients under the ADL scale were excluded. Level of physical activity was assessed by the Ricci and Gagnon questionnaire, which defines an active profile as a score≥18 points. Frailty was sought out by the Fried scale and the SEGA A grid. Multivariate analysis was performed to adjust frailty scores to age, gender, and level of physical activity. RESULTS: Out of the 70 patients included, 36 were active (51%) and 34 inactive (49%). They were predominantly female with 47 women (67%). Average age was 75.3years. Twelve patients were diagnosed as frail (17%) with the Fried scale and 24 (34%) with the SEGA A grid. Bivariate analysis revealed a greater frailty according to the Fried criteria in the inactive than in the active patients (mean for active patients 0.56 IC95 [0.31; 0.80], compared to 1.76 [1.21; 2.32] in the inactive patients, p<0.0001). The difference in mean was likewise significant regarding the SEGA A score (6.42 IC95 [5.34, 7.49] in the active population, as opposed to 8.65 IC95 [7.15, 10.15] among the inactive, p=0.017). In multivariate analysis, the Fried scale was primarily influenced by age and ADL, while the SEGA score was impacted by female gender and level of physical activity. CONCLUSION: Physical activity seems to have a positive effect on frailty. It would be interesting to propose systematic screening for frailty in general medicine and to institute preventive measures, including physical activity. Initiatives encouraging and promoting seniors' physical activity should be strengthened.

Pre- and postoperative anemia, acute kidney injury, and mortality after coronary artery bypass grafting surgery: a retrospective observational study.

BACKGROUND: Preoperative and postoperative anemia have been identified individually as potential risk factors for postoperative complications after coronary artery bypass grafting (CABG) surgery. Their interrelationship with acute kidney injury (AKI) and long-term mortality, however, has not been clearly defined and was the purpose of this study. METHODS: We retrospectively evaluated 6,130 adult patients undergoing CABG surgery performed at a single large academic medical center. Preoperative and postoperative hemoglobin concentrations were used as continuous predictors of postoperative AKI and mortality. Additionally, sex-specific preoperative (< 13 g·dL-1 in men and < 12 g·dL-1 in women) and postoperative anemia (the median of the lowest in-hospital values) were used as categorical predictors. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines, when serum creatinine rose ≥ 50% during the period between day of surgery and postoperative day ten, or when a 0.3 mg·dL-1 (26.5 µmol·L-1) increase was detected in a rolling 48-hr window from the day of surgery to the tenth postoperative day. The association of preoperative and postoperative hemoglobin levels and anemia patterns with postoperative AKI and mortality were assessed via univariable and multivariable Cox proportional hazard analyses with time-varying effects for postoperative serum hemoglobin concentrations. RESULTS: The median preoperative and median minimum postoperative serum hemoglobin concentrations were 13.1 g·dL-1 and 8.8 g·dL-1, respectively. The incidence of AKI was 58%. Overall, 1,880 (30.7%) patients died an average of 6.8 yr after surgery. After adjusting for differences in baseline and clinical characteristics, on any given day, patients with preoperative anemia (multivariable hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.13 to 1.33; P < 0.001) and those with a combination of preoperative and postoperative anemia (multivariable HR, 1.24; 95% CI, 1.09 to 1.40; P < 0.0008) were at an elevated risk for developing postoperative AKI and mortality (preoperative anemia: multivariable HR, 1.29; 95% CI, 1.15 to 1.44; P < 0.001; preoperative and postoperative anemia: multivariable HR, 1.50; 95% CI, 1.25 to 1.79; P < 0.001). CONCLUSIONS: Our findings suggest that preoperative anemia alone and preoperative anemia combined with postoperative anemia are associated with AKI and mortality after CABG surgery.

Prognostic accuracy of SIRS criteria, qSOFA score and GYM score for 30-day-mortality in older non-severely dependent infected patients attended in the emergency department.

The aim of this study was to determine the accuracy of systemic inflammatory response syndrome (SIRS), quick Sepsis-related Organ Failure Assessment (qSOFA) score and GYM score to predict 30-day mortality in older non-severely dependent patients attended for an episode of infection in the emergency department (ED). We performed an analytical, observational, prospective cohort study including patients 75 years of age or older, without severe functional dependence, attended for an infectious process in 69 Spanish EDs for 2-day three-seasonal periods. Demographic, clinical and analytical data were collected. The primary outcome was 30-day mortality after the index event. We included 1071 patients, with a mean age of 83.6 [standard deviation (SD) 5.6] years; 544 (50.8%) were men. Seventy-two patients (6.5%) died within 30 days. SIRS criteria ≥ 2 had a sensitivity of 65% [95% confidence interval (CI) 53.1-75.9] and a specificity of 49% (95% CI 46.0-52.3), a qSOFA score ≥ 2 had a sensitivity of 28% (95% CI 18.2-39.8) and a specificity of 94% (95% CI 91.9-95.1), and a GYM score ≥ 1 had a sensitivity of 81% (95% CI 69.2-88.6) and a specificity of 45% (95% CI 41.6-47.9). A GYM score ≥ 1 and a qSOFA score ≥ 2 were the cut-offs with the highest sensitivity (p < 0.001) and specificity (p < 0.001), respectively. The area under the curve (AUC) was 0.73 (95% CI 0.66-0.79; p < 0.001) for the GYM score, 0.69 (95% CI 0.61-0.76; p < 0.001) for the qSOFA score and 0.65 (95% CI 0.59-0.72; p < 0.001) for SIRS. A GYM score ≥ 1 may be the most sensitive score and a qSOFA score ≥ 2 the most specific score to predict 30-day mortality in non-severely dependent older patients attended for acute infection in EDs.

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

Cyclotetrahalo-p-phenylenes: simulations of halogen substituted cycloparaphenylenes and their interaction with C60.

Density functional calculations are used to study the role of edge-functionalization on the structure and electronic properties of cycloparaphenylene (CPPs) containing from six to twenty benzenoid rings. We substitute hydrogen by the halogens fluorine, chlorine and bromine. The resultant Cyclotetrahalo-p-phenylenes are compared with their hydrogenated equivalents, related linear paraphenyl and fluoro-paraphenyl polymers, and functionalised armchair edges in graphene nanoribbons. Notably we consider both structural and electronic evolution. Finally we examine C60@[10]CPP, i.e. C60 encapsulated within [10]CPP, with the various ring terminations. The effect of halogenation on electronic level position around the gap strongly affects their capacity to form donor-acceptor pairs with fullerenes.

Brain atrophy in natalizumab-treated patients: A 3-year follow-up.

BACKGROUND: A pseudoatrophy effect has been held responsible for the lack of net impact of natalizumab on brain volume outcomes in 2-year trials, but no data are available beyond 24 months. OBJECTIVE: We aimed to investigate brain volume dynamics in natalizumab-treated patients in up to 3 years after therapy initiation with clinical correlations. METHODS: Patients on natalizumab for at least 3 years were clinically assessed 3-monthly. Magnetic resonance imaging scans were performed at baseline and yearly. Brain volume changes were obtained with SIENA. Multivariate models were used to investigate the association between baseline inflammation and changes in brain volume and disability. RESULTS: Sixty-two patients with multiple sclerosis were analysed. Mean age and disease duration were 34.7 (SD: 8.3) and 10.4 (SD: 6.6) years. Presence of gadolinium enhancement at baseline was not associated with Expanded Disability Status Scale changes (p=0.468), but was associated with larger brain volume decreases (p=0.005) in the first (p=0.024) and second year (p=0.019) but not in the third year (p=0.863). Brain volume changes at 12 and 36 months were marginally associated with disability status at month 12 (p=0.094) and 36 (p=0.084), respectively. CONCLUSIONS: Baseline inflammation affects brain volume measures up to 24 months after natalizumab initiation. A marginal association of brain volume changes with disability is present.

Significant clinical worsening after natalizumab withdrawal: Predictive factors.

We aimed to single out multiple sclerosis (MS) cases with poor outcome after natalizumab withdrawal and to identify predictive variables. We ascertained 47 withdrawals, and compared their pre- and post-natalizumab periods. We objectively defined significant clinical worsening after natalizumab withdrawal as a 2-step increase in Expanded Disability Status Scale (EDSS). We performed regression models. As a group, post-natalizumab annualized relapse rate (ARR) was lower in the post-natalizumab period, and there were no differences in the mean number of gadolinium (Gd)-enhancing lesions between pre- and post-natalizumab magnetic resonance imaging (MRI). Corticosteroid treatment did not change the outcomes. Eight patients (19%) presented significant clinical worsening after natalizumab withdrawal, which was predicted by a higher baseline EDSS and a 1-step EDSS increase while on natalizumab.

Bile duct tumors.

Bile duct tumors are benign or malignant lesions which may be associated to risk factors or potentially malignant lesions. They constitute an heterogenous entities group with a different biological behavior and prognosis according to location and growth pattern. We revise the role of the radiologist in order to detect, characterize and stage these tumors, specially the importance of their classification when deciding an appropriate management and treatment.

Pulmonary dysfunction after lung transplantation: the dilemma of coexisting mitral regurgitation.

A case of MR progression after single-lung transplant as a significant contributor to postoperative respiratory failure is reported. Pre-existing MR may progress due to the decompressive effects of lung transplantation on RV dimension and consequent alteration of MV geometry. This case highlights the importance of intraoperative TEE findings, especially pertaining to valvulopathies in the setting of lung transplantation. Postoperative surveillance of significant findings is imperative when any new symptoms are being investigated.

Multinational institutional survey on patterns of intraoperative transesophageal echocardiography use in adult cardiac surgery.

OBJECTIVES: To assess institutional patterns of perioperative transesophageal echocardiography (TEE) usage. DESIGN: The authors hypothesized that TEE is performed more frequently and comprehensively in academic centers, mainly by anesthesiologists, and barriers to performing TEE are due to inadequate resources. A survey was deployed to selected participants. Collated responses were assessed for demographic patterns in TEE practice, and 2-category comparisons were made with Chi-squared association tests. SETTING: Web-based survey. PARTICIPANTS: Practitioners in cardiovascular anesthesia/surgery in 200 institutions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Surveys were completed by respondents representing 200 centers in 27 countries and 1,727 anesthesiologists with a mean annual institutional volume of 924 cases. Most centers were in the USA (53%) and were defined as academic (83%). Anesthesiologists performed (85%) and also read/reported TEEs (78%) in most centers. Three-dimensional TEE is performed routinely at 40% of centers. TEE is used routinely for valve surgery in 95% of institutions compared to 68% for coronary artery bypass graft surgery. Academic institutions assessed diastolic function more often than nonacademic centers (46% v 19%; p = 0.006). The most important reason cited for not using TEE in all cases was insufficient resource availability (47%). CONCLUSIONS: These results suggest that TEE is performed more comprehensively in academic centers, mainly by anesthesiologists, and that lack of resources is a significant barrier to routine TEE usage. TEE is used more often for valve surgery than for coronary artery bypass graft surgery, and many centers use 3D TEE. This survey describes international TEE practice patterns and identifies limitations to universal adoption of TEE in cardiac surgery.

hkb is required for DIP-α expression and target recognition in the Drosophila neuromuscular circuit.

Our nervous system contains billions of neurons that form precise connections with each other through interactions between cell surface proteins. In Drosophila, the Dpr and DIP immunoglobulin protein subfamilies form homophilic or heterophilic interactions to instruct synaptic connectivity, synaptic growth, and cell survival. However, the upstream regulatory mechanisms of Dprs and DIPs are not clear. On the other hand, while transcription factors have been implicated in target recognition, their downstream cell surface proteins remain mostly unknown. We conduct an F1 dominant modifier genetic screen to identify regulators of Dprs and DIPs. We identify huckebein (hkb), a transcription factor previously implicated in target recognition of the dorsal Is motor neuron. We show that hkb genetically interacts with DIP-α and loss of hkb leads to complete removal of DIP-α expression specifically in dorsal Is motor neurons. We then confirm that this specificity is through the dorsal Is motor neuron specific transcription factor, even-skipped (eve), which acts downstream of hkb. Analysis of the genetic interaction between hkb and eve reveals that they act in the same pathway to regulate dorsal Is motor neuron connectivity. Our study provides insight into the transcriptional regulation of DIP-α and suggests that distinct regulatory mechanisms exist for the same CSP in different neurons.

Consensus statement of the Spanish Society of Neurology on the treatment of multiple sclerosis and holistic patient management in 2023.

The last consensus statement of the Spanish Society of Neurology's Demyelinating Diseases Study Group on the treatment of multiple sclerosis (MS) was issued in 2016. Although many of the positions taken remain valid, there have been significant changes in the management and treatment of MS, both due to the approval of new drugs with different action mechanisms and due to the evolution of previously fixed concepts. This has enabled new approaches to specific situations such as pregnancy and vaccination, and the inclusion of new variables in clinical decision-making, such as the early use of high-efficacy disease-modifying therapies (DMT), consideration of the patient's perspective, and the use of such novel technologies as remote monitoring. In the light of these changes, this updated consensus statement, developed according to the Delphi method, seeks to reflect the new paradigm in the management of patients with MS, based on the available scientific evidence and the clinical expertise of the participants. The most significant recommendations are that immunomodulatory DMT be started in patients with radiologically isolated syndrome with persistent radiological activity, that patient perspectives be considered, and that the term "lines of therapy" no longer be used in the classification of DMTs (> 90% consensus). Following diagnosis of MS, the first DMT should be selected according to the presence/absence of factors of poor prognosis (whether epidemiological, clinical, radiological, or biomarkers) for the occurrence of new relapses or progression of disability; high-efficacy DMTs may be considered from disease onset.