eine Pilotstudie

Einleitung: Intraoperative Störungen der zerebralen Perfusion durch Lageveränderungen gelten als mögliche Ursache postoperativer kognitiver Störungen. Neben invasiven Verfahren zur Bestimmung zerebraler Perfusion kann regionale zerebrale Oxymetrie mithilfe neuerer, auf Nahinfrarotspektroskopie (NIRS) basierender Monitore Auskunft über die Sauerstoffsättigung der betrachteten Hirnareale (rSO2) geben. Fragestellung: In dieser Arbeit soll bei Patienten mit einer Wahrscheinlichkeit für lagerungsbedingte, intraoperative zerebrale rSO2-Abfälle (Gruppe A: „Trendelenburg-Lagerung“, Gruppe B: „Beach Chair-Lagerung“) neben der Inzidenz kritischer rSO2-Werte auch die kumulative Dauer von Abweichungen außerhalb der natürlichen Schwankung (> 5 % von der individuellen Baseline, im Wachzustand ermittelt) untersucht werden. Zudem sollen die bestimmenden Größen pulsoxymetrische Sauerstoffsättigung (SpO2) und mittlerer arterieller Blutdruck (MAD) sowie mögliche Unterschiede dieser Merkmale zwischen den Gruppen A und B sowie Patienten mit und ohne postoperatives kognitives Defizit (POCD) beschrieben werden. Methodik: Nach Zustimmung der lokalen Ethikkommission und zentraler Registrierung wurden 95 Patienten gescreent, davon 63 Patienten eingeschlossen, wovon letztlich 40 Datensätze (20 je Gruppe) für die Auswertung zur Verfügung standen. Zur Aufzeichnung der rSO2 nutzten wir den Monitor „EQUANOX® 7600“ (Nonin Medical, Inc., Plymouth, MN, USA). Eine SpO2 < 90 % sowie ein MAD < 60 mmHg wurden als kritische Grenzwerte festgelegt. Für die Erfassung des kognitiven Funktionsstatus nutzten wir eine entsprechend der ISPOCD I-Studie definierte, etablierte Testbatterie, welche prä- und postoperativ angewandt wurde. Ergebnisse: Bei 4 von 40 Patienten (10 %) traten kritische rSO2-Abfälle auf. In der Studienpopulation bestand kein signifikanter Zusammenhang zwischen einem kritischen MAD und zeitgleichem kritischem rSO2. Bei 7 Patienten (17,5 %) erfassten wir intraoperative Episoden kritischer SpO2-Werte, keine dieser Episoden war mit kritischen rSO2-Werten verbunden. Ebenfalls konnte kein Zusammenhang zwischen POCD und kritischen rSO2-Werten oder jeglicher rSO2-Abweichung außerhalb der natürlichen Schwankung gezeigt werden. Ein signifikanter Unterschied zwischen Gruppe A und B zeigte sich hinsichtlich des MAD. Weitere Gruppenvergleiche zeigten keine signifikanten Unterschiede in Bezug auf POCD-Inzidenz, MAD-Werte oder rSO2-Werte. Diskussion: Die unter dem angewandten Anästhesieregime erfassten rSO2-Werte sprechen zusammenfassend für ein sicheres Vorgehen in Bezug auf die Vermeidung von lagerungsbedingten postoperativen kognitiven Störungen. Die erfassten Effekte zeigen lediglich einen unkritischen Unterschied im MAD-Verhalten zwischen den Gruppen A und B; weitere Gruppenunterschiede zeigten sich nicht. Tendenzielle Unterschiede der POCD-Inzidenz zwischen den Gruppen sowie der rSO2 zwischen Patienten aus A und B sowie Patienten mit und ohne POCD legen eine Folgestudie mit einer höheren Patientenzahl nahe, gegebenenfalls unter Einbeziehung weiterer Verfahren zur genaueren Bestimmung des Herzzeitvolumens sowie einer Methodik zur Ermittlung des POCD unter Einbeziehung einer Kontrollgruppe zur Erfassung von Lerneffekten.Introduction: Intraoperative decreases in cerebral perfusion due to changes in position are considered a possible cause of postoperative cognitive dysfunction. Alongside invasive methods for measuring cerebral perfusion, regional cerebral oximetry can monitor oxygen saturation of select brain areas (rSO2) by means of more recent monitors utilizing near infrared spectroscopy (NIRS). Research Question: In this study, besides detecting incidence of critical rSO2 values, the cumulative duration of deviations outside of the natural fluctuation (> 5% of individual baseline, determined while awake) is investigated in patients with a probability of intraoperative cerebral rSO2 decrease caused by position (group A: "Trendelenburg", group B: "Beach Chair"). Additionally, pulse oximetry oxygen saturation (SpO2) and mean arterial blood pressure (MAD) and differences therein between groups A and B and patients with and without postoperative cognitive dysfunction (POCD) are described. Methods: After approval by the local ethics committee and central registration, 95 patients were screened, 63 included, of which 40 data sets (20 per group) were ultimately available for analysis. To record rSO2, we used the “EQUANOX® 7600” monitor (Nonin Medical, Inc.). SpO2 < 90 % and MAD < 60 mmHg were defined as critical limit values. To record cognitive functions, we used established tests analogous to the ISPOCD-I study, conducted pre- and postoperatively. Results: Critical rSO2 decreases occurred in 4 of 40 patients (10%). There was no significant correlation between critical MAD and simultaneous critical rSO2 in the study population. In 7 patients (17.5%) critical SpO2 occurred during surgery; none of these episodes were associated with critical rSO2 values. Likewise, no correlation showed between POCD and critical rSO2 values or any rSO2 deviation outside of natural fluctuation. There was a significant difference between group A and B in MAD. Further group comparisons showed no significant differences in terms of POCD incidence, MAD values or rSO2 values. Discussion: The recorded rSO2 values under the applied anesthesia approach suggest safe procedure in terms of avoiding postoperative cognitive dysfunction caused by positioning. The recorded data show a non-critical difference in MAD between groups A and B; no further group differences were found. Trends in POCD incidence and rSO2 between patients from group A and B as well as patients with and without POCD suggest a follow-up study with a higher count of patients, possibly using more precise determination of cardiac output and a method for detecting POCD that includes a control group to record learning effects

Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis.

OBJECTIVE: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. RESULTS: CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). CONCLUSION: Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. CLASSIFICATION OF EVIDENCE: This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study

Objective To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). Methods A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. Results Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. Conclusions Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progressionThis project was funded by The Motor Neurone Disease Association (Malaspina/Apr13/6097) and Barts and The London Charities (468/1714). LG is the Graham Watts Senior Research Fellow, funded by The Brain Research Trust and the European Community’s Seventh Framework Programme (FP7/2007-2013)

Progress and gaps in climate change adaptation in coastal cities across the globe

Coastal cities are at the frontlines of climate change impacts, resulting in an urgent need for substantial adaptation. To understand whether and to what extent cities are on track to prepare for climate risks, this paper systematically assesses the academic literature to evaluate climate change adaptation in 199 coastal cities worldwide. We show that adaptation in coastal cities is rather slow, of narrow scope, and not transformative. Adaptation measures are predominantly designed based on past and current, rather than future, patterns in hazards, exposure, and vulnerability. City governments, particularly in high-income countries, are more likely to implement institutional and infrastructural responses, while coastal cities in lower-middle income countries often rely on households to implement behavioral adaptation. There is comparatively little published knowledge on coastal urban adaptation in low and middle income economies and regarding particular adaptation types such as ecosystem-based adaptation. These insights make an important contribution for tracking adaptation progress globally and help to identify entry points for improving adaption of coastal cities in the future

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.

OBJECTIVE: To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. RESULTS: Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. CONCLUSIONS: Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression. TRAIL REGISTRATION NUMBER: NIHRID6160

Stretch-Induced Stress Fiber Remodeling and the Activations of JNK and ERK Depend on Mechanical Strain Rate, but Not FAK

BACKGROUND: Cells within tissues are subjected to mechanical forces caused by extracellular matrix deformation. Cells sense and dynamically respond to stretching of the matrix by reorienting their actin stress fibers and by activating intracellular signaling proteins, including focal adhesion kinase (FAK) and the mitogen-activated proteins kinases (MAPKs). Theoretical analyses predict that stress fibers can relax perturbations in tension depending on the rate of matrix strain. Thus, we hypothesized stress fiber organization and MAPK activities are altered to an extent dependent on stretch frequency. PRINCIPAL FINDINGS: Bovine aortic endothelial cells and human osteosarcoma cells expressing GFP-actin were cultured on elastic membranes and subjected to various patterns of stretch. Cyclic stretching resulted in strain rate-dependent increases in stress fiber alignment, cell retraction, and the phosphorylation of the MAPKs JNK, ERK and p38. Transient step changes in strain rate caused proportional transient changes in the levels of JNK and ERK phosphorylations without affecting stress fiber organization. Disrupting stress fiber contractile function with cytochalasin D or Y27632 decreased the levels of JNK and ERK phosphorylation. Previous studies indicate that FAK is required for stretch-induced cell alignment and MAPK activations. However, cyclic uniaxial stretching induced stress fiber alignment and the phosphorylation of JNK, ERK and p38 to comparable levels in FAK-null and FAK-expressing mouse embryonic fibroblasts. CONCLUSIONS: These results indicate that cyclic stretch-induced stress fiber alignment, cell retraction, and MAPK activations occur as a consequence of perturbations in fiber strain. These findings thus shed new light into the roles of stress fiber relaxation and reorganization in maintenance of tensional homeostasis in a dynamic mechanical environment

Plasma Neurofilament Heavy Chain Levels Correlate to Markers of Late Stage Disease Progression and Treatment Response in SOD1(G93A) Mice that Model ALS

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3–5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. Methodology/Principal Findings: In this study, using the well-established SOD1G93A mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1G93A mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. Conclusions/Significance: These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1G93A mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS

Structural basis of PROTAC cooperative recognition for selective protein degradation

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

Neonatal, infant, and under-5 mortality and morbidity burden in the Eastern Mediterranean region: findings from the Global Burden of Disease 2015 study

Objectives Although substantial reductions in under-5 mortality have been observed during the past 35 years, progress in the Eastern Mediterranean Region (EMR) has been uneven. This paper provides an overview of child mortality and morbidity in the EMR based on the Global Burden of Disease (GBD) study. Methods We used GBD 2015 study results to explore under-5 mortality and morbidity in EMR countries. Results In 2015, 755,844 (95% uncertainty interval (UI) 712,064–801,565) children under 5 died in the EMR. In the early neonatal category, deaths in the EMR decreased by 22.4%, compared to 42.4% globally. The rate of years of life lost per 100,000 population under 5 decreased 54.38% from 177,537 (173,812–181,463) in 1990 to 80,985 (76,308–85,876) in 2015; the rate of years lived with disability decreased by 0.57% in the EMR compared to 9.97% globally. Conclusions Our findings call for accelerated action to decrease child morbidity and mortality in the EMR. Governments and organizations should coordinate efforts to address this burden. Political commitment is needed to ensure that child health receives the resources needed to end preventable deaths