Mittregionales Pro-Atriales Natriuretisches Peptid als Teil einer dualen Biomarker-Strategie für den früheren Ausschluss des akuten Koronarsyndroms ohne ST-Strecken-Hebung

Background: Mr-proANP is a biomarker produced in atrial and left ventricular myocardium. We investigated the effect of combined measurement of mr-proANP and high-sensitive cardiac Troponin I assay of the penultimate generation (s-cTnI) for an early type-1 and type-2 NSTE-ACS rule-out with emphasis on the very early presenters' subgroup with symptom onset time (SOT) ≤ 2 h. Methods: This was a prospective cohort study of 311 consecutive patients admitted to ER with symptoms suggestive of an acute coronary syndrome (ACS). All patients had baseline mr-proANP and s-cTnI measurements. Results: Of the total cohort, 17.6% (n = 55) had final diagnosis of NSTE-ACS: 9.6% (n = 30) had an angiographically-confirmed type-1 infarction and 8.0% (n = 25) had type-2 infarction. In the subgroup of very early presenters (SOT ≤ 2 h) the negative predictive value (NPV) of s-cTnI for type-1 NSTEACS was 96.7% (95%-CI: 87.5–99.4) and the NPV of mr-proANP was 100% (95%-CI: 87.1–100). The dual biomarker strategy yielded an NPV of 100% (95%-CI: 86.7–100). In the same time-related subgroup, the NPV of s-cTnI alone for type-2 was 98.3% (95%-CI: 89.8–99.9) and the NPV of mr-proANP was 97.0% (95%-CI: 82.5–100). The combination of biomarker increased the NPV to 100% (95%-CI: 86.7–100). Conclusions: Our study demonstrated an immediate release pattern of mr-proANP in NSTE-ACS that may bridge the silent troponin time phenomenon when highest-sensitivity cardiac troponin assays are not used. This concept performed best in the very early presenters' subgroup with an excellent NPV of 100% and might result in an early rule-out of NSTE-ACS thus accelerating the diagnostic work-up.Mr-proANP ist ein Biomarker, der im atrialen und linksventrikulären Myokard produziert wird. Wir haben den Effekt der kombinierten Messung von mr-proANP und hochsensitivem kardialen Troponin I der vorletzten Generation (s-cTnI) für einen früheren Ausschluss vom NSTE-ACS Typ-1 und Typ- 2 untersucht mit Akzentsetzung auf jene Patienten, die sich sehr früh nach Symptombeginn (≤ 2 h) in der Notaufnahme vorstellten. Methoden: Es handelte sich um eine prospektive Kohortenstudie von 311 hintereinander kommenden Patienten, die sich in der Notaufnahme mit Symptomen, die auf ein akutes Koronarsyndrom (ACS) hindeuteten, vorstellten. Bei allen Patienten fand die Bestimmung von mr-proANP- und s-cTnI-Spiegel unmittelbar nach dem Eintreffen in der Notaufnahme statt. Ergebnisse: Von der Gesamtkohorte hatten 55 (17,6%) Patienten die endgültige Diagnose eines NSTE-ACS, 30 (9,6%) Patienten hatten einen angiographisch bestätigten Typ-1-Infarkt und 25 (8,0%) Patienten hatten einen Typ-2-Infarkt. In der Subgruppe der Patienten, die sich sehr früh nach Symptombeginn (SOT ≤ 2 h) vorstellten, betrug der negative prädiktive Wert (NPW) von s-cTnI für Typ-1-NSTE-ACS 96,7% (95% -CI: 87,5–99,4) und der NPW von mr-proANP 100% (95% -CI: 87,1–100). Die duale Biomarker-Strategie erbrachte einen NPW von 100% (95% -CI: 86,7–100). In derselben Subgruppe betrug der NPW von s-cTnI allein für Typ-2 98,3% (95% -CI: 89,8–99,9), der NPW von mr-proANP betrug 97,0% (95% -CI: 82,5– 100). Die Kombination zweier Biomarker erhöhte den NPW auf 100% (95% -CI: 86,7–100). Schlussfolgerungen: Unsere Studie zeigte ein sofortiges Freisetzungsmuster von mr-proANP in NSTE-ACS, was möglicherweise das Phänomen der „silent troponin time“ überbrücken könnte, wenn keine Herz-Troponin-Assays mit höchster Empfindlichkeit verwendet werden. Dieses Konzept erzielte in der Gruppe der Patienten, die sich sehr früh nach Symptombeginn vorstellten, einen NPW von 100%. Somit könnte ein früherer Ausschluss von NSTE-ACS erzielt werden, wodurch die gesamte diagnostische Aufarbeitung beschleunigt werden könnte

Building Envelope for Energy-Efficient Residential Homes, A Case Study for the U.S. Department of Energy Challenge Home Student Design Competition

With the continuous rise of population and expansion of urban areas, the need for additional housing and infrastructure is growing rapidly. Building sector is consuming a vast majority of the natural resources to meet the needs of urbanization and is in need of efficient, sustainable solutions that are viable for the customer, the economy and the environment. The building sector is both the problem and the solution to the issues of the carbon footprint of our society (Architecture 2030, 2011). The envelope (roofs, walls, and foundations) and windows typically account for 36% of overall energy use, or about 14.3 quads in residential and commercial buildings combined, at an annual cost of $133 Billion. A well designed building envelope can impact 51% of the building energy loads (U. S. Department of Energy National Energy Technology Laboratory, 2009). The purpose of this research is to assess selected types of residential home envelopes and their components. Comparative analysis was used to evaluate the thermal performance and thus the applicability of these components for modern residential buildings, as embodied energy and toxic emissions were also important factors. The research is mainly focused on townhomes as one of the sustainable types of neighborhood development (USGBC, LEED Neighborhood Development program). The assumption is that the high performance of the envelope is correlated to the reduction of heating and cooling loads in the interior and consequently, the overall energy and resource consumption of the building through its life-cycle. The derived hypothesis would be that by selecting an appropriate, high-performing building envelope assembly will ameliorate the overall performance of the building, thus lowering its environmental impact in terms of resource depletion and carbon emissions. Further benefits for the users include high levels of thermal comfort, health indoor air, lighting for daily tasks, noise control and an overall reduction in the whole-house energy consumption. This resource management could potentially reflect on the construction budget and later on, the utility costs. In order to address the research questions through the most relevant data, a mixed methods approach was selected. Exploratory method, focusing on qualitative research during the first phase was used to examine and document the correlation of different assembly types with their respected components and the thermal performance of the whole envelope. Moreover, quantitative data for the observed characteristic of the assembly components (mostly cavity insulation types) provided numerical values that were compared in order to derive conclusions about different components\u27 lifecycle performance and impact. The quantitative research portion gave firm data necessary for triangulation of the hypothesis and findings gathered in the qualitative, descriptive portion of the research. The research has been informed by examples and case studies elaborated in the literature review. The residential attached unit assessed as the case study was designed for the 2014. DOE Challenge Home Student Design Competition. This small footprint, two story townhome unit, was designed to achieve high-performance throughout its lifecycle. Several envelope assemblies were taken in consideration, the decisions being informed by the EEBA (The energy & Environmental building Alliance) and US Department of Energy\u27s Building America Program Houses That Work educational training course. The individual assembly parameters were assessed in energy modeling software (REM Rate and HEED) and addressing the issues considering maintenance and durability, as well as construction cost analyses, a specific combination of strategies has been selected. The 1,354 sq.ft residence features SIP and high mass concrete walls, Frost-Protected Shallow Foundations, high performance glazing (U-0.16; SHGC-0.561), a green roof and all ductwork distributed inside the conditioned space. Passive strategies are complemented with efficient active systems including ductless Mini-Split heating and cooling backup units, air circulation through integrated ERV and Radiant Floor Heating. Construction cost strategies included right-sizing and value engineering, elimination of duct systems, elimination of basement, application of prefab or engineered components that lower labor costs and reduce construction waste. As a result, this affordable end-unit part of a five-home row housing development for Denver\u27s Sustainability Park was designed to achieve LEED Platinum and Energy Star V3.0 Certification while remaining within financial reach to local families earning Denver\u27s median income. With a Home Energy Rating System (HERS) Index of 7 (100 being the `standard new home\u27), this all-electric home, is projected to use between 1,157 KWh/year (REM Rate) and 2,263 KWh/year (HEED) and 91% less energy than the LEED Reference Home (Tajsic et al. Aries House. U.S. Department of Energy Home Challenge Student Design Competition. Unpublished) High-performing building envelopes designed with sustainable practices in mind have a potential to lower the overall energy consumption of a building throughout its lifecycle and reduce its carbon footprint. Moreover, it\u27s important to select building materials that have the potential to offset the embodied energy of their production through the benefits of their performance within a system. Smart material procurement for wall and ceiling cavity insulation, its proper sizing, installation and maintenance are key for achieving maximum performance of the assembly. Durable, well-sealed sealed envelopes make up for a healthy, long lasting building enclosure that requires the least amount of maintenance or replacement and contribute to the indoor air quality and thermal comfort of the building. Topics relating to these issues have a high potential to be evaluated in other research endeavors or tested through different case studies

Indocyanine green fluorescence video angiography reduces vascular injury–related morbidity during micro-neurosurgical clipping of ruptured cerebral aneurysms: a retrospective observational study

Abstract: Background: Specific procedural complications in aneurysm surgery are broadly related to vascular territory compromise and brain/nerve retraction; vascular complications account for about half of this. Intraoperative indocyanine green video angiography (ICG-VA) provides real-time high spatial resolution imaging of the cerebrovascular architecture, allowing immediate quality assurance of aneurysm occlusion and vessel integrity. The aim of this study was to examine whether the routine use of ICG-VA reduced early procedural complications related to vascular compromise or injury during micro-neurosurgical clipping of ruptured cerebral aneurysms. Methods: Retrospective comparative observational study of 412 adult good-grade (WFNS 1 or 2) SAH patients who had undergone microsurgical clipping without (n = 200, 2001–2004) or with (n = 212, 2009–2015) ICG-VA in a high-volume neurosurgical centre. Results: The ICG-VA group had a significantly lower incidence of procedural vascular complications (7/212; 3.3%) compared with the non-ICG-VA group (19/200; 9.5%) (Fisher’s exact test p = 0.0137). Conclusions: ICG-VA is a straightforward, easy-to-use, intraoperative adjunct which significantly reduces avoidable ‘technical error’ related morbidity

Is 24/7 remote patient management in heart failure necessary? Results of the telemedical emergency service used in the TIM‐HF and in the TIM‐HF2 trials

Aims: Telemedical emergency services for heart failure (HF) patients are usually provided during business hours. However, many emergencies occur outside of business hours. This study evaluates if a 24/7 telemedical emergency service is needed for the remote management of high-risk HF patients. Methods: and results The study included 1119 patients merged from the TIM-HF and TIM-HF2 trials [age 69 +/- 11, 73% male, left ventricular ejection fraction 37% +/- 13, 557 New York Heart Association (NYHA) II/562 NYHA III]. Patients received a 24/7 physician-guided emergency service provided by the telemedical centre (TMC) in addition to remote management within business hours. During emergency calls, patient status, symptoms, electronic patient record, and instant telemonitoring data were evaluated by the TMC physician. Following diagnosis, patients were referred for hospital admission or instructed to stay at home. Apart from the TMC, patients could place a call to the public emergency service at any time. Seven hundred sixty-eight emergency calls were placed over 1383 patient years (0.56 calls/patient year). Five hundred twenty-six calls (69%) occurred outside business hours. There were 146 (19%) emergency calls for worsening HF, 297 (39%) other cardiovascular, and 325 (42%) non-cardiac causes, with a similar pattern inside and outside business hours. Of the 1119 patients, 417 (37%) placed at least one emergency call. Patients with NYHA Class III, higher N-terminal prohormone of brain natriuretic peptide (>1.400 pg/mL) levels, ischaemic aetiology of HF, implanted defibrillator, and impaired renal function had a higher probability of placing emergency calls. During study follow-up, patients who made an emergency call had a higher all-cause mortality (22% vs. 11%, P = 0.007 in TIM-HF; 16% vs. 4%, P < 0.001 in TIM-HF2) and more unplanned hospitalizations (324 vs. 162, P < 0.001 in TIM-HF; 545 vs. 180, P < 0.001 in TIM-HF2). Of the total 1,211 unplanned hospital admissions, 492 (41%) were initiated by a patient emergency call. Three hundred seventy-nine calls (49%) were placed to the TMC, whereas 389 calls (51%) were made to the public emergency service. Three hundred twenty-six (84%) of the calls to the public emergency service resulted in acute hospitalizations. The TMC initiated 202 (53%) hospital admissions; 177 (47%) patients were advised to stay at home. All patients that remained at home were alive during a prespecified safety period of 7 days post-call. Diagnoses made by the TMC physician were confirmed in 83% of cases by the hospital. Conclusion: A telemedical emergency service for high-risk HF patients is safe and should operate 24/7 to reduce unplanned hospitalizations. Emergency calls could be considered as a marker for higher morbidity and mortality

Dextran 500 Improves Recovery of Inflammatory Markers: An In Vitro Microdialysis Study.

Cerebral microdialysis (CMD) is used in severe traumatic brain injury (TBI) in order to recover metabolites in brain extracellular fluid (ECF). To recover larger proteins and avoid fluid loss, albumin supplemented perfusion fluid (PF) has been utilized, but because of regulatory changes in the European Union, this is no longer practicable. The aim with this study was to see whether fluid, absolute (AR), and relative (RR) recovery for the novel carrier, Dextran 500, was better than conventional PF for a range of cytokines and chemokines. An in vitro setup mimicking conditions observed in the neurocritical care of TBI patients was used, utilizing 100-kDa molecular-weight cut-off CMD catheters inserted through a triple-lumen bolt cranial access device into an external solution with diluted cytokine standards in known concentrations for 48 h (divided into 6-h epochs). Samples were run on a 39-plex Luminex (Luminex Corporation, Austin, TX) assay to assess cytokine concentrations. We found that fluid recovery was inadequate in 50% of epochs with conventional PF, whereas Dextran PF overcame this limitation. The AR was higher in the Dextran PF samples for a majority of cytokines, and RR was significantly increased for macrophage colony-stimulating factor and transforming growth factor-alpha. In summary, Dextran PF improved fluid and cytokine recovery as compared to conventional PF and is a suitable alternative to albumin supplemented PF for protein microdialysis.The work was supported by funding for SGC and KLHC from the National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). PJH is funded by a National Institute for Health Research (NIHR) Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship and the National Institute for Health Research Biomedical Research Centre, Cambridge. EPT has received salary support from Swedish Society for Medical Research. AH is supported by the Royal College of Surgeons of England and the National Institute for Health Research Biomedical Research Centre, Cambridge. The study consumables were purchased through the NIHR Research Professorship (Peter Hutchinson) and the Luminex 200 analyser was purchased with Medical Research Council (MRC) funding (G0600986 ID79068)

Cellular infiltration in traumatic brain injury

Abstract: Traumatic brain injury leads to cellular damage which in turn results in the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells to release cytokines and chemokines. These in turn rapidly recruit neutrophils, which assist in limiting the spread of injury and removing cellular debris. Microglia continuously survey the CNS (central nervous system) compartment and identify structural abnormalities in neurons contributing to the response. After some days, when neutrophil numbers start to decline, activated microglia and astrocytes assemble at the injury site—segregating injured tissue from healthy tissue and facilitating restorative processes. Monocytes infiltrate the injury site to produce chemokines that recruit astrocytes which successively extend their processes towards monocytes during the recovery phase. In this fashion, monocytes infiltration serves to help repair the injured brain. Neurons and astrocytes also moderate brain inflammation via downregulation of cytotoxic inflammation. Depending on the severity of the brain injury, T and B cells can also be recruited to the brain pathology sites at later time points

Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing

Prelamin A accumulation and persistent DNA damage response (DDR) are hallmarks of vascular smooth muscle cell (VSMC) ageing and dysfunction. Although prelamin A is proposed to interfere with DNA repair, our understanding of the crosstalk between prelamin A and the repair process remains limited. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) have emerged as key players in the DDR and are known to enhance ataxia telangiectasia-mutated protein (ATM)activity at DNA lesions, and in this study, we identified a novel relationship between prelamin A accumulation and ERK1/2 nuclear compartmentalisation during VSMC ageing. We show both prelamin A accumulation and increased DNA damage occur concomitantly, before VSMC replicative senescence, and induce the localisation of ERK1/2 to promyelocytic leukaemia protein nuclear bodies (PML NBs) at the sites of DNA damage via nesprin-2 and lamin A interactions. Importantly, VSMCs treated with DNA damaging agents also displayed prelamin A accumulation and ERK compartmentalisation at PML NBs, suggesting that prelamin A and nesprin-2 are novel components of the DDR. In support of this, disruption of ERK compartmentalisation at PML NBs, by either depletion of nesprin-2 or lamins A/C, resulted in the loss of ATM from DNA lesions. However, ATM signalling and DNA repair remained intact after lamins A/C depletion, whereas nesprin-2 disruptionablated downstream Chk2 activation and induced genomic instability. We conclude that lamins A/C and PML act as scaffolds to organise DNA-repair foci and compartmentalise nesprin-2/ERK signalling. However, nesprin-2/ERK signalling fidelity, but not their compartmentalisation at PML NBs, is essential for efficient DDR in VSMCs

Delineating Astrocytic Cytokine Responses in a Human Stem Cell Model of Neural Trauma

Neuroinflammation has been shown to mediate the pathophysiological response following traumatic brain injury (TBI). Accumulating evidence implicates astrocytes as key immune cells within the central nervous system (CNS), displaying both pro- and anti-inflammatory properties. The aim of this study was to investigate how in vitro human astrocyte cultures respond to cytokines across a concentration range that approximates the aftermath of human TBI. To this end, enriched cultures of human induced pluripotent stem cell (iPSC)-derived astrocytes were exposed to interleukin-1β (IL-1β) (1–10,000 pg/mL), IL-4 (1–10,000 pg/mL), IL-6 (100–1,000,000 pg/mL), IL-10 (1–10,000 pg/mL) and tumor necrosis factor (TNF)-α (1–10,000 pg/mL). After 1, 24, 48 and 72 h, cultures were fixed and immunolabeled, and the secretome/supernatant was analyzed at 24, 48, and 72 h using a human cytokine/chemokine 39-plex Luminex assay. Data were compared to previous in vitro studies of neuronal cultures and clinical TBI studies. The secretome revealed concentration-, time- and/or both concentration- and time-dependent production of downstream cytokines (29, 21, and 17 cytokines, respectively, p<0.05). IL-1β exposure generated the most profound downstream response (27 cytokines), IL-6 and TNF had intermediate responses (13 and 11 cytokines, respectively), whereas IL-4 and IL-10 only led to weak responses over time or in escalating concentration (8 and 8 cytokines, respectively). Notably, expression of IL-1β, IL-6, and TNF cytokine receptor mRNA was higher in astrocyte cultures than in neuronal cultures. Several secreted cytokines had temporal trajectories, which corresponded to those seen in the aftermath of human TBI. In summary, iPSC-derived astrocyte cultures exposed to cytokine concentrations reflecting those in TBI generated an increased downstream cytokine production, particularly IL-1β. Although more work is needed to better understand how different cells in the CNS respond to the neuroinflammatory milieu after TBI, our data shows that iPSC-derived astrocytes represent a tractable model to study cytokine stimulation in a cell type-specific manner

Isolated oculomotor nerve palsy in patients with mild head injury

Isolated oculomotor nerve palsy following head injury is uncommon. It can only be diagnosed with confidence if it is known to have developed immediately following trauma and if adequate investigations exclude secondary causes. The recovery is only partial and this has repercussion on patients' quality of life