Heparin is a highly sulfated glycosaminoglycan (GAG) of natural origin used as an anticoagulant and antithrombotic drug. These properties are principally based on the binding and activation of ...antithrombin (AT) through the pentasaccharide sequence GlcNAc/NS,6S‐GlcA‐GlcNS,3,6S‐IdoA2S‐GlcNS,6S (AGA*IA). Literature data show that the population of the 2S0 ring conformation of the 2‐O‐sulfo‐α‐l‐iduronic acid (IdoA2S) motif correlates with the affinity and activation of AT. It was recently demonstrated that two synthetic AGA*IA‐containing hexasaccharides (one G unit added at the reducing end), differing in the degree of sulfation of the IdoA unit, show comparable affinity and ability to activate AT, despite a different conformation of the IdoA residue. In this paper, the binding of these two glycans to AT was studied by isothermal titration microcalorimetry (ITC), transferred (tr‐) NOESY, saturation transfer difference (STD) NMR spectroscopy and molecular dynamics (MD) simulations. Results indicated that both the IdoA2S and the IdoA units assume a 2S0 conformation when bound with AT, and so present a common binding epitope for the two glycans, centred on the AGA*IA sequence.
Oligosaccharide anticoagulants: The conformation of the IdoA subunit in a pair of synthetic hexasaccharides is changed from 1C4 to 2S0 upon binding to antithrombin (AT), with the contact network between the AT heparin‐binding site (HBS) and residues surrounding the trisaccharide sequences GlcNS3S6S‐IdoA2S/IdoA‐GlcNS6S′′ playing a significant role, independently of the 2‐O‐sulfation state of IdoA.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•1,6-Anhydro-bearing tetrasaccharides were isolated from enoxaparin sample.•Their susceptibility to periodate oxidation was evaluated by NMR and LC/MS.•1,6-Anhydro-bridge is crucial for oxidation of ...1,6-anhydro-N-sulfo-mannosamine.•Reducing end N-sulfate hexosamine is affected by NaIO4 under drastic conditions.•It is possible to selectively split non-sulfated iduronic acids of enoxaparin chains.
There is a growing interest on glycol-split low-molecular weight heparins (gs-LMWHs), obtained by periodate oxidation of LMWHs, optionally followed by borohydride reduction, as potential anticancer and anti-inflammatory drugs. However, their structural characterization is still a challenging task, mainly because of the high microheterogeneity of the starting material. In addition, susceptibility to oxidation of some end-groups of LMWHs induces additional heterogeneity, making analysis of gs-LMWHs more complex. In our previous study we showed that 1,6-anhydro-d-mannosamine N-sulfate was affected by periodate, while its epimer 1,6-anhydro-d-glucosamine N-sulfate was resistant. In order to understand the apparently anomalous behavior of terminal 1,6-anhydro-d-mannosamine N-sulfate residues, in the present work we have studied by NMR spectroscopy and LC/MS the behavior of the reducing end amino sugar residues of the tetrasaccharides, isolated from the LMWH enoxaparin, in the presence of periodate. Their molecular mechanics conformational characterization has been also performed. We have shown that the C(2)–C(3) bond of the 1,6-anhydro-d-mannosamine residue can be split by periodate despite the N-substitution. Moreover, we have found that both terminal d-mannosamine N-sulfate and d-glucosamine N-sulfate, lacking the 1,6-anhydro-bridge, can be also oxidized by periodate but with a significantly lower rate. The present results suggest that the cis-e-/a-position of OH and NHSO3− groups of N-sulfated 1,6-anhydro-d-mannosamine is not the only factor that makes these end residues susceptible to the oxidation. The 1,6-anhydro-bridge that ‘blocks’ the ring conformation appears another crucial factor for oxidation to occur. Moreover, we have shown that controlling the reaction time could permit to selectively split non-sulfated iduronic acids of enoxaparin chains without oxidizing terminal amino sugar residues, a finding that may be useful to obtain more structurally homogeneous gs-LMHWs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The antithrombin (AT) binding properties of heparin and low molecular weight heparins are strongly associated to the presence of the pentasaccharide sequence AGA*IA ...(A(NAc,6S)-GlcUA-A(NS,3,6S)-I(2S)-A(NS,6S)). By using the highly chemoselective depolymerization to prepare new ultra low molecular weight heparin and coupling it with the original separation techniques, it was possible to isolate a polysaccharide with a biosynthetically unexpected structure and excellent antithrombotic properties. It consisted of a dodecasaccharide containing an unsaturated uronate unit at the nonreducing end and two contiguous AT-binding sequences separated by a nonsulfated iduronate residue. This novel oligosaccharide was characterized by NMR spectroscopy, and its binding with AT was determined by fluorescence titration, NMR, and LC-MS. The dodecasaccharide displayed a significantly increased anti-FXa activity compared with those of the pentasaccharide, fondaparinux, and low molecular weight heparin enoxaparin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Appropriate levels and patterns of sound and light in an intensive care room help to maintain the patient's normal physiological functions. High sound levels can disrupt the patient's normal sleep ...architecture, cause hearing deficits, and induce the onset of delirium. Intensive care unit patients frequently report poor sleep, partly due to the environment.
An observational pilot prospective study was designed to record sound pressure and light pollution levels in an Italian intensive care unit, without windows to provide natural light.
Sound levels were measured in decibel A (dBA) every 10 seconds. Sound data were analyzed for sound peak, defined as the number of times sound levels exceeded 45, 50, 60, 65, 70, 75, 80, and 85 dBA. Light measures were taken every 10 seconds on a continuous basis. Light data were analyzed for light "peaks," defined as the number of times light levels exceeded 100, 200, 300, 400, and 500 lux.
The overall median sound level during the study period was equal to 54.60 (interquartile range IQR, 51.70-57.70) dBA. The daytime median sound level was 56.00 (IQR, 53.00-59.50) dBA, and the nighttime median was 53.00 (IQR, 49.50-55.20) dBA (P < .001). The overall median light level was equal to 114 (IQR, 0-225) lux. The daytime median light level was 184 (IQR, 114-293) lux, and the nighttime median was 0 (IQR, 0-50) lux (P < .001). With respect to room lighting, rooms were observed to have "no lights on" 12.6% of daytime and 41% of nighttime.
The sound levels recorded in our sample demonstrated that peaks >45 dBA during daytime and nighttime are, respectively, equal to 99.9% and 98.6% of all readings. The Environmental Protection Agency/World Health Organization recommended thresholds for both day (45 dBA) and night (35 dBA). Sound levels reached "toxic levels" when sound-generating activities were performed by nurses and physicians.
Infection of host cells by SARS‐CoV‐2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and ...causing the subunit S1‐RBD to undergo a conformational change into the ‘open’ conformation. These two events promote the binding of S1‐RBD to the angiotensin converting enzyme 2 (ACE2) receptor, a preliminary step toward viral‐cell membrane fusion. Combining ligand‐based NMR spectroscopy with molecular dynamics, oligosaccharide analogues were used to explore the interactions between S1‐RBD of SARS CoV‐2 and HS, revealing several low‐specificity binding modes and previously unidentified potential sites for the binding of extended HS polysaccharide chains. The evidence for multiple binding modes also suggest that highly specific inhibitors will not be optimal against protein S but, rather, diverse HS‐based structures, characterized by high affinity and including multi‐valent compounds, may be required.
More than one way to get in: A hexasaccharide bound to site I of the spike protein in two binding modes (orange and green tubes) shows that multiple binding modes between heparan sulfate (HS) and S1 (electrostatic potential map on the surface) are allowed. The hypothetical macromolecular complex HS−S1 does not interfere with the interaction involving S1‐RBD and ACE2, thus supporting the co‐receptor role of HS in the activation of the SARS‐CoV‐2 S protein.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Extracorporeal membrane oxygenation (ECMO) is required for patients with refractory cardiac or respiratory failure. Inadequate securement of ECMO cannulae may lead to adverse events, ranging from ...line kinking to catastrophic accidents, such as air entrainment into the circuit or massive bleeding. Furthermore, the micro-motion of the cannulae at the entry site might increase the risk of local infections. Since 2015, we implemented a written protocol for management of ECMO cannulae and tubing, which specifically includes the securement of each cannula with three sutureless devices. The aim of the present study was to retrospectively assess cannulae micro-motion and the rate of bleeding events at the insertion site. Secondarily we aimed to evaluate the impact of prone positioning maneuvers during ECMO on these events. We performed a single-centre retrospective analysis of prospectively collected data on nursing care of ECMO cannulae. We included adult patients treated with veno-venous (V-V) or veno-arterial (V-A) ECMO between 2015 and 2018 in our general intensive care unit. The distance between the insertion site and the end of the wire-wound part of the cannula was recorded daily. Variations of this distance (defined as “cannula micro-motion”) were recorded. Forty-five ECMO consecutive adult patients (40 V-V and 5 V-A) were included. No accidental cannula dislodgement was recorded. Median daily “cannula micro-motion” was 0.0 (−0.5 to 0.2) cm, without any significant difference between ECMO configuration, cannula type, and insertion site. Twelve patients (26%) presented at least one bleeding episode at cannula insertion site, none of which required surgical intervention. In the subgroup of patients who underwent prone positioning, no difference in cannulae micro-motion was recorded. An ECMO nursing protocol for cannulae management providing sutureless devices for cannula and tubing securement allows safe line stabilization, with the potential to reduce complications related to ECMO vascular access.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Peripherally Inserted Central Catheters play an increasingly important role in Central Venous Access Devices. However, the use of these devices should be carefully considered in specific situations ...such as central catheterisation in patients with chronic kidney disease. When evaluating the feasibility of placement for a patient undergoing dialysis, the relationship between changes in circulating volume before and after dialysis treatment, and potential variations in the size of deep veins in the upper limbs, should be considered.
Upper limb veins, specifically the basilic or brachial veins, were identified and measured before and after dialysis treatment. Patient data and weight loss data during dialysis treatment were also collected. Linear regression analysis was performed to assess the correlation between the variables.
The average variation in vein size for the entire sample was +0.17 ± 0.43 mm. The mean volume removed was 2.2 ± 0.8 l. In subgroup 1 (fluid volume loss <2000 ml), the population experienced a decrease in the measured vein size after dialysis. In subgroup 2 (fluid volume loss ⩾2000 ml), the population experienced an increase in the measured vein size after dialysis.
Upper arm vascular access placement in dialysed patients with fluid removal of less than 2000 ml should be performed after the dialysis session. Conversely, in dialysed patients with fluid removal of more than 2000 ml, where a significant increase in vein size was observed, vascular access placement should be performed before the dialysis session when the veins are smaller. Additionally, it should be noted that in patients with chronic kidney disease, the venous system of the upper limbs should be preserved as much as possible to prevent thrombosis and stenosis in potential arteriovenous fistula creation.
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To retrospectively analyse the application of the Nursing Activities Score (NAS) in an intensive care department from January 2006 to December 2011.
The sample consists of 5856 patients in three ...intensive care units (GICU: General Intensive Care Unit, NeuroICU: Neurosurgical Intensive Care Unit, CICU: Cardiothoracic Intensive Care Unit) of an Italian University hospital.
The NAS was calculated for each patient every 24hours. In patients admitted to general ICU, the following scores: SAPS 2 and SAPS 3 (Simplified Acute Physiology Score), RASS (Richmond Agitation Sedation Scale) and Braden were also recorded along with the NAS.
The mean NAS for all patients was 65.97% (Standard Deviation±2.53), GICU 72.55% (±16.28), NeuroICU 59.33% (±16.54), CICU 63.51% (SD±14.69). The average length of hospital stay (LOS) was 4.82 (SD±8.68). The NAS was high in patients with increasing LOS (p<0.003) whilst there were no significant differences for age groups except for children 0–10 years (p<0.002). The correlation of NAS and SAPS 2 was r=0.24 (p=0.001), NAS and SAPS 3 r=−0.26 (p=0.77), NAS and RASS r=−0.23 (p=0.001), NAS and Braden r=0.22 (p=0.001).
This study described the daily use of the NAS for the determination of nursing workload and defines the staff required.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, VSZLJ
ABSTRACT
Background
Prolonged application time of helmet continuous positive airway pressure (CPAP) leads to better outcomes, but its timing can be influenced by the patient's tolerance.
Aims and ...objectives
To investigate patients' pain and tolerance experience related to different options of helmet fixing system: ‘armpits strap’ versus ‘counterweights system’.
Design
This was a non–randomized crossover study performed in a 10‐bed intensive care unit and referral extra corporeal membrane oxigenation (ECMO) centre of an Italian university hospital.
Results
Twenty patients were enrolled. For helmet‐CPAP cycles performed with the armpit straps option, the mean pain numerical rate on a 0–10 scale was: 0·5 ± 1·4 at T0 (baseline), 1·5 ± 2·0 at T1 (after 1 h) and 2·6 ± 2·5 at T2 (end of cycle) (p = 0·023). The same analysis was performed for the counterweights fixing option. The mean score was 0·3 ± 0·6 at T0, 0·3 ± 0·2 at T1 and 0·5 ± 0·7 at T2 (p = 0·069). The mean duration for CPAP cycles performed with armpits strap and counterweights system was 3·0 ± 1·0 and 3·9 ± 2·3 h, respectively (p < 0·001). The mean section of the Basilic vein that was investigated before wearing the helmet was equal to 0·23 ± 0·20 cm2. After 1 h of therapy with the counterweight option and armpit straps, the mean increase of the vein's section was 0·27 ± 0·21(p = 0·099) and 0·30 ± 0·25, respectively (p = 0·080).
Conclusions
The fixing system options in use to anchor the helmet during CPAP could worsen the pain experience level and cause device‐related pressure ulcers. When compared with the armpit straps option, the counterweights system appears to be a suitable approach to minimize the risks of pressure sores and pain during the treatment.
Relevance to practice
The helmet CPAP is a reliable therapy to manage acute respiratory failure. Major improvements regarding pulmonary alveolar recruitment and oxygen levels are strictly related to a prolonged time of helmet CPAP cycles. Using a counterweight fixing system, where the armpits straps are not necessary, could be helpful in reducing patients' pain experience.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Correct tip positioning is a critical aspect in central vascular access devices insertion. The verification of positioning at the cavo-atrial junction is usually performed by intracavitary ...electrocardiography. Recently, echocardiographic techniques were proposed, including the direct visualization of the catheter or the visualization of a saline/air bolus (i.e. "bubble test"). As for the latter, a push-to-bubbles delay time below 2 s was proposed to indicate a correct positioning of the catheter tip. The aim of this study was to measure the variations of the push-to-bubbles time at increasing distance from the cavo-atrial junction, to verify if a cut-off of 1-2 s correspond to a well-positioned catheter.
We performed a prospective study including patients with clinical indication of positioning a peripherally inserted central catheter. The catheter tip was positioned at the cavo-atrial junction (P0) via intracavitary electrocardiography, and the push-to-bubbles delay time was measured. The catheter was then retracted 5 cm (P1) and 10 cm (P2), and the test was repeated at this positioning. Push-to-bubbles time measurements were performed off-line by analyzing an audio/video recording which included the echography screen and the voice signal of the operator.
Forty-nine patients were included. The average push-to-bubble time when the catheter tip was in the reference position was 0.41 ± 0.21 s. Retraction of the PICC catheter of 5 and 10 cm determined a significant increase of the push-to-bubbles time: mean time difference was +0.34 (95% IC 0.25-0.43,
< 0.001) s between P0 and P1 (5 cm distance), and +0.77 (95% IC 0.62-0.92,
< 0.001) s between P0 and P2 (10 cm distance). When the catheter was at the reference position (i.e. cavo-atrial junction) only 2.1% of bubbles delay times were above 1 s.
The push-to-bubbles time is very low when the catheter tip is at the cavo-atrial junction. This delay increases progressively with increasing distance from the target. Push-to-bubbles delay time above 1 s might indicate a catheter not close to the cavo-atrial junction.
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