Antibody-mediated procoagulant platelets in SARS-CoV-2-vaccination associated immune thrombotic thrombocytopenia.

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. To prevent severe infection, mass COVID-19 vaccination campaigns with several vaccine types are currently underway. We report pathological and immunological findings in 8 patients who developed vaccine-induced immune thrombotic thrombocytopenia (VITT) after administration of SARS-CoV-2 vaccine ChAdOx1 nCoV-19. We analyzed patient material using enzyme immune assays, flow cytometry and heparin-induced platelet aggregation assay and performed autopsies on two fatal cases. Eight patients (5 female, 3 male) with a median age of 41.5 years (range, 24 to 53) were referred to us with suspected thrombotic complications 6 to 20 days after ChAdOx1 nCoV-19 vaccination. All patients had thrombocytopenia at admission. Patients had a median platelet count of 46.5 x109/L (range, 8 to 92). Three had a fatal outcome and 5 were successfully treated. Autopsies showed arterial and venous thromboses in various organs and the occlusion of glomerular capillaries by hyaline thrombi. Sera from VITT patients contain high titer antibodies against platelet factor 4 (PF4) (OD 2.59±0.64). PF4 antibodies in VITT patients induced significant increase in procoagulant markers (P-selectin and phosphatidylserine externalization) compared to healthy volunteers and healthy vaccinated volunteers. The generation of procoagulant platelets was PF4 and heparin dependent. We demonstrate the contribution of antibody-mediated platelet activation in the pathogenesis of VITT.

Relationship of the vascular territory affected by delayed cerebral ischemia and the location of the ruptured aneurysm in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To determine the area most at risk of delayed cerebral ischemia (DCI) in relation to the location of the ruptured aneurysm in patients with aneurysmal subarachnoid hemorrhage (aSAH) and, therefore, help to choose the site for focal multimodal neuromonitoring. METHODS: We retrospectively analyzed angiographic findings, CCT scans, and patient charts of patients who were admitted with aSAH to our neurosurgical intensive care unit between 2009 and 2017. DCI was defined as infarction on CCT 2-6 weeks after aSAH. RESULTS: DCI occurred in 17.9% out of 357 included patients. A DCI occurring in the vascular territory of the artery carrying the ruptured aneurysm was found in 81.0% of patients with anterior circulation aneurysms but only in 16.7% with posterior circulation aneurysms (Fisher's exact, p=0.003). The vascular territory most frequently showing a DCI was the ipsilateral MCA territory (86.7%) in ICA aneurysms, the contra- (71.4%) and the ipsilateral (64.3%) ACA territory in ACA aneurysms, the right (93.8%) and the left (81.3%) ACA territory in AcomA aneurysms, and the ipsilateral MCA territory in MCA aneurysms (69.2%) as well as in VA/PICA/SCA aneurysms (100.0%). DCI after the rupture of a BA aneurysm occurred with 33.3% in 6 out of 8 vascular territories, respectively. DCI of multiple vascular territories occurred in 100.0% of BA aneurysms, 87.5% of AcomA aneurysms, 71.4% of ACA aneurysms, 40.0% of ICA aneurysms, 38.5% of MCA aneurysms, and 33.3% of VA/PICA/SCA aneurysms. DISCUSSION: Few studies exist that could determine the area most at risk of a DCI after an aSAH. Our data could identify the territory most at risk for DCI with a probability of > 60% except for BA aneurysms, which showed DCI in various areas and patients suffering from multiple DCIs. Either the ipsilateral ACA or MCA were affected by the DCI in about 80% of ACA and more than 90% of AcomA, ICA, MCA, and VA/PICA/SCA aneurysms. Therefore, local intraparenchymal neuromonitoring in the ACA/MCA watershed area might detect the vast majority of DCIs for all aneurysm locations, except for BA aneurysms. In ACA and AcomA aneurysms, bilateral DCI of the ACA territory was common, and bilateral probe positioning might be considered for monitoring high-risk patients. Non-focal monitoring methods might be preferably used after BA aneurysm rupture.

Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage - Serum D-dimer and C-reactive Protein as Early Markers.

BACKGROUND: Identifying patients at risk for delayed cerebral ischemia after an aneurysmal subarachnoid hemorrhage remains challenging and both delayed treatment and over-treatment are reasonable concerns. OBJECTIVE: To evaluate the role of the serum markers C-reactive protein, white blood count, and d-dimer as prognostic factors for the occurrence of delayed cerebral ischemia. METHODS: All patients admitted within 24 hours after an aneurysmal subarachnoid hemorrhage were included over a 6-year period. The World Federation of Neurosurgery and Fisher grading scales as well as the extended Glasgow Outcome Scale were documented at discharge and after a 3-to-6-month follow-up period. C-reactive protein, d-dimer, white blood count, and procalcitonin were assessed on admission, day 1, day 4, day 9, day 14, and at discharge. Radiologically confirmed delayed cerebral ischemia before discharge was the primary endpoint. Severe angiographic vasospasm and outcome were used as secondary endpoints. RESULTS: Delayed cerebral ischemia occurred in 19.6% of the 138 patients included. Delayed cerebral ischemia correlated with severe vasospasm and with a worse outcome. Serum C-reactive protein levels were higher in patients with severe vasospasm during the period of vasospasm. D-dimer levels on admission correlated with Fisher grades. Delayed cerebral ischemia occurred more frequently in patients with Fisher grade IV hemorrhage, if d-dimer levels were higher on admission. The cut-off was .445 µg/ml. CONCLUSION: Our observations support a multifactorial genesis for delayed cerebral ischemia, including vasospasm and microthrombotic and inflammatory processes. Serum d-dimer levels greater than .445 µg/ml might be a predictor for the occurrence of delayed cerebral ischemia in patients with a Fisher grade IV aneurysmal subarachnoid hemorrhage.

[Disinfection, Bathing, Dressing: Avoiding Infections in the Intensive Care Unit]. / Desinfektion, Waschen, Kleben: Vermeiden von Infektionen auf der Intensivstation.

In German intensive care units, 10 000 to 15 000 patients die annually due to nosocomial infections. Estimated 20 to 30% of these infections are preventable. Disinfecting is one of the most effective measures to avoid these infections. Hand disinfection in particular is one of the most important components to prevent infections. Another tool is whole body bathing, but it is rarely used in intensive care units. Antiseptics-impregnated dressings represent a further possibility for reducing device-associated infections. However, recently there has been an increase in reports of resistance not only to antibiotics but also to antiseptics. Proper hygienic work and the rational use of antiseptics is a requirement for avoiding nosocomial infections and can reduce the development of resistance.

Propofol Related Infusion Syndrome: Ultrastructural Evidence for a Mitochondrial Disorder.

OBJECTIVE: The objective of this report of a fatal propofol-related infusion syndrome in a young adult was to present-to our knowledge for the first time-direct ultrastructural evidence for the central role of mitochondrial damage in the pathogenesis of this syndrome. DATA SOURCES: Histological and electron microscopical analysis of liver, skeletal, and heart muscle obtained by autopsy and blood obtained from patient. STUDY SELECTION: Case report. DATA EXTRACTION: In addition to conventional macroscopical and histological investigations, electron-microscopical analysis of myocardial- and skeletal muscle and liver tissue obtained at autopsy from a young man was performed in order to search for ultrastructural changes of mitochondria. Acylcarnitine concentrations of his blood were determined by ultra-high performance liquid chromatography mass spectrometry. DATA SYNTHESIS: A 19-year-old male was admitted with acute left-side hemiparesis. The patient was intubated, then propofol infusion started, and a craniotomy was performed to remove an intracerebral hematoma. In the postoperative period, the patient presented with elevated intracranial pressure and brain edema. After repeat surgery, the patient showed impaired systolic left ventricular function, increasing fever, anuria, hyperkalemia, and metabolic acidosis, and he finally expired. Electron microscopy revealed dark, electron dense amorphous structures associated with mitochondria in heart muscle and liver tissue obtained at autopsy. Peripheral blood analysis revealed increased levels of acetyl-, propionyl-, butyryl-, malonyl-, and valeryl-carnitine as an indicator for propofol-related infusion syndrome, as well as for propofol-mediated inhibition of free fatty acid uptake into mitochondria, affecting beta-oxidation. CONCLUSIONS: Electron dense bodies found in association with mitochondria in muscle and liver cells probably correspond to accumulation of free fatty acid provide direct morphological evidence for the mitochondrial damage in propofol-related infusion syndrome.

Al4(P(t)Bu2)6--a derivative of Al4H6--and other Al4 species: a challenge for bonding interpretation between Zintl ions and metalloid clusters.

The highly energetic molecule Al(4)H(6), with its distorted tetrahedral structure, was recently characterized via mass spectrometry and photoelectron spectroscopy investigations (Li, X.; et al. Science 2007, 315, 356). Here we present the preparation and structural investigation of the first analogous Al(4)R(6) cluster compound. In order to understand the bonding in this kind of Al(4) molecule, density functional theory and second-order Møller-Plesset perturbation theory calculations were performed. The results obtained are discussed in comparison with bonding in other Al(4) moieties, especially the aromatic bonding behavior in the dianionic planar Al(4)(2-) species (Li, X.; et al. Science 2001, 291, 859). Finally, on the basis of the results obtained for Al(4) species, a more general problem is discussed: the difference in bonding between Zintl ions and metalloid clusters.

Modeling of ETL-Processes and Processed Information in Clinical Data Warehousing.

BACKGROUND: Literature describes a big potential for reuse of clinical patient data. A clinical data warehouse (CDWH) is a means for that. OBJECTIVES: To support management and maintenance of processes extracting, transforming and loading (ETL) data into CDWHs as well as to ease reuse of metadata between regular IT-management, CDWH and secondary data users by providing a modeling approach. METHODS: Expert survey and literature review to find requirements and existing modeling techniques. An ETL-modeling-technique was developed extending existing modeling techniques. Evaluation by exemplarily modeling existing ETL-process and a second expert survey. RESULTS: Nine experts participated in the first survey. Literature review yielded 15 included publications. Six existing modeling techniques were identified. A modeling technique extending 3LGM2 and combining it with openEHR information models was developed and evaluated. Seven experts participated in the evaluation. CONCLUSION: The developed approach can help in management and maintenance of ETL-processes and could serve as interface between regular IT-management, CDWH and secondary data users.

Convergent syntheses of [Sn7{C6H3-2,6-(C6H3-2,6-iPr2)2}21: a cluster with a rare pentagonal bipyramidal motif.

Two complementary synthetic routes to a pentagonal bipyramidal Sn7 cluster, Sn7Aryl2 (Aryl = terphenyl ligand), are reported.

Effect of Intra-Arterial and Intravenous Nimodipine Therapy of Cerebral Vasospasm After Subarachnoid Hemorrhage on Cerebrovascular Reactivity and Oxygenation.

BACKGROUND: For the treatment and prevention of delayed cerebral ischemia after subarachnoid hemorrhage, the vasodilating agent nimodipine (NDP) is widely employed. This study investigates the effect of NDP on cerebrovascular autoregulation, assessed by pressure reactivity index (PRx), and brain tissue oxygenation (pbrO2) when given continuously intravenously as an intra-arterial bolus or during continuous intra-arterial therapy. METHODS: Computerized continuous neuromonitoring data (intracranial pressure, mean arterial pressure, cerebral perfusion pressure [CPP], pbrO2, PRx) of 105 patients with aneurysmal SAH were retrospectively evaluated. The effect of NDP on all parameters was compared when applied intra-arterially for the treatment of severe macrovasospasm leading to perfusion deficits as either bolus treatment (n = 111 in 37 patients) or continuous infusion (n = 20 patients) to patients without or with only mild macrovasospasm who received either intravenous NDP or no NDP at all. RESULTS: Compared with patients without treatment, the intravenous application of NDP was associated with a significantly higher PRx. Autoregulation was strongly and long lastingly affected (high PRx) in continuous intra-arterial NDP infusion, accompanied by a sustained improvement of pbrO2. Intra-arterial bolus NDP application resulted as well in a significant increase of pbrO2 and PRx; the induced effect, however, was transient and subsided within 6 hours. Intracranial pressure, mean arterial pressure, and CPP were not affected during the monitoring period. CONCLUSION: The pharmacologically induced alteration of the cerebrovascular autoregulation by NDP correlates with changes of pbrO2 and indicates a beneficial effect on cerebral blood flow if CPP is maintained. This effect is limited to a few hours after bolus treatment and milder for intravenous compared with intra-arterial application.

Long-Term, Continuous Intra-Arterial Nimodipine Treatment of Severe Vasospasm After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Secondary vasospasm and disturbances in cerebrovascular autoregulation are associated with the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. An intra-arterial application of nimodipine has been shown to increase the vessel diameter, although this effect is transient. The feasibility of long-term, continuous, intra-arterial nimodipine treatment and its effects on macrovasospasm, autoregulation parameters, and outcome were evaluated in patients with refractory severe macrovasospasm. METHODS: Ten patients were included with refractory macrovasospasm despite bolus nimodipine application (n = 4) or with primary severe vasospasm (n = 6). The patients were assessed with continuous multimodal neuromonitoring (mean arterial pressure, intraceranial pressure, cerebral perfusion pressure, brain tissue oxygen tension probe), daily transcranial Doppler examinations, and computed tomography angiography/perfusion. Autoregulation indices, the pressure reactivity index, and oxygen reactivity index were calculated. Indwelling microcatheters were placed in the extracranial internal carotid arteries and 0.4 mg nimodipine was continuously infused at 50 mL/hour. RESULTS: The duration of continuous, intra-arterial nimodipine ranged from 9 to 15 days. During treatment intracranial pressure remained stable, transcranial Doppler flow velocity decreased, and brain tissue oxygen tension improved by 37%. Macrovasospasm, as assessed via computed tomography angiography, had improved (n = 5) or disappeared (n = 5) at the end of treatment. Cerebrovascular autoregulation according to the pressure reactivity index and oxygen reactivity index significantly worsened during treatment. All patients showed a favorable outcome (median Glasgow Outcome Scale 5) at 3 months. CONCLUSIONS: In well-selected patients with prolonged severe macrovasospasm, continuous intra-arterial nimodipine treatment can be applied as a rescue therapy with relative safety for more than 2 weeks to prevent secondary cerebral ischemia. The induced impairment of cerebrovascular autoregulation during treatment seems to have no negative effects.

Different reactivity of the heavier group 14 element alkyne analogues Ar'MMAr' (M = Ge, Sn; Ar' = C6H3-2,6(C6H3-2,6-Pri2)2) with R2NO.

The reactions of the digermanium and ditin alkyne analogues Ar'MMAr' (M = Ge or Sn) with R2NO, (R2NO = Me2C(CH2)3CMe2NO or N2O), result in complete MM bond cleavage to afford the germylene :Ge(Ar')ONR2 or the germanium(II) or tin(II) hydroxides {M(Ar')(micro-OH)}2.

Synthesis and characterization of the unstable primary amido tin(ii) dimer Sn(2){N(H)Dipp}(4) (Dipp = C(6)H(3)-2,6-Pr(i)(2)) and the first sesqui-amido hemi-chloride derivative Sn(2){N(H)Dipp}(3)Cl: facile conversion of a primary amide to the imide (SnNDipp)(4).

The primary tin(ii) amido derivatives Sn(2){N(H)Dipp}(4) () and Sn(2){N(H)Dipp}(3)Cl () (Dipp = C(6)H(3)-2,6-Pr(i)(2)) have been prepared and characterized. Compound was obtained by the transamination of Sn{N(SiMe(3))(2)}(2) with H(2)NDipp in a 1 : 2 ratio or by the reaction of two equivalents of LiN(H)Dipp with SnCl(2). The attempted preparation of Sn(Cl){N(H)Dipp} by reaction of LiN(H)Dipp with SnCl(2) in a 1 : 1 ratio led to the isolation of the unique species Sn(2){N(H)Dipp}(3)Cl, which is the first example of a sesqui-amido derivative of a group 14 element. Both and were characterized by (1)H and (119)Sn NMR spectroscopy, X-ray crystallography and Mössbauer spectroscopy. The structures of and feature two tin centers bridged by -N(H)Dipp ligands with the terminal positions being occupied by two N(H)Dipp () or -N(H)Dipp and -Cl () groups. The compound was found to be unstable under ambient conditions and spontaneously converts to the imide tetramer (SnNDipp)(4) in solution over several days at room temperature, representing a new synthetic route to group 14 element imides.

Discussion on the formation and bonding in three [Ga8R10] compounds: the diversity in classical Ga-Ga bonds.

Herein we describe three Ga(8) compounds that feature gallium atoms in an oxidation state of 1.25 with normal valent 2e-2c bonding. Their structures and the influence of their ligands (phosphorus and nitrogen atoms directly bonded to the Ga(8) moieties) are discussed on the basis of DFT calculations, providing an insight into a probable mechanism for insertion reactions between GaX and GaX(3) species that lead to a reaction cascade via halides like Ga(2)X(4) and Ga(5)X(7) to Ga(8)X(10) and Ga(8)X(12) (2-), respectively. Finally, the Ga(8) cores of the three title compounds were compared with the topology of carbon atoms in C(8) alkanes.

A second metalloid Ga18 cluster and its topological similarity to the high-pressure Ga-II modification.

The topology of many modifications of elemental gallium is reflected in the large variety of metalloid Ga clusters that have been isolated as intermediates on the way from the metastable molecular GaX species (X=Cl, Br, I) by means of disproportionation to the bulk metal. Herein, we report the synthesis and characterization of the first metalloid cluster anion [Ga(18)(PtBu(2))(10)](3-) with the singular core topology that resembles the gallium high-pressure modification Ga-II. The stabilization of the cluster anion through ion-pair contacts with a chainlike "Li(4)Br(2) backbone" is discussed. Furthermore, the compound is discussed in context of the other metalloid clusters Ga(18)R(8) and Ga(22)R(8) (R=SitBu(3)) and their structural relation to the elemental modifications Ga-III and beta-Ga, respectively.

Diastereoselective synthesis of highly functionalized tetrahydroxanthenols--unprecedented access to privileged structural motifs.

Tetrahydroxanthenones, which can be easily prepared by a domino oxa-Michael aldol condensation, offer various possibilities for diastereoselective functionalization, giving access to the stereocontrolled synthesis of stereochemical triades or tetrades, which represent privileged structural motifs. In most cases, the relative stereochemistry was unequivocally established by crystal structure analysis.