Identification of von Willebrand factor D4 domain mutations in patients of Afro-Caribbean descent: In vitro characterization.

Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene (VWF) revealed the presence of multiple variants located throughout the gene, including variants located in the D4 domain of VWF: p.(Pro2145Thrfs*5) in one patient and p.(Cys2216Phefs*9) in the other patient. Interestingly, D4 variants have not been studied often. Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p.(Cys2216Phefs*9) influenced VWF biosynthesis/secretion and functions using in vitro assays. Methods: Recombinant VWF (rVWF), mutant or wild-type, was produced via transient transfection of the human embryonic kidney cell line 293T. The use of different tags for the wild-type and the mutant allele allowed us to distinguish between the two forms when measuring VWF antigen in medium and cell lysates. Binding of rVWF to its ligands, collagen, factor VIII, ADAMTS13, and platelet receptors was also investigated. Results: Homozygous expression of the p.(Cys2216Phefs*9)-rVWF mutation resulted in an almost complete intracellular retention of the protein. Heterozygous expression led to secretion of almost exclusively wild-type-rVWF, logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs*5)-rVWF exhibited reduced binding to type III collagen and αIIbß3 integrin compared to wild-type-rVWF. Conclusions: We report two mutations of the D4 domains that induced combined qualitative and quantitative defects.

The Damage Control Resuscitation and Surgical Team: The New French Paradigm for Management of Combat Casualties.

INTRODUCTION: The aim of this work was to introduce the new French forward resuscitation and surgical unit. It's also to discuss the choices and waivers granted to fit the tactical context of modern conflicts and the current epidemiology of combat casualties. MATERIALS AND METHODS: A multidisciplinary task force of 11 people proceeded to the conception and the creation of a new military resuscitation and surgical unit. The preliminary work included a scoping review of the combat casualties' epidemiology in modern conflicts and an analysis of the recent French medical-surgical treatment facilities lessons learned. In April 2019, a technical-operational evaluation was conducted to confirm all the technical, ergonomic, and organizational choices made during the design phase. RESULTS: The multidisciplinary task force resulted in the creation of the Damage Control Resuscitation and Surgical Team (DCRST). The DCRST focused on the resuscitation strategy, including transfusion of blood products, and the life-saving surgical procedures to be performed as close as possible to the point of injury. It was designed for the resuscitation of two patients: the life-saving surgery of two patients and the very short-term intensive care (<12 hours) of four patients at the same time. The DCRST provided sufficient autonomy to provide take care of four T1 and four T2 or T3 casualties per day for 48 hours. It was armed with 23 soldiers. The technical equipment represented 5,300 kg and 27 m3. All the technical medical equipment could be stored in two 20-foot containers. CONCLUSION: The DCRST represents a new paradigm in medical support of French military operations. It offers the advantage of two combat casualties' surgical management at the same time, as close as possible to the combat zone. It responds to a 2-fold epidemiological and logistical challenge.

Massive Ischemic Strokes in a Young Patient With Severe Coronavirus Disease 2019 Pneumonia.

Stroke is an identified sequela of severe coronavirus disease 2019 (COVID-19) infection. While the pathophysiology remains poorly understood, endothelial dysfunction and intravascular thrombosis secondary to sepsis-induced hypercoagulability likely increase the risk of stroke. This report describes the rare case of an otherwise healthy 42-year-old male who developed large bilateral ischemic infarcts during admission for severe hypoxemic respiratory failure secondary to COVID pneumonia. This report adds to scarce literature describing massive cerebrovascular injury in COVID patients and emphasizes the importance of increased clinical suspicion for stroke in patients who exhibit acute change in mental status or motor function, as well as rapid clinical deterioration.

Seizure control and side-effect profile after switching adult epileptic patients from standard to extended-release divalproex sodium.

OBJECTIVES: To assess changes in seizure frequency, medication side-effects (especially tremor) and formulation preference after switching patients overnight from immediate-release to extended-release divalproex sodium. METHODS: Prospective evaluation of consecutive adult outpatients at an urban public hospital who were followed for 6 months after switching drug formulations. Seizure frequency was estimated from patient self-reports. Medication side-effects were monitored with a structured interview (tremor, fatigue, GI upset, hair loss), physician exam (nystagmus, tremor), a drawing test (tremor) and a specific 25-item questionnaire assessing the impact of tremor on activities of daily living. RESULTS: Forty-seven patients were included in the study but six patients were either lost to follow-up or had insufficient data. Seizure frequency and side-effect profile did not change significantly after switching drug formulations. However, patients had significant subjective improvement in their tremor with the extended-release formulation as assessed by the 25-item questionnaire (p=0.009 at 3 months and p=0.04 at 6 months); other measures of tremor severity showed no change during the 6-month follow-up period. Most patients (71%) preferred the extended-release formulation. CONCLUSION: Patients with epilepsy can be switched overnight from standard to extended-release divalproex sodium, without significant change in seizure frequency and drug side-effect profile. Most patients prefer the extended-release formulation, in part due to subjective decrease in tremor during daily activities.

Hepatitis C virus (HCV) genotypes in the Caribbean island of Martinique: evidence for a large radiation of HCV-2 and for a recent introduction from Europe of HCV-4.

Molecular epidemiological studies of hepatitis C virus (HCV) in the Caribbean may help to specify the origin and spread of HCV infection. Indeed, the Caribbean population is intermixed from European and African origins and geographically close to the American continent. We characterized HCV genotypes in the Caribbean island of Martinique. HCV genotypes were analyzed by sequencing or reverse hybridization in the 5' noncoding region (5'NC) in 250 HCV-monoinfected and 85 HCV-human immunodeficiency virus (HIV)-coinfected patients. In addition, sequencing in the nonstructural 5B (NS5B) gene was required to determine the subtype or to perform phylogenetic analysis in selected samples. Genotypes 1 to 6 were found, respectively, in 84.4, 6.8, 5.2, 2.8, 0.4, and 0.4% of 250 HCV-monoinfected patients and in 71.7, 7.1, 15.3, 5.9, 0, and 0% of 85 HCV-HIV-coinfected patients. HCV-1b was found in 66.4% of the HCV-monoinfected patients and was associated with blood transfusion, whereas HCV-1a was detected in 41.2% of the HCV-HIV-coinfected patients and was associated with intravenous drug use (IVDU). The HCV-3 strains belonged to subtype 3a and were linked to IVDU. Phylogenetic analyses were focused on HCV-2 and HCV-4, which are common in Africa. Two opposite patterns were evidenced. NS5B sequences from 19 HCV-2 isolates were affiliated with many different subtypes described either in Europe or in West Africa, suggesting an ancient radiation. In contrast, seven of the nine HCV-4 NS5B sequences ranged within HCV-4a and HCV-4d clusters spreading in continental France by the IVDU route. Epidemiological data demonstrate the recent introduction of HCV-4a and -4d subtypes into the Caribbean.

Simultaneous acquisition of multiple orders of intermolecular multiple-quantum coherence images in vivo.

Until recently, NMR imaging with intermolecular multiple-quantum coherences (iMQCs) has been based on the acquisition of a single echo. In vivo studies of iMQC image contrast would greatly benefit from a method that could acquire several orders of quantum coherence during the same acquisition. This would enable comparison of the image contrast for various orders and eliminate image coregistration problems between scans. It has previously been demonstrated that multiple orders of iMQC images can be simultaneously acquired of a simple phantom. Here, we examine the technique and its effect on biological tissue, both in vivo and in vitro. First, we establish the effectiveness of the iMQC sequence in vivo using earthworms as specimens. We then further show that the multi-CRAZED sequence enhances detection of next generation (nanoparticle) contrast agents on excised tumor tissue.

Magnetization structure contrast based on intermolecular multiple-quantum coherences.

In vivo and ex vivo MRI based on intermolecular multiple-quantum coherences (iMQC) is predicted to provide a fundamentally different source of contrast for MRI. This article investigates the dependence of image contrast upon the choice of correlation distance for a heterogeneous material. A closely packed array of parallel hollow cylinders was used to demonstrate signal intensity variations when the correlation distance becomes comparable to the gap size between the cylinders. The observed effects agree well with three-dimensional calculations of the time evolution of magnetization under the nonlinear Bloch equations.