YokoCo

Oropouche virus (OROV; genus Orthobunyavirus) is the etiological agent of Oropouche fever, a debilitating febrile illness common in South America. We used recombinant expression of the OROV M polyprotein, which encodes the surface glycoproteins Gn and Gc plus the nonstructural protein NSm, to probe the cellular determinants for OROV assembly and budding. Gn and Gc self-assemble and are secreted independently of NSm. Mature OROV Gn has two predicted transmembrane domains that are crucial for glycoprotein translocation to the Golgi complex and glycoprotein secretion, and unlike related orthobunyaviruses, both transmembrane domains are retained during Gn maturation. Disruption of Golgi function using the drugs brefeldin A and monensin inhibits glycoprotein secretion. Infection studies have previously shown that the cellular endosomal sorting complexes required for transport (ESCRT) machinery is recruited to Golgi membranes during OROV assembly and that ESCRT activity is required for virus secretion. A dominant-negative form of the ESCRT-associated ATPase VPS4 significantly reduces recombinant OROV glycoprotein secretion and blocks virus release from infected cells, and VPS4 partly colocalizes with OROV glycoproteins and membranes costained with Golgi markers. Furthermore, immunoprecipitation and fluorescence microscopy experiments demonstrate that OROV glycoproteins interact with the ESCRT-III component CHMP6, with overexpression of a dominant-negative form of CHMP6 significantly reducing OROV glycoprotein secretion. Taken together, our data highlight differences in M polyprotein processing across orthobunyaviruses, indicate that Golgi and ESCRT function are required for glycoprotein secretion, and identify CHMP6 as an ESCRT-III component that interacts with OROV glycoproteins. Oropouche virus causes Oropouche fever, a debilitating illness common in South America that is characterized by high fever, headache, myalgia, and vomiting. The tripartite genome of this zoonotic virus is capable of reassortment, and there have been multiple epidemics of Oropouche fever in South America over the last 50 years, making Oropouche virus infection a significant threat to public health. However, the molecular characteristics of this arbovirus are poorly understood. We developed a recombinant protein expression system to investigate the cellular determinants of OROV glycoprotein maturation and secretion. We show that the proteolytic processing of the M polypeptide, which encodes the surface glycoproteins (Gn and Gc) plus a nonstructural protein (NSm), differs between OROV and its close relative Bunyamwera virus. Furthermore, we demonstrate that OROV M glycoprotein secretion requires the cellular endosomal sorting complexes required for transport (ESCRT) membrane-remodeling machinery and identify that the OROV glycoproteins interact with the ESCRT protein CHMP6.

Acute and hard-to-heal wounds are a significant burden to both a patient's quality of life and resources in healthcare systems. Here, we evaluate the outcomes of a non-comparative case series study in which Ringer's solution-preactivated polyacrylate dressings were used to treat acute and hard-to-heal wounds (the presence of Ringer's solution provides a wound dressing that allows, upon application, the immediate hydration of the underlying wound tissue).

Neuroprognostication in severe traumatic brain injury (sTBI) is challenging and occurs in critical care settings to determine withdrawal of life sustaining therapies (WSLT). However, formal pediatric sTBI neuroprognostication guidelines are lacking, brain death criteria vary and dilemmas regarding WLST persist which lead to institutional differences. We studied WLST practice and outcome in pediatric sTBI to provide insight into WLST-associated factors and survivor recovery trajectory ≥ 1 year post-sTBI. This retrospective, single center observational study included patients < 18 years admitted to the Pediatric Intensive Care Unit (PICU) of Erasmus MC-Sophia (a tertiary university hospital) between 2012 and 2020 with sTBI defined as a Glasgow Coma Scale (GCS) ≤ 8 and requiring intracranial pressure (ICP) monitoring. Clinical, neuroimaging and electroencephalogram (EEG) data were reviewed. Multidisciplinary follow-up included the Pediatric Cerebral Performance Category (PCPC) score, educational level and commonly cited complaints. Seventy-eight children with sTBI were included (median age 10.5 years; IQR 5.0 – 14.1; 56% male; 67% traffic-related accidents). Median ICP monitoring was 5 days [IQR 3-8], 19 (24%) underwent decompressive craniectomy. PICU mortality was 21% (16/78): clinical brain death (cBD, 5/16), WLST due to poor neurological prognosis (WLST_neuro, 11/16). Significant differences (p < 0.001) between survivors and nonsurvivors: first GCS score, first pupillary reaction and first lactate, Injury Severity Score (ISS), pre-hospital cardiopulmonary resuscitation and Rotterdam CT score. WLST_neuro decision timing ranged from 0 to 31 days [median 2 days, IQR 0-5]. WLST_neuro decision (n=11) was based on neurologic examination (100%), brain imaging (100%) and refractory intracranial hypertension (5/11; 45%). WLST discussions were multidisciplinary with 100% agreement. Immediate agreement between medical team and caregivers was 81%. The majority (42/62, 68%) of survivors were poor outcome (PCPC score 3 to 5) at PICU discharge, of which 12 (19%) in a vegetative state. One year post-injury no patients were in a vegetative state and the median PCPC score had improved to 2 [IQR 2-3]. No patients died after PICU discharge. Twenty percent of survivors could not attend school two years post-injury. Survivors requiring an adjusted educational level increased to 45% within this timeframe. Chronic complaints were headache, behavioral and sleeping problems. In conclusion, two thirds of sTBI PICU mortality was secondary to WLST_neuro and occurred early post-injury. Median survivor PCPC score improved from 4 to 2 with no vegetative patients one year post-sTBI. Our findings show the WLST decision process was multidisciplinary and guided by specific clinical features at presentation, clinical course and (serial) neurological diagnostic modalities of which the testing combination was determined by case-to-case variation. This stresses the need for international guidelines to provide accurate neuroprognostication within an appropriate timeframe whereby overall survivor outcome data provides valuable context and guidance in the acute phase decision process.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) remains a promising strategy for neurorehabilitation. The stimulation intensity (SI) influences the after-effects observed. Here, we examined if single sessions of a HF-rTMS protocol, administered at different suprathreshold SI, can be safely administered to able-bodied (AB) individuals.

The aim of this study was to evaluate the outcomes following acute repair of the ulnar collateral ligament of the thumb metacarpophalangeal joint (thumb UCL) using a suture anchor technique. From 2011 to 2019, we retrospectively identified 40 adult patients from a single centre who had undergone an acute thumb UCL repair (≤6 weeks post-injury). The mean age of the study cohort was 37 years (range 16-70) and 68% ( = 27/40) were male. The short-term outcomes included postoperative complications and failure of repair. The long-term outcomes were QuickDASH, the EuroQol 5-Dimension (EQ-5D), Visual Analogue Scale (EQ-VAS), return to sport and work and satisfaction with outcome. The outcomes survey was completed at a mean of 4.3 years (range 1.0-9.2) for 33 patients (83%). Postoperative complications included self-limiting sensory disturbance (7.5%, = 3/40), superficial infection (requiring oral antibiotics; 5%, = 2/40) and wound dehiscence (requiring surgical debridement and re-closure; 2.5%, = 1/40). No failures of repair were reported. The mean QuickDASH was 3.7 (range 0-27.3), EQ-5D 0.821 (range -0.041 to 1) and EQ-VAS 84 (range 60-100). Of the 32 employed patients, all returned to work at a median of 0.5 weeks (range 0-416) and the mean QuickDASH Work Module was 4.1 (range 0-50). Of the 24 patients playing sport prior to injury, 96% ( = 23/24) returned at a median of 16 weeks (range 5-52) and the mean QuickDASH Sport Module was 4.6 (range 0-25). All the patients were satisfied with their outcome (mean satisfaction score 9.8/10 [8-10O]). Thumb UCL repair using a suture anchor technique is safe and effective up to 6 weeks post injury. Pain and stiffness may persist in the longer term, but most patients report excellent upper limb function and health-related quality of life. The majority return to work and sport and are highly satisfied with their outcome. Level IV (Therapeutic).

In this study, a series of structurally novel N-(benzene sulfonyl) acetamide derivatives were designed, synthesized, and biologically evaluated as COX-2/5-LOX/TRPV1 multitarget inhibitors for anti-inflammatory and analgesic therapy. Among them, 9a and 9b displayed favorable COX-2 (9a IC=0.011 μM, 9b IC=0.023 μM), 5-LOX (9a IC=0.046 μM, 9b IC=0.31 μM) and TRPV1 (9a IC=0.008 μM, 9b IC=0.14 μM) inhibitory activities. The pharmacokinetic (PK) study of 9a in SD rats at the dosage of 10 mg/kg demonstrated a high oral exposure, an acceptable clearance and a favorable bioavailability (Cmax=5807.18 ± 2657.83 ng/mL, CL=3.24 ± 1.47 mL/min/kg, F=96.8%). Further in vivo efficacy studies illustrated that 9a was capable of ameliorating formalin-induced pain and inhibiting capsaicin-induced ear edema.

Saprochaete capitata is a rare cause of invasive fungal infection in immunocompromised patients with high mortality and antifungal resistance. We present the case of a 5-year-old boy with bone marrow aplasia, who underwent hematopoietic stem cell transplantation (HSCT) and presented persistent febrile neutropenia, abdominal pain, appearance of maculopapular lesions on the skin, and impaired renal function. The presence of S. capitata was identified by blood culture from a central venous catheter. This invasive fungal infection is rare but emergent and life-threatening, especially in immunocompromised patients with persistent febrile neutropenia and prolonged use of invasive devices such as central venous catheters.

Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps.

Pruritus is a hallmark feature in pemphigoid diseases, where it can be severe and greatly impact the quality of life of affected patients. Despite being a key symptom, the exact pathophysiological mechanisms involved in pruritus in pemphigoid are yet to be fully elucidated and effective therapies addressing them are limited. This review summarizes the present understanding of pruritus specific to pemphigoid diseases, especially the pruritogens that induce it, and the therapeutic options that have been explored so far. The majority of the available evidence is on bullous pemphigoid and epidermolysis bullosa acquisita. Histamine derived from basophils correlates with pruritus severity, with omalizumab demonstrating promising efficacy in pruritus for bullous pemphigoid. IL-4/-13 contribute to itch in bullous pemphigoid with dupilumab being evaluated in clinical trials. Other pruritogens of interest include substance P, tryptase, and thymic stromal lymphopoetin, with therapies targeting them requiring further investigation. Scratching behaviors contribute directly to blister formation through various mechanisms, such as pathological autoantibody recruitment, T helper cell type 1 polarization, and exposure of intracellular autoantigens. Treatments addressing these pathways may contribute to decreasing disease severity. Additional studies are needed to fully characterize how pruritus is regulated in pemphigoid diseases, to help pave the way to develop novel and effective therapeutics that will not only address pruritic symptoms but also decrease disease severity.

To study the oral 11 beta-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor BI 187004 (NCT02150824), as monotherapy and in combination with metformin, versus placebo in patients with type 2 diabetes mellitus (T2DM) affected by overweight or obesity.