Jamestown Canyon Virus in Collected Mosquitoes,Maine, United States, 2017–2019

Jamestown Canyon virus (JCV) is a mosquito-borne arbovirus that circulates in North America. We detected JCV in 4 pools of mosquitoes collected from midcoastal Maine, USA, during 2017–2019. Phylogenetic analysis of a JCV sequence obtained from Aedes cantator mosquitoes clustered within clade A, which also circulates in Connecticut, USA.     

Characterizing the Mechanical Behavior of Bone and Bone Surrogates in Compression Using pQCT

Many axial and appendicular skeleton bones are subjected to repetitive loading during daily activities. Until recently, the structural analysis of fractures has been limited to 2D sections, and the dynamic assessment of fracture progression has not been possible. The structural failure was analyzed using step-wise micro-compression combined with time-lapsed micro-computed tomographic imaging. The structural failure was investigated in four different sample materials (two different bone surrogates, lumbar vertebral bodies from bovine and red deer). The samples were loaded in different force steps based on uniaxial compression tests. The micro-tomography images were used to create three-dimensional models from which various parameters were calculated that provide information about the structure and density of the samples. By superimposing two 3D images and calculating the different surfaces, it was possible to precisely analyze which trabeculae failed in which area and under which load. According to the current state of the art, bone mineral density is usually used as a value for bone quality, but the question can be raised as to whether other values such as trabecular structure, damage accumulation, and bone mineralization can predict structural competence better than bone mineral density alone.     

QTQTN motif upstream of the furin-cleavage site plays a key role in SARS-CoV-2 infection and pathogenesis

The furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates. To determine whether the QTQTN motif is critical to SARS-CoV-2 replication and pathogenesis, we generated a mutant deleting the QTQTN motif (ΔQTQTN). Here, we report that the QTQTN deletion attenuates viral replication in respiratory cells in vitro and attenuates disease in vivo. The deletion results in a shortened, more rigid peptide loop that contains the FCS and is less accessible to host proteases, such as TMPRSS2. Thus, the deletion reduced the efficiency of spike processing and attenuates SARS-CoV-2 infection. Importantly, the QTQTN motif also contains residues that are glycosylated, and disruption of its glycosylation also attenuates virus replication in a TMPRSS2-dependent manner. Together, our results reveal that three aspects of the S1/S2 cleavage site—the FCS, loop length, and glycosylation—are required for efficient SARS-CoV-2 replication and pathogenesis.

SARS-CoV-2 emerged in late 2019 and has caused the largest pandemic since the 1918 influenza outbreak (1). An unusual feature of SARS-CoV-2 is the presence of a furin cleavage site (FCS) in its spike protein (2). The CoV spike is a trimer of spike proteins composed of the S1 and S2 subunits, responsible for receptor binding and membrane fusion, respectively (1). After receptor binding, the spike protein is proteolytically cleaved at the S1/S2 and S2′ sites to activate the fusion machinery. For SARS-CoV-2, the spike protein contains a novel cleavage motif recognized by the host cell furin protease (PRRAR) directly upstream of the S1/S2 cleavage site that facilitates cleavage prior to virion release from the producer cell. This FCS, not found in other group 2B CoVs, plays a key role in spike processing, infectivity, and pathogenesis as shown by our group and others (3, 4).Importantly, another novel amino acid motif, QTQTN, is found directly upstream of the FCS. This QTQTN motif, also absent in other group 2B CoVs, is often deleted and has been pervasive in cultured virus stocks of the alpha, beta, and delta variants (5–8). In addition, the QTQTN deletion has been observed in a small subset of patient samples as well (9–11). Because this deletion has been frequently identified, we set out to characterize it and determine whether it has consequences for viral replication and virulence. Using our infectious clone (12, 13), we demonstrated that the loss of this motif attenuates SARS-CoV-2 replication in respiratory cells in vitro and pathogenesis in hamsters. The QTQTN deletion results in reduced spike cleavage and diminished capacity to use serine proteases on the cell surface for entry. Importantly, mutations of glycosylation-enabling residues in the QTQTN motif results in similar replication attenuation despite intact spike processing. Together, our results highlight elements in the SARS-CoV-2 spike in addition to the FCS that contribute to increased replication and pathogenesis.     

Effect of Paclitaxel Drug-Coated Balloon Angioplasty of Infrapopliteal Lesions on Mortality

BackgroundMeta-analyses of randomized controlled trials have suggested an increased long-term mortality risk following femoropopliteal and infrapopliteal angioplasty using paclitaxel-coated devices. This study was conducted to evaluate long-term mortality after paclitaxel drug-coated balloon (DCB) and plain old balloon angioplasty (POBA) of infrapopliteal lesions in real-world practice.MethodsA retrospective mortality analysis of patients with at least 3 years of follow-up who underwent balloon-based endovascular therapy of infrapopliteal lesions was performed.ResultsOverall, 2,424 patients with infrapopliteal lesions were treated within the study period. Five hundred seventy-six patients fulfilled the study criteria. Of those, 269 patients were treated with uncoated devices without crossover to a paclitaxel-coated device during follow-up and 307 patients with DCB angioplasty. Mean (SD) follow-up was 46.48 (32.77) months. The mortality rate was 66.9% after POBA and 46.9% after DCB (P < .001). In the matched-pair cohort, 164 patients died after uncoated treatment (66.7%), and 119 in the DCB group died (48.4%; P < .001). There was no correlation between DCB length and mortality rate (P = .357). For the entire cohort, multivariate logistic regression analysis showed type of treatment (uncoated device vs DCB; P = .002), age (P < .001), stroke (P = .005), renal insufficiency (P = .014), and critical limb ischemia (P = .001) to be independent predictors of all-cause mortality. There was no significant difference in mortality among the paclitaxel exposure groups.ConclusionIn this real-world retrospective analysis, the long-term mortality rate was lower after DCB angioplasty than after POBA of infrapopliteal lesions.     

经皮椎体注入骨水泥治疗老年脊椎骨质疏松压缩性骨折

目的:观察经皮椎体内注入骨水泥(聚甲基丙烯酸甲酯)治疗脊椎骨质疏松压缩性骨折的疗效。方法:自2005-06/2006-06吉林大学中日联谊医院骨科及大庆龙南医院骨科对35例40个椎体的骨质疏松压缩性骨折患者使用经皮椎体内注射骨水泥,行椎体成形术。成形材料:美国KYPHON公司生产的骨水泥,生产准许号:(GB/T19001-2000和YY/T0287-1996)。结果:35例患者均参加随访6个月。术后均未出现骨水泥外漏、脊髓或马尾神经损伤等并发症。35例患者中5例出现穿刺部位局部疼痛,服用镇痛药物后均缓解。疼痛完全消失25例,占71.4%;明显缓解8例,占22.6%;轻度缓解2例,占6.0%;无缓解0例。15例患者在术后72h内均能下床活动。术后未再发生压缩性骨折及疼痛。结论:经皮椎体注入骨水泥可以有效改善椎体骨质疏松压缩性骨折患者疼痛症状,随访6个月未出现充填剂不良性宿主反应,临床疗效较好。     

Immune-checkpoint inhibitor-associated grade 3 hepatotoxicity managed with enteric-coated budesonide monotherapy: A case report

Rationale:The introduction of immune-checkpoint inhibitors (ICPI) in recent years has changed the natural course of many neoplasms. However, patients receiving these medications may present immune-mediated adverse events; management includes temporary or permanent cessation of treatment and corticosteroids, occasionally combined with other immunomodulators. Such immunosuppression, however, also has numerous adverse events and even if it is effective in controlling toxicity, it delays immunotherapy reinitiation, as current evidence requires dose tapering to ≤10 mg prednisolone equivalent before rechallenge. Enteric-coated budesonide is a corticosteroid formulation acting primarily to the intestine and liver, as a result of its extensive first-pass hepatic metabolism.Patient concerns:A 76-year-old woman treated with ipilimumab for metastatic melanoma presented with abdominal pain, vomiting, and diarrhea for at least the previous 4 days. Laboratory tests, among others, revealed elevated aminotransferases and C-reactive protein. During hospitalization, the patient also developed fever.Diagnosis:The patient, after excluding alternative causes of aminotransferase elevation, was diagnosed with grade 3 ipilimumab-associated hepatotoxicity.Interventions:Budesonide monotherapy was administered; initial daily dose was 12 mg.Outcomes:Fever subsided after the first dose of budesonide. Aminotransferases returned to normal-near normal approximately 1 month after the first dose of budesonide. After this point, daily dose was reduced by 3 mg every 2 weeks, with no clinical or biochemical relapse.Conclusions:This case of ICPI hepatitis is, to our knowledge, the first in the literature managed with budesonide monotherapy. Therefore, budesonide may be a potentially attractive option for the management of ICPI-associated liver injury in cases where corticosteroid treatment is necessary due to its safety profile and the potential advantage of faster immunotherapy rechallenge in selected patients without requiring dose tapering, in contrast to systemically acting corticosteroids. Clinical trials should be conducted in the future in order to validate or refute these findings.     

Ophthalmoscopic contact lenses for transpupillary thermotherapy

Ophthalmoscopic contact lenses for transpupillary thermotherapy (TTT) must provide effective visualization of retinal treatment sites and transmission of infrared diode laser radiation. Selection and proper use of retinal laser lenses requires knowledge of their lateral magnification, laser beam magnification factor, field of view and resolution. Optical performance is analyzed for Goldmann-type lenses and a series of inverted image lenses of differing magnification. Goldmann lenses have the highest resolution, but inverted image lenses of comparable magnification have 2.5 times or more their field of view. Inverted image lenses of similar magnification can differ in resolution. They require 2-4% more incident laser power to produce the same retinal irradiance as a Goldmann lens, but this difference is small in comparison to other clinical variables. Tilting an ophthalmoscopic contact lens up to 15° causes little distortion in the circularity of the retinal spot formed by a laser beam or difference in retinal irradiance across the spot. Inverted image lenses produce higher anterior segment irradiances than Goldmann-type lenses, but anterior segment injuries are less likely in TTT than conventional visible light, short-pulse retinal photocoagulation because of the comparatively low irradiances used in TTT and the decreased absorption of diode laser infrared radiation in ocular media and melanin.