Medial cortex strain distribution during noncemented total hip arthroplasty

Intraoperative proximal femur fractures are a significant concern during noncemented total hip arthroplasty. The current study was performed to investigate the hypothesis that broaching the femur and inserting the stem without using mallet applied impact loads will reduce the risk of intraoperative fracture. Rosette strain gauges were applied to the medial and anteromedial cortex of six human anatomic specimen femurs to compare the strain distribution for broaching and stem insertion. Eight additional femurs were used to compare the strain distribution for stem insertion using impact loading and constant rate stem insertion. For the impact loading stem insertions, the soft tissues surrounding the femur were modeled. Constant rate stem insertions were performed using a mechanical testing machine. The largest strains measured at the medial and anteromedial sites primarily were aligned with the femur hoop axis. The largest strain magnitude, orientation, and sign (tensile or compressive) varied widely among femurs. The stem insertion strains were significantly larger than the broaching strains (two-way analysis of variance with replication). The impact stem insertion strains were not significantly different from the constant rate stem insertion strains. The results indicate that the femur geometry and material properties have a greater influence on the strain distribution than does the implantation technique.     

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.     

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.     

Pain relief by continuous intraperitoneal nebulization of ropivacaine during gynecologic laparoscopic surgery--a randomized study and review of the literature

STUDY OBJECTIVE: To evaluate the efficacy of intraperitoneal nebulization of ropivacaine on pain relief during and after gynecologic laparoscopic procedures including a review of the literature. DESIGN: Double-blinded, randomized, controlled, clinical trial (Canadian Task Force classification I). SETTING: University hospital ambulatory gynecoendoscopic department. PATIENTS: Forty patients (20 patients in each arm) undergoing elective gynecologic same-day outpatient laparoscopic surgery including unilateral/bilateral salpingo-oophorectomy or unilateral/bilateral ovarian cystectomy. INTERVENTIONS: The study group received 10 mL of 1% ropivacaine and the control group received 10 mL of sterile water by intraperitoneal nebulization. During surgery, vital signs were recorded and summarized. Postoperatively patients were followed up for 24 hours including visual analog scale scores and analgesic use. MEASUREMENTS AND MAIN RESULTS: No significant differences existed between the groups during surgery and at the recovery department in terms of arterial blood pressure (p = .42) or heart rate (p = .60). Regarding postoperative analgesia, no difference existed between the groups in terms of morphine consumption (p = .52) or other analgesics (p = .53). No significant difference existed between the groups in postoperative visual analog scale scores including visceral, abdominal wall, and shoulder pain during rest and during cough at the different time frames (30, 60, and 120 minutes and 6 and 24 hours after surgery). CONCLUSION: Our study is the first to examine the effects of intraperitoneal nebulization of ropivacaine throughout laparoscopic gynecologic procedures on patients undergoing general anesthesia. Nebulization of 100 mg of ropivacaine under our specific regimen of anesthesia does not improve patients' outcome in terms of intraoperative and postoperative pain along with consumption of analgesics. Further research with other regimens is required.     

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.     

“Spontaneously” hypertensive mice: A potential genetic model for the study of the relationship between heart size and blood pressure

Abstract

Mice selected genetically for high and low blood pressure (BP) were compared with regard to heart weight and heart/body ratios. Two experiments were performed with mice ranging in age from 1.3 to 9 months and 11 to 23 months respectively. In a third experiment C57BL/6J mice were compared to the high and low BP mice. Heart/body ratios and heart weights, adjusted for body weight via covariance analysis, were significantly greater for the high BP mice, but no Age x BP Genotype interaction was observed. Results were discussed in terms of a possible relationship between heart weight and BP via genetic linkage or pleiotropy. The possibility was also raised that compensatory mechanisms for high blood pressure, e.g., cardiac hypertrophy, may operate very early in development for animals who are hypertensive by virtue of selective breeding for blood pressure extremes.