Comparison of protection against mpox following mRNA or modified vaccinia Ankara vaccination in nonhuman primates.

In 2022, mpox virus (MPXV) spread worldwide, causing 99,581 mpox cases in 121 countries. Modified vaccinia Ankara (MVA) vaccine use reduced disease in at-risk populations but failed to deliver complete protection. Lag in manufacturing and distribution of MVA resulted in additional MPXV spread, with 12,000 reported cases in 2023 and an additional outbreak in Central Africa of clade I virus. These outbreaks highlight the threat of zoonotic spillover by Orthopoxviruses. mRNA-1769, an mRNA-lipid nanoparticle (LNP) vaccine expressing MPXV surface proteins, was tested in a lethal MPXV primate model. Similar to MVA, mRNA-1769 conferred protection against challenge and further mitigated symptoms and disease duration. Antibody profiling revealed a collaborative role between neutralizing and Fc-functional extracellular virion (EV)-specific antibodies in viral restriction and ospinophagocytic and cytotoxic antibody functions in protection against lesions. mRNA-1769 enhanced viral control and disease attenuation compared with MVA, highlighting the potential for mRNA vaccines to mitigate future pandemic threats.

An mpox virus mRNA-lipid nanoparticle vaccine confers protection against lethal orthopoxviral challenge.

Mpox virus (MPXV) caused a global outbreak in 2022. Although smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after complete immunization. Given the threat of additional zoonotic events and the virus's evolving ability to drive human-to-human transmission, there is an urgent need for an MPXV-specific vaccine that confers protection against evolving MPXV strains and related orthopoxviruses. Here, we demonstrate that an mRNA-lipid nanoparticle vaccine encoding a set of four highly conserved MPXV surface proteins involved in virus attachment, entry, and transmission can induce MPXV-specific immunity and heterologous protection against a lethal vaccinia virus (VACV) challenge. Compared with modified vaccinia virus Ankara (MVA), which forms the basis for the current MPXV vaccine, immunization with an mRNA-based MPXV vaccine generated superior neutralizing activity against MPXV and VACV and more efficiently inhibited spread between cells. We also observed greater Fc effector TH1-biased humoral immunity to the four MPXV antigens encoded by the vaccine, as well as to the four VACV homologs. Single MPXV antigen-encoding mRNA vaccines provided partial protection against VACV challenge, whereas multivalent vaccines combining mRNAs encoding two, three, or four MPXV antigens protected against disease-related weight loss and death equal or superior to MVA vaccination. These data demonstrate that an mRNA-based MPXV vaccine confers robust protection against VACV.

Exploring the Roles of HERC2 and the NEDD4L HECT E3 Ubiquitin Ligase Subfamily in p53 Signaling and the DNA Damage Response.

Cellular homeostasis is governed by the precise expression of genes that control the translation, localization, and termination of proteins. Oftentimes, environmental and biological factors can introduce mutations into the genetic framework of cells during their growth and division, and these genetic abnormalities can result in malignant transformations caused by protein malfunction. For example, p53 is a prominent tumor suppressor protein that is capable of undergoing more than 300 posttranslational modifications (PTMs) and is involved with controlling apoptotic signaling, transcription, and the DNA damage response (DDR). In this review, we focus on the molecular mechanisms and interactions that occur between p53, the HECT E3 ubiquitin ligases WWP1, SMURF1, HECW1 and HERC2, and other oncogenic proteins in the cell to explore how irregular HECT-p53 interactions can induce tumorigenesis.

Thoracoscopic anterior instrumented fusion for adolescent idiopathic scoliosis with emphasis on the sagittal plane.

BACKGROUND CONTEXT: Anterior fusion through an open thoracotomy restores kyphosis more reliably than posterior techniques in patients with thoracic adolescent idiopathic scoliosis (AIS). Video-assisted thoracoscopic spinal fusion and instrumentation (VATS) minimizes the morbidity, from soft tissue and muscle dissection that accompanies traditional open thoracotomy. To our knowledge, there has not been a comprehensive analysis of VATS with respect to radiographic and clinical outcomes in the sagittal plane. PURPOSE: To measure the radiographic and clinical outcomes after VATS with emphasis on the sagittal plane. STUDY DESIGN/SETTING: A retrospective, radiographic review of 26 consecutive patients with Lenke type-I AIS who underwent VATS. METHODS: Radiographs of 26 consecutive patients with Lenke type-I AIS curves operated by a single surgeon were retrospectively reviewed after VATS. Sagittal and coronal parameters were compared with reported data for open anterior and posterior procedures. RESULTS: There was an increase in kyphosis from baseline to final follow-up by 6.6 degrees (25%) from T2 to T12 (p<.0001), 8.7 degrees (50%) from T5 to T12 (p<.0001), and 8 degrees (54%) in the instrumented segment (p<.0001). Junctional kyphosis did not occur. No differences were detected in sagittal measurements between the first postoperative erect and the final radiographs. Patients experienced significant improvements from baseline to 2 years in Scoliosis Research Society-22 Health-Related Quality-of-Life Outcome Questionnaire scores (p<.0001). CONCLUSIONS: Video-assisted thoracoscopic spinal fusion and instrumentation, in agreement with results reported for open anterior instrumentation, reliably restores or increases thoracic kyphosis while preserving junctional alignment in thoracic AIS.

Reuse of external fixation components: a randomized trial.

OBJECTIVES: External fixation devices are sold in the United States as single-use devices and can be costly. Approved processes for refurbishment of nonimplantable components are available. We evaluated one such program for safety, efficacy, and fiscal ramifications. DESIGN: Randomized clinical trial SETTING: Single center, Level I trauma center PATIENTS/PARTICIPANTS: During the 30-month enrollment period (November 16, 2001 to May 16, 2004), 41 patients (13%) of 315 patients were not able to consent and were excluded. A total of 178 (65%) of the 274 eligible patients who were offered entry into a randomized trial of new versus refurbished external fixation components for their injury refused to participate, leaving 96 (35%) of the 274 eligible patients entered into the study. INTERVENTION: Consented patients were entered into a trial of new versus refurbished nonimplantable external fixation components for their injury (all pins were new). MAIN OUTCOME MEASUREMENTS: The frames were evaluated at the time of removal for efficacy and the complications of pin tract infections, loss of fixation, or loosening of components. RESULTS: A total of 48 distal radius fractures, 29 pilon fractures, and 19 tibial plateau fractures were entered into the study. With the 96 fractures treated in our study (50 new frames, 46 reused frames), we found no statistical differences in the incidence of pin tract infections (46% versus 52%, P=0.32), loss of fixation (4% versus 4%, P=0.70), or loosening of the components (1% versus 1%, P=1.0). CONCLUSIONS: Sixty-five percent of consentable patients did not wish to have an external fixation frame with refurbished clamps. Our study demonstrated that this type of program is safe and effective with an actual cost savings of $65,452. The potential savings of such a program is 25% of the cost of all new frames.

Mini-open thoracoscopically assisted thoracotomy versus video-assisted thoracoscopic surgery for anterior release in thoracic scoliosis and kyphosis: a comparison of operative and radiographic results.

BACKGROUND CONTEXT: Combining anterior release and interbody fusion with posterior instrumented fusion is an accepted treatment for severe rigid spinal deformity. Video-assisted thoracoscopic surgery (VATS) and mini-open thoracoscopically assisted thoracotomy (MOTA) are two minimally invasive approaches to the thoracic spine. Both reduce surgical trauma, improve cosmesis and provide effective exposure for release and fusion. Published data and the authors' surgical experience have demonstrated that both techniques are equivalent in degree of release to traditional open thoracotomy, but no comparison between these two minimally invasive alternatives has been published to our knowledge. PURPOSE: This study compared MOTA and VATS under the hypothesis that both result in similar corrections and comparable operative parameters when used in conjunction with posterior instrumented fusion. STUDY DESIGN/SETTING: Retrospective chart review of consecutive case series by two surgeons. PATIENT SAMPLE: Twenty-one (13 female, 8 male) patients underwent MOTA and 24 patients (17 female, 7 male) underwent VATS for anterior release, discectomy and fusion prior to posterior instrumented fusion. OUTCOME MEASURES: Outcomes were measured at a minimum of 1-year follow-up and included radiographic Cobb measurements and operative parameters. METHODS: The indications for surgery included rigid and severe scoliosis or thoracic kyphosis. Data collection included preoperative demographics, number of levels released, primary curve correction, operative time and blood loss. Data were normalized per number of levels released anteriorly. Statistical analysis of results was done using a two-sample t test assuming equal variances with two-tail p values less than .05. RESULTS: More anterior levels were operated on average in the VATS group (6.33 vs. 4.38 levels). Curve correction per anterior level released was similar in both groups (8.7 and 8.8 degrees/level for MOTA and VATS, respectively). There was a significant difference in operative time with MOTA averaging 131.7 minutes and VATS averaging 162.8 minutes. However, a comparison of the operative time per anterior level operated, approached statistical significance in favor of VATS (33.0 vs. 28.4 minutes, p=.08). There was no significant difference in estimated blood loss during the anterior portion of the surgeries. There was a trend toward decreased blood loss per operated level favoring VATS (68.4 vs. 38.9 cc, p=.09). CONCLUSIONS: Both approaches resulted in corrections that compare favorably with open thoracotomy. We suggest that a factor in choosing between these two minimally invasive techniques is the number of thoracic levels requiring release. For four levels or less, MOTA provides an excellent alternative to standard thoracotomy. For five or more levels, VATS provides for excellent exposure of additional levels with the advantages of less operative time and blood loss per operated level.