The Effect of Intraoperative Overdistraction on Subsidence Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study was to evaluate the effect of overdistraction on interbody cage subsidence. BACKGROUND: Vertebral overdistraction due to the use of large intervertebral cage sizes may increase the risk of postoperative subsidence. METHODS: Patients who underwent anterior cervical discectomy and fusion between 2016 and 2021 were included. All measurements were performed using lateral cervical radiographs at 3 time points - preoperative, immediate postoperative, and final follow-up >6 months postoperatively. Anterior and posterior distraction were calculated by subtracting the preoperative disc height from the immediate postoperative disc height. Cage subsidence was calculated by subtracting the final follow-up postoperative disc height from the immediate postoperative disc height. Associations between anterior and posterior subsidence and distraction were determined using multivariable linear regression models. The analyses controlled for cage type, cervical level, sex, age, smoking status, and osteopenia. RESULTS: Sixty-eight patients and 125 fused levels were included in the study. Of the 68 fusions, 22 were single-level fusions, 35 were 2-level, and 11 were 3-level. The median final follow-up interval was 368 days (range: 181-1257 d). Anterior disc space subsidence was positively associated with anterior distraction (beta = 0.23; 95% CI: 0.08, 0.38; P = 0.004), and posterior disc space subsidence was positively associated with posterior distraction (beta = 0.29; 95% CI: 0.13, 0.45; P < 0.001). No significant associations between anterior distraction and posterior subsidence (beta = 0.07; 95% CI: -0.06, 0.20; P = 0.270) or posterior distraction and anterior subsidence (beta = 0.06; 95% CI: -0.14, 0.27; P = 0.541) were observed. CONCLUSIONS: We found that overdistraction of the disc space was associated with increased postoperative subsidence after anterior cervical discectomy and fusion. Surgeons should consider choosing a smaller cage size to avoid overdistraction and minimize postoperative subsidence.

A review of the mesotheliogenic potency of cleavage fragments found in talc.

It has long been recognized that amphibole minerals, such as cleavage fragments of tremolite and anthophyllite, may exist in some talc deposits. We reviewed the current state of the science regarding the factors influencing mesotheliogenic potency of cleavage fragments, with emphasis on those that may co-occur in talc deposits, including dimensional and structural characteristics, animal toxicology, and the most well-studied cohort exposed to talc-associated cleavage fragments. Based on our review, multiple lines of scientific evidence demonstrate that inhaled cleavage fragments associated with talc do not pose a mesothelioma hazard.

Comprehensive mutagenesis maps the effect of all single-codon mutations in the AAV2 rep gene on AAV production.

Recombinant adeno-associated viruses (rAAVs) are the predominant gene therapy vector. Several rAAV vectored therapies have achieved regulatory approval, but production of sufficient rAAV quantities remains difficult. The AAV Rep proteins, which are essential for genome replication and packaging, represent a promising engineering target for improvement of rAAV production but remain underexplored. To gain a comprehensive understanding of the Rep proteins and their mutational landscape, we assayed the effects of all 39,297 possible single-codon mutations to the AAV2 rep gene on AAV2 production. Most beneficial variants are not observed in nature, indicating that improved production may require synthetic mutations. Additionally, the effects of AAV2 rep mutations were largely consistent across capsid serotypes, suggesting that production benefits are capsid independent. Our results provide a detailed sequence-to-function map that enhances our understanding of Rep protein function and lays the groundwork for Rep engineering and enhancement of large-scale gene therapy production.

CT109-SN-38, a Novel Antibody-drug Conjugate with Dual Specificity for CEACAM5 and 6, Elicits Potent Killing of Pancreatic Cancer Cells.

BACKGROUND: CEACAM5 and CEACAM6 are glycosylphosphatidylinositol (GPI)- linked members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which are frequently upregulated in epithelial cancers where they contribute to invasion, metastasis, immune evasion, and resistance to anoikis. CT109 is a novel antibody with dual specificity to both CEACAM5 and 6. OBJECTIVES: In this study, we aimed to perform the preclinical characterization of CT109 and antibody- drug conjugate (ADCs) derivatives of CT109, focusing on CT109-SN-38. METHODS: CT109's cognate epitope was characterized by scanning mutagenesis. CT109 specificity and internalization kinetics were assessed by immunoblot and flow cytometry, respectively. Cognate antigen expression prevalence in colorectal cancer and normal tissue arrays was determined by immunohistochemistry. CT109 conjugations were generated by the reaction of reduced CT109 cysteines with maleimide-functionalized payload linkers. In vitro cytotoxic activity of CT109 ADCs was characterized on antigen-positive and negative pancreatic ductal adenocarcinoma cell (PDAC) lines using a luminometric viability assay. In vivo efficacy of CT109-SN-38 was assessed on a PDAC tumor xenograft model at 10 and 25 mg/kg concentrations. RESULTS: CT109 was shown to bind a glycoepitope centered on N309. CT109 is internalized in the CEACAM5+/CEACAM6+ double-positive PDAC line, BxPC-3, with a t1/2 of 2.3 hours. CT109 ADCs elicit a dose and antigen-dependent cytotoxic effect, with CT109-SN-38 exhibiting an IC50 value of 21 nM in BxPC-3 cells. In a BxPC-3 tumor xenograft model, CT109-SN-38 reduced tumor growth and induced regression in 3/10 mice at a concentration 25 mg/kg. CONCLUSION: These data suggest that further preclinical and clinical development of CT109-SN-38 is warranted.

Assessment of worst-case potential airborne asbestos exposure associated with the use of cosmetic talc: application of an exponential decay model.

Talc is used in cosmetic products to confer desirable properties, such as moisture absorption and smooth texture, to the finished products. Concerns have been raised about the potential presence of asbestos in products containing cosmetic talc. Reconstruction of potential asbestos exposure from the use of cosmetic talc products (assuming a trace level of asbestos) requires consideration of consumer use patterns. Although application generally only lasts seconds, exposure theoretically may continue if the consumer remains in the immediate vicinity. Most published exposure measurements have not adequately characterized the potential for continued exposure. In this analysis, estimates and measurements of airborne asbestos fiber concentrations associated with cosmetic talc use from 10 published studies were used as inputs to an exponential decay model to estimate "worst-case" exposure during and following application. The resulting geometric mean 30-min time-weighted average (TWA) concentrations were 0.006 f/cc for both puff and shaker application, for diapering, 0.0001 f/cc (adult applying baby powder) and 0.0002 f/cc (infant), and for makeup application, 0.0005 f/cc. Application of an exponential decay model to measured or estimated asbestos concentrations associated with the use of cosmetic talc products yields a conservative means to comprehensively reconstruct such exposures. Moreover, our results support that, if a cosmetic talc powder product contained a trace level of asbestos fibers, the "worst-case" airborne asbestos exposure associated with its application is low.

Mechanics of lumenless pacing lead strength during extraction procedures based on laboratory bench testing.

BACKGROUND: With the advent of conduction system pacing, use of the Medtronic SelectSecure Model 3830 lead has increased substantially. However, with this increased use, the potential need for lead extraction also will increase. Lumenless lead construction requires an understanding of both applicable tensile forces as well as lead preparation techniques that can influence consistent extraction. OBJECTIVE: The purpose of this study was to use bench testing methodologies to characterize the physical properties of lumenless leads and to describe related lead preparation methods that support known extraction techniques. METHODS: Multiple 3830 lead preparation techniques, commonly used in extraction practices, were compared on the bench to assess rail strength (RS) in simple traction and use conditions with simulated scar. Retention of the IS1 connector vs severing the lead body preparation techniques were compared. Distal snare and rotational extraction tools were evaluated. RESULTS: The retained connector method provided higher RS compared to the modified cut lead method: mean 11.42 lbf (9.85-12.73 lbf) vs 8.51 lbf (1.66-14.32 lbf), respectively. Snare use distally did not significantly affect RS: mean 11.05 lbf (8.58-13.95 lbf). Lead damage occurred with the TightRail extraction tool at angles ≥90°, which could occur with right-sided implants. CONCLUSIONS: When extracting SelectSecure leads, the retained connector method to maintain cable engagement benefits preservation of the extraction RS. Limiting traction force to <10 lbf (4.5 kgf) and avoiding poor lead preparation methods are critical to consistent extraction. Femoral snaring does not change RS when needed and offers a method to regain lead rail in cases of distal cable fracture.