Revisiting the role of the spindle assembly checkpoint in the formation of gross chromosomal rearrangements in Saccharomyces cerevisiae.

Multiple pathways are known to suppress the formation of gross chromosomal rearrangements (GCRs), which can cause human diseases including cancer. In contrast, much less is known about pathways that promote their formation. The spindle assembly checkpoint (SAC), which ensures the proper separation of chromosomes during mitosis, has been reported to promote GCR, possibly by delaying mitosis to allow GCR-inducing DNA repair to occur. Here we show that this conclusion is the result of an experimental artifact arising from the synthetic lethality caused by disruption of the SAC and loss of the CIN8 gene, which is often lost in the genetic assay used to select for GCRs. After correcting for this artifact, we find no role of the SAC in promoting GCR.

Gasdermin D and Gasdermin E Are Dispensable for Silica-Mediated IL-1ß Secretion from Mouse Macrophages.

Silica crystals activate the NLRP3 inflammasome in macrophages, resulting in the caspase-1-dependent secretion of the proinflammatory cytokine IL-1ß. Caspase-1-mediated cleavage of gasdermin D (GSDMD) triggers the formation of GSDMD pores, which drive pyroptotic cell death and facilitate the rapid release of IL-1ß. However, the role of GSDMD in silica-induced lung injury is unclear. In this study, we show that although silica-induced lung injury is dependent on the inflammasome adaptor ASC and IL-1R1 signaling, GSDMD is dispensable for acute lung injury. Although the early rapid secretion of IL-1ß in response to ATP and nigericin was GSDMD dependent, GSDMD was not required for IL-1ß release at later time points. Similarly, secretion of IL-1ß from macrophages in response to silica and alum proceeded in a GSDMD-independent manner. We further found that gasdermin E did not contribute to macrophage IL-1ß secretion in the absence of GSDMD in vitro and was also not necessary for silica-induced acute lung injury in vivo. These findings demonstrate that GSDMD and gasdermin E are dispensable for IL-1ß secretion in response to silica in vitro and in silica-induced acute lung injury in vivo.

Declining Medicare reimbursement in spinal imaging: a 15-year review.

OBJECTIVE: To analyze and quantify the change in United States of America Medicare reimbursement rates for the 30 most commonly performed spinal imaging procedures. MATERIALS AND METHODS: The Physician Fee Schedule Look-Up Tool from the Centers for Medicare & Medicaid Services was utilized to find and extract the 28 most billed spinal imaging procedures. All data was adjusted for inflation and listed in 2020 US dollars. Percent change in reimbursement and Relative Value Units between 2005 and 2020, both unadjusted and adjusted, were calculated and compared. Additionally, percent change per year and compound annual growth rate were calculated and compared. RESULTS: After adjusting for inflation, the average reimbursement for all analyzed spinal imaging procedures between the years 2005 and 2020 decreased by 45.9%. The adjusted reimbursement rate for all procedures decreased at an average 4.3% per year and experienced an average compound annual growth rate (CAGR) of - 4.4%. Magnetic resonance imaging (MRI) had the most substantial adjusted decline of all imaging modalities at - 72.6%, whereas x-ray imaging had the smallest decline at - 27.33%. The average total RVUs per procedure decreased by 50.1%, from 7.96 to 3.97. CONCLUSION: From the years 2005 to 2020, Medicare reimbursement significantly decreased for all advanced imaging modalities involving the most common spinal imaging procedures. Among all practices, imaging procedures may be experiencing some of the largest decreases from Medicare reimbursement cutbacks.

The best of both worlds: Chemigenetic fluorescent sensors for biological imaging.

Synthetic-based fluorescent chemosensors and protein-based fluorescent biosensors are two well-established classes of tools for visualizing and monitoring biological processes in living tissues. Chemigenetic sensors, created using a combination of both synthetic parts and protein parts, are an emerging class of tools that aims to combine the strengths, and overcome the drawbacks, of traditional chemosensors and biosensors. This review will survey the landscape of strategies used for fluorescent chemigenetic sensor design. These strategies include: attachment of synthetic elements to proteins using in vitro protein conjugation; attachment of synthetic elements to proteins using autonomous protein labeling; and translational incorporation of unnatural amino acids.

Challenges and Opportunities in Developing an Oncology Clinical Trial Network in the United States Veterans Affairs Health Care System: The VA STARPORT Experience.

The United States Veterans Affairs (VA) Health Care System has a strong history of conducting impactful oncology randomized clinical trials (RCTs). We developed a phase II/III RCT to test the use of metastasis-directed therapy in Veterans with oligometastatic prostate cancer (OMPC)-the first VA RCT in OMPC that leverages novel imaging and advanced radiotherapy techniques. To accomplish this, we developed a clinical trial network to conduct the study. In this manuscript, we describe several challenges we encountered in study development/conduct and our strategies to address them, with the goal of helping investigators establish robust study networks to conduct clinical trials. In the study start-up, we encountered challenges in timely site activation, and leveraged project management to maximize efficiency. Additionally, there were several changes in the clinical paradigms in imaging and treatment that led to protocol amendments to ensure maximum equipoise, recruitment, and impact of the study. Specifically, we amended the trial to add de novo OMPC patients (from initially only recurrent OMPC) and expanded the study to allow up to 10 metastases (from initially five). Finally, in order to maintain local study team engagement, we developed initiatives to maximize collaboration and add value to the overall clinical program through study participation.

Comparative analysis of traditional machine learning and automated machine learning: advancing inverted papilloma versus associated squamous cell carcinoma diagnosis.

KEY POINTS: Inverted papilloma conversion to squamous cell carcinoma is not always easy to predict. AutoML requires much less technical knowledge and skill to use than traditional ML. AutoML surpassed the traditional ML algorithm in differentiating IP from IP-SCC.

Pursuing multifaceted-disciplinarity to enrich the future of justice in sustainability science.

Although sustainability issues disproportionately affect disenfranchised populations, justice considerations are often left to social scientists in sustainability research. As early-career researchers pursuing doctoral degrees in diverse disciplines focusing on sustainability, we reflect on the unintentional exclusion of justice in sustainability research. Building on our individual and collective research experiences, we propose a critical multifaceted-disciplinary perspective, advocating for the holistic creation of interdisciplinary academic teams involving scholars from diverse racial, social, cultural, and economic contexts. By embracing multifaceted-disciplinarity, we can step toward establishing and nurturing spaces that enrich justice considerations in sustainability science, forming a more comprehensive understanding of sustainability predicaments and building sustainable and humane futures for all.

Sports and Recreation-Related Wrist Fractures: An Epidemiological Study.

Background Wrist fractures have increased over the past several decades. The objective of this study was to identify all-cause and sports-related incidence rates of wrist fractures presenting to emergency departments (EDs) in the United States (U.S.) from 2013 to 2022. A secondary aim of the study was to identify if wrist fractures significantly decreased during 2020. Methodology The National Electronic Injury Surveillance System database was queried to identify the number of wrist fractures presenting to U.S. EDs from 2013 to 2022. Incidence rates in 100,000 person-years were calculated by sport, age, sex, and year. Results From 2013 to 2022, there were 2,027,131 wrist fractures evaluated at U.S. EDs. Injuries peaked in the 10-14-year-old age group, followed by the 5-9 and 85+-year-old age groups. In total, 1,096,598 were sustained during sports and recreation. Cycling, playgrounds, and skateboarding were the leading sports and recreation-related activities. Sports-related wrist fractures followed a unimodal distribution peaking in the 10-14-year-old age group. Females sustained 52% of wrist fractures overall but only 39% of sports-related wrist fractures. All-terrain vehicle and skateboarding-related wrist fractures significantly increased over the study period. Playground and soccer-related wrist fractures significantly decreased in 2020. Conclusions All-cause wrist fractures presenting to U.S. EDs significantly increased from 2013 to 2022 though sports-related wrist fractures did not. Pediatric males and elderly females are most at risk for wrist fractures overall while sports-related wrist fractures predominate in the pediatric population. Youth sports and recreation officials should be aware of the risks to mitigate the incidence of sports-related wrist fractures.

Distinct Longitudinal Trajectories of Symptom Burden Predict Clinical Outcomes in End-Stage Liver Disease.

INTRODUCTION: Little has been reported about the clinical relevance and trajectories of symptoms in end-stage liver disease (ESLD). The purpose of this prospective study was to identify trajectories of change in symptom burden over the course of 12 months in adults with ESLD. METHODS: Patients were recruited from hepatology clinics at 2 healthcare systems. Validated measures were used to assess physical and psychological symptoms. Latent growth mixture modeling and survival and growth modeling were used to analyze the survey data. RESULTS: Data were available for 192 patients (mean age 56.5 ± 11.1 years, 64.1% male, mean Model for ESLD (MELD) 3.0 19.2 ± 5.1, ethyl alcohol as primary etiology 33.9%, ascites 88.5%, encephalopathy 70.8%); there were 38 deaths and 39 liver transplantations over 12 months. Two symptom trajectories were identified: 62 patients (32.3%) had high and unmitigated symptoms, and 130 (67.7%) had lower and improving symptoms. Patients with high and unmitigated symptoms had twice the hazard of all-cause mortality (subhazard ratio 2.53, 95% confidence interval: 1.32-4.83) and had worse physical ( P < 0.001) and mental quality of life ( P = 0.012) compared with patients with lower and improving symptoms. Symptom trajectories were not associated with MELD 3.0 scores ( P = 0.395). Female sex, social support, and level of religiosity were significant predictors of symptom trajectories ( P < 0.05 for all). DISCUSSION: There seems to be 2 distinct phenotypes of symptom experience in patients with ESLD that is independent of disease severity and associated with sex, social support, religiosity, and mortality. Identifying patients with high symptom burden can help optimize their care.

Circulating microRNAs May Be Predictive of Degenerative Cervical Myelopathy.

STUDY DESIGN: Basic Science. OBJECTIVE: The objective of this study was to identify a unique serum profile of circulating miRNAs and inflammatory markers in patients with degenerative cervical myelopathy (DCM) compared with healthy controls (HC). SUMMARY OF BACKGROUND DATA: Currently, DCM is diagnosed with a combination of history, physical examination, and close correlation to advanced imaging. To date, no serum marker has been identified to be diagnostic of this condition. METHODS: Whole venous blood was collected from patients with DCM as well as healthy age-matched and gender-matched controls. miRNA was extracted from venous blood, and a screening analysis was initially conducted to identify miRNA dysregulation in DCM patients. RT-qPCR was used to analyze the expression of 2 specific miRNAs based on screening analysis and literature review. Bioinformatics analysis was used to identify gene networks and potential targets of the miRNA. In addition, the serum inflammatory profile of DCM and HC groups was differentiated using a pro-inflammatory panel. RESULTS: Thirty-six patients were enrolled in the DCM group (36.1% male, 61.5±9.5 y), while 35 patients were enrolled in the HC group (31.4% male, 57.5±8.9 y). Of the 15 total miRNAs differentially expressed between DCM and HC groups, two were selected for further analysis: miR-223-3p (upregulated) and miR-451a (downregulated). Functional gene network analysis revealed the highest-ranking gene network was involved in neurological disease, while the most overexpressed miRNA in this network (miR-233-3p) was noted to have over 100 targets, including CDKN1B and the insulin receptor. Serum cytokine analysis showed significant upregulation of several pro-inflammatory cytokines in the DCM cohort compared with the HC group. CONCLUSION: DCM patients demonstrated a set of unique circulating miRNAs in addition to a different serum inflammatory profile compared with HC. These miRNAs may potentially serve as targets for future therapeutic intervention or diagnostic/prognostic testing.

The Utility of a "Second-Look" Debridement Following Endonasal Skull Base Surgery in the Pediatric Population.

Background Sinonasal debridement is typically performed in the weeks following endonasal skull base surgery (ESBS). In the pediatric population, this second-look procedure may require general anesthesia; however, there is currently little evidence assessing the benefit of this practice. Methods This was a multicenter retrospective study of pediatric patients (age <18 years) undergoing a planned second-look debridement under general anesthesia following ESBS. Intraoperative findings, interventions performed, and perioperative complications were reviewed. Multivariate regression analysis was performed to identify associations between intraoperative findings and clinical factors. Results We reviewed 69 cases of second-look debridements (age mean 8.6 ± 4.2 years, range: 2-18 years), occurring a mean of 18.3 ± 10.3 days following ESBS. All abnormal findings were noted in patients age ≤12 years. Synechiae were noted in 8.7% of cases, bacterial rhinosinusitis in 2.9%, and failed reconstruction with cerebrospinal fluid leak in 4.5% (two cases of flap malposition and one case of flap necrosis). All failed reconstructions were noted following expanded endonasal cases for craniopharyngioma, and in each case, a revision reconstruction was performed during the second-look surgery. Synechiae were not significantly associated with younger age, revision cases, or cases with reconstructive flaps. There were no perioperative complications. Conclusion Second-look debridement under general anesthesia may be useful in the identification and intervention of sinonasal pathology following endoscopic skull base surgery, particularly in children ≤12 years old or those with pedicled flap reconstructions. Larger controlled studies are warranted to validate this practice and refine indications and timing of this second procedure.

The Effect of Aromatherapy on Anxiety and Pain in Patients Undergoing Oculoplastic Surgery.

PURPOSE: To determine the effect of aromatherapy on postoperative anxiety and pain in patients undergoing oculoplastic surgery. METHODS: A randomized controlled study of 60 patients who underwent monitored anesthesia care sedation for oculoplastic procedures from August 2018 to November 2020. Patients were randomized to an aromatherapy (n = 32) or placebo (n = 28) condition. Anxiety was measured with State-Trait Anxiety Inventory and visual analog scale for anxiety. Pain was measured with a visual analog scale for pain. RESULTS: Compared with control patients, aromatherapy patients had significantly lower postoperative State-Trait Anxiety Inventory state anxiety (24.1 vs. 29.1; p = 0.05) and visual analog scale pain scores (1.9 vs. 3.2; p = 0.05). Aromatherapy patients also had shorter stays in the postanesthesia care unit than control patients (57.7 vs. 79.4 minutes; p = 0.03). CONCLUSIONS: Patients who received aromatherapy reported lower postoperative anxiety and pain. Aromatherapy may be a useful adjuvant analgesic and/or anxiolytic for patients undergoing oculoplastic procedures with monitored anesthesia care sedation.

Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid ß precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.

Complications and outcomes after three-column osteotomy: a 5-year follow-up.

BACKGROUND: Three-column spinal osteotomies (3-CO) are powerful techniques used to correct spinal deformity. These surgeries are associated with an elevated risk of complications. While outcomes have been reported in the literature with 2 years follow-up, longer-term outcomes of three-column osteotomies remain understudied. OBJECTIVES: This study aims to examine patient reported outcomes and complications for three-column osteotomies at 5 years. STUDY DESIGN: Retrospective review of a prospectively collected spinal deformity cases database. PATIENT SAMPLE: All consecutive adult patients at a single spine surgery center treated with either a pedicle subtraction osteotomy (PSO) or vertebral column resection (VCR) for spinal deformity, and with a minimum 5-year follow-up were included. OUTCOME MEASURES: Visual-analog scale (VAS) for back pain score (0 to 10), Oswestry Disability Index (ODI) score (0 to 100), number of complications, revision rate, sagittal balance, lumbar lordosis at preoperative and at 5-year visit. METHODS: Data was extracted from a prospectively collected spinal deformity surgery database continuously updated since 2002 with data from operative reports, patients' medical visit notes and patients' self-reported VAS and ODI questionnaires completed at each office visit. Radiographic measurements were performed on standing full-length spine radiographs taken at preop and 5-year visits. Descriptive statistics, comparison of means and proportions among groups, and a logistic regression analysis were conducted using the statistical software package SPSS version 28. Statistical significance was set at p<.05. RESULTS: Of 127 consecutive adult patients with minimum of 5-year follow-up undergoing a 3-CO posterior spinal surgery for spinal deformity were identified and included in the study, 79 (62%) were treated with PSO, and 48 (38%) with VCR. Both PSO and VCR groups demonstrated significant improvements in VAS (PSO preop: 6.7, 5-year: 4.6, p<.001; VCR preop: 7.1, 5-year: 5.2, p<.001), and ODI (PSO preop: 52.9, 5-year: 45.4, p<.001; VCR preop: 57.5, 5-year 43.0, p<.001) that were maintained at 5 years. Major and minor complications occurring within 5 years were not statistically different between the PSO and VCR groups (major: 59.5% vs 56.3%, p=.85; minor: 45.6% vs 37.5%, p=.46). The rate of revision surgery within 5 years was 39.4% overall. Of the fifty patients requiring revision, 37.5% were for nonunion, 27.1% instrumentation failure, 14.6% proximal junctional kyphosis (PJK), 12.5% vertebral fracture, 6.3% motor weakness, and 2.1% infection. Improvements in lumbar lordosis were maintained at 5 years in both the PSO (29.9° vs 47.2°, p<.001) and VCR (34.6° vs 48.5°, p<.001) groups while sagittal balance maintained significant improvement in the VCR group (9.5 cm vs 6.3 cm, p=.008) but not the PSO (11.4 cm vs 9.3 cm, p=.065). CONCLUSION: Patients undergoing three-column osteotomies had a major complication rate of 57.5% and a minor complication rate of 42.5% after 5 years. Improvements in lumbar lordosis were maintained at 5-year follow-up, but sagittal balance was only maintained in the VCR group. Despite these radiographic findings, both VCR and PSO groups maintained significant clinical improvements in both VAS and ODI scores at 5-year follow up.

The impact of macro- and micro-steatosis on the outcomes of patients who undergo liver transplant: Analysis of the UNOS-STAR database.

BACKGROUND AND AIMS: The presence of steatosis in a donor liver and its relation to post-transplantation outcomes are not well defined. This study evaluates the effect of the presence and severity of micro- and macro-steatosis of a donor graft on post-transplantation outcomes. METHODS: The UNOS-STAR registry (2005-2019) was used to select patients who received a liver transplant graft with hepatic steatosis. The study cohort was stratified by the presence of macro- or micro-vesicular steatosis, and further stratified by histologic grade of steatosis. The primary endpoints of all-cause mortality and graft failure were compared using sequential Cox regression analysis. Analysis of specific causes of mortality was further performed. RESULTS: There were 9184 with no macro-steatosis (control), 150 with grade 3 macro-steatosis, 822 with grade 2 macro-steatosis and 12 585 with grade 1 macro-steatosis. There were 10 320 without micro-steatosis (control), 478 with grade 3 micro-steatosis, 1539 with grade 2 micro-steatosis and 10 404 with grade 1 micro-steatosis. There was no significant difference in all-cause mortality or graft failure among recipients who received a donor organ with any evidence of macro- or micro-steatosis, compared to those receiving non-steatotic grafts. There was increased mortality due to cardiac arrest among recipients of a grade 2 macro-steatosis donor organ. CONCLUSION: This study shows no significant difference in all-cause mortality or graft failure among recipients who received a donor liver with any degree of micro- or macro-steatosis. Further analysis identified increased mortality due to specific aetiologies among recipients receiving donor organs with varying grades of macro- and micro-steatosis.

Changes in the number of new takeaway food outlets associated with adoption of management zones around schools: A natural experimental evaluation in England.

By the end of 2017, 35 local authorities (LAs) across England had adopted takeaway management zones (or "exclusion zones") around schools as a means to curb proliferation of new takeaways. In this nationwide, natural experimental study, we evaluated the impact of management zones on takeaway retail, including unintended displacement of takeaways to areas immediately beyond management zones, and impacts on chain fast-food outlets. We used uncontrolled interrupted time series analyses to estimate changes from up to six years pre- and post-adoption of takeaway management zones around schools. We evaluated three outcomes: mean number of new takeaways within management zones (and by three identified sub-types: full management, town centre exempt and time management zones); mean number on the periphery of management zones (i.e. within an additional 100 m of the edge of zones); and presence of new chain fast-food outlets within management zones. For 26 LAs, we observed an overall decrease in the number of new takeaways opening within management zones. Six years post-intervention, we observed 0.83 (95% CI -0.30, -1.03) fewer new outlets opening per LA than would have been expected in absence of the intervention, equivalent to an 81.0% (95% CI -29.1, -100) reduction in the number of new outlets. Cumulatively, 12 (54%) fewer new takeaways opened than would have been expected over the six-year post-intervention period. When stratified by policy type, effects were most prominent for full management zones and town centre exempt zones. Estimates of intervention effects on numbers of new takeaways on the periphery of management zones, and on the presence of new chain fast-food outlets within management zones, did not meet statistical significance. Our findings suggest that management zone policies were able to demonstrably curb the proliferation of new takeaways. Modelling studies are required to measure the possible population health impacts associated with this change.