Identifying and Responding to Lead in Drinking Water in a University Setting.

Lead is an established neurotoxicant, and it has known associations with adverse neurodevelopmental and reproductive outcomes. Exposure to lead at any level is unsafe, and the United States (US) has enacted various federal and state legislations to regulate lead levels in drinking water in K-12 schools and childcare facilities; however, no regulations exist for higher education settings. Upon the discovery of lead in drinking water fixtures in the University of North Carolina at Chapel Hill (UNC-CH) campus, a cross-campus water testing network and sampling plan was developed and deployed. The campaign was based on the US Environmental Protection Agency's (EPA) 3Ts (Training, Testing, and Taking Action) guidance. The seven-month campaign involved 5954 tests on 3825 drinking water fixtures across 265 buildings. A total of 502 (8.43%) tests showed lead above the limit of detection (1 part per billion, ppb), which represented 422 (11.03%) fixtures. Fewer than 1.5% of the tests were above the EPA action level for public water systems (15 ppb). In conclusion, systematic testing of all the fixtures across campus was required to identify localized contamination, and each entity in the cross-campus network undertook necessary roles to generate a successful testing campaign. UNC-CH established preventative measures to test drinking water fixtures every three years, which provide a framework for other higher education institutions in responding to lead contamination.

Investigating viral and autoimmune T cell responses associated with post-acute sequelae of COVID-19.

Post-acute sequelae of COVID-19 (PASC), or Long COVID, is a chronic condition following acute SARS-CoV-2 infection. Symptoms include exertion fatigue, respiratory issues, myalgia, and neurological manifestations such as 'brain fog,' posing concern for their debilitating nature and potential role in other neurological disorders. However, the underlying potential pathogenic mechanisms of the neurological complications of PASC is largely unknown. Herein, we investigated differences in antigen-specific T cell responses from the peripheral blood towards SARS-CoV-2, latent viruses, or neuronal antigens in 14 PASC individuals with neurological manifestations (PASC-N) versus 22 individuals fully recovered from COVID-19. We employed Activation Induced Marker (AIM), ICS and FluoroSpot assays to determine the specificity and magnitude of CD4+ and CD8+ T cell responses towards SARS-CoV-2 (Spike and rest of proteome), latent viruses (CMV, EBV), and several neuronal antigens. Overall, we observed similar antigen-specific T cell frequencies and cytokine effector T cell responses between PASC donors compared to recovered controls for all antigens tested (viral or autoantigen) in both CD4+ and CD8+ T cell compartments. Our findings suggest that PASC-N does not appear to be associated with changes in antigen-specific T cell responses towards a subset of disease-relevant targets, but more studies in a larger cohort are needed to confirm these unaltered responses.

ST6GAL1 is associated with poor response to chemoradiation in rectal cancer.

INTRODUCTION: Colorectal cancer is the third most common cause of cancer death. Rectal cancer makes up a third of all colorectal cases. Treatment for locally advanced rectal cancer includes chemoradiation followed by surgery. We have previously identified ST6GAL1 as a cause of resistance to chemoradiation in vitro and hypothesized that it would be correlated with poor response in human derived models and human tissues. METHODS: Five organoid models were created from primary human rectal cancers and ST6GAL1 was knocked down via lentivirus transduction in one model. ST6GAL1 and Cleaved Caspase-3 (CC3) were assessed after chemoradiation via immunostaining. A tissue microarray (TMA) was created from twenty-six patients who underwent chemoradiation and had pre- and post-treatment specimens of rectal adenocarcinoma available at our institution. Immunohistochemistry was performed for ST6GAL1 and percent positive cancer cell staining was assessed and correlation with pathological grade of response was measured. RESULTS: Organoid models were treated with chemoradiation and both ST6GAL1 mRNA and protein significantly increased after treatment. The organoid model targeted with ST6GAL1 knockdown was found to have increased CC3 after treatment. In the tissue microarray, 42 percent of patient samples had an increase in percent tumor cell staining for ST6GAL1 after treatment. Post-treatment percent staining was associated with a worse grade of treatment response (p = 0.01) and increased staining post-treatment compared to pre-treatment was also associated with a worse response (p = 0.01). CONCLUSION: ST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.

PINK1 is a target of T cell responses in Parkinson's disease.

Parkinson's disease (PD) is associated with autoimmune T cells that recognize the protein alpha-synuclein in a subset of individuals. Multiple neuroantigens are targets of autoinflammatory T cells in classical central nervous system autoimmune diseases such as multiple sclerosis (MS). Here, we explored whether additional autoantigenic targets of T cells in PD. We generated 15-mer peptide pools spanning several PD-related proteins implicated in PD pathology, including GBA, SOD1, PINK1, parkin, OGDH, and LRRK2. Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. This approach identified unique epitopes and their HLA restriction from the mitochondrial-associated protein PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells. The T cell reactivity was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.

Monitoring the abundance of flying insects and atmospheric conditions during a 9-month campaign using an entomological optical sensor.

Monitoring the dynamics of insect populations is key to assessing the impact of human activities on insect populations. However, traditional methodologies relying on physical traps have inherent limitations in accurately monitoring insect abundance. Here, we present findings from a 9-month campaign conducted in New Jersey, USA, utilizing a near-infrared optical sensor known as eBoss. From April to December 2022, the eBoss derived the aerial density (insect/m3) and biomass density (mg/m3) with a 1-min resolution from a total of 302,093 insect observations. The data collected were analyzed in relation to air temperature, relative humidity, and wind speed. The results revealed that the abundance of flying insects exhibited an initial increase from April to June, reaching a peak of 0.094 insect/m3 and 1.34 mg/m3, followed by a subsequent decline towards the end of the year. Our investigation showed a surge in insect abundance above 12.5 °C, with particularly high levels observed between 19 and 31 °C. The impact of relative humidity and wind speed on insect populations was also explored. Overall, this campaign demonstrated the efficacy of photonic sensors in gathering novel and extensive data for the field of entomology, paving the way for improved understanding and management of insect populations.

Aerosol Particle Size Influences the Infectious Dose and Disease Severity in a Golden Syrian Hamster Model of Inhalational COVID-19.

Background: Significant evidence suggests that SARS-CoV-2 can be transmitted via respiratory aerosols, which are known to vary as a function of respiratory activity. Most animal models examine disease presentation following inhalation of small-particle aerosols similar to those generated during quiet breathing or speaking. However, despite evidence that particle size can influence dose-infectivity relationships and disease presentation for other microorganisms, no studies have examined the infectivity of SARS-CoV-2 contained in larger particle aerosols similar to those produced during coughing, singing, or talking. Therefore, the aim of the present study was to assess the influence of aerodynamic diameter on the infectivity and virulence of aerosols containing SARS-CoV-2 in a hamster model of inhalational COVID-19. Methods: Dose-response relationships were assessed for two different aerosol particle size distributions, with mass median aerodynamic diameters (MMADs) of 1.3 and 5.2 µm in groups of Syrian hamsters exposed to aerosols containing SARS-CoV-2. Results: Disease was characterized by viral shedding in oropharyngeal swabs, increased respiratory rate, decreased activity, and decreased weight gain. Aerosol particle size significantly influenced the median doses to induce seroconversion and viral shedding, with both increasing ∼30-fold when the MMAD was increased. In addition, disease presentation was dose-dependent, with seroconversion and viral shedding occurring at lower doses than symptomatic disease characterized by increased respiratory rate and decreased activity. Conclusions: These results suggest that aerosol particle size may be an important factor influencing the risk of COVID-19 transmission and needs to be considered when developing animal models of disease. This result agrees with numerous previous studies with other microorganisms and animal species, suggesting that it would be generally translatable across different species. However, it should be noted that the absolute magnitude of the observed shifts in the median doses obtained with the specific particle sizes utilized herein may not be directly applicable to other species.

Postoperative Proton Pump Inhibitors are associated with a significantly higher rate of delayed gastric emptying after pancreatoduodenectomy.

BACKGROUND: Proton pump inhibitors (PPIs) are effective in reducing marginal ulcers after pancreatoduodenectomy. However, their impact on perioperative complications has not been defined. METHODS: We retrospectively analyzed the effect of postoperative PPIs on 90-day perioperative outcomes in all patients who underwent pancreatoduodenectomy at our institution from April 2017 to December 2020. RESULTS: 284 patients were included; 206 (72.5%) received perioperative PPIs, 78 (27.5%) did not. The two cohorts were similar in demographics and operative variables. Postoperatively, the PPI cohort had significantly higher rates of overall complications (74.3% vs. 53.8%) and delayed gastric emptying (28.6% vs. 11.5%), p < 0.05. However, no differences in infectious complications, postoperative pancreatic fistula, or anastomotic leaks were seen. On multivariate analysis, PPI was independently associated with a higher risk of overall complications (OR 2.46, CI 1.33-4.54) and delayed gastric emptying (OR 2.73, CI 1.26-5.91), p = 0.011. Four patients developed marginal ulcers within 90-days postoperatively; all were in the group who received PPIs. CONCLUSION: Postoperative proton pump inhibitor use was associated with a significantly higher rate of overall complications and delayed gastric emptying after pancreatoduodenectomy.

Video Interviews and Surgical Applicants' Ability to Assess Fit to Residency Programs.

INTRODUCTION: Due to the COVID-19 pandemic, the recruitment cycle for the 2021 Match was performed virtually. This Association for Surgical Education (ASE)-sponsored survey set out to study applicants' ability to assess the factors contributing to fit through video interviews. METHODS: An IRB-approved, online, anonymous survey was distributed to surgical applicants at a single academic institution and through the ASE clerkship director distribution list between the rank order list certification deadline and Match Day. Applicants used 5-point Likert-type scales to rate factors for importance to fit and their ease of assessment through video interviewing. A variety of recruitment activities were also rated by applicants for their perceived helpfulness in assessment of fit. RESULTS: One hundred and eighty-three applicants responded to the survey. The three most important factors for applicant fit were how much the program cared, how satisfied residents seem with their program, and how well residents get along. Resident rapport, diversity of the patient population, and quality of the facilities were hardest to assess through video interviews. In general, diversity-related factors were more important to female and non-White applicants, but not more difficult to assess. Interview day and resident-only virtual panels were the most helpful recruitment activities, while virtual campus tours, faculty-only panels, and a program's social media were the least helpful. CONCLUSIONS: This study provides valuable insight into the limitations of virtual recruitment for surgical applicants' perception of fit. These findings and the recommendations herein should be taken into consideration by residency program leadership to ensure successful recruitment of diverse residency classes.

Microhabitat modeling of the invasive Asian longhorned tick (Haemaphysalis longicornis) in New Jersey, USA.

The Asian longhorned tick (Haemaphysalis longicornis) is a vector of multiple arboviral and bacterial pathogens in its native East Asia and expanded distribution in Australasia. This species has both bisexual and parthenogenetic populations that can reach high population densities under favorable conditions. Established populations of parthenogenetic H. longicornis were detected in the eastern United States in 2017 and the possible range of this species at the continental level (North America) based on climatic conditions has been modeled. However, little is known about factors influencing the distribution of H. longicornis at geographic scales relevant to local surveillance and control. To examine the importance of local physiogeographic conditions such as geology, soil characteristics, and land cover on the distribution of H. longicornis we employed ecological niche modeling using three machine learning algorithms - Maxent, Random Forest (RF), and Generalized Boosting Method (GBM) to estimate probability of finding H. longicornis in a particular location in New Jersey (USA), based on environmental predictors. The presence of H. longicornis in New Jersey was positively associated with Piedmont physiogeographic province and two soil types - Alfisols and Inceptisols. Soil hydraulic conductivity was the most important predictor explaining H. longicornis habitat suitability, with more permeable sandy soils with higher hydraulic conductivity being less suitable than clay or loam soils. The models were projected over the state of New Jersey creating a probabilistic map of H. longicornis habitat suitability at a high spatial resolution of 90×90 meters. The model's sensitivity was 87% for locations sampled in 2017-2019 adding to the growing evidence of the importance of soil characteristics to the survival of ticks. For the 2020-2022 dataset the model fit was 57%, suggestive of spillover to less optimal habitats or, alternatively, heterogeneity in soil characteristics at the edges of broad physiographic zones. Further modeling should incorporate abundance and life-stage information as well as detailed characterization of the soil at collection sites. Once critical parameters that drive the survival and abundance of H. longicornis are identified they can be used to guide surveillance and control strategies for this invasive species.

Insect biomass density: measurement of seasonal and daily variations using an entomological optical sensor.

Insects are major actors in Earth's ecosystems and their recent decline in abundance and diversity is alarming. The monitoring of insects is paramount to understand the cause of this decline and guide conservation policies. In this contribution, an infrared laser-based system is used to remotely monitor the biomass density of flying insects in the wild. By measuring the optical extinction caused by insects crossing the 36-m long laser beam, the Entomological Bistatic Optical Sensor System used in this study can evaluate the mass of each specimen. At the field location, between July and December 2021, the instrument made a total of 262,870 observations of insects for which the average dry mass was 17.1 mg and the median 3.4 mg. The daily average mass of flying insects per meter cube of air at the field location has been retrieved throughout the season and ranged between near 0 to 1.2 mg/m3. Thanks to its temporal resolution in the minute range, daily variations of biomass density have been observed as well. These measurements show daily activity patterns changing with the season, as large increases in biomass density were evident around sunset and sunrise during Summer but not during Fall.

Unaltered T cell responses to common antigens in individuals with Parkinson's disease.

BACKGROUND AND OBJECTIVES: Parkinson's disease (PD) is associated with a heightened inflammatory state, including activated T cells. However, it is unclear whether these PD T cell responses are antigen specific or more indicative of generalized hyperresponsiveness. Our objective was to measure and compare antigen-specific T cell responses directed towards antigens derived from commonly encountered human pathogens/vaccines in patients with PD and age-matched healthy controls (HC). METHODS: Peripheral blood mononuclear cells (PBMCs) from 20 PD patients and 19 age-matched HCs were screened. Antigen specific T cell responses were measured by flow cytometry using a combination of the activation induced marker (AIM) assay and intracellular cytokine staining. RESULTS: Here we show that both PD patients and HCs show similar T cell activation levels to several antigens derived from commonly encountered human pathogens/vaccines in the general population. Similarly, we also observed no difference between HC and PD in the levels of CD4 and CD8 T cell derived cytokines produced in response to any of the common antigens tested. These antigens encompassed both viral (coronavirus, rhinovirus, respiratory syncytial virus, influenza, cytomegalovirus) and bacterial (pertussis, tetanus) targets. CONCLUSIONS: These results suggest the T cell dysfunction observed in PD may not extend itself to abnormal responses to commonly encountered or vaccine-target antigens. Our study supports the notion that the targets of inflammatory T cell responses in PD may be more directed towards autoantigens like α-synuclein (α-syn) rather than common foreign antigens.

4,300 steps per day prior to surgery are associated with improved outcomes after pancreatectomy.

BACKGROUND: Decreased preoperative physical fitness and low physical activity have been associated with preoperative functional reserve and surgical complications. We sought to evaluate daily step count as a measure of physical activity and its relationship with post-pancreatectomy outcomes. METHODS: Patients undergoing pancreatectomy were given a remote telemonitoring device to measure their preoperative levels of physical activity. Patient activity, demographics, and perioperative outcomes were collected and compared in univariate and multivariate logistic regression analysis. RESULTS: 73 patients were included. 45 (61.6%) patients developed complications, with 17 (23.3%) of those patients developing severe complications. These patients walked 3437.8 (SD 1976.7) average daily steps, compared to 5918.8 (SD 2851.1) in patients without severe complications (p < 0.001). In logistic regression analysis, patients who walked less than 4274.5 steps had significantly higher odds of severe complications (OR = 7.5 (CI 2.1, 26.8), p = 0.002). CONCLUSION: Average daily steps below 4274.5 before surgery are associated with severe complications after pancreatectomy. Preoperative physical activity levels may represent a modifiable target for prehabilitation protocols.

Biomechanical comparison of subsidence performance among three modern porous lateral cage designs.

BACKGROUND: Cage subsidence remains a major complication after spinal surgery. The goal of this study was to compare the subsidence performance of three modern porous cage designs. METHODS: Three porous cages were evaluated: a porous titanium cage, a porous polyetheretherketone cage and a truss titanium cage. Mechanical testing was performed for each cage per the American Society for Testing and Materials F2077 and F2267 standards to evaluate cage stiffness and block stiffness, and per a novel clinically relevant dynamic subsidence testing method simulating cyclic spine loading during 3-months postoperatively to evaluate the subsidence displacement. FINDINGS: The porous polyetheretherketone cage demonstrated the lowest cage stiffness (21.0 ± 1.1 kN/mm), less than half of both titanium cages (truss titanium cage, 49.1 kN/mm; porous titanium cage, 43.6 kN/mm). The block stiffness was greatest for the porous titanium cage (2867.7 ± 105.3 N/mm), followed by the porous polyetheretherketone (2563.4 ± 72.9 N/mm) and truss titanium cages (2213.7 ± 21.8 N/mm). The dynamic subsidence displacement was greatest for the truss titanium cage, which was 1.5 and 2.5 times the subsidence displacement as the porous polyetheretherketone and porous titanium cages respectively. INTERPRETATIONS: Specific porous cage design plays a crucial role in the cage subsidence performance, to a greater degree than the selection of cage materials. A porous titanium cage with body lattice and microporous endplates significantly outperformed a truss titanium cage with a similar cage stiffness in subsidence performance, and a porous polyetheretherketone cage with half of its stiffness.

Central and Peripheral Inflammation: Connecting the Immune Responses of Parkinson's Disease.

Inflammation has increasingly become a focus of study in regards to Parkinson's disease (PD). Moreover, both central and peripheral sources of inflammation have been implicated in the pathogenesis of PD. Central inflammation consisting of activated microglia, astroglia, and T cell responses within the PD central nervous system; and peripheral inflammation referring to activated innate cells and T cell signaling in the enteric nervous system, gastrointestinal tract, and blood. This review will highlight important work that further implicates central and peripheral inflammation in playing a role in PD. We also discuss how these two distant inflammations appear related and how that may be mediated by autoantigenic responses to α-syn.

Increased Morbidity and Mortality After Hepatectomy for Colorectal Liver Metastases in Frail Patients is Largely Driven by Worse Outcomes After Minor Hepatectomy: It's Not "Just a Wedge".

BACKGROUND: Frailty is associated with postoperative mortality, but its significance after hepatectomy for colorectal liver metastases (CRLM) is poorly defined. This study evaluated the impact of frailty after hepatectomy for CRLM. METHODS: The study identified 8477 patients in National Surgical Quality Improvement Program databases from 2014 to 2019 and stratified them by frailty score using the risk analysis index as very frail (>90th percentile), frail (75th-90th percentile), or non-frail (< 75th percentile). Multivariate regression models determined the impact of frailty on perioperative outcomes, including by the extent of hepatectomy. RESULTS: The procedures performed were 2752 major hepatectomies (left hepatectomy, right hepatectomy, trisectionectomy) and 5725 minor hepatectomies (≤2 segments) for 870 (10.3%) very frail, 1680 (19.8%) frail, and 5927 (69.9%) non-frail patients. Postoperatively, the very frail and frail patients experienced more complications (very frail [41.8%], frail [35.1%], non-frail [31.0%]), which resulted in a longer hospital stay (very-frail [5.7 days], frail [5.8 days], non-frail [5.1 days]), a higher 30-day mortality (very-frail [2.2%], frail [1.3%], non-frail [0.5%]), and more discharges to a facility (very frail [6.8%], frail [3.7%], non-frail [2.6%]) (p < 0.05) although they underwent similarly extensive (major vs. minor) hepatectomies. In the multivariate analysis, frailty was independently associated with complications (very-frail [odds ratio {OR}, 1.70], frail [OR, 1.25]) and 30-day mortality (very-frail [OR, 4.24], frail [OR, 2.41]) (p < 0.05). After minor hepatectomy, the very frail and frail patients had significantly higher rates of complications and 30-day mortality than the non-frail patients, and in the multivariate analysis, frailty was independently associated with complications (very frail [OR, 1.97], frail [OR, 1.27]) and 30-day mortality (very frail [OR, 6.76], frail [OR, 3.47]) (p < 0.05) after minor hepatectomy. CONCLUSIONS: Frailty predicted significantly poorer outcomes after hepatectomy for CRLM, even after only a minor hepatectomy.

Cause and outcome of aborting a difficult laparoscopic cholecystectomy due to severe inflammation: a study of operative notes.

BACKGROUND: Upon encountering a difficult cholecystectomy in which, after a reasonable trial of dissection, anatomical identification has not been attained due to severe inflammation, and the risk of additional dissection is deemed to be hazardous, "bail-out" strategies are encouraged safety valves. One strategy is to abort the cholecystectomy and refer the patient to a HPB center for further management. METHODS: A retrospective review was conducted of cholecystectomies performed by HPB surgeons at our center between 2005 and 2019. We identified 63 patients who had an aborted cholecystectomy because of acute or chronic cholecystitis and were referred for additional care. Of these, operative notes and other clinical records were available for 43 patients who were included in this study. RESULTS: 42 cholecystectomies (98%) were started laparoscopically. 25 patients (58%) had chronic cholecystitis, and 18 (42%) had acute cholecystitis. 40 cases (93%) fell into the highest level of difficulty on the Nassar scale (Grade 4). Procedures were aborted at the following stages of dissection: in 10 patients (23%), none of the gallbladder was identified; in another 11 (26%), only the dome of gallbladder was identified; the body of the gallbladder was exposed in 13 (30%); and dissection of the hepatocystic triangle was attempted unsuccessfully in 9 (21%). Following referral to our center, 30 patients (70%) were managed with total cholecystectomy while in 13 cases (30%), subtotal cholecystectomy was performed. CONCLUSION: Aborting cholecystectomy and referring the patient to an HPB center is rarely needed but is an effective bail-out strategy for general surgeons encountering highly difficult operative conditions due to inflammation.

Transcriptional analysis of peripheral memory T cells reveals Parkinson's disease-specific gene signatures.

Parkinson's disease (PD) is a multi-stage neurodegenerative disorder with largely unknown etiology. Recent findings have identified PD-associated autoimmune features including roles for T cells. To further characterize the role of T cells in PD, we performed RNA sequencing on PBMC and peripheral CD4 and CD8 memory T cell subsets derived from PD patients and age-matched healthy controls. When the groups were stratified by their T cell responsiveness to alpha-synuclein (α-syn) as a proxy for an ongoing inflammatory autoimmune response, the study revealed a broad differential gene expression profile in memory T cell subsets and a specific PD associated gene signature. We identified significant enrichment of transcriptomic signatures previously associated with PD, including for oxidative stress, phosphorylation, autophagy of mitochondria, cholesterol metabolism and inflammation, and the chemokine signaling proteins CX3CR1, CCR5, and CCR1. In addition, we identified genes in these peripheral cells that have previously been shown to be involved in PD pathogenesis and expressed in neurons, such as LRRK2, LAMP3, and aquaporin. Together, these findings suggest that features of circulating T cells with α-syn-specific responses in PD patients provide insights into the interactive processes that occur during PD pathogenesis and suggest potential intervention targets.

Choice of Spinal Interbody Fusion Cage Material and Design Influences Subsidence and Osseointegration Performance.

OBJECTIVE: The objective of the study was to quantify the effect of cage material (titanium-alloy vs. polyetheretherketone or PEEK) and design (porous vs. solid) on subsidence and osseointegration. METHODS: Three lateral cages (solid PEEK, solid titanium, and 3-dimension-printed porous titanium cages) were evaluated for cage stiffness, subsidence compression stiffness, and dynamic subsidence displacement under simulated postoperative spine loading. Dowel-shaped implants made of grit-blasted solid titanium alloy (solid titanium) and porous titanium were fabricated using commercially available processes. Samples were processed for mechanical push-out testing and polymethylmethacrylate histology following an established ovine bone implantation model. RESULTS: The solid titanium cage exhibited the greatest stiffness (57.1 ± 0.6 kN/mm), followed by the porous titanium cage (40.4 ± 0.3 kN/mm) and the solid PEEK cage (37.1 ± 1.2 kN/mm). In the clinically relevant dynamic subsidence, the porous titanium cage showed the least amount of subsidence displacement (0.195 ± 0.012 mm), significantly less than that of the solid PEEK cage (0.328 ± 0.020 mm) and the solid titanium cage (0.538 ± 0.027 mm). Bony on-growth was noted histologically on all implant materials; however, only the porous titanium supported bony ingrowth with marked quantities of bone formed within the interconnected pores through 12 weeks. Functional differences in osseointegration were noted between groups during push-out testing. The porous titanium showed the highest maximum shear stress at 12 weeks and was the only group that demonstrated significant improvement (4-12 weeks). CONCLUSIONS: The choice of material and design is critical to cage mechanical and biological performances. A porous titanium cage can reduce subsidence risk and generate biological stability through bone on-growth and ingrowth.

Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer.

Treatment of locally advanced rectal cancer includes chemoradiation and surgery, but patient response to treatment is variable. Patients who have a complete response have improved outcomes; therefore, there is a critical need to identify mechanisms of resistance to circumvent them. DNA-PK is involved in the repair of DNA double-strand breaks caused by radiation, which we found to be increased in rectal cancer after treatment. We hypothesized that inhibiting this complex with a DNA-PK inhibitor, Peposertib (M3814), would improve treatment response. We assessed pDNA-PK in a rectal cancer cell line and mouse model utilizing western blotting, viability assays, γH2AX staining, and treatment response. The three treatment groups were: standard of care (SOC) (5-fluorouracil (5FU) with radiation), M3814 with radiation, and M3814 with SOC. SOC treatment of rectal cancer cells increased pDNA-PK protein and increased γH2AX foci, but this was abrogated by the addition of M3814. Mice with CT26 tumors treated with M3814 with SOC did not differ in average tumor size but individual tumor response varied. The clinical complete response rate improved significantly with the addition of M3814 but pathological complete response did not. We investigated alterations in DNA repair and found that Kap1 and pATM are increased after M3814 addition suggesting this may mediate resistance. When the DNA-PK inhibitor, M3814, is combined with SOC treatment, response improved in some rectal cancer models but an increase in other repair mechanisms likely diminishes the effect. A clinical trial is ongoing to further explore the role of DNA-PK inhibition in rectal cancer treatment.

Subsidence and fusion performance of a 3D-printed porous interbody cage with stress-optimized body lattice and microporous endplates - a comprehensive mechanical and biological analysis.

BACKGROUND CONTEXT: Cage subsidence remains a serious complication after spinal fusion surgery. Novel porous designs in the cage body or endplate offer attractive options to improve subsidence and osseointegration performance. PURPOSE: To elucidate the relative contribution of a porous design in each of the two major domains (body and endplates) to cage stiffness and subsidence performance, using standardized mechanical testing methods, and to analyze the fusion progression via an established ovine interbody fusion model to support the mechanical testing findings. STUDY DESIGN/SETTING: A comparative preclinical study using standardized mechanical testing and established animal model. METHODS: To isolate the subsidence performance contributed by each porous cage design feature, namely the stress-optimized body lattice (vs. a solid body) and microporous endplates (vs. smooth endplates), four groups of cages (two-by-two combination of these two features) were tested in: (1) static axial compression of the cage (per ASTM F2077) and (2) static subsidence (per ASTM F2267). To evaluate the progression of fusion, titanium cages were created with a microporous endplate and internal lattice architecture analogous to commercial implants used in subsidence testing and implanted in an endplate-sparing, ovine intervertebral body fusion model. RESULTS: The cage stiffness was reduced by 16.7% by the porous body lattice, and by 16.6% by the microporous endplates. The porous titanium cage with both porous features showed the lowest stiffness with a value of 40.4±0.3 kN/mm (Mean±SEM) and a block stiffness of 1976.8±27.4 N/mm for subsidence. The body lattice showed no significant impact on the block stiffness (1.4% reduction), while the microporous endplates decreased the block stiffness significantly by 24.9% (p<.0001). All segments implanted with porous titanium cages were deemed rigidly fused by manual palpation, except one at 12 weeks, consistent with robotic ROM testing and radiographic and histologic observations. A reduction in ROM was noted from 12 to 26 weeks (4.1±1.6° to 2.2±1.4° in lateral bending, p<.05; 2.1±0.6° to 1.5±0.3° in axial rotation, p<.05); and 3.3±1.6° to 1.9±1.2° in flexion extension, p=.07). Bone in the available void improved with time in the central aperture (54±35% to 83±13%, p<.05) and porous cage structure (19±26% to 37±21%, p=.15). CONCLUSIONS: Body lattice and microporous endplates features can effectively reduce the cage stiffness, therefore reducing the risk of stress shielding and promoting early fusion. While body lattice showed no impact on block stiffness and the microporous endplates reduced the block stiffness, a titanium cage with microporous endplates and internal lattice supported bone ingrowth and segmental mechanical stability as early as 12 weeks in ovine interbody fusion. CLINICAL SIGNIFICANCE: Porous titanium cage architecture can offer an attractive solution to increase the available space for bone ingrowth and bridging to support successful spinal fusion while mitigating risks of increased subsidence.