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OBJECTIVES: Surgical resection remains the primary treatment for early-stage non-small cell lung cancer (NSCLC), with lobectomy considered the standard approach. However, recent evidence suggests that sublobar resection may be an alternative option for select patients. MATERIALS AND METHODS: A systematic review and meta-analysis were conducted following PRISMA guidelines. Randomized controlled trials (RCTs) and propensity-score matched (PSM) cohort studies comparing lobectomy and sublobar resection in NSCLC patients were included. The primary outcome was overall survival (OS), and secondary outcomes included disease-free survival (DFS), 30-day mortality, and cancer recurrence rates. Individual patient data (IPD) were reconstructed from Kaplan-Meier curves, and one-stage and two-stage meta-analyses were performed. RESULTS: A total of 18 studies involving 6,075 NSCLC patients (3,119 undergoing lobectomy, 2,956 undergoing sublobar resection) were included. Lobectomy was associated with significantly better OS compared to sublobar resection (hazard ratio [HR]: 0.78, 95 % confidence interval [CI]: 0.68-0.89, p < 0.001). However, when sublobar resection was further divided into segmentectomy and wedge resection, no significant difference in OS was observed between lobectomy and segmentectomy (HR:0.92, 95 %CI: 0.75-1.14, p = 0.464) whereas lobar resection was associated with better OS compared to wedge resection (HR:0.52, 95 %CI: 0.41-0.67, p < 0.001). DFS outcomes were similar between lobectomy and sublobar resection (HR:0.98, 95 %CI: 0.84-1.14, p = 0.778). CONCLUSION: Lobectomy is associated with better overall survival compared to sublobar resection in NSCLC patients. However, when sublobar resection is subdivided, segmentectomy shows comparable outcomes to lobectomy, while wedge resection is inferior. These findings support the consideration of segmentectomy as the surgical option of choice for Stage IA NSCLC patients.
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Purpose: Meniscal injuries are common in knee surgery and often require preservation techniques to prevent secondary osteoarthritis. Despite advancements in repair techniques, some patients undergo partial meniscectomy, which can lead to postmeniscectomy syndrome. To address these challenges, meniscal substitution techniques like scaffolds have been developed. However, a comprehensive synthesis of the existing evidence through an umbrella review is lacking. Methods: A comprehensive search was conducted in the MEDLINE, Embase and Scopus databases to identify relevant systematic reviews and meta-analyses. Studies were screened based on predefined inclusion and exclusion criteria. The quality of included studies was assessed using the AMSTAR-2 tool. Results: A total of 17 studies met the inclusion criteria and were included in the review. Most studies focused on the use of collagen-based scaffolds, with fewer studies evaluating synthetic scaffolds. The majority of studies (52.9%) were rated as having 'Critically Low' overall confidence, with only one study (5.9%) rated as 'High' confidence and most studies exhibiting methodological limitations, such as small sample sizes and lack of long-term follow-up. Despite these limitations, the majority of studies reported positive short-term outcomes, including pain relief and functional improvement, following scaffold implantation. However, some studies noted a relatively high failure rate. Radiographically, outcomes also varied, with some studies reporting morphological deterioration of the implant seen on MRI, while others noted possible chondroprotective effects. Conclusions: Meniscal scaffold-based approaches show promise in the management of meniscal deficiency; however, the current evidence is limited by methodological shortcomings. One notable gap in the literature is the lack of clear guidelines for patient selection and surgical technique. Future research should focus on conducting well-designed randomized controlled trials with long-term follow-up to further elucidate the benefits and indications of these techniques in clinical practice. Additionally, efforts should be made to develop consensus guidelines to standardize the use of meniscal scaffolds and improve patient outcomes. Despite limited availability, synthesizing the literature on meniscal scaffold-based approaches is crucial for understanding research, guiding clinical decisions and informing future directions. Level of Evidence: Level IV.
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Randomized controlled trials (RCT) are the gold standard in determining efficacy of cancer screening tests. Yet, systematic differences between RCT and the general populations eligible for screening raise concerns about the generalizability and relevance of RCT findings to guide the development and dissemination of cancer screening programs. Observational studies from clinical practice settings have documented selective uptake in screening-i.e., variation across subgroups regarding who is screened and not screened-as well as suboptimal adherence to screening recommendations, including follow-up of positive findings with subsequent imaging studies and diagnostic invasive procedures. When the effectiveness of a screening intervention varies across subgroups, and there is selective uptake and suboptimal adherence to screening in clinical practice relative to that in the RCT, the effects of screening reported in RCTs are not expected to generalize to clinical practice settings. Understanding the impacts of selective uptake and suboptimal adherence on estimates of the effectiveness of cancer screening in clinical practice will generate evidence that can be used to inform future screening recommendations and enhance shared decision-making tools.
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Detecção Precoce de Câncer , Neoplasias , Humanos , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Neoplasias/diagnóstico , Cooperação do Paciente/estatística & dados numéricos , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Programas de Rastreamento/normas , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The current National Comprehensive Cancer Network advises neoadjuvant chemoradiotherapy followed by surgery for locally advanced cases of esophageal cancer. The role of immunotherapy in this context is under heavy investigation. METHODS: Patients with esophageal adenocarcinoma were identified in the National Cancer Database (NCDB) from 2004 to 2019. Three groups were generated as follows: (a) no immunotherapy, (b) neoadjuvant immunotherapy, and (c) adjuvant immunotherapy. Overall survival was evaluated using the Kaplan-Meier method and Cox proportional hazard analysis, adjusting for previously described risk factors for mortality. RESULTS: Of the total 14,244 patients diagnosed with esophageal adenocarcinoma who received neoadjuvant chemoradiation, 14,065 patients did not receive immunotherapy, 110 received neoadjuvant immunotherapy, and 69 received adjuvant immunotherapy. When adjusting for established risk factors, adjuvant immunotherapy was associated with significantly improved survival compared to no immunotherapy and neoadjuvant immunotherapy during a median follow-up period of 35.2 months. No difference was noted among patients who received no immunotherapy vs. neoadjuvant immunotherapy in the same model. CONCLUSIONS: In this retrospective analysis of the NCDB, receiving adjuvant immunotherapy offered a significant survival advantage compared to no immunotherapy and neoadjuvant immunotherapy in the treatment of esophageal adenocarcinoma. The addition of neoadjuvant immunotherapy to patients treated with neoadjuvant chemoradiation did not improve survival in this cohort. Further studies are warranted to investigate the long-term outcomes of immunotherapy in esophageal cancer.
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We conducted a cross-sectional multi-center study to compare the demographics, clinical characteristics, and lung cancer screening (LCS) results among those eligible for LCS per 2013 vs 2021 US Preventive Services Task Force (USPSTF) recommendations. Statistical tests are two-sided, with p < .05 considered statistically significant. Among 17,702 screened individuals (85.2% 2013 Eligible, 14.8% 2021 Newly Eligible), a higher proportion of those screened per 2021 vs 2013 criteria were female (56.1% vs 48.1%, p < .0001) and non-Hispanic Black (19.3% vs 13.4%, p < .0001). The risk of developing and dying from lung cancer per 1000 was statistically significantly higher among those eligible per 2013 vs 2021 criteria. A higher proportion of LCS exams had an increased suspicion of lung cancer in the 2013 vs 2021 criteria groups. Our data suggest that, as intended, updated 2021 USPSTF recommendations are leading to a higher proportion of LCS exams among non-Hispanic Black individuals and women.
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BACKGROUND: Human genetic studies have identified several mitochondrial amidoxime-reducing component 1 (MTARC1) variants as protective against metabolic dysfunction-associated steatotic liver disease. The MTARC1 variants are associated with decreased plasma lipids and liver enzymes and reduced liver-related mortality. However, the role of mARC1 in fatty liver disease is still unclear. METHODS: Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine-conjugated mouse Mtarc1 siRNA, applying it in multiple in vivo models to investigate the role of mARC1 using multiomic techniques. RESULTS: In ob/ob mice, knockdown of Mtarc1 in mouse hepatocytes resulted in decreased serum liver enzymes, LDL-cholesterol, and liver triglycerides. Reduction of mARC1 also reduced liver weight, improved lipid profiles, and attenuated liver pathological changes in 2 diet-induced metabolic dysfunction-associated steatohepatitis mouse models. A comprehensive analysis of mARC1-deficient liver from a metabolic dysfunction-associated steatohepatitis mouse model by metabolomics, proteomics, and lipidomics showed that Mtarc1 knockdown partially restored metabolites and lipids altered by diet. CONCLUSIONS: Taken together, reducing mARC1 expression in hepatocytes protects against metabolic dysfunction-associated steatohepatitis in multiple murine models, suggesting a potential therapeutic approach for this chronic liver disease.
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Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Hepatócitos , Animais , Camundongos , Hepatócitos/metabolismo , Fígado/metabolismo , Masculino , RNA Interferente Pequeno/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Camundongos Endogâmicos C57BLRESUMO
Borrelia miyamotoi disease is an emerging tick-borne human illness in the United States caused by Borrelia miyamotoi (Spirochaetales: Spirochaetaceae) bacterium. With Pennsylvania reporting thousands of tick-borne disease cases annually, determining the minimum infection rate (MIR) of B. miyamotoi in Ixodes scapularis (Say, Acari: Ixodidae) adults within Pennsylvania is of utmost importance. Active surveillance was performed from October 2019 to April 2020 to collect a minimum of 50 I. scapularis ticks from every county within Pennsylvania and then screened for B. miyamotoi via qPCR. Ticks were collected from all 67 counties with the majority of those being adult I. scapularis. Additional ticks collected were Dermacentor albipictus (Packard, Acari: Ixodidae), Haemaphysalis longicornis (Neumann, Acari: Ixodidae), and immature I. scapularis. Adult I. scapularis were pooled and tested for B. miyamotoi. MIR for positive B. miyamotoi pools and density of infected adult I. scapularis varied by county, with positive pools from 38 Pennsylvania counties. This is the first statewide evaluation of B. miyamotoi in Pennsylvania in questing adult I. scapularis. These prevalence and distribution data will aid health care practitioners within the state of Pennsylvania and the northeast United States to understand potential risk and bring awareness to the lesser known human Borrelia illness, Borrelia miyamotoi disease.
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Borrelia , Ixodes , Animais , Pennsylvania/epidemiologia , Borrelia/isolamento & purificação , Ixodes/microbiologia , Ixodes/crescimento & desenvolvimento , Feminino , Masculino , Spirochaetales/isolamento & purificação , Febre Recorrente/transmissão , Febre Recorrente/microbiologia , Febre Recorrente/epidemiologia , HumanosAssuntos
Imageamento por Ressonância Magnética , Articulação Metacarpofalângica , Humanos , Articulação Metacarpofalângica/diagnóstico por imagem , Articulação Metacarpofalângica/patologia , Diagnóstico Diferencial , Imageamento por Ressonância Magnética/métodos , Masculino , Edema/diagnóstico por imagem , FemininoAssuntos
Imageamento por Ressonância Magnética , Articulação Metacarpofalângica , Humanos , Articulação Metacarpofalângica/diagnóstico por imagem , Articulação Metacarpofalângica/patologia , Diagnóstico Diferencial , Imageamento por Ressonância Magnética/métodos , Masculino , Edema/diagnóstico por imagem , FemininoRESUMO
PURPOSE: A decline in youth running was observed at the start of the COVID-19 pandemic. We investigated whether the resumption of organized running after social distancing restrictions changed running habits or injury frequency in adolescent runners. METHODS: Adolescents (age = 16.1 [2.1] y) who participated in long-distance running activities completed an online survey in the Spring and Fall of 2020. Participants self-reported average weekly running habits and whether they sustained an injury during the Fall 2020 season. Poisson regression models and 1-way analysis of variance compared running habits while Fisher exact test compared differences in frequencies of injuries during Fall 2020 among season statuses (full, delayed, and canceled). RESULTS: All runners, regardless of season status, increased weekly distance during Fall 2020. Only runners with a full Fall 2020 season ran more times per week and more high-intensity runs per week compared with their Spring 2020 running habits. There were no differences in running volume or running-related injury frequency among Fall 2020 season statuses. CONCLUSIONS: There were no significant differences in running-related injury (RRI) frequency among runners, regardless of season status, following the resumption of cross-country. Health care providers may need to prepare for runners to increase running volume and intensity following the resumption of organized team activities.
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COVID-19 , Corrida , Humanos , Adolescente , Pandemias , Estudos Prospectivos , Fatores de Risco , HábitosRESUMO
Background: Video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS) are two viable options in patients undergoing lobectomy for non-small cell lung cancer (NSCLC); however, the debate on which one is superior is unceasing. Methods: PubMed and Scopus databases were queried for studies including patients who underwent either VATS or RATS lobectomy. This meta-analysis is in accordance with the recommendations of the PRISMA statement. Individual patient data on overall survival (OS) and disease-free survival (DFS) were extracted from Kaplan-Meier curves. One- and two-stage survival analyses, and random-effects meta-analyses were conducted. Results: Ten studies met our eligibility criteria, incorporating 1,231 and 814 patients in the VATS and RATS groups, respectively. Patients who underwent VATS had similar OS compared with those who underwent RATS [hazard ratio (HR): 1.05, 95% confidence interval (CI): 0.88-1.27, P=0.538] during a weighted median follow-up of 51.7 months, and this was validated by the two-stage meta-analysis (HR: 1.27, 95% CI: 0.85-1.90, P=0.24, I2=68.50%). Regarding DFS, the two groups also displayed equivalent outcomes (HR: 1.07, 95% CI: 0.92-1.25, P=0.371) and this was once again validated by the two-stage meta-analysis (HR: 1.05, 95% CI: 0.85-1.30, P=0.67, I2=28.27%). Both RATS and VATS had similar postoperative complication rates, prolonged air leak, conversion to thoracotomy and operative times. RATS was found to be superior to VATS in terms of length of hospital stay and number of lymph nodes dissected. Conclusions: In patients undergoing lobectomy for NSCLC, VATS and RATS have equivalent overall and DFS at a median follow-up of 51.7 months.
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Background: Total shoulder arthroplasty (TSA) is the preferred treatment for glenohumeral arthritis refractory to nonoperative measures. However, some surgeons have argued for a role for hemiarthroplasty (HA) in the setting of a smooth glenoid that articulates appropriately with the humeral head. The purpose of this study is to evaluate long-term revision rates and short-term postoperative complications in patients undergoing either HA or TSA for glenohumeral arthritis. Methods: A retrospective review of patients who underwent HA and TSA was conducted using a commercially available national database. Demographics, postoperative complications, risk factors, revision rates, and costs were analyzed using 2 sample t-tests, chi-squared tests, and multivariate logistic regressions. Results: Patients were stratified by operation: (1) HA (n = 1615) or 2) TSA (n = 7845). Patients undergoing primary TSA had higher rates of prior ipsilateral rotator cuff repair and corticosteroid injections. At 2 years, patients who underwent HA, 3.0% of patients had revision surgery, compared to 1.6% of patients who underwent TSA (P = .002); at 5 years, 3.7% of the HA cohort (P < .0001) had revision surgery, compared to 1.9% of patients who underwent TSA. Conclusions: Patients undergoing TSA or RTSA for glenohumeral arthritis had higher preoperative co-morbidities but had no difference in short-term complication rates with a lower risk of revision surgery at both 2-year and 5-year follow-up when compared to HA. Increasing age, female sex, hyperlipidemia, postoperative infection, shoulder instability, and thromboembolism all independently increased odds for revision shoulder arthroplasty for glenohumeral arthritis. Level of evidence Level: III.
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Chickens genetically resistant to avian influenza could prevent future outbreaks. In chickens, influenza A virus (IAV) relies on host protein ANP32A. Here we use CRISPR/Cas9 to generate homozygous gene edited (GE) chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction. After IAV challenge, 9/10 edited chickens remain uninfected. Challenge with a higher dose, however, led to breakthrough infections. Breakthrough IAV virus contained IAV polymerase gene mutations that conferred adaptation to the edited chicken ANP32A. Unexpectedly, this virus also replicated in chicken embryos edited to remove the entire ANP32A gene and instead co-opted alternative ANP32 protein family members, chicken ANP32B and ANP32E. Additional genome editing for removal of ANP32B and ANP32E eliminated all viral growth in chicken cells. Our data illustrate a first proof of concept step to generate IAV-resistant chickens and show that multiple genetic modifications will be required to curtail viral escape.
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Vírus da Influenza A , Influenza Aviária , Embrião de Galinha , Animais , Influenza Aviária/genética , Edição de Genes , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Galinhas/genética , Vírus da Influenza A/genética , Vírus da Influenza A/metabolismoRESUMO
Importance: The COVID-19 pandemic led to the use of lung transplant as a lifesaving therapy for patients with irreversible lung injury. Limited information is currently available regarding the outcomes associated with this treatment modality. Objective: To describe the outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis. Design, Setting, and Participants: In this cohort study, lung transplant recipient and donor characteristics and outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis were extracted from the US United Network for Organ Sharing database from March 2020 to August 2022 with a median (IQR) follow-up period of 186 (64-359) days in the acute respiratory distress syndrome group and 181 (40-350) days in the pulmonary fibrosis group. Overall survival was calculated using the Kaplan-Meier method. Cox proportional regression models were used to examine the association of certain variables with overall survival. Exposures: Lung transplant following COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis. Main Outcomes and Measures: Overall survival and graft failure rates. Results: Among 385 included patients undergoing lung transplant, 195 had COVID-19-related acute respiratory distress syndrome (142 male [72.8%]; median [IQR] age, 46 [38-54] years; median [IQR] allocation score, 88.3 [80.5-91.1]) and 190 had COVID-19-related pulmonary fibrosis (150 male [78.9%]; median [IQR] age, 54 [45-62]; median [IQR] allocation score, 78.5 [47.7-88.3]). There were 16 instances of acute rejection (8.7%) in the acute respiratory distress syndrome group and 15 (8.6%) in the pulmonary fibrosis group. The 1-, 6-, and 12- month overall survival rates were 0.99 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.91-0.98), and 0.88 (95% CI, 0.80-0.94) for the acute respiratory distress syndrome cohort and 0.96 (95% CI, 0.92-0.98), 0.92 (95% CI, 0.86-0.96), and 0.84 (95% CI, 0.74-0.90) for the pulmonary fibrosis cohort. Freedom from graft failure rates were 0.98 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.90-0.97), and 0.88 (95% CI, 0.79-0.93) in the 1-, 6-, and 12-month follow-up periods in the acute respiratory distress cohort and 0.96 (95% CI, 0.92-0.98), 0.93 (95% CI, 0.87-0.96), and 0.85 (95% CI, 0.74-0.91) in the pulmonary fibrosis cohort, respectively. Receiving a graft from a donor with a heavy and prolonged history of smoking was associated with worse overall survival in the acute respiratory distress syndrome cohort, whereas the characteristics associated with worse overall survival in the pulmonary fibrosis cohort included female recipient, male donor, and high recipient body mass index. Conclusions and Relevance: In this study, outcomes following lung transplant were similar in patients with irreversible respiratory failure due to COVID-19 and those with other pretransplant etiologies.
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COVID-19 , Transplante de Pulmão , Fibrose Pulmonar , Síndrome do Desconforto Respiratório , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Fibrose Pulmonar/cirurgia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/mortalidade , Estudos de Coortes , Pandemias , COVID-19/complicações , Transplante de Pulmão/mortalidade , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/cirurgiaRESUMO
OBJECTIVE: COVID-19 may lead to a range of clinical outcomes among older people with psychiatric and medical conditions. Evidence guiding management of future outbreaks among this vulnerable population in psychiatric hospital settings are sparse. In this study, we examined the correlates of poor clinical outcomes related to COVID-19 and explored the perspectives of COVID-19 survivors hospitalized in psychiatry settings. METHOD: The correlates of poor clinical outcomes related to COVID-19 were examined using a retrospective chart review of 81 older people hospitalized in psychiatry settings. Correlates of clinical outcomes related to COVID-19 were assessed by multiple logistic regression models. In addition, the perspectives of 10 COVID-19 survivors were explored by qualitative interviews. The qualitative data was subject to thematic analysis. RESULTS: Although 25.9% (n = 21) participants were asymptomatic, there was high COVID-19 related mortality (14.8%; n = 12). Vitamin-D deficiency, anticholinergic burden, and isolation policies within psychiatric wards were significantly (p < 0.05) related to COVID-19 related deaths. In qualitative interviews, participants emphasized the importance of strengthening local support networks and making vaccination centers more accessible. CONCLUSIONS: Reducing anticholinergic prescriptions and improving isolation policies may help to mitigate poor clinical outcomes. Future research investigating the impact of vitamin-D supplementation on COVID-19 related outcomes is warranted.
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COVID-19 , Transtornos Mentais , Humanos , Idoso , COVID-19/epidemiologia , SARS-CoV-2 , Estudos Retrospectivos , Suplementos Nutricionais , Vitamina D , Vitaminas , Antagonistas ColinérgicosRESUMO
Honey bees (Apis mellifera L.) are critical to the pollination of many important crops in the United States, and one crop that demands large numbers of colonies early each year is almonds. To provide adequate numbers of colonies for almond pollination, many beekeepers move colonies of bees to high-density holding yards in California in late fall, where the bees can fly and forage, but little natural pollen and nectar is available. In recent years, high colony losses have occurred in some operations following this management strategy, and alternative approaches, including indoor storage of colonies, have become more commonly used. The current study evaluated colonies kept indoors (refrigerated and/or controlled atmosphere) for the winter compared with those kept outdoors in either Washington or California. Colonies were evaluated for strength (frames of bees), brood area, lipid composition of worker bees, colony weight and survival, parasitic mites (Varroa mites, tracheal mites), and pathogens (Nosema spp.). No differences were found in colony weight, survival, parasitic mite levels, or pathogen prevalence among the treatments. Colonies stored indoors and outdoors in WA had significantly more frames of bees and less brood present after the storage period than colonies stored outdoors in CA. Lipid composition of honey bees stored indoors was significantly higher than colonies stored outdoors in WA or CA. The implications of these findings for overall colony health and improved pollination activity are discussed.
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Himenópteros , Prunus dulcis , Varroidae , Abelhas , Estados Unidos , Animais , Washington , LipídeosRESUMO
This cohort study evaluates associations of communication methods and content of positive lung cancer screening findings with receipt of recommended follow-up care.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Assistência ao Convalescente , Detecção Precoce de Câncer , Sobreviventes , ComunicaçãoRESUMO
STUDY DESIGN: A laboratory study comparing polyether ether ketone (PEEK)-zeolite and PEEK spinal implants in an ovine model. OBJECTIVE: This study challenges a conventional spinal implant material, PEEK, to PEEK-zeolite using a nonplated cervical ovine model. SUMMARY OF BACKGROUND DATA: Although widely used for spinal implants due to its material properties, PEEK is hydrophobic, resulting in poor osseointegration, and elicits a mild nonspecific foreign body response. Zeolites are negatively charged aluminosilicate materials that are hypothesized to reduce this pro-inflammatory response when used as a compounding material with PEEK. MATERIALS AND METHODS: Fourteen skeletally mature sheep were, each, implanted with one PEEK-zeolite interbody device and one PEEK interbody device. Both devices were packed with autograft and allograft material and randomly assigned to one of 2 cervical disc levels. The study involved 2 survival time points (12 and 26 weeks) and biomechanical, radiographic, and immunologic endpoints. One sheep expired from complications not related to the device or procedure. A biomechanical evaluation was based on measures of segmental flexibility, using 6 degrees of freedom pneumatic spine tester. Radiographic evaluation was performed using microcomputed tomography scans in a blinded manner by 3 physicians. Levels of the pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha at the implant, were quantified using immunohistochemistry. RESULTS: PEEK-zeolite and PEEK exhibited an equivalent range of motion in flexion extension, lateral bending, and axial torsion. A motion was significantly reduced for implanted devices at both time points as compared with native segments. Radiographic assessments of fusion and bone formation were similar for both devices. PEEK-zeolite exhibited lower levels of IL-1ß ( P = 0.0003) and IL-6 ( P = 0.03). CONCLUSION: PEEK-zeolite interbody fusion devices provide initial fixation substantially equivalent to PEEK implants but exhibit a reduced pro-inflammatory response. PEEK-zeolite devices may reduce the chronic inflammation and fibrosis previously observed with PEEK devices.
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Fusão Vertebral , Zeolitas , Animais , Ovinos , Microtomografia por Raio-X/métodos , Interleucina-6 , Polietilenoglicóis/química , Cetonas/química , Éteres , Fusão Vertebral/métodos , Fenômenos BiomecânicosRESUMO
ANP32 proteins, which act as influenza polymerase cofactors, vary between birds and mammals. In mammals, ANP32A and ANP32B have been reported to serve essential but redundant roles to support influenza polymerase activity. The well-known mammalian adaptation PB2-E627K enables influenza polymerase to use mammalian ANP32 proteins. However, some mammalian-adapted influenza viruses do not harbor this substitution. Here, we show that alternative PB2 adaptations, Q591R and D701N, also allow influenza polymerase to use mammalian ANP32 proteins, whereas other PB2 mutations, G158E, T271A, and D740N, increase polymerase activity in the presence of avian ANP32 proteins as well. Furthermore, PB2-E627K strongly favors use of mammalian ANP32B proteins, whereas D701N shows no such bias. Accordingly, PB2-E627K adaptation emerges in species with strong pro-viral ANP32B proteins, such as humans and mice, while D701N is more commonly seen in isolates from swine, dogs, and horses, where ANP32A proteins are the preferred cofactor. Using an experimental evolution approach, we show that the passage of viruses containing avian polymerases in human cells drove acquisition of PB2-E627K, but not in the absence of ANP32B. Finally, we show that the strong pro-viral support of ANP32B for PB2-E627K maps to the low-complexity acidic region (LCAR) tail of ANP32B. IMPORTANCE Influenza viruses naturally reside in wild aquatic birds. However, the high mutation rate of influenza viruses allows them to rapidly and frequently adapt to new hosts, including mammals. Viruses that succeed in these zoonotic jumps pose a pandemic threat whereby the virus adapts sufficiently to efficiently transmit human-to-human. The influenza virus polymerase is central to viral replication and restriction of polymerase activity is a major barrier to species jumps. ANP32 proteins are essential for influenza polymerase activity. In this study, we describe how avian influenza viruses can adapt in several different ways to use mammalian ANP32 proteins. We further show that differences between mammalian ANP32 proteins can select different adaptive changes and are responsible for some of the typical mutations that arise in mammalian-adapted influenza polymerases. These different adaptive mutations may determine the relative zoonotic potential of influenza viruses and thus help assess their pandemic risk.