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PURPOSE: To determine if an explainable artificial intelligence (XAI) model enhances the accuracy and transparency of predicting embryo ploidy status based on embryonic characteristics and clinical data. METHODS: This retrospective study utilized a dataset of 1908 blastocyst embryos. The dataset includes ploidy status, morphokinetic features, morphology grades, and 11 clinical variables. Six machine learning (ML) models including Random Forest (RF), Linear Discriminant Analysis (LDA), Logistic Regression (LR), Support Vector Machine (SVM), AdaBoost (ADA), and Light Gradient-Boosting Machine (LGBM) were trained to predict ploidy status probabilities across three distinct datasets: high-grade embryos (HGE, n = 1107), low-grade embryos (LGE, n = 364), and all-grade embryos (AGE, n = 1471). The model's performance was interpreted using XAI, including SHapley Additive exPlanations (SHAP) and Local Interpretable Model-agnostic Explanations (LIME) techniques. RESULTS: The mean maternal age was 38.5 ± 3.85 years. The Random Forest (RF) model exhibited superior performance compared to the other five ML models, achieving an accuracy of 0.749 and an AUC of 0.808 for AGE. In the external test set, the RF model achieved an accuracy of 0.714 and an AUC of 0.750 (95% CI, 0.702-0.796). SHAP's feature impact analysis highlighted that maternal age, paternal age, time to blastocyst (tB), and day 5 morphology grade significantly impacted the predictive model. In addition, LIME offered specific case-ploidy prediction probabilities, revealing the model's assigned values for each variable within a finite range. CONCLUSION: The model highlights the potential of using XAI algorithms to enhance ploidy prediction, optimize embryo selection as patient-centric consultation, and provides reliability and transparent insights into the decision-making process.
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Radiotherapy is one of the mainstay treatment modalities for the management of non-metastatic head and neck cancer (HNC). Notable improvements in treatment outcomes have been observed in the recent decades. Modern radiotherapy techniques, such as intensity-modulated radiotherapy and charged particle therapy, have significantly improved tumor target conformity and enabled better preservation of normal structures. However, because of the intricate anatomy of the head and neck region, multiple critical neurological structures such as the brain, brainstem, spinal cord, cranial nerves, nerve plexuses, autonomic pathways, brain vasculature, and neurosensory organs, are variably irradiated during treatment, particularly when tumor targets are in close proximity. Consequently, a diverse spectrum of late neurological sequelae may manifest in HNC survivors. These neurological complications commonly result in irreversible symptoms, impair patients' quality of life, and contribute to a substantial proportion of non-cancer deaths. Although the relationship between radiation dose and toxicity has not been fully elucidated for all complications, appropriate application of dosimetric constraints during radiotherapy planning may reduce their incidence. Vigilant surveillance during the course of survivorship also enables early detection and intervention. This article endeavors to provide a comprehensive review of the various neurological complications of modern radiotherapy for HNC, summarize the current incidence data, discuss methods to minimize their risks during radiotherapy planning, and highlight potential strategies for managing these debilitating toxicities.
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Neoplasias de Cabeza y Cuello , Traumatismos por Radiación , Humanos , Neoplasias de Cabeza y Cuello/radioterapia , Traumatismos por Radiación/etiología , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Dosificación Radioterapéutica , Enfermedades del Sistema Nervioso/etiología , Calidad de VidaRESUMEN
BACKGROUND: Prognostic factors for total shoulder arthroplasty (TSA) clinical outcomes are incompletely understood. This study investigates the associations of preoperative patient, disease-specific, and surgical factors with 1-year postoperative PENN Shoulder Score (PSS) in patients undergoing primary TSA. METHODS: Cleveland Clinic patients undergoing primary anatomic TSA (aTSA) or reverse TSA (rTSA) for glenohumeral osteoarthritis (GHOA) or rotator cuff tear arthropathy (CTA) between February 2015 and August 2019, and having complete preoperative and 1-year postoperative patient-reported outcome measures (PROMs), were included. Twenty preselected preoperative patient, disease-specific, and surgical factors were used to fit multivariable models for 1-year PSS and its subscores. RESULTS: Of 1427 eligible primary TSAs, 1174 had 1-year follow-up by PROMs (82%), with 1042 analyzed after additional exclusions, including 30% rTSAs for CTA (n = 308), 26% rTSAs for GHOA (n = 275), and 44% aTSAs for GHOA (n = 459). All PROMs showed statistically significant improvements postoperatively, with 89% of patients reaching an acceptable symptom state. Lower 1-year PSS was associated with younger age, female sex, current smoking, chronic pain diagnosis, history of prior surgery, worker's compensation claim, lower preoperative mental health, lower baseline PSS, absence of glenoid bone loss, and diagnosis-arthroplasty type (CTA-rTSA < GHOA-rTSA < GHOA-aTSA). The most important prognostic factors associated with 1-year PSS were diagnosis-arthroplasty type, baseline mental health status, and insurance status. CONCLUSIONS: Disease diagnosis, arthroplasty type, and several other baseline factors are strongly and individually associated with PROMs following primary TSA, with patients undergoing aTSA for GHOA demonstrating the highest PROM scores at 1-year follow-up. Patient, disease-specific, and surgical factors can be used to guide postoperative prognosis following primary TSA for improved preoperative patient counseling regarding expected outcomes of these procedures.
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Artroplastía de Reemplazo de Hombro , Osteoartritis , Medición de Resultados Informados por el Paciente , Humanos , Artroplastía de Reemplazo de Hombro/métodos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Osteoartritis/cirugía , Articulación del Hombro/cirugía , Artropatía por Desgarro del Manguito de los Rotadores/cirugía , Estudios RetrospectivosRESUMEN
Background: Trials have shown non-inferiority of non-operative management (NOM) for appendicitis, although critically ill patients have been often excluded. The purpose of this study is to evaluate surgical versus NOM outcomes in critically ill patients with appendicitis by measuring mortality and hospital length of stay (LOS). Patients and Methods: The Healthcare Cost and Utilization Project's (HCUP) Database was utilized to analyze data from 10 states between 2008 and 2015. All patients with acute appendicitis by International Classification of Diseases, Ninth Revision (ICD-9) codes over the age of 18 were included. Negative binomial and logistic regression were used to determine the association of acute renal failure (ARF), cardiovascular failure (CVF), pulmonary failure (PF), and sepsis by treatment strategy (laparoscopic, open, both, or no surgery) on mortality and hospital LOS. Results: Among 464,123 patients, 67.5%, 23.3%, 8.2%, and 0.8% underwent laparoscopic, open, NOM, or both laparoscopic and open surgery, respectively. Patients who underwent surgery had 58% lower odds of mortality and 34% shorter hospital LOS compared with NOM patients. Patients with ARF, CVF, PF, and sepsis had 102%, 383%, 475%, and 666% higher odds of mortality and a 47%, 46%, 71%, and 163% longer hospital LOS, respectively, compared with patients without these diagnoses on admission. Conclusions: Critical illness on admission increases mortality and hospital LOS. Patients who underwent laparoscopic, and to a lesser extent, open appendectomy had improved mortality compared with those who did not undergo surgery regardless of critical illness status.
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Apendicitis , Laparoscopía , Sepsis , Humanos , Adulto , Persona de Mediana Edad , Enfermedad Crítica , Apendicitis/cirugía , Apendicitis/diagnóstico , Tiempo de Internación , Enfermedad Aguda , Apendicectomía/efectos adversos , Sepsis/etiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening sequela of SARS-CoV-2 infection. Limited data are available regarding risk-stratification or long-term outcomes in MIS-C. This study sought to determine associations between serologic markers and severity of illness and understand long-term cardiac outcomes. This series includes 46 cases (mean age 8.1 years; 63.0% male) of MIS-C. Pearson's chi-squared analysis showed an erythrocyte sedimentation rate (ESR) greater than 30 mm/h and 50 mm/h were disproportionately associated with pediatric intensive care unit (PICU) admission (χ2 = 4.44, P = .04) and use of vasopressors (χ2 = 6.06, P = .01), respectively. Ferritin less than 175.6 ng/mL was associated with use of vasopressors (χ2 = 5.28, P = .02). There was a negative correlation between ESR and ejection fraction (EF) (r = -0.39, P = .009). Most patients with abnormal echocardiograms had resolution of abnormalities within 30 days. Therefore, inflammatory markers may be helpful in predicting which patients may require specific interventions or experience cardiac dysfunction, but MIS-C does not appear to be associated with complications at 1 year.
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COVID-19 , SARS-CoV-2 , Niño , Humanos , Masculino , Femenino , COVID-19/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/terapia , HospitalizaciónRESUMEN
STUDY OBJECTIVE: Enoxaparin is standard of care for venous thromboembolism (VTE) prophylaxis in adult trauma patients, but fixed-dose protocols are suboptimal. Dosing based on body mass index (BMI) or total body weight (TBW) improves target prophylactic anti-Xa level attainment and reduces VTE rates. A novel strategy using estimated blood volume (EBV) may be more effective based on results of a single-center study. This study compared BMI-, TBW-, EBV-based, and hybrid enoxaparin dosing strategies at achieving target prophylactic anti-Factor Xa (anti-Xa) levels in trauma patients. DESIGN: Multicenter, retrospective review. DATA SOURCE: Electronic health records from participating institutions. PATIENTS: Adult trauma patients who received enoxaparin twice daily for VTE prophylaxis and had at least one appropriately timed anti-Xa level (collected 3 to 6 hours after the previous dose after three consecutive doses) from January 2017 through December 2020. Patients were excluded if the hospital-specific dosing protocol was not followed or if they had thermal burns with > 20% body surface area involvement. INTERVENTION: Dosing strategy used to determine initial prophylactic dose of enoxaparin. MEASUREMENTS: The primary end point was percentage of patients with peak anti-Xa levels within the target prophylactic range (0.2-0.4 units/mL). MAIN RESULTS: Nine hospitals enrolled 742 unique patients. The most common dosing strategy was based on BMI (43.0%), followed by EBV (29.0%). Patients dosed using EBV had the highest percentage of target anti-Xa levels (72.1%). Multiple logistic regression demonstrated EBV-based dosing was significantly more likely to yield anti-Xa levels at or above target compared to BMI-based dosing (adjusted odds ratio (aOR) 3.59, 95% confidence interval (CI) 2.29-5.62, p < 0.001). EBV-based dosing was also more likely than hybrid dosing to yield an anti-Xa level at or above target (aOR 2.30, 95% CI 1.33-3.98, p = 0.003). Other pairwise comparisons between dosing strategy groups were nonsignificant. CONCLUSIONS: An EBV-based dosing strategy was associated with higher odds of achieving anti-Xa level within target range for enoxaparin VTE prophylaxis compared to BMI-based dosing and may be a preferred method for VTE prophylaxis in adult trauma patients.
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Quemaduras , Tromboembolia Venosa , Adulto , Humanos , Enoxaparina , Anticoagulantes , Tromboembolia Venosa/tratamiento farmacológico , Pruebas de Coagulación SanguíneaRESUMEN
PURPOSE: Our aim is to describe a patient with delayed closure of a stage 3 full thickness macular hole after pars plana vitrectomy. METHODS: A retrospective case report. Details of the case were obtained from the electronic patient record system, Medisoft. RESULTS: A 65-year-old male was referred with a left stage 3 full thickness macular hole measuring 720 microns and visual acuity of 6/36. He underwent phaco-vitrectomy, ILM peel with an inverted ILM flap and C3F8 gas tamponade. 7 weeks after surgery, the macular hole was smaller at 196 microns but remained open. The patient was listed for repeat surgery, however another 13 weeks later the full thickness macular hole demonstrated type 2 closure without further intervention. DISCUSSION/CONCLUSION: Delayed macular hole closure after pars plana vitrectomy is rare. In cases where there has been a substantial decrease in the size of a full thickness macular hole after surgery without full closure, a short period of observation to allow for further closure may be appropriate before reconsidering surgery.
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Background: This study's purpose was to investigate the extent to which differences among operating surgeons may influence 1-year patient-reported outcome measures (PROMs) in patients undergoing rotator cuff repair (RCR) surgery, after controlling for general and disease-specific patient factors. We hypothesized that surgeon would be additionally associated with 1-year PROMs, specifically the baseline to 1-year improvement in Penn Shoulder Score (PSS). Methods: We used mixed multivariable statistical modeling to assess the influence of surgeon (and alternatively surgical case volume) on 1-year PSS improvement in patients undergoing RCR at a single health system in 2018, controlling for eight patient- and six disease-specific preoperative factors as possible confounders. Contributions of predictors to explaining variation in 1-year PSS improvement were measured and compared using Akaike's Information Criterion. Results: 518 cases performed by 28 surgeons met inclusion criteria, with median (quartiles) baseline PSS of 41.9 (31.9, 53.9) and 1-year PSS improvement of 42 (29.1, 55.3) points. Contrary to expectation, surgeon and surgical case volume were neither statistically significantly nor clinically meaningfully associated with 1-year PSS improvement. Baseline PSS and mental health status (VR-12 MCS) were the dominant and only statistically significant predictors of 1-year PSS improvement, with lower baseline PSS and higher VR-12 MCS predicting larger 1-year PSS improvement. Conclusion: Patients generally reported excellent 1-year outcomes following primary RCR. This study did not find evidence that the individual surgeon or surgeon case volume influences 1-year PROMs, independently of case-mix factors, following primary RCR in a large employed hospital system.
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Many surgeons seek to optimize their patients' comorbid conditions preoperatively to reduce postoperative complications. To effectively optimize patients before total shoulder arthroplasty, the surgeon should be familiar with recognizing and treating common medical comorbidities found in an orthopedic patient including anemia, diabetes, malnutrition, cardiovascular conditions, and history of deep venous thrombosis. Screening for depression or other mental illness should also be conducted preoperatively and managed accordingly before surgery. Preoperative opioid use and smoking have significant effects on postoperative outcomes and should be addressed before surgery.
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Artroplastía de Reemplazo de Hombro , Articulación del Hombro , Humanos , Estudios Retrospectivos , Artroplastia , Complicaciones Posoperatorias/epidemiología , Comorbilidad , Articulación del Hombro/cirugía , Resultado del TratamientoRESUMEN
Background: Deep infection after rotator cuff repair (RCR) can cause significant morbidity and healthcare burden. Outcomes of surgical treatment of infection following RCR are limited. This study aimed to assess the clinical course and outcomes related to surgical management of deep infection following RCR. Methods: Patients treated with debridement for infection after RCR at a single institution were included. Postoperative deep infection included the following criteria: persistent drainage more than five days from index surgery, development of a sinus tract to the joint, ≥ 2 positive cultures at the time of revision surgery with the same bacteria, or presence of purulence. Functional outcomes (ASES, SANE, SF-12) were assessed at a minimum of 1-year post-debridement. Results: Twenty-three patients were included and analyzed at mean six years post-debridement. All were free of infection at the final follow-up. The average age was 55 years; fifteen (65.2%) had infection after primary RCR and eight (34.8%) after revision RCR. Twelve (52.2%) patients required a repeat debridement prior to eradicating infection for an average of 1.9 surgeries before clearance of infection. Statistically significant predictors of need for a repeat debridement included initial open RCR (P = .02), open debridement (P = .002) and infection requiring IV antibiotics (P = .014). Postoperative ASES, SANE, SF-12M, SF-12P, and satisfaction scores were 71.7±25.7, 67.0±28.1, 55.5±6.5, 38.4±14.3 and 3.7±1.3, respectively. Conclusion: Deep infection after RCR can be treated with open or arthroscopic debridement. However, more than 50% of patients may require multiple debridements. Final functional results after infection control following RCR are satisfactory. However, chronic infection predicts worse functional outcomes.
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PURPOSE OF REVIEW: As reverse total shoulder arthroplasty indications have expanded and the incidence of its use has increased, developments in implant design have been a critical component of its success. The purpose of this review is to highlight the recent literature regarding the effect of implant design on reverse total shoulder arthroplasty biomechanics. RECENT FINDINGS: Implant design for reverse total shoulder arthroplasty has evolved considerably from the modern design developed by Paul Grammont. The Grammont design had a medialized center of rotation and distalized humerus resulting from a 155° humeral neck shaft angle. These changes intended to decrease the forces on the glenoid component, thereby decreasing the risk for implant loosening and improving the deltoid moment arm. However, these features also led to scapular notching. The Grammont design has been modified over the last 20 years to increase the lateral offset of the glenosphere and decrease the prosthetic humeral neck shaft angle to 135°. These changes were made to optimize functional range of motion while minimizing scapular notching and improving active external rotation strength. Lastly, the introduction of preoperative planning and patient-specific instrumentation has improved surgeon ability to accurately place implants and optimize impingement-free range of motion. Success and durability of the reverse total shoulder arthroplasty has been contingent upon changes in implant design, starting with the Grammont-style prosthesis. Current humeral and glenoid implant designs vary in parameters such as humeral and glenoid offset, humeral tray design, liner thickness, and neck-shaft angle. A better understanding of the biomechanical implications of these design parameters will allow us to optimize shoulder function and minimize implant-related complications after reverse total shoulder arthroplasty.
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Background: The aim of this study is to address the paucity of epidemiological data regarding the characteristics, treatment patterns and survival outcomes of Chinese glioblastoma patients. Methods: This was a population-level study of Hong Kong adult (>18 years) Chinese patients with newly diagnosed histologically confirmed glioblastoma between 2006 and 2019. The age standardized incidence rate (ASIR), patient-, tumor- treatment-related characteristics, overall survival (OS) as well as its predictors were determined. Results: One thousand and ten patients with a median follow-up of 10.0 months were reviewed. The ASIR of glioblastoma was 1.0 per 100 000 population with no significant change during the study period. The mean age was 57 + 14 years. The median OS was 10.6 months (IQR: 5.2-18.4). Independent predictors for survival were: Karnofsky performance score >80 (adjusted OR: 0.8; 95% CI: 0.6-0.9), IDH-1 mutant (aOR: 0.7; 95% CI: 0.5-0.9) or MGMT methylated (aOR: 0.7; 95% CI: 0.5-0.8) glioblastomas, gross total resection (aOR: 0.8; 95% CI: 0.5-0.8) and temozolomide chemoradiotherapy (aOR 0.4; 95% CI: 0.3-0.6). Despite the significant increased administration of temozolomide chemoradiotherapy from 39% (127/326) of patients in 2006-2010 to 63% (227/356) in 2015-2019 (P-value < .001), median OS did not improve (2006-2010: 10.3 months vs 2015-2019: 11.8 months) (OR: 1.1; 95% CI: 0.9-1.3). Conclusions: The incidence of glioblastoma in the Chinese general population is low. We charted the development of neuro-oncological care of glioblastoma patients in Hong Kong during the temozolomide era. Although there was an increased adoption of temozolomide chemoradiotherapy, a corresponding improvement in survival was not observed.
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BACKGROUND: As a major driver of lymphocyte proliferation and activation interleukin 2 (IL-2) is a crucial mediator for antitumor responses. Despite promising activity in a subset of patients, wider therapeutic utility of IL-2 (aldesleukin) has been hampered by severe dose-limiting toxicities, the expansion of immunosuppressive regulatory T cells and a poor pharmacokinetic (PK) profile. Recent engineering efforts, including non-α IL-2 variants, have lowered the toxicity profile, but have yet to induce meaningful antitumor activity in a wider patient population. METHODS: We engineered INBRX-120, a CD8α-targeted Cisleukin™ molecule consisting of an affinity tuned IL-2 (IL2-x) connected to two high affinity CD8α-specific single domain antibodies via an effector-silenced Fc domain. To show that this large affinity differential enables directed IL-2 cis-signaling exclusively on CD8α-expressing tumoricidal effector cell populations, INBRX-120 effects on target cell expansion, activation and antitumor activity were tested in vitro. In vivo antitumor efficacy was evaluated in syngeneic mouse models alone or in combination with programmed cell death protein-1 (PD-1) blockade. Preclinical safety, as well as pharmacodynamic (PD) and PK profiling was carried out in non-human primates. RESULTS: INBRX-120 effectively expanded and enhanced the cytotoxic capacity of CD8 T cells and natural killer cells towards tumor cells without affecting regulatory T cells in vitro and in vivo. In syngeneic mouse models, INBRX-120 surrogate showed safe, potent, and durable antitumor efficacy alone and in combination with PD-1 blockade. In non-human primates, INBRX-120 expanded and activated CD8α-expressing effector cells, showed a favorable PK profile, and was well tolerated up to a dose of 1 mg/kg. CONCLUSIONS: Through its unique cis-signaling activity on CD8α-expressing effector cells, INBRX-120 overcomes the major limitations of IL-2-based therapy and effectively harnesses IL-2's potent intrinsic antitumor activity. This novel therapeutic strategy promises safer clinical activity that could induce meaningful antitumor efficacy in a wider set of patients with various cancer indications.
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Interleucina-2 , Neoplasias , Animales , Ratones , Humanos , Interleucina-2/farmacología , Interleucina-2/uso terapéutico , Receptor de Muerte Celular Programada 1 , Citotoxicidad Inmunológica , Linfocitos T CD8-positivosRESUMEN
INTRODUCTION: In contrast to standard-of-care treatment of newly diagnosed glioblastoma, there is limited consensus on therapy upon disease progression. The role of resection for recurrent glioblastoma remains unclear. This study aimed to identify factors for overall survival (OS) and post-progression survival (PPS) as well as to validate an existing prediction model. METHODS: This was a multi-centre retrospective study that reviewed consecutive adult patients from 2006 to 2019 that received a repeat resection for recurrent glioblastoma. The primary endpoint was PPS defined as from the date of second surgery until death. RESULTS: 1032 glioblastoma patients were identified and 190 (18%) underwent resection for recurrence. Patients that had second surgery were more likely to be younger (<70 years) (adjusted OR: 0.3; 95% CI: 0.1-0.6), to have non-eloquent region tumours (aOR: 1.7; 95% CI: 1.1-2.6) and received temozolomide chemoradiotherapy (aOR: 0.2; 95% CI: 0.1-0.4). Resection for recurrent tumour was an independent predictor for OS (aOR: 1.5; 95% CI: 1.3-1.7) (mOS: 16.9 months versus 9.8 months). For patients that previously received temozolomide chemoradiotherapy and subsequent repeat resection (137, 13%), the median PPS was 9.0 months (IQR: 5.0-17.5). Independent PPS predictors for this group were a recurrent tumour volume of >50cc (aOR: 0.6; 95% CI: 0.4-0.9), local recurrence (aOR: 1.7; 95% CI: 1.1-3.3) and 5-ALA fluorescence-guided resection during second surgery (aOR: 1.7; 95% CI: 1.1-2.8). A National Institutes of Health Recurrent Glioblastoma Multiforme Scale score of 0 conferred an mPPS of 10.0 months, a score of 1-2, 9.0 months and a score of 3, 4.0 months (log-rank test, p-value < 0.05). CONCLUSION: Surgery for recurrent glioblastoma can be beneficial in selected patients and carries an acceptable morbidity rate. The pattern of recurrence influenced PPS and the NIH Recurrent GBM Scale was a reliable prognostication tool.
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Background: Magnetic resonance imaging (MRI)-based rotator cuff assessment is often qualitative and subjective; few studies have tried to validate such preoperative assessments. This study investigates relationships of preoperative MRI assessments made by conventional approaches to intraoperative findings of tear type, location, and size or MRI-assessed muscle occupation ratio. Methods: Intraoperatively, surgeons assessed tear type, location, anterior-posterior (AP) width, and medial-lateral length in 102 rotator cuff repair patients. Two musculoskeletal radiologists independently assessed the preoperative MRI scans for these same parameters and supraspinatus muscle atrophy by both Warner classification and quantitative occupation ratio. Exact agreement proportions, kappa statistics, and correlation coefficients were used to quantify agreement relationships. Results: Agreement between MRI readers' and surgeons' observations of tear status averaged 93% with κ = 0.38, and that of tear location averaged 77% with κ = 0.50. Concordance correlations of MRI and intraoperative measures of anterior-posterior and medial-lateral tear length averaged 0.59 and 0.56 across readers, respectively. Despite excellent interrater agreement on Warner classification (exact agreement proportion 0.91) and occupation ratio (concordance correlation 0.93) separately, correlations between these 2 measures were -0.54 and -0.64 for the 2 readers, respectively. Patients with Warner grade 0 had occupation ratios ranging from 0.5 to 1.5. Conclusion: Correlations of preoperative MRI tear dimensions and muscle atrophy assessed by conventional approaches with intraoperatively measured tear dimensions and quantitative occupation ratio, respectively, were only fair. Since tear size and muscle atrophy are known strong predictors of outcomes following rotator cuff repair that may influence treatment decisions, surgeons need to be aware of the limitations of MRI methods. Continued development and validation of quantitative preoperative imaging methods to accurately assess these parameters are needed to improve surgical planning and prognosis.
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BACKGROUND: The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted. METHODS: Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells. FINDINGS: We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion. CONCLUSIONS: Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases. FUNDING: This research was funded by Janssen, Pharmaceutical Companies of Johnson & Johnson.
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Barrera Hematoencefálica , Transcitosis , Barrera Hematoencefálica/metabolismo , Transcitosis/fisiología , Receptores de Transferrina , Transporte Biológico/fisiología , AnticuerposRESUMEN
PURPOSE: Many cancer centers engage in multidisciplinary tumor board meetings to determine the optimal approach to complex cancer care. With the onset of the COVID-19 pandemic, many institutions changed the format of these meetings from in-person to virtual. The aim of this study was to determine if the change to a virtual meeting format had an impact on attendance and cases presented. METHODS: Tumor board records were analyzed to obtain attendance and case presentation information at a National Cancer Institute-designated Comprehensive Cancer Center. Twelve-month in-person tumor board data were compared with 12-month virtual tumor board data to assess for difference in attendance and case presentation patterns. RESULTS: Seven separate weekly tumor board meetings at the beginning of the study (breast, GI, gynecology, liver, lung, melanoma, and urology) were expanded to nine meetings on the virtual platform (+endocrine and pancreas). Overall attendance increased by 46% on the virtual platform compared with in-person meetings (4,030 virtual attendances v 2,753 in-person, P < .001). Increased attendance was present across all specialties on the virtual platform. In addition, the number of patient cases discussed increased from 2,127 in in-person meeting to 2,656 on the virtual platform (a 20% increase, P < .001). CONCLUSION: A significant increase was observed in overall tumor board attendance and in case presentations per meeting, requiring the expansion of additional weekly meetings. Furthermore, in a major cancer center with multiple community affiliates, virtual tumor boards may encourage increased participation from remote sites with the benefit of obtaining expert specialist advice as compared with geographically challenging in-person meetings.
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COVID-19 , Neoplasias , COVID-19/epidemiología , Humanos , Neoplasias/complicaciones , Neoplasias/terapia , PandemiasRESUMEN
Super-resolution imaging is a family of techniques in which multiple lower-resolution images can be merged to produce a single image at higher resolution. While super-resolution is often applied to optical systems, it can also be used with other imaging modalities. Here we demonstrate a 512 × 256 CMOS sensor array for micro-scale super-resolution electrochemical impedance spectroscopy (SR-EIS) imaging. The system is implemented in standard 180 nm CMOS technology with a 10 µm × 10 µm pixel size. The sensor array is designed to measure the mutual capacitance between programmable sets of pixel pairs. Multiple spatially-resolved impedance images can then be computationally combined to generate a super-resolution impedance image. We use finite-element electrostatic simulations to support the proposed measurement approach and discuss straightforward algorithms for super-resolution image reconstruction. We present experimental measurements of sub-cellular permittivity distribution within single green algae cells, showing the sensor's capability to produce microscale impedance images with sub-pixel resolution.