Examining the Effect of Missing Data and Unmeasured Confounding on External Comparator Studies: Case Studies and Simulations.

BACKGROUND AND OBJECTIVE: Missing data and unmeasured confounding are key challenges for external comparator studies. This work evaluates bias and other performance characteristics depending on missingness and unmeasured confounding by means of two case studies and simulations. METHODS: Two case studies were constructed by taking the treatment arms from two randomised controlled trials and an external real-world data source that exhibited substantial missingness. The indications of the randomised controlled trials were multiple myeloma and metastatic hormone-sensitive prostate cancer. Overall survival was taken as the main endpoint. The effects of missing data and unmeasured confounding were assessed for the case studies by reporting estimated external comparator versus randomised controlled trial treatment effects. Based on the two case studies, simulations were performed broadening the settings by varying the underlying hazard ratio, the sample size, the sample size ratio between the experimental arm and the external comparator, the number of missing covariates and the percentage of missingness. Thereby, bias and other performance metrics could be quantified dependent on these factors. RESULTS: For the multiple myeloma external comparator study, results were in line with the randomised controlled trial, despite missingness and potential unmeasured confounding, while for the metastatic hormone-sensitive prostate cancer case study missing data led to a low sample size, leading overall to inconclusive results. Furthermore, for the metastatic hormone-sensitive prostate cancer study, missing data in important eligibility criteria led to further limitations. Simulations were successfully applied to gain a quantitative understanding of the effects of missing data and unmeasured confounding. CONCLUSIONS: This exploratory study confirmed external comparator strengths and limitations by quantifying the impact of missing data and unmeasured confounding using case studies and simulations. In particular, missing data in key eligibility criteria were seen to limit the ability to derive the external comparator target analysis population accurately, while simulations demonstrated the magnitude of bias to expect for various settings.

Demographics and outcomes of patients younger than 75 years undergoing aortic valve interventions in Rotterdam.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is considered a safe and effective alternative to surgical aortic valve replacement (SAVR) for elderly patients across the operative risk spectrum. In the Netherlands, TAVI is reimbursed only for patients with a high operative risk. Despite this, one fifth of TAVI patients are < 75 years of age. We aim to compare patient characteristics and outcomes of TAVI and SAVR patients < 75 years. METHODS: This study included all patients < 75 years without active endocarditis undergoing TAVI or SAVR for severe aortic stenosis, mixed aortic valve disease or degenerated aortic bioprosthesis between 2015 and 2020 at the Erasmus University Medical Centre. Dutch authority guidelines were used to classify operative risk. RESULTS: TAVI was performed in 292 patients, SAVR in 386 patients. Based on the Dutch risk algorithm, 59.6% of TAVI patients and 19.4% of SAVR patients were at high operative risk. There was no difference in 30-day all-cause mortality between TAVI and SAVR (2.4% vs 0.8%, p = 0.083). One-year and 5­year mortality was higher after TAVI than after SAVR (1-year: 12.5% vs 4.3%, p < 0.001; 5­year: 36.8% vs 12.0%, p < 0.001). Within risk categories we found no difference between treatment strategies. Independent predictors of mortality were cardiovascular comorbidities (left ventricular ejection fraction < 30%, atrial fibrillation, pulmonary hypertension) and the presence of malignancies, liver cirrhosis or immunomodulatory drug use. CONCLUSION: At the Erasmus University Medical Centre, in patients < 75 years, TAVI is selected for higher-risk phenotypes and overall has higher long-term mortality than SAVR. We found no evidence for worse outcome within risk categories.

Epstein-Barr virus protein EBNA-LP engages YY1 through leucine-rich motifs to promote naïve B cell transformation.

Epstein-Barr Virus (EBV) is associated with numerous cancers including B cell lymphomas. In vitro, EBV transforms primary B cells into immortalized Lymphoblastoid Cell Lines (LCLs) which serves as a model to study the role of viral proteins in EBV malignancies. EBV induced cellular transformation is driven by viral proteins including EBV-Nuclear Antigens (EBNAs). EBNA-LP is important for the transformation of naïve but not memory B cells. While EBNA-LP was thought to promote gene activation by EBNA2, EBNA-LP Knockout (LPKO) virus-infected cells express EBNA2-activated cellular genes efficiently. Therefore, a gap in knowledge exists as to what roles EBNA-LP plays in naïve B cell transformation. We developed a trans-complementation assay wherein transfection with wild-type EBNA-LP rescues the transformation of peripheral blood- and cord blood-derived naïve B cells by LPKO virus. Despite EBNA-LP phosphorylation sites being important in EBNA2 co-activation; neither phospho-mutant nor phospho-mimetic EBNA-LP was defective in rescuing naïve B cell outgrowth. However, we identified conserved leucine-rich motifs in EBNA-LP that were required for transformation of adult naïve and cord blood B cells. Because cellular PPAR-g coactivator (PGC) proteins use leucine-rich motifs to engage transcription factors including YY1, a key regulator of DNA looping and metabolism, we examined the role of EBNA-LP in engaging transcription factors. We found a significant overlap between EBNA-LP and YY1 in ChIP-Seq data. By Cut&Run, YY1 peaks unique to WT compared to LPKO LCLs occur at more highly expressed genes. Moreover, Cas9 knockout of YY1 in primary B cells prior to EBV infection indicated YY1 to be important for EBV-mediated transformation. We confirmed EBNA-LP and YY1 biochemical association in LCLs by endogenous co-immunoprecipitation and found that the EBNA-LP leucine-rich motifs were required for YY1 interaction in LCLs. We propose that EBNA-LP engages YY1 through conserved leucine-rich motifs to promote EBV transformation of naïve B cells.

Untargeted metabolomics analysis of serum and urine unveils the protective effect of cilastatin on altered metabolic pathways during cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is one of the most serious complications of cisplatin anticancer therapies. Cilastatin is a highly promising nephroprotective agent to eventually enter clinical use, but its biochemical mechanism is still not fully understood. We have employed an untargeted metabolomics approach based on capillary electrophoresis mass spectrometry (CE-MS) analysis of serum and urine from an in vivo rat model, to explore the metabolic pathways involved in cisplatin-induced AKI and cilastatin nephroprotection. A total of 155 and 76 identified metabolites were found to be significantly altered during cisplatin treatment in urine and serum, respectively. Most of these altered metabolites were either partially or totally recovered by cilastatin and cisplatin co-treatment. The main metabolic pathways disturbed by cisplatin during AKI involved diverse amino acids metabolism and biosynthesis, tricarboxylic acids (TCA) cycle, nicotinate and nicotinamide metabolism, among others. Cilastatin was proved to protect diverse cisplatin-altered pathways involving metabolites related to immunomodulation, inflammation, oxidative stress and amino acid metabolism in proximal tubules. However, cisplatin-altered mitochondrial metabolism (especially, the energy-producing TCA cycle) remained largely unprotected by cilastatin, suggesting an unresolved mitochondrial direct damage. Multivariate analysis allowed effective discrimination of cisplatin-induced AKI and cilastatin renoprotection based on metabolic features. A number of potential serum and urine biomarkers could also be foreseen for cisplatin-induced AKI detection and cilastatin nephroprotection.

Pulmonary strain and end-expiratory lung volume during apnea test: a comparative analysis using electrical impedance tomography / Stress pulmonar y volumen pulmonar de fin de es piración durante el test de apnea: estudio compara tivo utilizando tomografía por impedancia eléctrica

Abstract The apnea test, employed for brain death assessment, aims to demonstrate the absence of respiratory drive due to hypercapnia. The tracheal oxygen insufflation apnea test mode (I-AT) involves disconnecting the pa tient from invasive mechanical ventilation (iMV) for ap proximately 8 minutes while maintaining oxygenation. This test supports the diagnosis of brain death based on a specified increase in PaCO2. Common complications include hypoxemia and hemodynamic instability, and lung collapse-induced reduction in end-expiratory lung volume (EELV). In our case series utilizing electrical impedance to mography (EIT), we observed that continuous positive airway pressure during the apnea test (CPAP-AT) effec tively mitigated lung collapse. This resulted in improved pulmonary strain compared to the disconnection of iMV. These findings suggest the potential benefits of routine CPAP-AT, particularly for potential lung donors, emphasizing the relevance of our study in providing quantitative insights into EELV loss and its association with pulmonary strain and potential lung injury.

Resumen La prueba de apnea es una técnica diagnóstica am pliamente utilizada para la evaluación de la muerte cerebral, con el objetivo de demostrar la ausencia de impulso respiratorio debido a la hipercapnia. La variante de la prueba de apnea con insuflación de oxígeno traqueal (I-AT) implica desconectar al pacien te de la ventilación mecánica invasiva (iVM) durante aproximadamente 8 minutos, manteniendo la oxigena ción mediante un catéter de insuflación. Esta prueba respalda el diagnóstico de muerte cerebral cuando se determina un aumento de la PaCO2 superior a 20 mmHg en comparación con el valor inicial o un nivel de PaCO2 superior a 60 mmHg al final de la prueba. En nuestra serie de casos, la implementación de la tomografía de impedancia eléctrica (EIT) reveló que la prueba de apnea con presión positiva continua (CPAP-AT) mitiga eficazmente el colapso pulmonar. Este enfo que resulta en una mejora en la tensión pulmonar en comparación con la desconexión de iMV, demostrando su relevancia en el contexto de potenciales donantes de pulmones.

Mixed Reality in the Operating Room: An Initial Use in Frontal Sinus Setback in Gender-affirming Facial Surgery.

Demand for gender-affirming facial surgery is growing rapidly. Frontal sinus setback, one of the key procedures used in gender-affirming facial surgery, has a particularly high impact on gender perception. Mixed reality (MR) allows a user to view and virtually overlay three-dimensional imaging on the patient and interact with it in real time. We used the Medivis's SurgicalAR system in conjunction with the Microsoft HoloLens Lucille2 (Microsoft). Computed tomography imaging was uploaded to SurgicalAR, and a three-dimensional (3D) hologram was projected onto the display of the HoloLens. The hologram was registered and matched to the patient, allowing the surgeon to view bony anatomy and underlying structures in real time on the patient. The surgeon was able to outline the patient's frontal sinuses using the hologram as guidance. A 3D printed cutting guide was used for comparison. Negligible difference between the mixed reality-based outline and 3D-printed outline was seen. The process of loading the hologram and marking the frontal sinus outline lasted less than 10 minutes. The workflow and usage described here demonstrate significant promise for the use of mixed reality as imaging and surgical guidance technology in gender-affirming facial surgery.

Diagnostic Value of Aortic Valve Calcification Levels in the Assessment of Low-Gradient Aortic Stenosis.

BACKGROUND: In patients with low-gradient aortic stenosis (AS) and low transvalvular flow, dobutamine stress echocardiography (DSE) is recommended to determine AS severity, whereas the degree of aortic valve calcification (AVC) supposedly correlates with AS severity according to current European and American guidelines. OBJECTIVES: The purpose of this study was to assess the relationship between AVC and AS severity as determined using echocardiography and DSE in patients with aortic valve area <1 cm2 and peak aortic valve velocity <4.0 m/s. METHODS: All patients underwent DSE to determine AS severity and multislice computed tomography to quantify AVC. Receiver-operating characteristics curve analysis was used to assess the diagnostic value of AVC for AS severity grading as determined using echocardiography and DSE in men and women. RESULTS: A total of 214 patients were included. Median age was 78 years (25th-75th percentile: 71-84 years) and 25% were women. Left ventricular ejection fraction was reduced (<50%) in 197 (92.1%) patients. Severe AS was diagnosed in 106 patients (49.5%). Moderate AS was diagnosed in 108 patients (50.5%; in 77 based on resting transthoracic echocardiography, in 31 confirmed using DSE). AVC score was high (≥2,000 for men or ≥1,200 for women) in 47 (44.3%) patients with severe AS and in 47 (43.5%) patients with moderate AS. AVC sensitivity was 44.3%, specificity was 56.5%, and positive and negative predictive values for severe AS were 50.0% and 50.8%, respectively. Area under the receiver-operating characteristics curve was 0.508 for men and 0.524 for women. CONCLUSIONS: Multi-slice computed tomography-derived AVC scores showed poor discrimination between grades of AS severity using DSE and cannot replace DSE in the diagnostic work-up of low-gradient severe AS.

Pediatric Facial Fractures: Demographics, Injury Patterns, and Associated Injuries in 3334 Patients.

Pediatric craniofacial fractures are fundamentally distinct from their adult counterparts because of unique injury patterns and effects on future growth. Understanding patterns and injury context informs management and risk mitigation. Previous studies include only inpatients, operative patients, or are specialty-specific. In contrast, our study presents a comprehensive assessment of all pediatric facial fracture patients seen at a single institution. Patients under 18 years old who were evaluated for facial fractures at a level I pediatric trauma center between 2006 and 2021 were reviewed. Subanalysis was performed for groups defined by age. Variables studied included demographics, etiology, fracture pattern, associated injuries, management, and outcomes. Three thousand thirty-four patients were included. Mean age at presentation was 11.5 to 4.9 years. The majority were Caucasian (82.6%) and male (68.4%). Sports were the leading cause of injury in older patients (42.2% of patients over 12 y), compared with activities of daily living in patients under 6 years (45.5%). Thirty-two percent of patients were hospitalized, 6.0% required ICU care, and 48.4% required surgery. Frequency of ICU admission decreased with age (P<0.001), whereas operative intervention increased with age (P<0.001). Zygomaticomaxillary complex (P=0.002) and nasal fractures (P<0.001) were common in older patients, whereas younger patients experienced more skull (P<0.001) and orbital fractures (P<0.001). The most associated injuries were soft tissue (55.7%) and neurologic (23.6%). This large-scale study provides updated characterization of craniofacial fractures in the pediatric population, providing a necessary framework for future studies on outcomes assessments and preventative care.

Immediate or staged complete revascularisation in patients presenting with acute coronary syndrome by number of diseased vessels: a substudy of the BIOVASC randomised trial.

BACKGROUND: In patients presenting with acute coronary syndrome (ACS), the number of diseased vessels may affect the efficacy of a complete revascularisation strategy. AIMS: The authors sought to evaluate the safety and efficacy of immediate complete revascularisation (ICR) and staged complete revascularisation (SCR) in patients presenting with ACS stratified by the number of diseased vessels. METHODS: In this prespecified analysis of the BIOVASC trial, ICR was compared with SCR in patients with two-vessel disease (2VD) or three-vessel disease (3VD). The primary endpoint was a composite of all-cause mortality, myocardial infarction (MI), any unplanned ischaemia-driven revascularisation or cerebrovascular events at 1 year after the index procedure. Comparisons were performed using Cox regression. RESULTS: A total of 1,525 patients were enrolled in the BIOVASC trial, of whom 1,177 presented with 2VD and 265 with 3VD. In the 2VD group, 613 patients were assigned to ICR and 564 to SCR. In the 3VD group, 117 patients were assigned to ICR and 148 to SCR. ICR and SCR led to similar results in both the 2VD (hazard ratio [HR] 0.76, 95% confidence interval [CI]: 0.50-1.13; p=0.18) and 3VD groups (HR 0.79, 95% CI: 0.39-1.59; p=0.51) (pinteraction=0.91) in terms of the primary endpoint. ICR was associated with a lower rate of MI in patients with 3VD (HR 0.21, 95% CI: 0.046-0.93; p=0.04) (pinteraction=0.30). CONCLUSIONS: ICR might be an option in patients presenting with extensive 3VD and might be associated with a lower rate of myocardial infarction compared with SCR.

Challenges, Preoperative Assessment, and Surgical Strategies for the Left-Sided Gallbladder.

Left-sided gallbladder positioning, or sinistroposition, is a rare anatomical variation that poses challenges during surgical intervention due to associated vascular and biliary anomalies. While existing literature suggests an incidence of approximately 0.04-1.1%, it remains an underreported phenomenon that falls well outside the realm of "expected" anatomical variation and are rarely identified on preoperative imaging. Here, we present a case of acute cholecystitis in a patient with unexpected left-sided gallbladder, highlighting the associated challenges and outlining both preoperative and intraoperative strategies for managing this rare but consequential anatomical variant. In this case, a 49-year-old woman with a prior history of bilateral ovarian cysts presented with clinical, laboratory, and imaging findings consistent with acute cholecystitis. She underwent laparoscopic cholecystectomy and was found to have a severely inflamed left-sided gallbladder that was obscured by omentum. Her gallbladder was found in the midline immediately beneath the falciform ligament, with most of the gallbladder body and fundus attached to liver segment III, situated to the left of the midline. An additional left-sided mid-abdominal port was required to enhance retraction, and an intraoperative cholangiogram (IOC) was performed given the elevated risk of structural injury. This case underscores the heightened intraoperative risk associated with deviations in vascular and biliary anatomy and provides recommendations for intraoperative adaptations to mitigate these risks.

Transcatheter or Surgical Aortic Valve Replacement in Women With Small Annuli at Low or Intermediate Surgical Risk.

There are limited data from randomized controlled trials assessing the impact of transcatheter aortic valve replacement (TAVR) or surgery in women with aortic stenosis and small aortic annuli. We evaluated 2-year clinical and hemodynamic outcomes after aortic valve replacement to understand acute valve performance and early and midterm clinical outcomes. This post hoc analysis pooled women enrolled in the randomized, prospective, multicenter Evolut Low Risk and Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) intermediate risk trials. Women with severe aortic stenosis at low or intermediate surgical risk who had a computed tomography-measured annular perimeter of ≤72.3 mm were included and underwent self-expanding, supra-annular TAVR or surgery. The primary end point was 2-year all-cause mortality or disabling stroke rate. The study included 620 women (323 TAVR, 297 surgery) with a mean age of 78 years. At 2 years, the all-cause mortality or disabling stroke was 6.5% for TAVR and 8.0% for surgery, p = 0.47. Pacemaker rates were 20.0% for TAVR and 8.3% for surgery, p <0.001. The mean effective orifice area at 2 years was 1.9 ± 0.5 cm2 for TAVR and 1.6 ± 0.5 cm2 for surgery and the mean gradient was 8.0 ± 4.1 versus 12.7 ± 6.0 mm Hg, respectively (both p <0.001). Moderate or severe patient-prothesis mismatch at discharge occurred in 10.9% of patients who underwent TAVR and 33.2% of patients who underwent surgery, p <0.001. In conclusion, in women with small annuli, the clinical outcomes to 2 years were similar between self-expanding, supra-annular TAVR and surgery, with better hemodynamics in the TAVR group and fewer pacemakers in the surgical group.

A Novel Class of Human ADAM8 Inhibitory Antibodies for Treatment of Triple-Negative Breast Cancer.

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange-mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment.

The essential malaria protein PfCyRPA targets glycans to invade erythrocytes.

Plasmodium falciparum is a human-adapted apicomplexan parasite that causes the most dangerous form of malaria. P. falciparum cysteine-rich protective antigen (PfCyRPA) is an invasion complex protein essential for erythrocyte invasion. The precise role of PfCyRPA in this process has not been resolved. Here, we show that PfCyRPA is a lectin targeting glycans terminating with α2-6-linked N-acetylneuraminic acid (Neu5Ac). PfCyRPA has a >50-fold binding preference for human, α2-6-linked Neu5Ac over non-human, α2-6-linked N-glycolylneuraminic acid. PfCyRPA lectin sites were predicted by molecular modeling and validated by mutagenesis studies. Transgenic parasite lines expressing endogenous PfCyRPA with single amino acid exchange mutants indicated that the lectin activity of PfCyRPA has an important role in parasite invasion. Blocking PfCyRPA lectin activity with small molecules or with lectin-site-specific monoclonal antibodies can inhibit blood-stage parasite multiplication. Therefore, targeting PfCyRPA lectin activity with drugs, immunotherapy, or a vaccine-primed immune response is a promising strategy to prevent and treat malaria.

Feasibility and Usability of Augmented Reality Technology in the Orthopaedic Operating Room.

PURPOSE OF REVIEW: Augmented reality (AR) has gained popularity in various sectors, including gaming, entertainment, and healthcare. The desire for improved surgical navigation within orthopaedic surgery has led to the evaluation of the feasibility and usability of AR in the operating room (OR). However, the safe and effective use of AR technology in the OR necessitates a proper understanding of its capabilities and limitations. This review aims to describe the fundamental elements of AR, highlight limitations for use within the field of orthopaedic surgery, and discuss potential areas for development. RECENT FINDINGS: To date, studies have demonstrated evidence that AR technology can be used to enhance navigation and performance in orthopaedic procedures. General hardware and software limitations of the technology include the registration process, ergonomics, and battery life. Other limitations are related to the human response factors such as inattentional blindness, which may lead to the inability to see complications within the surgical field. Furthermore, the prolonged use of AR can cause eye strain and headache due to phenomena such as the vergence-convergence conflict. AR technology may prove to be a better alternative to current orthopaedic surgery navigation systems. However, the current limitations should be mitigated to further improve the feasibility and usability of AR in the OR setting. It is important for both non-clinicians and clinicians to work in conjunction to guide the development of future iterations of AR technology and its implementation into the OR workflow.

A Longitudinal Analysis of Pre- and Post-Operative Dysmorphology in Metopic Craniosynostosis.

OBJECTIVE: The purpose of this study is to objectively quantify the degree of overcorrection in our current practice and to evaluate longitudinal morphological changes using CranioRateTM, a novel machine learning skull morphology assessment tool.  . DESIGN: Retrospective cohort study across multiple time points. SETTING: Tertiary care children's hospital. PATIENTS: Patients with preoperative and postoperative CT scans who underwent fronto-orbital advancement (FOA) for metopic craniosynostosis. MAIN OUTCOME MEASURES: We evaluated preoperative, postoperative, and two-year follow-up skull morphology using CranioRateTM to generate a Metopic Severity Score (MSS), a measure of degree of metopic dysmorphology, and Cranial Morphology Deviation (CMD) score, a measure of deviation from normal skull morphology. RESULTS: Fifty-five patients were included, average age at surgery was 1.3 years. Sixteen patients underwent follow-up CT imaging at an average of 3.1 years. Preoperative MSS was 6.3 ± 2.5 (CMD 199.0 ± 39.1), immediate postoperative MSS was -2.0 ± 1.9 (CMD 208.0 ± 27.1), and longitudinal MSS was 1.3 ± 1.1 (CMD 179.8 ± 28.1). MSS approached normal at two-year follow-up (defined as MSS = 0). There was a significant relationship between preoperative MSS and follow-up MSS (R2 = 0.70). CONCLUSIONS: MSS quantifies overcorrection and normalization of head shape, as patients with negative values were less "metopic" than normal postoperatively and approached 0 at 2-year follow-up. CMD worsened postoperatively due to postoperative bony changes associated with surgical displacements following FOA. All patients had similar postoperative metopic dysmorphology, with no significant association with preoperative severity. More severe patients had worse longitudinal dysmorphology, reinforcing that regression to the metopic shape is a postoperative risk which increases with preoperative severity.

Adherent skin barrier drape use is associated with a reduced risk of cardiac implantable device infection: Results from a prospective study of 14,225 procedures.

Background: Cardiac implantable electronic device (CIED) infection is a costly and highly morbid complication. Perioperative interventions, including the use of antibiotic pouches and intensified perioperative antibiotic regimens, have demonstrated marginal efficacy at reducing CIED infection. Additional research is needed to identify additional interventions to reduce infection risk. Objective: We sought to evaluate whether adherent skin barrier drape use is associated with a reduction in CIED infection. Methods: A prospective registry of all CIED implantation procedures was established at our institution in January 2007. The registry was established in collaboration with our hospital infection prevention team with a specific focus on prospectively identifying all potential CIED infections. All potential CIED infections were independently adjudicated by 2 physicians blinded to the use of an adherent skin barrier drape. Results: Over a 13-year period, 14,225 procedures were completed (mean age 72 ± 14 years; female 4,918 (35%); new implants 10,005 (70%); pulse generator changes 2585 (18%); upgrades 1635 (11%). Of those, 2469 procedures (17.4%) were performed using an adherent skin barrier drape. There were 103 adjudicated device infections (0.73%). The infection rate in patients in the barrier use groups was 8 of 2469 (0.32%) as compared with 95 of 11,756 (0.8%) in the nonuse group (P = .0084). In multivariable analysis, the use of an adherent skin barrier drape was independently associated with a reduction in infection (odds ratio 0.32; 95% confidence interval 0.154-0.665; P = .002). Conclusion: The use of an adherent skin barrier drape at the time of cardiac device surgery is associated with a lower risk of subsequent infection.

True Incidence of Marginal Mandibular Nerve Palsy Following Neonatal Mandibular Distraction Osteogenesis.

INTRODUCTION: In children with PRS, MDO is routinely performed to alleviate airway obstruction; however, it involves risk of injury to the MMN. We hypothesize that MMN palsy incidence following MDO, reported at 1-15%, is underestimated. This study investigates the true incidence of MMN palsy after MDO to better guide follow-up care and improve treatment of this complication. METHODS: A retrospective review of PRS patients who underwent MDO at a single, tertiary pediatric hospital between September 2007 and March 2021 was conducted. Patients who underwent MDO under one year of age and had postoperative clinical evaluations detailing MMN function were included. Logistic regression analysis was performed to investigate predictors of MMN injury. RESULTS: Of 93 patients who underwent MDO, 59.1% met inclusion criteria. 56.4% were female, 43.6% were syndromic, and average age at MDO was 1.52 ± 2.04 months. The average length of mandibular distraction was 17.3 ± 4.36mm, average duration of intubation was 6.57 ± 2.37 days, and average time until hardware removal was 111.1 ± 23.6 days. Sixteen patients (29.1%) presented with permanent MMN dysfunction, comprised of 8 patients with bilateral weakness and 8 with unilateral weakness. An additional five patients (9.1%) presented with transient MMN weakness that resolved within a year. Average length of follow-up postoperatively was 6.02 years, and no significant predictors of nerve injury were found. CONCLUSION: In this 14-year review of patients with PRS who underwent MDO, 38.2% demonstrated evidence of MMN palsy (29.1% permanent, 9.1% transient), which is much greater than previously described.

Development and Preclinical Evaluation of [211At]PSAt-3-Ga: An Inhibitor for Targeted α-Therapy of Prostate Cancer.

The application of prostate-specific membrane antigen (PSMA)-targeted α-therapy is a promising alternative to ß--particle-based treatments. 211At is among the potential α-emitters that are favorable for this concept. Herein, 211At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. Methods: To identify a 211At-labeled lead, a surrogate strategy was applied. Because astatine does not exist as a stable nuclide, it is commonly replaced with iodine to mimic the pharmacokinetic behavior of the corresponding 211At-labeled compounds. To facilitate the process of structural design, iodine-based candidates were radiolabeled with the PET radionuclide 68Ga to study their preliminary in vitro and in vivo properties before the desired 211At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be 211At-labeled and tested in biodistribution studies. Results: All 68Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified [68Ga]PSGa-3 as the lead compound. Subsequently, [211At]PSAt-3-Ga was synthesized in a radiochemical yield of 35% and showed tumor uptake of 19 ± 8 percentage injected dose per gram of tissue (%ID/g) at 1 h after injection and 7.6 ± 2.9 %ID/g after 24 h. Uptake in off-target tissues such as the thyroid (2.0 ± 1.1 %ID/g), spleen (3.0 ± 0.6 %ID/g), or stomach (2.0 ± 0.4 %ID/g) was low, indicating low in vivo deastatination of [211At]PSAt-3-Ga. Conclusion: The reported findings support the use of iodine-based and 68Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm [211At]PSAt-3 as a promising radiopharmaceutical for targeted α-therapy.

Epstein-Barr virus protein EBNA-LP engages YY1 through leucine-rich motifs to promote naïve B cell transformation.

Epstein-Barr Virus (EBV) is associated with numerous cancers including B cell lymphomas. In vitro, EBV transforms primary B cells into immortalized Lymphoblastoid Cell Lines (LCLs) which serves as a model to study the role of viral proteins in EBV malignancies. EBV induced cellular transformation is driven by viral proteins including EBV-Nuclear Antigens (EBNAs). EBNA-LP is important for the transformation of naïve but not memory B cells. While EBNA-LP was thought to promote gene activation by EBNA2, EBNA-LP Knock Out (LPKO) virus-infected cells express EBNA2-activated genes efficiently. Therefore, a gap in knowledge exists as to what roles EBNA-LP plays in naïve B cell transformation. We developed a trans-complementation assay wherein transfection with wild-type EBNA-LP rescues the transformation of peripheral blood- and cord blood-derived naïve B cells by LPKO virus. Despite EBNA-LP phosphorylation sites being important in EBNA2 co-activation; neither phospho-mutant nor phospho-mimetic EBNA-LP was defective in rescuing naïve B cell outgrowth. However, we identified conserved leucine-rich motifs in EBNA-LP that were required for transformation of adult naïve and cord blood B cells. Because cellular PPAR-γ coactivator (PGC) proteins use leucine-rich motifs to engage transcription factors including YY1, a key regulator of DNA looping and metabolism, we examined the role of EBNA-LP in engaging cellular transcription factors. We found a significant overlap between EBNA-LP and YY1 in ChIP-Seq data and confirmed their biochemical association in LCLs by endogenous co-immunoprecipitation. Moreover, we found that the EBNA-LP leucine-rich motifs were required for YY1 interaction in LCLs. Finally, we used Cas9 to knockout YY1 in primary total B cells and naïve B cells prior to EBV infection and found YY1 to be essential for EBV-mediated transformation. We propose that EBNA-LP engages YY1 through conserved leucine-rich motifs to promote EBV transformation of naïve B cells.