Chemical Production of Cytotoxic Bispecific Antibodies Using the Ugi Multicomponent Reaction.

Bispecific antibodies (bsAbs) have recently emerged as a promising platform for the treatment of several conditions, most importantly cancer. Based on the combination of two different antigen-binding motifs in a single macromolecule; bsAbs can either display the combined characteristics of their parent antibodies, or new therapeutic features, inaccessible by the sole combination of two distinct antibodies. While bsAbs are traditionally produced by molecular biology techniques, the chemical development of bsAbs holds great promises and strategies have just begun to surface. In this context, we took advantage of a chemical strategy based on the use of the Ugi reaction for the site-selective conjugation of whole antibodies and coupled the resulting conjugates in a bioorthogonal manner with Fab fragments, derived from various antibodies. We thus managed to produce five different bsAbs with 2:1 valency, with yields ranging from 20% to 48%, and showed that the affinity of the parent antibody was preserved in all bsAbs. We further demonstrated the interest of our strategy by producing two other bsAbs behaving as cytotoxic T cell engagers with IC50 values in the picomolar range in vitro.

Association of cardiac biomarkers with long-term cardiovascular events in a community cohort.

MATERIALS AND METHODS: The study assessed major adverse cardiac events (MACE) (myocardial infarction, coronary artery bypass graft, percutaneous intervention, stroke, and death. Cox proportional hazards models assessed apolipoprotein AI (ApoA1), apolipoprotein B (ApoB), ceramide score, cystatin C, galectin-3 (Gal3), LDL-C, Non-HDL-C, total cholesterol (TC), N-terminal B-type natriuretic peptide (NT proBNP), high-sensitivity cardiac troponin (HscTnI) and soluble interleukin 1 receptor-like 1. In adjusted models, Ceramide score was defined by from N-palmitoyl-sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], N-nervonoyl-sphingosine [Cer(24:1)] and N-lignoceroyl-sphingosine [Cer(24:0)]. Multi-biomarker models were compared with C-statistics and Integrated Discrimination Index (IDI). RESULTS: A total of 1131 patients were included. Adjusted NT proBNP per 1 SD resulted in a 31% increased risk of MACE/death (HR = 1.31) and a 31% increased risk for stroke/MI (HR = 1.31). Adjusted Ceramide per 1 SD showed a 13% increased risk of MACE/death (HR = 1.13) and a 29% increased risk for stroke/MI (HR = 1.29). These markers added to clinical factors for both MACE/death (p = 0.003) and stroke/MI (p = 0.034). HscTnI was not a predictor of outcomes when added to the models. DISCUSSION: Ceramide score and NT proBNP improve the prediction of MACE and stroke/MI in a community primary prevention cohort.

In a community cohort, where a wide range of biomarkers were evaluated, Ceramide score provided additive value over traditional cardiac risk factors alone for predicting stroke/MI. NT ProBNP provided additive value in prediction of MACE/death. Other biomarkers failed to improve the discrimination of these models.

The Natural History of Atrial Functional Mitral Regurgitation.

BACKGROUND: The natural history of moderate/severe atrial functional mitral regurgitation (AFMR) is unknown. OBJECTIVES: The authors sought to study the incidence of left ventricular (LV) systolic dysfunction (LVSD), progression or regression of ≥mild-moderate AFMR, and impact on mortality. METHODS: Adults with left atrial (LA) volume index ≥40 mL/m2, ≥mild-moderate AFMR, and follow-up echocardiogram were followed for incident LVSD (ejection fraction <50% and ≥10% lower than baseline), progression of mild-moderate/moderate AFMR to severe, and persistent regression of AFMR to no/trivial. Relation of AFMR progression or regression as time-dependent covariates with all-cause mortality was studied. Incidence of LVSD was compared with patients with no/mild AFMR matched on age, sex, comorbidities and ejection fraction. Patients were followed until mitral intervention, myocardial infarction, or last follow-up. RESULTS: A total of 635 patients (median age 75 years, 51% female, 96% mild-moderate/moderate AFMR, 4% severe AFMR) were included. Over a median 2.2 years (Q1-Q3: 1.0-4.3 years), incidence rates per 100 person-years were 3.2 for LVSD (P = 0.52 vs patients with no/mild AFMR), 1.9 for progression of AFMR, and 3.9 for regression. Female sex and larger LA volume index were independently associated with progression, whereas younger age, male sex, absent atrial fibrillation, and higher LA emptying fraction were independently associated with regression. Neither AFMR progression nor regression was independently associated with mortality. Instead, independent risk factors for mortality included older age, concentric LV geometry, and higher estimated LV filling and pulmonary pressures. CONCLUSIONS: In patients with predominantly mild-moderate/moderate AFMR, regression of MR was more common than progression, but neither was associated with mortality. Instead, diastolic function abnormalities were more important. Over a median 2-year follow-up, LVSD risk was not increased.

The association between patient preoperative disposition and outcomes after diagnostic lung biopsy.

Background: Surgical diagnostic lung biopsy (DLB) is performed to guide the management of pulmonary disease with unclear etiology. However, the utilization of surgical DLB in critically ill patients remains unclear. The purpose of this study was to determine if patient preoperative disposition impacts complication rates after DLB. Methods: This was retrospective cohort study using electronic health record (EHR) data at one academic institution [2013-2021]. Patients who underwent DLB were identified using current procedural terminology (CPT) codes and cohorted based on preoperative disposition. The primary outcome was 30-day mortality; secondary outcomes were overall morbidity, individual complications, and changes to medical therapy. Complication rates were compared using chi-squared tests, Fisher's exact tests, or analysis of variance (ANOVA). Multivariable logistic regression was performed to generate risk-adjusted odds ratios (ORs) for each complication. Results: Of 285 patients, 238 (83.5%) presented from home, 26 (9.1%) from inpatient floor units, and 21 (7.4%) from intensive care units (ICUs). Patients requiring ICU had the highest 30-day rates of mortality, overall morbidity, and all individual complications (all P<0.05). After risk adjustment, non-ICU inpatients had higher odds of postoperative ventilator use, prolonged ventilation, and ICU need than outpatients (all P<0.05). Preoperative ICU disposition was associated with increased OR of 30-day mortality [OR, 70.92; 95% confidence interval (CI): 5.55-906.32] and overall morbidity (OR, 7.27; 95% CI: 1.93-27.42) compared to patients with other preoperative dispositions. There were no differences in changes to medical therapy between the cohorts. Conclusions: Patients requiring ICU before DLB had significantly higher risk-adjusted rates of mortality and postoperative complications than outpatients and other inpatients. A clear benefit from tissue diagnosis should be defined prior to performing DLB on critically ill patients.

Nanoencapsulation of MDM2 Inhibitor RG7388 and Class-I HDAC Inhibitor Entinostat Enhances their Therapeutic Potential Through Synergistic Antitumor Effects and Reduction of Systemic Toxicity.

Inhibitors of the p53-MDM2 interaction such as RG7388 have been developed to exploit latent tumor suppressive properties in p53 in 50% of tumors in which p53 is wild-type. However, these agents for the most part activate cell cycle arrest rather than death, and high doses in patients elicit on-target dose-limiting neutropenia. Recent work from our group indicates that combination of p53-MDM2 inhibitors with the class-I HDAC inhibitor Entinostat (which itself has dose-limiting toxicity issues) has the potential to significantly augment cell death in p53 wild-type colorectal cancer cells. We investigated whether coencapsulation of RG7388 and Entinostat within polymeric nanoparticles (NPs) could overcome efficacy and toxicity limitations of this drug combination. Combinations of RG7388 and Entinostat across a range of different molar ratios resulted in synergistic increases in cell death when delivered in both free drug and nanoencapsulated formats in all colorectal cell lines tested. Importantly, we also explored the in vivo impact of the drug combination on murine blood leukocytes, showing that the leukopenia induced by the free drugs could be significantly mitigated by nanoencapsulation. Taken together, this study demonstrates that formulating these agents within a single nanoparticle delivery platform may provide clinical utility beyond use as nonencapsulated agents.

Anatomic Lung Resection Outcomes After Implementation of a Universal Thoracic ERAS Protocol Across a Diverse Health Care System.

OBJECTIVE: We sought to evaluate how implementing a thoracic enhanced recovery after surgery (ERAS) protocol impacted surgical outcomes after elective anatomic lung resection. BACKGROUND: The effect of implementing the ERAS Society/European Society of Thoracic Surgery thoracic ERAS protocol on postoperative outcomes throughout an entire health care system has not yet been reported. METHODS: This was a prospective cohort study within one health care system (January 2019-March, 2023). A thoracic ERAS protocol was implemented on May 1, 2021 for elective anatomic lung resections, and postoperative outcomes were tracked using the electronic health record and Vizient data. The primary outcome was overall morbidity; secondary outcomes included individual complications, length of stay, opioid use, chest tube duration, and total cost. Patients were grouped into pre-ERAS and post-ERAS cohorts. Bivariable comparisons were performed using independent t -test, χ 2 , or Fisher exact tests, and multivariable logistic regression was performed to control for confounders. RESULTS: There were 1007 patients in the cohort; 450 (44.7%) were in the post-ERAS group. Mean age was 66.2 years; most patients were female (65.1%), white (83.8%), had a body mass index between 18.5 and 29.9 (69.7%), and were ASA class 3 (80.6%). Patients in the postimplementation group had lower risk-adjusted rates of any morbidity, respiratory complication, pneumonia, surgical site infection, arrhythmias, infections, opioid usage, ICU use, and shorter postoperative length of stay (all P <0.05). CONCLUSIONS: Postoperative outcomes were improved after the implementation of an evidence-based thoracic ERAS protocol throughout the health care system. This study validates the ERAS Society/European Society of Thoracic Surgery guidelines and demonstrates that simultaneous multihospital implementation can be feasible and effective.

The Use and Outcomes of 3D Printing in Pediatric Craniofacial Surgery: A Systematic Review.

Three-dimensional (3D) printing has demonstrated efficacy in multiple surgical specialties. As accessibility improves, its use in specific fields deserves further attention. We conducted a systematic review of the implementation and outcomes of 3D printing in pediatric craniofacial surgery, as none has been performed. A systematic review was conducted according to Cochrane and PRISMA guidelines. PubMed, Embase, Cochrane library, and Clinicaltrials.gov were queried with combinations of the terms: "3D printing," "craniofacial," "surgery," and "pediatric." Original human studies containing patients <18 years old implementing 3D printing to aid in craniofacial surgery were included. Study selection, grading, and data extraction were performed independently by multiple authors. After screening 120 articles, 7 (3 case series and 4 case reports) were included, published from 2017 to 2022. All studies addressed patients with different disease processes including craniosynostosis, cleft lip/palate, and mandibular hypoplasia. 3D printing was used to create mock surgical models in 2 studies, intraoperative cutting guides/molds (CGs) in 6 studies, and cranioplasty implants in 2 studies. Two case series determined the accuracy of the CGs was acceptable within historical comparison, while 4 articles included subjective statements on improved accuracy. Five studies noted reduced operating time, 2 noted reduced intraoperative blood loss, and 1 felt the use of 3D printed materials was responsible for shorter hospitalization duration. No adverse events were reported. Despite the limitations of the current literature, all studies concluded that the use of 3D printing in pediatric craniofacial surgery was beneficial. Definitive conclusions cannot be made until further controlled research is performed.

Artificial intelligence of arterial Doppler waveforms to predict major adverse outcomes among patients with diabetes mellitus.

OBJECTIVE: Patients with diabetes mellitus (DM) are at increased risk for peripheral artery disease (PAD) and its complications. Arterial calcification and non-compressibility may limit test interpretation in this population. Developing tools capable of identifying PAD and predicting major adverse cardiac event (MACE) and limb event (MALE) outcomes among patients with DM would be clinically useful. Deep neural network analysis of resting Doppler arterial waveforms was used to detect PAD among patients with DM and to identify those at greatest risk for major adverse outcome events. METHODS: Consecutive patients with DM undergoing lower limb arterial testing (April 1, 2015-December 30, 2020) were randomly allocated to training, validation, and testing subsets (60%, 20%, and 20%). Deep neural networks were trained on resting posterior tibial arterial Doppler waveforms to predict all-cause mortality, MACE, and MALE at 5 years using quartiles based on the distribution of the prediction score. RESULTS: Among 11,384 total patients, 4211 patients with DM met study criteria (mean age, 68.6 ± 11.9 years; 32.0% female). After allocating the training and validation subsets, the final test subset included 856 patients. During follow-up, there were 262 deaths, 319 MACE, and 99 MALE. Patients in the upper quartile of prediction based on deep neural network analysis of the posterior tibial artery waveform provided independent prediction of death (hazard ratio [HR], 3.58; 95% confidence interval [CI], 2.31-5.56), MACE (HR, 2.06; 95% CI, 1.49-2.91), and MALE (HR, 13.50; 95% CI, 5.83-31.27). CONCLUSIONS: An artificial intelligence enabled analysis of a resting Doppler arterial waveform permits identification of major adverse outcomes including all-cause mortality, MACE, and MALE among patients with DM.

Risk Factors for Pediatric Facial Trauma in an Appalachian Region: An Epidemiological Review at a Single Institution.

BACKGROUND: Rural and low-income pediatric populations are at higher risk for trauma. Craniomaxillofacial (CMF) trauma in this population has not been studied. PURPOSE: This study's purpose was to determine if rural populations or low-income populations are at higher risk for pediatric CMF trauma than urban or high-income populations, respectively, and to determine differences in mechanism of injury (MOI). STUDY DESIGN, SETTING, SAMPLE: A retrospective cohort study of CMF trauma patients younger than 17 years-old, living in the region served by one institution in Tennessee, and requiring oral and maxillofacial surgery consultation between January 2011 and December 2022 was performed. Exclusion criteria were incomplete medical records. PREDICTOR VARIABLE: The primary predictor variable was geographic residence of the patient grouped into two categories: rural or urban defined by the state of Tennessee. Secondary variables were postal code (PC) average median household income (MHI) and PC population density. MAIN OUTCOME VARIABLE(S): The main outcome variable was pediatric CMF injury rate per 100,000 people. MOI is a secondary outcome variable. COVARIATE(S): Covariates included sex, age, and race. ANALYSES: Frequencies and percentages, Fisher's exact test, and Poisson regression models were utilized. Statistical significance was assumed at P-value <.05. RESULTS: Rural or urban county designation was not associated with differing trauma rates (incident risk ratio (IRR) = 0.91; 95% confidence interval (CI) 0.78 to 1.05; P = .18) by itself. One standard deviation increase in MHI decreased CMF trauma rates in rural designation counties by 24% (IRR: 0.76, 95% CI: 0.66, 0.88) and 6% in urban designation counties (IRR: 0.94, 95% CI: 0.87, 1.02). Lower rates of CMF trauma were associated with residence in higher income PCs (IRR = 0.91; 95% (CI) 0.86 to 0.97; P = .004), and higher population density (IRR = 0.87; 95% CI 0.79 to 0.94; P < .001). Dog bites and falls were more common in infancy and early childhood. Interpersonal violence was more common in older patients. CONCLUSIONS AND RELEVANCE: Patients in PCs with lower population density or incomes were at highest risk for CMF injuries. MOI differences by age were similar to findings in other studies. Tennessee's urban/rural county designation has complex interactions with MHI and pediatric CMF trauma rates.

Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors.

PURPOSE: Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. EXPERIMENTAL DESIGN: Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction. RESULTS: Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. CONCLUSIONS: This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.

Five-Year Sustained Impact of a Thoracic Enhanced Recovery After Surgery Program.

BACKGROUND: Our thoracic enhanced recovery program (ERP) decreased the use of postoperative morphine equivalents and hospital costs 1 year after implementation at our tertiary center. The sustainability and potential increasing benefit of this program were evaluated. METHODS: From 2015 to 2021, we prospectively analyzed the outcomes of patients who underwent elective pleural, pulmonary, or mediastinal operations at our institution. Patients were separated on the basis of the incision (video-assisted thoracoscopic surgery [VATS] or thoracotomy). The ERP protocol was initiated on May 1, 2016, and includes preoperative education, carbohydrate loading, opioid-sparing analgesia, conservative fluid management, protective ventilation, and early ambulation. Outcomes of patients before (2015, pre-VATS and pre-thoracotomy) and after (May 1, 2016, to December 31, 2021, ERP-VATS and ERP-thoracotomy) ERP implementation were compared. RESULTS: The cohort included 1079 patients (pre-ERP era, n = 224 [21%]; ERP era, n = 855 [79%]). There was a median reduction of 1.5 hospital days per patient for ERP-thoracotomy and 1 hospital day per patient for ERP-VATS. Median postoperative morphine equivalents decreased in both groups (125 vs 45 mg, in ERP-thoracotomy; 84 vs 23 mg, ERP-VATS; P < .001), as did total admission cost ($32,118 vs $23,775, ERP-thoracotomy; $17,367 vs $11,560, ERP-VATS; P < .001). Median total fluid balance during the hospital stay decreased significantly. Rates of postoperative atrial fibrillation and urinary retention decreased across both subgroups. CONCLUSIONS: ERP for thoracic surgery is sustainable and has been demonstrated to improve patient outcomes, to decrease opioid use, and to lower hospital costs. Therefore, it has the potential to become the standard of care.

PolySialic acid-nanoparticles inhibit macrophage mediated inflammation through Siglec agonism: a potential treatment for age related macular degeneration.

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1ß, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of non-exudative AMD.

Rapid Access to Potent Bispecific T Cell Engagers Using Biogenic Tyrosine Click Chemistry.

Bispecific antibodies as T cell engagers designed to display binding capabilities to both tumor-associated antigens and antigens on T cells are considered promising agents in the fight against cancer. Even though chemical strategies to develop such constructs have emerged, a method that readily converts a therapeutically applied antibody into a bispecific construct by a fully non-genetic process is not yet available. Herein, we report the application of a biogenic, tyrosine-based click reaction utilizing chemoenzymatic modifications of native IgG1 antibodies to generate a synthetic bispecific antibody construct that exhibits tumor-killing capability at picomolar concentrations. Control experiments revealed that a covalent linkage of the different components is required for the observed biological activities. In view of the highly potent nature of the constructs and the modular approach that relies on convenient synthetic methods utilizing therapeutically approved biomolecules, our method expedites the production of potent bispecific antibody constructs with tunable cell killing efficacy with significant impact on therapeutic properties.

Cathepsin V regulates cell cycle progression and histone stability in the nucleus of breast cancer cells.

Introduction: We previously identified that Cathepsin V (CTSV) expression is associated with poor prognosis in ER+ breast cancer, particularly within the Luminal A subtype. Examination of the molecular role of the protease within Luminal A tumours, revealed that CTSV promotes tumour cell invasion and proliferation, in addition to degradation of the luminal transcription factor, GATA3, via the proteasome. Methods: Cell line models expressing CTSV shRNA or transfected to overexpress CTSV were used to examine the impact of CTSV on cell proliferation by MTT assay and flow cytometry. Western blotting analysis was used to identify the impact of CTSV on histone and chaperone protein expression. Cell fractionation and confocal microscopy was used to illustrate the presence of CTSV in the nuclear compartment. Results: In this work we have identified that CTSV has an impact on breast cancer cell proliferation, with CTSV depleted cells exhibiting delayed progression through the G2/M phase of the cell cycle. Further investigation has revealed that CTSV can control nuclear expression levels of histones H3 and H4 via regulating protein expression of their chaperone sNASP. We have discovered that CTSV is localised to the nuclear compartment in breast tumour cells, mediated by a bipartite nuclear localisation signal (NLS) within the CTSV sequence and that nuclear CTSV is required for cell cycle progression and histone stability in breast tumour cells. Discussion: Collectively these findings support the hypothesis that targeting CTSV may have utility as a novel therapeutic target in ER+ breast cancer by impairing cell cycle progression via manipulating histone stabilisation.

Health diplomacy in action: The cancer legacy of the Good Friday Agreement.

2023 marks the 25th anniversary of the Good Friday Agreement, which led peace in Northern Ireland. As well as its impact on peace and reconciliation, the Good Friday Agreement has also had a lasting positive impact on cancer research and cancer care across the island of Ireland. Pursuant to the Good Friday Agreement, a Memorandum of Understanding (MOU) was signed between the respective Departments of Health in Ireland, Northern Ireland and the US National Cancer Institute (NCI), giving rise to the Ireland - Northern Ireland - National Cancer Institute Cancer Consortium, an unparalleled tripartite agreement designed to nurture and develop linkages between cancer researchers, physicians and allied healthcare professionals across Ireland, Northern Ireland and the US, delivering world class research and better care for cancer patients on the island of Ireland and driving research and innovation in the US.

Bicuspid aortic valve: long-term morbidity and mortality.

BACKGROUND AND AIMS: Bicuspid aortic valve (BAV) is the most common congenital heart anomaly. Lifetime morbidity and whether long-term survival varies according to BAV patient-sub-groups are unknown. This study aimed to assess lifetime morbidity and long-term survival in BAV patients in the community. METHODS: The authors retrospectively identified all Olmsted County (Minnesota) residents with an echocardiographic diagnosis of BAV from 1 January 1980 to 31 December 2009, including patients with typical valvulo-aortopathy (BAV without accelerated valvulo-aortopathy or associated disorders), and those with complex valvulo-aortopathy (BAV with accelerated valvulo-aortopathy or associated disorders). RESULTS: 652 consecutive diagnosed BAV patients [median (IQR) age 37 (22-53) years; 525 (81%) adult and 127 (19%) paediatric] were followed for a median (IQR) of 19.1 (12.9-25.8) years. The total cumulative lifetime morbidity burden (from birth to age 90) was 86% (95% CI 82.5-89.7); cumulative lifetime progression to ≥ moderate aortic stenosis or regurgitation, aortic valve surgery, aortic aneurysm ≥45 mm or z-score ≥3, aorta surgery, infective endocarditis and aortic dissection was 80.3%, 68.5%, 75.4%, 27%, 6% and 1.6%, respectively. Survival of patients with typical valvulo-aortopathy [562 (86%), age 40 (28-55) years, 86% adults] was similar to age-sex-matched Minnesota population (P = .12). Conversely, survival of patients with complex valvulo-aortopathy [90 (14%), age 14 (3-26) years, 57% paediatric] was lower than expected, with a relative excess mortality risk of 2.25 (95% CI 1.21-4.19) (P = .01). CONCLUSION: The BAV condition exhibits a high lifetime morbidity burden where valvulo-aortopathy is close to unavoidable by age 90. The lifetime incidence of infective endocarditis is higher than that of aortic dissection. The most common BAV clinical presentation is the typical valvulo-aortopathy with preserved expected long-term survival, while the complex valvulo-aortopathy presentation incurs higher mortality.

Incidence, risk factors, and outcomes of atrial functional mitral regurgitation in patients with atrial fibrillation or sinus rhythm.

AIMS: Atrial functional mitral regurgitation (AFMR) has been associated with atrial fibrillation (AF) and heart failure with preserved ejection fraction. However, data on incident AFMR are scarce. We aimed to study the incidence, risk factors, and clinical significance of AFMR in AF or sinus rhythm (SR). METHODS AND RESULTS: Adults with new diagnosis of AF and adults in SR were identified. Patients with >mild MR at baseline, primary mitral disease, cardiomyopathy, left-sided valve disease, previous cardiac surgery, or with no follow-up echocardiogram were excluded. Diastolic dysfunction (DD) was indicated by ≥2/4 abnormal diastolic function parameters [mitral medial e', mitral medial E/e', tricuspid regurgitation velocity, left atrial volume index (LAVI)]. Overall, 1747 patients with AF and 29 623 in SR were included. Incidence rate of >mild AFMR was 2.6 per 100 person-year in new-onset AF and 0.7 per 100 person-year in SR, P < 0.001. AF remained associated with AFMR in a propensity score-matched analysis based on age, sex, and comorbidities between AF and SR [hazard ratio: 3.80 (95% confidence interval 3.04-4.76)]. Independent risk factors associated with incident AFMR were age ≥65 years, female sex, LAVI, and DD in both AF and SR, in addition to rate (vs. rhythm) control in AF. Incident AFMR was independently associated with all-cause death in both groups (both P < 0.001). CONCLUSIONS: AF conferred a three-fold increase in the risk of incident AFMR. DD, older age, left atrial size, and female sex were independent risk factors in both SR and AF, while rhythm control was protective. AFMR was universally associated with worse mortality.

Preoperative Nutritional Laboratory Values, Demographics, and Wound Healing Following Facial Trauma Surgery: Which Variables Predict Postoperative Complications?

In individuals who have sustained maxillofacial trauma, inadequate nutrition is often a sequela and may lead to complications. The purpose of this study was to investigate the association between preoperative laboratory values and postoperative complications in patients with maxillofacial trauma requiring surgical intervention. A retrospective cohort study of patients with maxillofacial trauma requiring surgical repair from 2014 to 2020 was performed at a single academic Level I Trauma Center. The primary predictor variables were preoperative laboratory values including serum albumin, white blood cell count, absolute neutrophil count, and lymphocyte count. Complications related to surgical reconstruction of facial injuries represented the primary outcome variable. The patient cohort included 152 patients, of whom 50 (32.9%) were female. When controlling for all other variables, female gender (odds ratio=2.08, 95% confidence interval, 1.02-4.21; P =0.04) and number of procedures performed ( P =0.02) were the only statistically significant predictors of postoperative complications. There were no significant differences between the complication groups for age ( P =0.89), injury severity score ( P =0.59), hospital length of stay ( P =0.30), serum albumin ( P =0.86), hemoglobin ( P =0.06), white blood cell count ( P =0.20), absolute neutrophil count ( P =0.95), lymphocyte count ( P =0.23), or absolute neutrophil/lymphocyte count ratio ( P =0.09). In this study, it was found that only gender and the number of procedures performed significantly predicted postoperative complications, while preoperative nutritional laboratory values did not. Further study with a larger cohort of patients is likely required.

Long-Term Patient-Reported Symptom Improvement and Quality of Life after Transthoracic Diaphragm Plication in Adults.

BACKGROUND: Open and robotic-assisted transthoracic approaches for diaphragm plication are accepted surgical interventions for diaphragm paralysis and eventration. However, long-term patient-reported symptom improvement and quality of life (QOL) remains unclear. STUDY DESIGN: A telephone-based survey was developed focusing on postoperative symptom improvement and QOL. Patients who underwent open or robotic-assisted transthoracic diaphragm plication (2008-2020) across three institutions were invited to participate. Patients who responded and provided consent were surveyed. Likert responses on symptom severity were dichotomized and rates before and after surgery were compared using McNemar's test. RESULTS: Forty-one percent of patients participated (43 of 105 responded, mean age 61.0 years, 67.4% male, 37.2% robotic-assisted surgery), with an average time between surgery and survey of 4.1 ± 3.2 years. Patients reported significant improvement in dyspnea while lying flat (67.4% pre- vs 27.9% postoperative, p < 0.001), dyspnea at rest (55.8% pre- vs 11.6% postoperative, p < 0.001), dyspnea with activity (90.7% pre- vs 55.8% postoperative, p < 0.001), dyspnea while bending over (79.1% pre- vs 34.9% postoperative, p < 0.001), and fatigue (67.4% pre- vs 41.9% postoperative, p = 0.008). There was no statistical improvement in chronic cough. 86% of patients reported improved overall QOL, 79% had increased exercise capacity, and 86% would recommend surgery to a friend with a similar problem. Analysis comparing open and robotic-assisted approaches found no statistically significant differences in symptom improvement or QOL responses between the groups. CONCLUSIONS: Patients report significantly improved dyspneic and fatigue symptoms after transthoracic diaphragm plication, regardless of open or robotic-assisted approach. The majority of patients report improved QOL and exercise capacity.

Functionalization of polymeric nanoparticles with targeting VNAR ligands using vinyl sulfone conjugation.

Actively targeted drug loaded nanoparticles represent an exciting new form of therapeutics for cancer and other diseases. These formulations are complex and in order to realize their ultimate potential, optimization of their preparation is required. In this current study, we have examined the conjugation of a model targeting ligand, conjugated in a site-specific manner using a vinyl sulfone coupling approach. A disulfide-functionalized poly(L-lactide)-b-poly(oligo(ethylene glycol) methacrylate)-stat-(bis(2-methacryloyl)oxyethyl disulfide) (PLA-b-P(OEGMA-stat-DSDMA)) diblock copolymer was synthesized by simultaneous ring opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. Subsequently, the disulfide bonds of the polymer were reduced to thiols and divinyl sulfone was attached to the polymer using thiol-ene chemistry to produce the vinyl sulfone (VS)-functionalized PLA-b-P(OEGMA-stat-VSTEMA) amphiphilic block copolymer. Single emulsion - solvent evaporation was employed using a blend of this polymer with poly(D,L-lactide-co-glycolide) (PLGA) to produce VS-functionalized polymeric nanoparticles. The ability of these novel nanoparticles to attach ligands was then exemplified using a single domain variable new antigen receptor (VNAR) with a free carboxyl terminal cysteine residue. The resulting VNAR-functionalized nanoparticles were found to maintain specific affinity to their cognate antigen (DLL4) for at least 72 h at 4 °C. The simplicity of the degradable amphiphilic block copolymer synthesis and the efficiency of VNAR conjugation to the VS-functionalized nanoparticles show the potential of this platform for therapeutic development.