Reintervention and mortality risk after total anomalous pulmonary venous connection repair.

BACKGROUND: Management of total anomalous pulmonary venous connections has been extensively studied to further improve outcomes. Our institution previously reported factors associated with mortality, recurrent obstruction, and reintervention. The study purpose was to revisit the cohort of patients and evaluate factors associated with reintervention, and mortality in early and late follow-up. METHODS: A retrospective review at our institution identified 81 patients undergoing total anomalous pulmonary venous connection repair from January 2002 to January 2018. Demographic and operative variables were evaluated. Anastomotic reintervention (interventional or surgical) and/or mortality were primary endpoints. RESULTS: Eighty-one patients met the study criteria. Follow-up ranged from 0 to 6,291 days (17.2 years), a mean of 1263 days (3.5 years). Surgical mortality was 16.1% and reintervention rates were 19.8%. In re-interventions performed, 80% occurred within 1.2 years, while 94% of mortalities were within 4.1 months. Increasing cardiopulmonary bypass times (p = 0.0001) and the presence of obstruction at the time of surgery (p = 0.025) were predictors of mortality, while intracardiac total anomalous pulmonary venous connection type (p = 0.033) was protective. Risk of reintervention was higher with increasing cardiopulmonary bypass times (p = 0.015), single ventricle anatomy (p = 0.02), and a post-repair gradient >2 mmHg on transesophageal echocardiogram (p = 0.009). CONCLUSIONS: Evaluation of a larger cohort with longer follow-up demonstrated the relationship of anatomic complexity and symptoms at presentation to increased mortality risk after total anomalous pulmonary venous connection repair. The presence of a single ventricle or a post-operative confluence gradient >2 mmHg were risk factors for reintervention. These findings support those found in our initial study.

Stable gold(III) catalysts by oxidative addition of a carbon-carbon bond.

Low-valent late transition-metal catalysis has become indispensable to chemical synthesis, but homogeneous high-valent transition-metal catalysis is underdeveloped, mainly owing to the reactivity of high-valent transition-metal complexes and the challenges associated with synthesizing them. Here we report a carbon-carbon bond cleavage at ambient conditions by a Au(i) complex that generates a stable Au(iii) cationic complex. In contrast to the well-established soft and carbophilic Au(i) catalyst, this Au(iii) complex exhibits hard, oxophilic Lewis acidity. For example, we observed catalytic activation of α,ß-unsaturated aldehydes towards selective conjugate additions as well as activation of an unsaturated aldehyde-allene for a [2 + 2] cycloaddition reaction. The origin of the regioselectivity and catalytic activity was elucidated by X-ray crystallographic analysis of an isolated Au(iii)-activated cinnamaldehyde intermediate. The concepts revealed suggest a strategy for accessing high-valent transition-metal catalysis from readily available precursors.

Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89Zr-immunoPET.

PURPOSE: Currently, the most commonly used chelator for labelling antibodies with 89Zr for immunoPET is desferrioxamine B (DFO). However, preclinical studies have shown that the limited in vivo stability of the 89Zr-DFO complex results in release of 89Zr, which accumulates in mineral bone. Here we report a novel chelator DFOcyclo*, a preorganized extended DFO derivative that enables octacoordination of the 89Zr radiometal. The aim was to compare the in vitro and in vivo stability of [89Zr]Zr-DFOcyclo*, [89Zr]Zr-DFO* and [89Zr]Zr-DFO. METHODS: The stability of 89Zr-labelled chelators alone and after conjugation to trastuzumab was evaluated in human plasma and PBS, and in the presence of excess EDTA or DFO. The immunoreactive fraction, IC50, and internalization rate of the conjugates were evaluated using HER2-expressing SKOV-3 cells. The in vivo distribution was investigated in mice with subcutaneous HER2+ SKOV-3 or HER2- MDA-MB-231 xenografts by PET/CT imaging and quantitative ex vivo tissue analyses 7 days after injection. RESULTS: 89Zr-labelled DFO, DFO* and DFOcyclo* were stable in human plasma for up to 7 days. In competition with EDTA, DFO* and DFOcyclo* showed higher stability than DFO. In competition with excess DFO, DFOcyclo*-trastuzumab was significantly more stable than the corresponding DFO and DFO* conjugates (p < 0.001). Cell binding and internalization were similar for the three conjugates. In in vivo studies, HER2+ SKOV-3 tumour-bearing mice showed significantly lower bone uptake (p < 0.001) 168 h after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5 ± 0.3%ID/g, knee 2.1 ± 0.4%ID/g) or [89Zr]Zr-DFO*-trastuzumab (femur 2.0 ± 0.3%ID/g, knee 2.68 ± 0.4%ID/g) than after injection with [89Zr]Zr-DFO-trastuzumab (femur 4.5 ± 0.6%ID/g, knee 7.8 ± 0.6%ID/g). Blood levels, tumour uptake and uptake in other organs were not significantly different at 168 h after injection. HER2- MDA-MB-231 tumour-bearing mice showed significantly lower tumour uptake (p < 0.001) after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (16.2 ± 10.1%ID/g) and [89Zr]Zr-DFO-trastuzumab (19.6 ± 3.2%ID/g) than HER2+ SKOV-3 tumour-bearing mice (72.1 ± 14.6%ID/g and 93.1 ± 20.9%ID/g, respectively), while bone uptake was similar. CONCLUSION: 89Zr-labelled DFOcyclo* and DFOcyclo*-trastuzumab showed higher in vitro and in vivo stability than the current commonly used 89Zr-DFO-trastuzumab. DFOcyclo* is a promising candidate to become the new clinically used standard chelator for 89Zr immunoPET.

Azotides as Modular Peptide-Based Ligands for Asymmetric Lewis Acid Catalysis.

Synthesis of azotides and evaluation of these as ligands for enantioselective Lewis acid catalysis is reported. The ligands were readily prepared from the chiral pool of amino acids and perform well in the cobalt(II)-catalyzed formation of asymmetric hetero Diels-Alder adducts. A rational for the observed enantioselectivity and conversion rate supported by computational calculations is provided.

Mechanism and Scope of Base-Controlled Catalyst-Free N-Arylation of Amines with Unactivated Fluorobenzenes.

A general method for transition metal-free N-arylation of amines has been developed. Mechanistic studies have revealed that the ability of the base to facilitate the desired amination without promoting unwanted side reactions is the guiding factor. By employing lithium bis(trimethylsilyl)amide as a base the resultant deprotonated amines readily react with a range of unactivated fluorobenzene derivatives. This new arylation method is utilized for the simple two-step synthesis of the antidepressant Vortioxetine.

A participatory physical and psychosocial intervention for balancing the demands and resources among industrial workers (PIPPI): study protocol of a cluster-randomized controlled trial.

BACKGROUND: Need for recovery and work ability are strongly associated with high employee turnover, well-being and sickness absence. However, scientific knowledge on effective interventions to improve work ability and decrease need for recovery is scarce. Thus, the present study aims to describe the background, design and protocol of a cluster randomized controlled trial evaluating the effectiveness of an intervention to reduce need for recovery and improve work ability among industrial workers. METHODS/DESIGN: A two-year cluster randomized controlled design will be utilized, in which controls will also receive the intervention in year two. More than 400 workers from three companies in Denmark will be aimed to be cluster randomized into intervention and control groups with at least 200 workers (at least 9 work teams) in each group. An organizational resources audit and subsequent action planning workshop will be carried out to map the existing resources and act upon initiatives not functioning as intended. Workshops will be conducted to train leaders and health and safety representatives in supporting and facilitating the intervention activities. Group and individual level participatory visual mapping sessions will be carried out allowing team members to discuss current physical and psychosocial work demands and resources, and develop action plans to minimize strain and if possible, optimize the resources. At all levels, the intervention will be integrated into the existing organization of work schedules. An extensive process and effect evaluation on need for recovery and work ability will be carried out via questionnaires, observations, interviews and organizational data assessed at several time points throughout the intervention period. DISCUSSION: This study primarily aims to develop, implement and evaluate an intervention based on the abovementioned features which may improve the work environment, available resources and health of industrial workers, and hence their need for recovery and work ability.

Span of control and well-being outcomes among hospital frontline managers: too much to handle?

PURPOSE: To examine the consequences of broader spans of control for well-being outcomes among frontline managers. METHOD: Healthcare managers were surveyed in collaboration with the Central Denmark Region. The response rate was 74.5%. Using regression analysis, we investigate how span of control is associated with outcomes related to well-being understood as perceived stress, burnout, job satisfaction, satisfaction with the work environment, intention to quit their current job and work-life balance. FINDINGS: Span of control may be an important factor in establishing well-being among frontline managers in the Danish hospital sector on several parameters. Span of control is associated the strongest with work-life balance and intention to quit, least but significantly with perceived stress and not significantly with burnout. PRACTICAL IMPLICATIONS: We recommend that healthcare organisations consider whether it could be more optimal to reduce the span of control for some managers. Furthermore, we recommend that future studies pay attention to span of control and provide stronger causal evidence about its impact on healthcare workers.

The link between physician motivation and care.

Studies report an unexplained variation in physicians' care. This variation may to some extent be explained by differences in their work motivation. However, empirical evidence on the link between physician motivation and care is scarce. We estimate the associations between different types of work motivation and care. Motivation is measured using validated questions from a nation-wide survey of Danish general practices and linked to high-quality register data on their care in 2019. Using a series of regression models, we find that more financially motivated practices generate more fee-for-services per patient, whereas practices characterised by greater altruistic motivation towards the patient serve a larger share of high-need patients and issue more prescriptions for antibiotics per patient. Practices with higher altruism towards society generate lower medication costs per patient and prescribe a higher rate of narrow-spectrum penicillin, thereby reducing the risk of antimicrobial resistance in the population. Together, our results suggest that practices' motivation is associated with several dimensions of healthcare, and that both their financial motivation and altruism towards patients and society play a role. Policymakers should, therefore, consider targeting all provider motivations when introducing organisational changes and incentive schemes; for example, by paying physicians to adhere to clinical guidelines, while at the same time clearly communicating the guidelines' value from both a patient and societal perspective.

State of the Science in Tracheal Stents: A Scoping Review.

OBJECTIVE: Recent material science advancements are driving tracheal stent innovation. We sought to assess the state of the science regarding materials and preclinical/clinical outcomes for tracheal stents in adults with benign tracheal disease. METHODS: A comprehensive literature search in April 2021 identified 556 articles related to tracheal stents. One-hundred and twenty-eight full-text articles were reviewed and 58 were included in the final analysis. Datapoints examined were stent materials, clinical applications and outcomes, and preclinical findings, including emerging technologies. RESULTS: In the 58 included studies, stent materials were metals (n = 28), polymers (n = 19), coated stents (n = 19), and drug-eluting (n = 5). Metals included nitinol, steel, magnesium alloys, and elgiloy. Studies utilized 10 different polymers, the most popular included polydioxanone, poly-l-lactic acid, poly(d,l-lactide-co-glycolide), and polycaprolactone. Coated stents employed a metal or polymer framework and were coated with polyurethane, silicone, polytetrafluoroethylene, or polyester, with some polymer coatings designed specifically for drug elution. Drug-eluting stents utilized mitomycin C, arsenic trioxide, paclitaxel, rapamycin, and doxycycline. Of the 58 studies, 18 were human and 40 were animal studies (leporine = 21, canine = 9, swine = 4, rat = 3, ovine/feline/murine = 1). Noted complications included granulation tissue and/or stenosis, stent migration, death, infection, and fragmentation. CONCLUSION: An increasing diversity of materials and coatings are employed for tracheal stents, growing more pronounced over the past decade. Though most studies are still preclinical, awareness of tracheal stent developments is important in contextualizing novel stent concepts and clinical trials. Laryngoscope, 132:2111-2123, 2022.

Lung lobectomy surgical approach and resource utilization differ by anatomic lobe in a statewide discharge registry.

Background: Anatomic lobe-specific differences with respect to pulmonary lobectomy have been suggested in the thoracic surgery literature but hard data has been lacking in larger population studies in part due to coding systems that do not distinguish pulmonary lobectomy by anatomic lobe. International Classification of Diseases, Tenth Revision (ICD-10) procedure codes, adopted in the United States in 2015, may provide novel methodologic accessibility for pulmonary lobectomy studies as they classify lobectomy operations by specific anatomic lobe. We queried the Texas Inpatient Public Use Data File (TPUDF) ICD-10 codes for both open and endoscopic approach lobectomy with a specific view to differences based on anatomic lobes. Methods: Between fourth fiscal quarter (Q4) 2015 and Q4 2017, all pulmonary lobectomy operations performed in Texas state-licensed hospitals were identified by querying the TPUDF for ICD-10 procedure codes for pulmonary lobectomy as classified by anatomic lobe. Surgical approach, additional procedures and diagnosis codes, length of hospital stay (LOS), and discharge status were recorded with aggregate values undergoing statistical analysis. Results: Right and left upper versus lower lobe resections were more prevalent however minimally invasive surgery was less commonly performed for upper than right lower lobectomy. LOS, irrespective of surgical approach, was longer for upper versus lower lobe resection as was need for transfer to additional inpatient facilities. LOS was longer and need for additional surgical or procedural interventions days after the primary procedure of lobectomy was greater for right versus left upper lobe resection, suggesting some differential properties of the right versus left pleural space. Conclusions: The marked clinical differences between anatomic lobes in the setting of pulmonary lobectomy observed in this study have the potential to translate to differences in expected hospital and health system costs and surgeon time-expenditure and experience premium that currently have no mechanism for their accounting. These findings highlight the value of ICD-10 coding for analysis of pulmonary lobectomy in administrative databases and suggest a possible path to more informed patient counseling and equitable hospital and surgeon reimbursement based on payment adjustment by anatomic lobe in pulmonary lobectomy operations.

Comparison of the Tissue Distribution of a Long-Circulating Glucagon-like Peptide-1 Agonist Determined by Positron Emission Tomography and Quantitative Whole-Body Autoradiography.

Positron emission tomography (PET) is a molecular imaging modality that enables non-invasive visualization of tracer distribution and pharmacology. Recently, peptides with long half-lives allowed once-a-week dosing of glucagon-like peptide-1 receptor (GLP-1R) agonists with therapeutic applications in diabetes and obesity. PET imaging for such long-lived peptides is hindered by the typically used short-lived radionuclides. Zirconium-89 (89Zr) emerged as a promising PET radionuclide with a sufficiently long half-life to be applied for biodistribution studies of long-circulating biomolecules. A comparison between the biodistribution profiles obtained via 89Zr-PET and the current standard, quantitative whole-body autoradiography (QWBA), will be valuable for the development of novel peptide drugs. We determined the PET biodistribution of a 89Zr-labeled acylated peptide agonist of GLP-1R and compared it to the profile obtained by QWBA using analogous tritiated tracers for up to 1 week after administration. The plasma metabolic profile was obtained and identification was done for the tritiated tracers. We found that, at early time points, the biodistribution profiles agreed between PET and QWBA. At the latertime points, the 89Zr tracer remained primarily trapped in the kidneys. The introduction of desferrioxamine (DFO) chelator reduced the peptide stability, and UPLC-MS analysis identified a circulating metabolite arising from DFO hydrolysis. Kidney accumulation of radiolabeled peptides and DFO metabolic instability may compromise biodistribution studies using 89Zr-PET to support the development of new biopharmaceuticals. PET and QWBA biodistribution data correlated well during the absorption phase, but new and more stable 89Zr chelators are needed for a more accurate description of the elimination phase.

Asymmetric organocatalytic monofluorovinylations.

The development of highly enantio- and diastereoselective organocatalytic monofluorovinylations is presented. Based on the application of α-fluoro-ß-keto-benzothiazolesulfones, the formal addition of a monofluorovinylic anion synthon to a range of acyclic and cyclic enones, as well as imines, is shown. These procedures give selective access to both E- and Z-isomers of the monofluorovinylated products, which are isolated as the pure diastereoisomers in good to excellent yields with up to 99% ee. Furthermore, the application of this concept for the formation of highly enantioenriched bicylic compounds containing a monofluorovinyl moiety is also described. In addition, a mechanistic rationale for the observed E:Z-selectivities is presented.

Recombinant activated factor VII is reabsorbed in renal proximal tubules and is a ligand to megalin and cubilin.

BACKGROUND/AIMS: Recombinant activated factor VIIa (rFVIIa) is used for treatment of haemophilia patients with inhibitors. Tissue distribution studies in rats have shown that injected (125)I-rFVIIa accumulates in organs such as the liver and the kidneys. In this study, we explored which mechanism could be involved in renal clearance of rFVIIa. METHODS: Immunohistochemistry was used for examination of the renal distribution in detail after injection of rFVIIa to mice and rats. Surface plasmon resonance evaluated specific binding of rFVIIa to megalin and cubilin. The biological function of megalin and cubilin in rFVIIa endocytosis was explored in opossum kidney (OK) cells. RESULTS: Staining of rFVIIa was observed only in endosomes and lysosomes within proximal convoluted tubules from renal cortex of mice and rats. Specific binding of rFVIIa to megalin and cubilin was in the presence of receptor-associated protein (RAP) obliterated and reduced by approximately 50%, respectively. Immunofluorescence microscopy and a quantitative cellular endocytosis showed uptake in OK cells of either rFVIIa or (125)I-rFVIIa, and this uptake was significantly decreased in the presence of RAP. CONCLUSION: We suggest that the renal cortex plays a significant role in clearance of injected rFVIIa and that endocytosis and degradation of rFVIIa in proximal tubule cells is mediated via binding to megalin and cubilin.

MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation.

Essential effector functions of innate immunity are mediated by complement activation initiated by soluble pattern recognition molecules: mannan-binding lectin (MBL) and the ficolins. We present a novel, phylogenetically conserved protein, MAp44, which is found in human serum at 1.4 microg/ml in Ca(2+)-dependent complexes with the soluble pattern recognition molecules. The affinity for MBL is in the nanomolar range (K(D) = 0.6 nM) as determined by surface plasmon resonance. The first eight exons of the gene for MAp44 encode four domains shared with MBL-associated serine protease (MASP)-1 and MASP-3 (CUB1-EGF-CUB2-CCP1), and a ninth exon encodes C-terminal 17 aa unique to MAp44. mRNA profiling in human tissues shows high expression in the heart. MAp44 competes with MASP-2 for binding to MBL and ficolins, resulting in inhibition of complement activation. Our results add a novel mechanism to those known to control the innate immune system.

Transition-metal-free formal Sonogashira coupling and alpha-carbonyl arylation reactions.

Transition-metal-free formal Sonogashira coupling and alpha-carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S(N)Ar) of beta-carbonyl sulfones to electron-deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or alpha-aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two-step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and alpha-carbonyl arylated products from a range of electron-deficient aryl fluorides with a variety of functional groups and aryl-, heteroaryl-, alkyl-, and alkoxy-substituted sulfone nucleophiles. These transition-metal-free reactions complement the metal-catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.

Sortilin is essential for proNGF-induced neuronal cell death.

Sortilin (approximately 95 kDa) is a member of the recently discovered family of Vps10p-domain receptors, and is expressed in a variety of tissues, notably brain, spinal cord and muscle. It acts as a receptor for neurotensin, but predominates in regions of the nervous system that neither synthesize nor respond to this neuropeptide, suggesting that sortilin has additional roles. Sortilin is expressed during embryogenesis in areas where nerve growth factor (NGF) and its precursor, proNGF, have well-characterized effects. These neurotrophins can be released by neuronal tissues, and they regulate neuronal development through cell survival and cell death signalling. NGF regulates cell survival and cell death via binding to two different receptors, TrkA and p75NTR (ref. 10). In contrast, proNGF selectively induces apoptosis through p75NTR but not TrkA. However, not all p75NTR-expressing cells respond to proNGF, suggesting that additional membrane proteins are required for the induction of cell death. Here we report that proNGF creates a signalling complex by simultaneously binding to p75NTR and sortilin. Thus sortilin acts as a co-receptor and molecular switch governing the p75NTR-mediated pro-apoptotic signal induced by proNGF.

Asymmetric organocatalysis with sulfones.

Asymmetric organocatalysis has become a powerful tool for the synthesis of optically active compounds. Whereas early research mainly focused on combining simple reagents as a proof-of-concept for asymmetric organocatalysis, recent investigations are directed towards extending the concept to more target- and diversity-oriented synthesis. As a result of the many transformation possibilities and their ability to generate both nucleophilic and electrophilic reaction partners, sulfones have become especially important substrates in the field of organocatalysis.

Jet Ventilation in the Pregnant Patient with Airway Stenosis: Surgical Safety and Outcomes.

OBJECTIVE: To review pregnancy outcomes and the safety of jet ventilation use in the gravid patient undergoing surgical airway intervention. METHODS: A multi-institutional retrospective review of medical records was performed to identify women who underwent low-frequency jet ventilation during pregnancy for surgical treatment of airway stenosis. Postoperative complications were noted, and patients were interviewed regarding pregnancy outcomes. RESULTS: Six women were included in this series. No immediate complications relating to anesthesia or surgical intervention were noted in five of the six women. One patient with a well-known history of uncontrolled seizures experienced seizure activity postoperatively. One patient returned to the operating room at a later date for debridement of tracheal crusts. Five mothers delivered via cesarean section and one via spontaneous vaginal delivery. The mean gestation age was 37.3 weeks. One of the six infants delivered prematurely and three were delivered at low birth weight. Three of the six infants required elevated care immediately post-delivery but, at present, all are in good health. CONCLUSION: Low-frequency jet ventilation and surgical management of airway stenosis should be recognized as a safe treatment option in the gravid patient. Surgical intervention should not be delayed in patients with severe symptoms, particularly given the potential risk associated with prolonged corticosteroid use. LEVEL OF EVIDENCE: 4.

Synthesis and evaluation of zirconium-89 labelled and long-lived GLP-1 receptor agonists for PET imaging.

INTRODUCTION: Lately, zirconium-89 has shown great promise as a radionuclide for PET applications of long circulating biomolecules. Here, the design and synthesis of protracted and long-lived GLP-1 receptor agonists conjugated to desferrioxamine and labelled with zirconium-89 is presented with the purpose of studying their in vivo distribution by PET imaging. The labelled conjugates were evaluated and compared to a non-labelled GLP-1 receptor agonist in both in vitro and in vivo assays to certify that the modification did not significantly alter the peptides' structure or function. Finally, the zirconium-89 labelled peptides were employed in PET imaging, providing visual verification of their in vivo biodistribution. METHODS: The evaluation of the radiolabelled peptides and comparison to their non-labelled parent peptide was performed by in vitro assays measuring binding and agonistic potency to the GLP-1 receptor, physicochemical studies aiming at elucidating change in peptide structure upon bioconjugation and labelling as well as an in vivo food in-take study illustrating the compounds' pharmacodynamic properties. The biodistribution of the labelled GLP-1 analogues was determined by ex vivo biodistribution and in vivo PET imaging. RESULTS: The results indicate that it is surprisingly feasible to design and synthesize a protracted, zirconium-89 labelled GLP-1 receptor agonist without losing in vitro potency or affinity as compared to a non-labelled parent peptide. Physicochemical properties as well as pharmacodynamic properties are also maintained. The biodistribution in rats shows high accumulation of radiolabelled peptide in well-perfused organs such as the liver, kidney, heart and lungs. The PET imaging study confirmed the findings from the biodistribution study with a significant high uptake in kidneys and presence of activity in liver, heart and larger blood vessels. CONCLUSIONS AND ADVANCES IN KNOWLEDGE: This initial study indicates the potential to monitor the in vivo distribution of long-circulating incretin hormones using zirconium-89 based PET.