Two months outcomes following delirium in the pediatric intensive care unit.

The lasting consequences of delirium in children are not well characterized. This study aimed to compare the two-month outcomes in pediatric intensive care unit (PICU) survivors according to the presence of delirium. Post-hoc analysis of a single-center prospective study of mechanically ventilated (invasive ventilation or non-invasive ventilation) children followed at the CHU Sainte-Justine PICU follow-up clinic two months after PICU discharge, between October 2018 and August 2022. Delirium was defined as one or more Cornell Assessment of Pediatric Delirium (CAPD) scores ≥ 9. Primary outcome was survivors' quality of life and secondary outcomes were sleep and posttraumatic stress and anxiety and depression in parents. Multivariable linear and logistic regression models assessed the independent associations between delirium and outcomes while adjusting for age, sex, comorbidity, diagnosis, severity of illness, PICU length of stay, and invasive mechanical ventilation. Of the 179 children included over a 47 month-period, 117 (65.4%) had delirium. Children with delirium were more commonly intubated (91.5% vs. 30.7%, p < 0.001) and had higher PELOD-2 scores (10 vs. 4, p < 0.001). On multivariable analysis, delirium was associated with a decreased quality of life at 2.3 months post discharge (p = 0.03). The severity of the delirium episode (higher scores of CAPD) was associated with a higher likelihood of sleep disturbances (OR 1.13, p = 0.01) and parental anxiety (OR 1.16, p = 0.01), in addition to lower quality of life (p = 0.03).Conclusions: Two months following their PICU stay, children with delirium had a lower quality of life, suggesting a lasting effect of delirium on children and their families.

Percutaneous heart valves demonstrating long-term durability: A case series of Melody valves in the pulmonary position lasting up to 19 years.

It is uncertain how long catheter delivered percutaneous heart valves may last. In congenital cardiology, stenosis and regurgitation of right ventricular to pulmonary artery conduits and valves is common, leading to repeated operations for young patients with concomitant mortality and morbidity. It has also been unclear whether percutaneous pulmonary valves last as long as surgical pulmonary valves. When the current generation of the percutaneous pulmonary valve was first implanted in the United Kingdom from 2003, randomized trials were initially not performed, decided on a case-by-case basis in congenital cardiology, nor long-term registries kept. We describe three cases where such percutaneous heart valves have lasted up to 19 years. All valves were working without significant stenosis and minor degrees of regurgitation on long-term echocardiographic follow-up, patients being asymptomatic. This demonstrates that percutaneous pulmonary valves can achieve long-term durability and may prevent the need for otherwise high-risk surgery in congenital cardiac patients.

Wide variation in surgical techniques to repair incisional hernias: a survey of practice patterns among general surgeons.

BACKGROUND: The purpose of this research was to examine the self-reported practice patterns of Canadian general surgeons regarding the elective repair of incisional hernias. METHODS: A mail survey was sent to all general surgeons in Canada. Data were collected regarding surgeon training, years in practice, practice setting and management of incisional hernias. Surgeons were asked to describe their usual surgical approach for a patient with a midline incisional hernia and a 10 × 6 cm fascial defect. RESULTS: Of the 1876 surveys mailed out 555 (30%) were returned and 483 surgeons indicated that they perform incisional hernia repair. The majority (62%) have been in practice > 10 years and 73% regularly repair incisional hernias. In response to the clinical scenario of a patient with an incisional hernia, 74% indicated that they would perform an open repair and 18% would perform a laparoscopic repair. Ninety eight percent of surgeons would use mesh, 73% would perform primary fascial closure and 47% would perform a component separation. The most common locations for mesh placement were intraperitoneal (46%) and retrorectus/preperitoneal (48%). The most common repair, which was reported by 37% of surgeons, was an open operation, with mesh, with primary fascial closure and a component separation. CONCLUSIONS: While almost all surgeons who perform incisional hernia repairs would use permanent mesh, there was substantial variation reported in surgical approach, mesh location, fascial closure and use of component separation techniques. It is unclear how this variability may impact healthcare resources and patient outcomes.

Late-Stage Functionalization by Chan-Lam Amination: Rapid Access to Potent and Selective Integrin Inhibitors.

A late-stage functionalization of the aromatic ring in amino acid derivatives is described. The key step is a copper-catalysed diversification of a boronate ester by amination (Chan-Lam reaction) that can be carried out on a complex ß-aryl-ß-amino acid scaffold. This not only considerably extends the substrate scope of amination partners, but also delivers an array of potent and selective integrin inhibitors as potential treatment agents of idiopathic pulmonary fibrosis (IPF). This versatile chemical strategy, which is amenable to high-throughput-array protocols, allows the installation of pharmaceutically valuable heteroaromatic fragments at a late stage by direct coupling to NH heterocycles, leading to compounds with drug-like attributes. It thus constitutes a useful addition to the medicinal chemist's repertoire.

Molecular Simulation of αvß6 Integrin Inhibitors.

The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin αvß6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of αvß6 in complex with its natural ligand, pro-TGF-ß1, show the persistence over time of a bidentate Arg-Asp ligand-receptor interaction and a metal chelate interaction between an aspartate on the ligand and an Mg2+ ion in the active site. This is typical of RGD binding ligands. Additional binding site interactions, which are not observed in the static crystal structure, are also identified. We investigate an RGD mimetic, which serves as a framework for a series of potential αvß6 antagonists. The scaffold includes a derivative of the widely utilized 1,8-naphthyridine moiety, for which we present force field parameters, to enable MD and relative free energy perturbation (FEP) simulations. The MD simulations highlight the importance of hydrogen bonding and cation-π interactions. The FEP calculations predict relative binding affinities, within 1.5 kcal mol-1, on average, of experiments.

Partial anomalous pulmonary venous drainage in patients presenting with suspected pulmonary hypertension: A series of 90 patients from the ASPIRE registry.

BACKGROUND AND OBJECTIVE: There are limited data regarding patients with PAPVD with suspected and diagnosed PH. METHODS: Patients with PAPVD presenting to a large PH referral centre during 2007-2017 were identified from the ASPIRE registry. RESULTS: Ninety patients with PAPVD were identified; this was newly diagnosed at our unit in 71 patients (78%), despite 69% of these having previously undergone CT. Sixty-seven percent had a single right superior and 23% a single left superior anomalous vein. Patients with an SV-ASD had a significantly larger RV area, pulmonary artery and L-R shunt and a higher % predicted DLCO (all P < 0.05). Sixty-five patients were diagnosed with PH (defined as mPAP ≥ 25 mm Hg), which was post-capillary in 24 (37%). No additional causes of PH were identified in 28 patients; 17 of these (26% of those patients with PH) had a PVR > 3 WU. Seven of these patients had isolated PAPVD, five of whom (8% of those patients with PH) had anomalous drainage of a single pulmonary vein. CONCLUSION: Undiagnosed PAPVD with or without ASD may be present in patients with suspected PH; cross-sectional imaging should therefore be specifically assessed whenever this diagnosis is considered. Radiological and physiological markers of L-R shunt are higher in patients with an associated SV-ASD. Although many patients with PAPVD and PH may have other potential causes of PH, a proportion of patients diagnosed with PAH have isolated PAPVD in the absence of other causative conditions.

An αv-RGD Integrin Inhibitor Toolbox: Drug Discovery Insight, Challenges and Opportunities.

There is a requirement for efficacious and safe medicines to treat diseases with high unmet need. The resurgence in αv-RGD integrin inhibitor drug discovery is poised to contribute to this requirement. However, drug discovery in the αv integrin space is notoriously difficult due to the receptors being structurally very similar as well as the polar zwitterionic nature of the pharmacophore. This Review aims to guide drug discovery research in this field through an αv inhibitor toolbox, consisting of small molecules and antibodies. Small-molecule αv tool compounds with extended profiles in αvß1, 3, 5, 6 and 8 cell adhesion assays, with key physicochemical properties, have been collated to assist in the selection of the right tool for the right experiment. This should also facilitate an understanding of partial selectivity profiles of compounds generated in different assays across research institutions. Prospects for further αv integrin research and the critical importance of target validation are discussed, where increased knowledge of the selectivity for individual RGD αv integrins is key. Insights into the design of small-molecule RGD chemotypes for topical or oral administration are provided and clinical findings on advanced molecules are examined.

Synthesis and determination of absolute configuration of a non-peptidic αvß6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis.

A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).

A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development.

AIMS: Myocardial development is dependent on concomitant growth of cardiomyocytes and a supporting vascular network. The coupling of myocardial and coronary vascular development is partly mediated by vascular endothelial growth factor (VEGFA) signalling and additional unknown mechanisms. We examined the cardiomyocyte specific role of the transcriptional co-activator Cited2 on myocardial microstructure and vessel growth, in relation to Vegfa expression. METHODS AND RESULTS: A cardiomyocyte-specific knockout of mouse Cited2 (Cited2(Nkx)) was analysed using magnetic resonance imaging and histology. Ventricular septal defects and significant compact layer thinning (P < 0.02 at right ventricular apex, P < 0.009 at the left ventricular apex in Cited2(Nkx) vs. controls, n = 11 vs. n = 7, respectively) were found. This was associated with a significant decrease in the number of capillaries to larger vessels (ratio 1.56 ± 0.56 vs. 3.25 ± 1.63, P = 2.7 × 10(-6) Cited2(Nkx) vs. controls, n = 11 vs. n = 7, respectively) concomitant with a 1.5-fold reduction in Vegfa expression (P < 0.02, Cited2(Nkx) vs. controls, n = 12 vs. n = 12, respectively). CITED2 was subsequently found at the Vegfa promoter in mouse embryonic hearts using chromatin immunoprecipitation, and moreover found to stimulate human VEGFA promoter activity in cooperation with TFAP2 transcription factors in transient transfection assays. There was no change in the myocardial expression of the left-right patterning gene Pitx2c, a previously known target of CITED2. CONCLUSIONS: This study delineates a novel cell-autonomous role of Cited2 in regulating VEGFA transcription and the development of myocardium and coronary vasculature in the mouse. We suggest that coupling of myocardial and coronary growth in the developing heart may occur in part through a Cited2→Vegfa pathway.

A comparison of pain scores and medication use in patients undergoing single-bundle or double-bundle anterior cruciate ligament reconstruction.

BACKGROUND: No gold standard exists for the management of postoperative pain following anterior cruciate ligament reconstruction (ACLR). We compared the pain scores and medication use of patients undergoing single-bundle (SB) or double-bundle (DB) ACLR in the acute postoperative period. Pain and medication use was also analyzed for spinal versus general anesthesia approaches within both surgery types. METHODS: We assessed 2 separate cohorts of primary ACLR patients, SB and DB, for 14 days postoperatively. We used a standard logbook to record self-reported pain scores and medication use. Pain was assessed using a 100 mm visual analogue scale (VAS). Medications were divided into 3 categories: oral opioids, oral nonsteroidal anti-inflammatories and acetaminophen. RESULTS: A total of 88 patients undergoing SB and 41 undergoing DB ACLR were included in the study. We found no significant difference in VAS pain scores between the cohorts. Despite similar VAS pain scores, the DB cohort consumed significantly more opioid and analgesia medication (p = 0.011). Patients who underwent DB with spinal anesthesia experienced significantly less pain over the initial 14-day postoperative period than those who received general anesthesia (p < 0.001). CONCLUSION: Adequate pain relief was provided to all ACLR patients in the initial postoperative period. Patients in the DB cohort experienced more pain, as evidenced by the significant diffrence in consumption of opioids and acetaminophen, than the SB cohort. Patients who underwent spinal anesthesia experienced less pain in the acute postoperative period than those who received general anesthesia.

CONTEXTE: Il n'existe pas de norme établie pour la prise en charge de la douleur postopératoire après la reconstruction du ligament croisé antérieur (RLCA). Nous avons comparé les scores de douleur et le recours aux analgésiques chez des patients soumis à une RLCA simple faisceau (SF) ou double faisceau (DF) durant la période postopératoire immédiate. La douleur et l'utilisation des analgésiques ont aussi été analysées en rapport avec l'anesthésie utilisée, rachidienne ou générale, dans les 2 types de chirurgie. MÉTHODES: Nous avons évalué 2 cohortes distinctes de patients soumis à une RLCA primaire, SF et DF, pendant les 14 premiers jours postopératoires. Les patients ont consigné leurs scores de douleur et leur utilisation d'analgésiques dans des carnets de bord standard. La douleur était évaluée au moyen d'une échelle analogique visuelle (ÉAV) de 100 mm. Les analgésiques étaient regroupés sous 3 catégories, soit opiacés oraux, antiinflammatoires non stéroïdiens oraux et acétaminophène. RÉSULTATS: En tout, 88 patients soumis à une RLCA SF et 41 à une RLCA DF ont été inclus dans l'étude. Nous n'avons observé aucune différence significative quant au score de douleur à l'ÉAV entre les cohortes. Malgré des scores de douleur similaires à l'ÉAV, la cohorte soumise à l'intervention DF a utilisé significativement plus d'opiacés et autres analgésiques (p = 0.011). Comparativement aux patients sous anesthésie générale, les patients soumis à l'intervention DF sous anesthésie rachidienne ont éprouvé significativement moins de douleur au cours des 14 premiers jours postopératoires (p < 0.001). CONCLUSION: Tous les patients qui ont subi une RLCA ont obtenu un soulagement adéquat de leur douleur durant la période postopératoire initiale. Les patients de la cohorte DF ont éprouvé davantage de douleur, comme en témoigne la différence significative de consommation d'opiacés et d'acétaminophène comparativement à la cohorte SF. Les patients qui ont subi une anesthésie rachidienne ont éprouvé moins de douleur pendant la période postopératoire immédiate, comparativement aux patients sous anesthésie générale.

Outcomes of patients supported by mechanical ventilation and their families two months after discharge from pediatric intensive care unit.

Introduction: The outcomes of children undergoing mechanical ventilation (MV) in a Pediatric Intensive Care Unit (PICU) remain poorly characterized and increasing knowledge in this area may lead to strategies that improve care. In this study, we reported the outcomes of children receiving invasive mechanical ventilation (IMV) and/or non-invasive ventilation (NIV), 2 months after PICU discharge. Methods: This is a post-hoc analysis of a single-center prospective study of PICU children followed at the PICU follow-up clinic at CHU Sainte-Justine. Eligible children were admitted to the PICU with ≥2 days of IMV or ≥4 days of NIV. Two months after PICU discharge, patients and families were evaluated by physicians and filled out questionnaires assessing Quality of life (Pediatric Quality of Life Inventory™), development milestones (Ages and Stages Questionnaire), and parental anxiety and depression (Hospital Anxiety and Depression Scale). Results: One hundred and fifty patients were included from October 2018 to December 2021; 106 patients received IMV (±NIV), and 44 patients received NIV exclusively. Admission diagnoses differed between groups, with 30.2% of patients in the IMV group admitted for a respiratory illness vs. 79.5% in the NIV group. For the entire cohort, QoL scores were 78.1% for the physical domain and 80.1% for the psychological domain, and were similar between groups. Children with a respiratory illness exhibited similar symptoms at follow-up whether they were supported by IMV vs. NIV. For developmental outcomes, only 22.2% of pre-school children had normal scores in all ASQ domains. In the entire cohort, symptoms of anxiety were reported in 29.9% and depression in 24.6 of patients. Conclusions: PICU survivors undergoing mechanical ventilation, and their families, experienced significant morbidities 2 months after their critical illness, whether they received IMV or NIV. Children with respiratory illness exhibited a higher prevalence of persistent respiratory difficulties post PICU, whether they underwent IMV or NIV. Patients' quality of life and parental symptoms of anxiety and depression did not differ according to the type of respiratory support. These findings justify the inclusion of patients receiving NIV in the PICU in follow-up assessments as well as those receiving IMV.

Effect of Sodium-Glucose Cotransporter 2 Inhibitors in Adults With Congenital Heart Disease.

BACKGROUND: Heart failure (HF) is the principal cause of morbidity and mortality in adults with congenital heart disease (ACHD). Robust evidence-based treatment options are lacking. OBJECTIVES: This study aims to evaluate the safety, tolerability, and short-term HF-related effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a real-world ACHD population. METHODS: All patients with ACHD treated with SGLT2i in 4 European ACHD centers were included in this retrospective study. Data were collected from 1 year before starting SGLT2i to the most recent follow-up. Data on side effects, discontinuation, mortality, and hospitalizations were collected. RESULTS: In total, 174 patients with ACHD were treated with SGLT2i from April 2016 to July 2023. The mean age was 48.7 ± 15.3 years, 72 (41.4%) were female, and 29 (16.7%) had type 2 diabetes mellitus. Ten (5.7%) patients had mild, 75 (43.1%) moderate, and 89 (51.1%) severe congenital heart disease. HF was the most frequent starting indication (n = 162, 93.1%), followed by type 2 diabetes (n = 11, 6.3%) and chronic kidney disease (n = 1, 0.6%). At median follow-up of 7.7 months (Q1-Q3: 3.9-13.2 months), 18 patients (10.3%) reported side effects, 12 (6.9%) permanently discontinued SGLT2i, and 4 (2.3%) died of SGLT2i-unrelated causes. A significant reduction in the HF hospitalization rate was observed from 6 months before to 6 months after starting SGLT2i (relative rate = 0.30; 95% CI: 0.14-0.62; P = 0.001). CONCLUSIONS: SGLT2i generally seem safe, well-tolerated, and potentially beneficial in patients with ACHD. SGLT2i was associated with a 3-fold reduction in the 6-month HF hospitalization rate. These results warrant prospective randomized investigation of the potential benefits of SGLT2i for patients with ACHD.

Initial use of the new GORE(®) septal occluder in patent foramen ovale closure: implantation and preliminary results.

BACKGROUND: A number of devices are available for percutaneous closure of a clinically significant patent foramen ovale (PFO). The new GORE(®) septal occluder (GSO) is a nonself-centering device consisting of an expanded polytetrafluoroethylene tube supported by a frame of nitinol wire conforming into a double disk. This study reports the first clinical GSO implantation experience. METHODS: GSO implantation in 20 consecutive patients is reported. Inclusion criteria were all patients referred with a significant PFO implicated in paradoxical embolism or transient right to left shunting causing desaturation. Procedures were performed under local anaesthesia and intracardiac echocardiography (ICE) in addition to fluoroscopy. Procedural data, acute and early closure rates were examined. RESULTS: All patients underwent successful day-case device implantation. Eleven patients had previous stroke, five had transient ischemic attacks, two had a history suspicious of PFO-related desaturation, and two had a history suspicious of PFO-related peripheral thromboembolism. Acute closure rates on IVC injection bubble testing were 100% at implant and 100% (14/14) at 1 month. Average PFO balloon size was 8.0 ± 3.6(range 2.0-16.7) mm, mean fluoroscopic implantation time 3.0 ± 1.7(range 0.7-6.3) min, radiation dose 283 ± 340 (range 6-1,431) µGym(2), and total procedural time 34.8 ± 8.0 (range 22-53) min. 5 × 20 mm(2), 7 × 25 m(2), 8 × 30 mm(2) GSO devices were implanted, aiming for device size at least twice balloon PFO size. Cases included aneurysmal septums with up to 30 mm deviation and tunnels up to 12 mm long. Removal and repositioning of two devices was performed on two occasions after uncertainty about device locking. At 1 month follow-up, two patients had brief self-terminating episodes of suspected atrial fibrillation, all had normal resting ECGs. No thromboembolic/neurological events were reported. CONCLUSIONS: The GSO can be implanted under local anaesthesia and ICE with low procedural and fluoroscopy times with high procedural success as a day case. No residual shunts were seen. This initial experience suggests that it is a safe and effective device for PFO closure.

Telescopic catheter-in-long sheath and parallel to a stiff guide wire technique for complex pulmonary artery anatomy.

Selective catheterization and procedures in pulmonary arteries may be very challenging. We developed a technique in which an extra-stiff guide wire was placed in a pulmonary artery. Across it a long sheath was placed proximally or controlateral to the lesion to be treated. An angiographic catheter was then placed parallel to the guide wire in a telescopic way within the long sheath. This system facilitated greater stability, allowing fine tuning of catheter position to reach and treat the target lesion. Here, we present five cases in whom this technique was used; a patient with multiple arteriovenous fistulas in a difficult to reach area and four subjects with complex pulmonary artery stenoses.

Over-the-wire-technique device implantation.

INTRODUCTION: Transcatheter closure of cardiac defects is a mainstay of treatment in congenital and structural heart disease. Occasionally, the devices used are useful in nonstandard or difficult positions but device embolization and malposition can be complicating factors necessitating percutaneous retrieval or emergency surgery. We describe a new "over-the-wire" technique that allows guided safe deployment and easy retrievability if required. METHODS: We describe 5 cases in which Amplatzer devices were delivered over a wire in challenging anatomy in high-risk patients. These cases included baffle leak in complex congenital heart disease, paravalvular leak, a large patent ductus arteriosus, and complex ventricular septal defects. In each case, the device was punctured close to the release mechanism and a guidewire fed through it, the device and guidewire then being loaded into the appropriate delivery system. The procedure is described in each case, illustrating the use of the technique. CONCLUSION: We describe a novel over-the-wire technique that is useful in deployment of Amplatzer devices in difficult and challenging anatomy, allowing careful controlled delivery and easy retrieval. This will help minimize procedural patient risk in complex cases.

Novel synthetic route to the C-nucleoside, 2-deoxy benzamide riboside.

2-Deoxy-C-nucleosides are a subcategory of C-nucleosides that has not been explored extensively, largely because the synthesis is less facile. Flexible synthetic procedures giving access to 2-deoxy-C-nucleosides are therefore of interest. To exemplify the versatility and highlight the limitations of a synthetic route recently developed to that effect, the first synthesis of 2-deoxy benzamide riboside is reported. Biological properties of this novel C-nucleoside are also discussed.

Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor.

Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the "meta" channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators.

How Diverse Is Medicinal Chemistry? Insights into Race, Ethnicity, Origin, Gender, and Geography.

A bibliometric study of authors across medicinal chemistry journals over 20 years reveals important trends. Most United States (US) based authors are assigned as racially/ethnically Asian or White; few are Black or Hispanic. More US coauthors have the same race/ethnicity as the corresponding author than expected. The percentage of female authors increased globally, but only slowly. Since 2010, the number of female and male authors declined by 9% and 30%, respectively. Geographically, most authors are male except in Italy where there is gender balance. Gender homophily is observed globally. Geographically, the discipline is now more widely practiced. Article output doubled from 2000 to 2010 with a large increase in articles from China. China excepted, output has since declined. The average number of authors per article rose by a third since 2000. The value of high diversity groups in education, research, and industry cannot be overstated. We recommend diversity is addressed by every medicinal chemist.

Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators.

Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site. Herein, we describe the design, synthesis, and biological evaluation of a focused library of novel steroid-derived analogues targeting the bimetallic catalytic site, representing an entirely unique class of ATX inhibitors of type V designation, which demonstrate significant pathway-relevant biochemical and phenotypic biological effects. The current compounds modulated LPA-mediated ATX allostery and achieved indirect blockage of LPA1 internalization, in line with the observed reduction in downstream signaling cascades and chemotaxis induction. These novel type V ATX inhibitors represent a promising tool to inactivate the ATX-LPA signaling axis.

Protein-losing enteropathy resolved by percutaneous intervention.

The extracardiac total cavopulmonary connection is the final stage of palliation of hearts with single-ventricle physiology. Protein-losing enteropathy (PLE) and plastic bronchitis are catastrophic sequale that may occur in patients with the total cavopulmonary connection and may complicate the early and long-term follow-up. Here we report on the successful treatment of a 16-year boy affected by PLE by percutaneous closure of a persistent anterograde pulmonary blood flow by using an 8-mm Amplatzer VSD Occluder.