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BackgroundDecision-making in initiating life-sustaining health technology is complex and often conducted at time-critical junctures in clinical care. Many of these decisions have profound, often irreversible, consequences for the child and family, as well as potential benefits for functioning, health and quality of life. Yet little is known about what influences these decisions. A systematic review of reasoning identified the range of reasons clinicians give in the literature when initiating technology dependence in a child, and as a result helps determine the range of influences on these decisions.MethodsMedline, EMBASE, CINAHL, PsychINFO, Web of Science, ASSIA and Global Health Library databases were searched to identify all reasons given for the initiation of technology dependence in a child. Each reason was coded as a broad and narrow reason type, and whether it supported or rejected technology dependence.Results53 relevant papers were retained from 1604 publications, containing 116 broad reason types and 383 narrow reason types. These were grouped into broad thematic categories: clinical factors, quality of life factors, moral imperatives and duty and personal values; and whether they supported, rejected or described the initiation of technology dependence. The majority were conceptual or discussion papers, less than a third were empirical studies. Most discussed neonates and focused on end-of-life care.ConclusionsThere is a lack of empirical studies on this topic, scant knowledge about the experience of older children and their families in particular; and little written on choices made outside ‘end-of-life’ care. This review provides a sound basis for empirical research into the important influences on a child’s potential technology dependence.

Noyori-Ikariya type [(arene)RuCl(TsDPEN)] (TsDPEN, sulfonated diphenyl ethylenediamine) complexes are widely used C=O and C=N reduction catalysts that produce chiral alcohols and amines via a key ruthenium-hydride intermediate that determines the stereochemistry of the product. Whereas many details about the interactions of the pro-chiral substrate with the hydride complex and the nature of the hydrogen transfer from the latter to the former have been investigated over the past 25 years, the role of the stereochemical configuration at the stereogenic ruthenium center in the catalysis has not been elucidated so far. Using operando FlowNMR spectroscopy and nuclear Overhauser effect spectroscopy, we show the existence of two diastereomeric hydride complexes under reaction conditions, assign their absolute configurations in solution, and monitor their interconversion during transfer hydrogenation catalysis. Configurational analysis and multifunctional density functional theory (DFT) calculations show the λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to be both thermodynamically and kinetically favored over its λ-(R,R)RRu isomer with the opposite configuration at the metal. Computational analysis of both diastereomeric catalytic manifolds show the major λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to dominate asymmetric ketone reduction catalysis with the minor λ-(R,R)RRu [(mesitylene)RuH(TsDPEN)] stereoisomer being both less active and less enantioselective. These findings also hold true for a tethered catalyst derivative with a propyl linker between the arene and TsDPEN ligands and thus show enantioselective transfer hydrogenation catalysis with Noyori-Ikariya complexes to proceed via a lock-and-key mechanism.

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

The implementation of machine learning models has brought major changes in the decision-making process for materials design. One matter of concern for the data-driven approaches is the lack of negative data from unsuccessful synthetic attempts, which might generate inherently imbalanced datasets. We propose the application of the one-class classification methodology as an effective tool for tackling these limitations on the materials design problems. This is a concept of learning based only on a well-defined class without counter examples. An extensive study on the different one-class classification algorithms is performed until the most appropriate workflow is identified for guiding the discovery of emerging materials belonging to a relatively small class, that being the weakly bound polyaromatic hydrocarbon co-crystals. The two-step approach presented in this study first trains the model using all the known molecular combinations that form this class of co-crystals extracted from the Cambridge Structural Database (1722 molecular combinations), followed by scoring possible yet unknown pairs from the ZINC15 database (21 736 possible molecular combinations). Focusing on the highest-ranking pairs predicted to have higher probability of forming co-crystals, materials discovery can be accelerated by reducing the vast molecular space and directing the synthetic efforts of chemists. Further on, using interpretability techniques a more detailed understanding of the molecular properties causing co-crystallization is sought after. The applicability of the current methodology is demonstrated with the discovery of two novel co-crystals, namely pyrene-6H-benzo[c]chromen-6-one (1) and pyrene-9,10-dicyanoanthracene (2)., Machine learning using one class classification on a database of existing co-crystals enables the identification of co-formers which are likely to form stable co-crystals, resulting in the synthesis of two co-crystals of polyaromatic hydrocarbons.

BACKGROUND Although many children with medical complexity (CMC) use home health care (HHC), little is known about all pediatric HHC utilizers. Our objective was to assess characteristics of pediatric HHC recipients, providers, and payments. METHODS We conducted a retrospective analysis of 5 209 525 children age 0-to-17 years enrolled Medicaid in the 2016 IBM Watson MarketScan Medicaid Database. HHC utilizers had ≥ 1 HHC claim. Healthcare Common Procedure Coding System (HCPCS) and Current Procedural Terminology (CPT) codes were reviewed to codify provider types when possible: registered nurse (RN), licensed practical nurse (LPN), home health aide (HHA), certified nursing assistant (CNA), or companion/personal attendant. Enrollee clinical characteristics, HHC provider type, and payments were assessed. Chronic conditions were evaluated with Agency for Healthcare Research and Quality’s Chronic Condition Indicators and Feudtner’s Complex Chronic Conditions. RESULTS Of the 0.8% of children who used HHC, 43.8% were age CONCLUSIONS Children using HHC are a heterogeneous population who receive it from a variety of providers. Future investigations should explore the role of nonnurse caregivers, particularly with CMC.

Introduction: Efficient interpretation of dermoscopic images relies on pattern recognition, and the development of expert-level proficiency typically requires extensive training and years of practice. While traditional methods of transferring knowledge have proven effective, technological advances may significantly improve upon these strategies and better equip dermoscopy learners with the pattern recognition skills required for real-world practice. Objectives: A narrative review of the literature was performed to explore emerging directions in medical image interpretation education that may enhance dermoscopy education. This article represents the first of a two-part review series on this topic. Methods: To promote innovation in dermoscopy education, the International Skin Imaging Collaboration (ISIC)assembled a 12-member Education Working Group that comprises international dermoscopy experts and educational scientists. Based on a preliminary literature review and their experiences as educators, the group developed and refined a list of innovative approaches through multiple rounds of discussion and feedback. For each approach, literature searches were performed for relevant articles. Results: Through a consensus-based approach, the group identified a number of emerging directions in image interpretation education. The following theory-based approaches will be discussed in this first part: whole-task learning, microlearning, perceptual learning, and adaptive learning. Conclusions: Compared to traditional methods, these theory-based approaches may enhance dermoscopy education by making learning more engaging and interactive and reducing the amount of time required to develop expert-level pattern recognition skills. Further exploration is needed to determine how these approaches can be seamlessly and successfully integrated to optimize dermoscopy education.

BACKGROUND AND OBJECTIVES Children with neurologic impairment (NI) are a growing subset of children who frequently use health care. We examined health care use and spending trends across services for children with NI during their first 5 years of life. METHODS This was a retrospective study of 13 947 children with NI in the multistate IBM Medicaid MarketScan Database (2009–2017). We established birth cohorts of children with NI and analyzed claims from birth to 5 years. NI, identified by using International Classification of Diseases, 9th Revision, diagnosis codes, was defined as ≥1 neurologic diagnosis that was associated with functional and/or intellectual impairment. We measured annual health care use and per-member-per-year spending by inpatient, emergency department (ED), and outpatient services. Population trends in use and spending were assessed with logistic and linear regression, respectively. RESULTS During their first versus fifth year, 66.8% vs 5.8% of children with NI used inpatient services, and 67.8% vs 44.4% used ED services. Annual use in both categories decreased over 0–5 years (inpatient odds ratio: 0.35, 95% confidence interval: 0.34 to 0.36; ED odds ratio: 0.78, 95% confidence interval: 0.77 to 0.79). The use of outpatient services (primary care, specialty care, home health) decreased gradually. Per-member-per-year spending on inpatient services remained the largest spending category: $83 352 (90.2% of annual spending) in the first year and $1944 (25.5%) in the fifth year. CONCLUSIONS For children with early-onset NI from 0–5 years, use and spending on inpatient services decreased dramatically; ED and outpatient service use decreased more gradually. These findings may help systems, clinicians, and families optimize care by anticipating and adjusting for shifting use of health care services.

In modern drug discovery, detection of a compound's potential mutagenicity is crucial. However, the traditional method of mutagenicity detection using the Ames test is costly and time consuming as the compounds need to be synthesised and then tested and the results are not always accurate and reproducible. Therefore, it would be advantageous to develop robust in silico models which can accurately predict the mutagenicity of a compound prior to synthesis to overcome the inadequacies of the Ames test. After curation of a previously defined compound mutagenicity library, over 5000 molecules had their chemical fingerprints and molecular properties calculated. Using 8 classification modelling algorithms, including support vector machine (SVM), random forest (RF) and extreme gradient boosting (XGB), a total of 112 predictive models have been constructed. Their performance has been assessed using 10-fold cross validation and a hold-out test set and some of the top performing models have been assessed using the y-randomisation approach. As a result, we have found SVM and XGB models to have good performance during the 10-fold cross validation (AUROC >0.90, sensitivity >0.85, specificity >0.75, balanced accuracy >0.80, Kappa >0.65) and on the test set (AUROC >0.65, sensitivity >0.65, specificity >0.60, balanced accuracy >0.65, Kappa >0.30). We have also identified molecular properties that are the most influential for mutagenicity prediction when combined with chemical molecular fingerprints. Using the Class A mutagenic compounds from the Ames/QSAR International Challenge Project, we were able to verify our models perform better, predicting more mutagens correctly then the StarDrop Ames mutagenicity prediction and TEST mutagenicity prediction.

Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF‐β driven via Smad (canonical) and ERK (non‐canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF‐β‐driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF‐β‐dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF‐β‐dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a ‘mixed’ contractile‐synthetic phenotype in MFS aortic aneurysm; and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation.

Children dependent on long-term ventilation need the planning, provision and monitoring of complex services generally provided at home by professionals belonging to different care settings. The collaboration among professionals improves the efficiency and the continuity of care especially when treating children with complex care needs. In this paper, the Unified Modelling Language (UML) has been adopted to detect the variety of the patterns of collaboration as well as to represent and compare the different processes of care across the 30 EU/EEA countries of the MOCHA project.Conclusion: Half of the analysed countries have a multidisciplinary team with different degrees of team composition, influencing organisational features such as the development of the personalised plan as well as the provision of preventive and curative services. This approach provides indications on the efficiency in performing and organising the delivery of care in terms of family involvement, interactions among professionals and availability of ICT. What is known: • Children with CCNs require a coordination of efforts before and after discharge in a continuum of care delivery dependent on the level of integrated care solutions adopted at country level. What is new: •The adoption of a business process method contributes to perform a cross-country analysis highlighting the variability of team composition and its influence on the delivery of care. • This approach provides indications on the efficiency in performing and organising the delivery of care in terms of family involvement, interactions among professionals and availability of ICT.

Background Many classifiers have been developed that can distinguish different types of skin lesions (e.g., benign nevi, melanoma) with varying degrees of success.1–5 However, even successfully trained classifiers may perform poorly on images that include artefacts. While problems created by hair and ink markings have been published, quantitative measurements of blur, colour and lighting variations on classification accuracy has not yet been reported to our knowledge. Objectives We created a system that measures the impact of various artefacts on machine learning accuracy. Our objectives were to (1) quantitatively identify the most egregious artefacts and (2) demonstrate how to assess a classification algorithm's accuracy when input images include artefacts. Methods We injected artefacts into dermatologic images using techniques that could be controlled with a single variable. This allows us to quantitatively evaluate the impact on the accuracy. We trained two convolutional neural networks on two different binary classification tasks and measured the impact on dermoscopy images over a range of parameter values. The area under the curve and specificity‐at‐a‐given‐sensitivity values were measured for each artefact induced at each parameter. Results General blur had the strongest negative effect on the melanoma versus other task. Conversely, shifting the hue towards blue had a more pronounced effect on the suspicious versus follow task. Conclusions Classifiers should either mitigate artefacts or detect them. Images should be excluded from diagnosis/recommendation when artefacts are present in amounts outside the machine perceived quality range. Failure to do so will reduce accuracy and impede approval from regulatory agencies.

Children’s hospitals responded to COVID-19 by limiting nonurgent healthcare encounters, conserving personal protective equipment, and restructuring care processes to mitigate viral spread. We assessed year-over-year trends in healthcare encounters and hospital charges across US children’s hospitals before and during the COVID-19 pandemic. We performed a retrospective analysis, comparing healthcare encounters and inflation-adjusted charges from 26 tertiary children’s hospitals reporting to the PROSPECT database from February 1 to June 30 in 2019 (before the COVID-19 pandemic) and 2020 (during the COVID-19 pandemic). All children’s hospitals experienced similar trends in healthcare encounters and charges during the study period. Inpatient bed-days, emergency department visits, and surgeries were lower by a median 36%, 65%, and 77%, respectively, per hospital by the week of April 15 (the nadir) in 2020 compared with 2019. Across the study period in 2020, children’s hospitals experienced a median decrease of $276 million in charges.

Background In the past two decades, genetic testing for cancer risk assessment has entered mainstream clinical practice due to the availability of low-cost panels of multiple cancer-associated genes. However, the clinical value of multiple-gene panels for cancer susceptibility is not well established, especially in cases where panel testing identifies more than one pathogenic variant. The risk for specific malignancies as a result of a mutated gene is complex and likely influenced by superimposed modifier variants and/or environmental effects. Recent data suggests that the combination of multiple pathogenic variants may be fewer than reported by chance, suggesting that some mutation combinations may be detrimental. Management of patients with “incidentally” discovered mutations can be particularly challenging, especially when established guidelines call for radical procedures (e.g. total gastrectomy in CDH1) in patients and families without a classic clinical history concerning for that cancer predisposition syndrome. Case presentation We present two cases, one of an individual and one of a family, with multiple pathogenic mutations detected by multi-gene panel testing to highlight challenges practitioners face in counseling patients about pathogenic variants and determining preventive and therapeutic interventions. Conclusions Ongoing investigation is needed to improve our understanding of inherited susceptibility to disease in general and cancer predisposition syndromes, as this information has the potential to lead to the development of more precise and patient-specific counseling and surveillance strategies. The real-world adoption of new or improved technologies into clinical practice frequently requires medical decision-making in the absence of established understanding of gene-gene interactions. In the meantime, practitioners must be prepared to apply a rationale based on currently available knowledge to clinical decision-making. Current practice is evolving to rely heavily on clinical concordance with personal and family history in making specific therapeutic decisions.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata511 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata511 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Background: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence. Methods: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users. Findings: During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p Interpretation: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Synthetic triterpenoids including CDDO, its methyl ester (CDDO-Me, bardoxolone methyl), and its imidazolide (CDDO-Im) enhance Nrf2-mediated antioxidant and anti-inflammatory activity in many diseases by reacting with thiols on the adaptor protein, Keap1. Unlike monofunctional CDDO-Me, the bifunctional analog, CDDO-Im, has a second reactive site (imidazolide) and can covalently bind to amino acids other than cysteine on target proteins such as glutathione S-transferase pi (GSTP), serum albumin, or Keap1. Here we show for the first time that bifunctional CDDO-Im (in contrast to CDDO-Me), as low as 50 nM, can covalently transacylate arginine and serine residues in GSTP and cross-link them to adjacent cysteine residues. Moreover, we show that CDDO-Im binds covalently to Keap1 by forming permanent Michael adducts with eight different cysteines, and acyl adducts with lysine and several tyrosine residues. Modeling studies suggest that the Tyr 85 adduct stabilizes the Keap1-Cul3 complex, thereby enhancing the potency of CDDO-Im.

Background Lung-protective ventilation (LPV) improves outcomes for patients with acute respiratory distress syndrome (ARDS) through the administration of low tidal volumes (≤ 6.5 ml/kg predicted body weight [PBW]) with co-titration of positive end-expiratory pressure and fraction of inspired oxygen. Many patients with ARDS, however, are not managed with LPV. The purpose of this study was to understand the implementation barriers and facilitators to the use of LPV and a computerized LPV clinical decision support (CDS) tool in intensive care units (ICUs) in preparation for a pilot hybrid implementation-effectiveness clinical trial. Methods We performed an explanatory sequential mixed methods study from June 2018 to March 2019 to evaluate the variation in LPV adherence across 17 ICUs in an integrated healthcare system with > 4000 mechanically ventilated patients annually. We analyzed 47 key informant interviews of ICU physicians, respiratory therapists (RTs), and nurses in 3 of the ICUs using a qualitative content analysis paradigm to investigate site variation as defined by adherence level (low, medium, high) and to identify barriers and facilitators to LPV and LPV CDS tool use. Results Forty-two percent of patients had an initial set tidal volume of ≤ 6.5 ml/kg PBW during the measurement period (site range 21–80%). LPV CDS tool use was 28% (site range 6–91%). This study’s main findings revealed multi-factorial facilitators and barriers to use that varied by ICU site adherence level. The primary facilitator was that LPV and the LPV CDS tool could be used on all mechanically ventilated patients. Barriers included a persistent gap between clinician attitudes regarding the use of LPV and actual use, the perceived loss of autonomy associated with using a computerized protocol, the nature of physician-RT interaction in ventilation management, and the lack of clear organization measures of success. Conclusions Variation in adherence to LPV persists in ICUs within a healthcare delivery system that was an early adopter of LPV. Potentially promising strategies to increase adherence to LPV and the LPV CDS tool for ARDS patients include initiating low tidal ventilation on all mechanically ventilated patients, establishing and measuring adherence measures, and focused education addressing the physician-RT interaction. These strategies represent a blueprint for a future hybrid implementation-effectiveness trial.

Objective To compare hospital outcomes associated with commonly used antibiotic therapies for aspiration pneumonia in children with neurologic impairment (NI). Design/methods A retrospective study of children with NI hospitalized with aspiration pneumonia at 39 children's hospitals in the Pediatric Health Information System database. Exposure was empiric antibiotic therapy classified by antimicrobial activity. Outcomes included acute respiratory failure, intensive care unit (ICU) transfer, and hospital length of stay (LOS). Multivariable regression evaluated associations between exposure and outcomes and adjusted for confounders, including medical complexity and acute illness severity. Results In the adjusted analysis, children receiving Gram-negative coverage alone had two-fold greater odds of respiratory failure (odds ratio [OR] 2.15; 95% CI: 1.41-3.27), greater odds of ICU transfer (OR 1.80; 95% CI: 1.03-3.14), and longer LOS [adjusted rate ratio (RR) 1.28; 95% CI: 1.16-1.41] than those receiving anaerobic coverage alone. Children receiving anaerobic and Gram-negative coverage had higher odds of respiratory failure (OR 1.65; 95% CI: 1.19-2.28) than those receiving anaerobic coverage alone, but ICU transfer (OR 1.15; 95% CI: 0.73-1.80) and length of stay (RR 1.07; 95% CI: 0.98-1.16) did not statistically differ. For children receiving anaerobic, Gram-negative, and P. aeruginosa coverage, LOS was shorter (RR 0.83; 95% CI: 0.76-0.90) than those receiving anaerobic coverage alone; odds of respiratory failure and ICU transfer rates did not significantly differ. Conclusions Anaerobic therapy appears to be important in the treatment of aspiration pneumonia in children with NI. While Gram-negative coverage alone was associated with worse outcomes, its addition to anaerobic therapy may not yield improved outcomes.

This cross-sectional study uses data from the 2017 National Survey of Children’s Health to assess whether social challenges increase with higher medical condition complexity among US children.

Background Abacavir is associated with hypersensitivity reactions in individuals positive for the HLA‐B*57:01 allele. The drug binds within the peptide binding groove of HLA‐B*57:01 altering peptides displayed on the cell surface. Presentation of these HLA‐abacavir‐peptide complexes to T‐cells is hypothesized to trigger a CD8+ T‐cell response underpinning the hypersensitivity. Thus, the aim of this study was to explore the relationship between the structure of abacavir with HLA‐B*57:01 binding and the CD8+ T‐cell activation. Methods Seventeen abacavir analogues were synthesized and cytokine secretion from abacavir/abacavir analogue‐responsive CD8+ T‐cell clones was measured using IFN‐γ ELIspot. In silico docking studies were undertaken to assess the predicted binding poses of the abacavir analogues within the HLA‐B*57:01 peptide binding groove. In parallel, the effect of selected abacavir analogues on the repertoire of self‐peptides presented by cellular HLA‐B*57:01 was characterized using mass spectrometry. Results Abacavir and ten analogues stimulated CD8+ T‐cell IFN‐γ release. Molecular docking of analogues that retained antiviral activity demonstrated a relationship between predicted HLA‐B*57:01 binding orientations and the ability to induce a T‐cell response. Analogues that stimulated T‐cells displayed a perturbation of the natural peptides displayed by HLA‐B*57:01. The antigen‐specific CD8+ T‐cell response was dependent on the enantiomeric form of abacavir at both cyclopropyl and cyclopentyl regions. Conclusion Alteration of the chemical constitution of abacavir generates analogues that retain a degree of pharmacological activity, but have variable ability to activate T‐cells. Modelling and immunopeptidome analysis delineate how drug HLA‐B*57:01 binding and peptide display by antigen presenting cells relate to the activation of CD8+ T‐cells.

Background The number of children requiring long-term home ventilation has consistently increased over the last 25 years. Given the growing population of children with complex care needs (CCNs), this was an important area of focus within the Models of Child Health Appraised (MOCHA) project, funded by the European Union (EU) under the Horizon 2020 programme. We examined the structures and processes of care in place for children with CCNs and identified key constituents for effective integration of care for these children at the community and acute care interface across 30 EU/ European Economic Area (EEA) countries. Methods This was a non-experimental descriptive study with an embedded qualitative element. Data were collected by a Country Agent in each of the 30 countries, a local expert in child health services. Data were analysed using descriptive statistics and a thematic analysis was undertaken of the free text data provided. Results A total of 27 surveys were returned from a possible 30 countries (90.0%) countries. One respondent indicated that their country does not have children on long-term ventilation (LTV) in the home, therefore, responses of 26 countries (86.7%) were analysed. None of the responding countries reported that they had all of the core components in place in their country. Three themes emerged from the free text provided: ‘family preparedness for transitioning to home’, ‘coordinated pathway to specialist care’ and ‘legal and governance structures’. Conclusions While the clinical care of children on LTV in the acute sector has received considerable attention, the results identify the need for an enhanced focus on the care required following discharge to the community setting. The results highlight the need for a commitment to supporting care delivery that acknowledges the complexity of contemporary child health issues and the context of the families that become their primary care givers.

The opportunistic pathogen Pseudomonas aeruginosa employs the type III secretion system (T3SS) and four effector proteins, ExoS, ExoT, ExoU, and ExoY, to disrupt cellular physiology and subvert the host’s innate immune response. Of the effector proteins delivered by the T3SS, ExoU is the most toxic. In P. aeruginosa infections, where the ExoU gene is expressed, disease severity is increased with poorer prognoses. This is considered to be due to the rapid and irreversible damage exerted by the phospholipase activity of ExoU, which cannot be halted before conventional antibiotics can successfully eliminate the pathogen. This review will discuss what is currently known about ExoU and explore its potential as a therapeutic target, highlighting some of the small molecule ExoU inhibitors that have been discovered from screening approaches.

A new porous and flexible metal–organic framework (MOF) has been synthesized from the flexible asymmetric linker N-(4-carboxyphenyl)succinamate (CSA) and heptanuclear zinc oxo-clusters of formula [Zn7O2(carboxylate)10DMF2] involving two coordinated terminal DMF ligands. The structural response of this MOF to the removal or exchange of its guest molecules has been probed using a combination of experimental and computational approaches. The topology of the material, involving double linker connections in the a and b directions and single linker connections along the c axis, is shown to be key in the material’s anisotropic response. The a and b directions remain locked during guest removal, whereas the c axis linker undergoes large changes significantly reducing the material’s void space. The changes to the c axis linker involve a combination of a hinge motion on the linker’s rigid side and conformational rearrangements on its flexible end, which were probed in detail during this process despite the presence of crystallographic disorder along this axis, which prevented accurate characterization by experimental methods alone. Although inactive during guest removal, the flexible ends of the a and b axis linkers are observed to play a prominent role during DMF to DMSO solvent exchange, facilitating the exchange reaction arising in the cluster., The synthesis and flexibility of a new zinc-carboxylate MOF (ZnCSA) is reported via a combination of crystallographic and computational approaches. The anisotropic structural response exhibited during exchange or removal of the guest species in the pore reveals that the behavior is linked to both the framework’s topology and the nature of the asymmetric flexible linker used in its construction.

[Image: see text] A series of 2-pyrazolyl quinolones has been designed and synthesized in 5–7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC(50) (concentration of drug required to achieve half maximal growth suppression) values in the range of 15–33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Q(i) site of the parasite bc(1) complex, which is supported by crystallographic studies of bovine cytochrome bc(1) complex.

Introduction: Children dependent on Long-Term Ventilation (LTV) need the planning, provision and monitoring of complex services generally provided at home by professionals belonging to different settings. The collaboration among professionals improves the efficiency and the continuity of care especially when treating children with complex needs. In this paper patterns of collaboration have been analysed across the 30 EU/EEA countries of the MOCHA project using Unified Modelling Language (UML). Methods: The level of collaboration was defined analysing the answers provided by local Country Agents (CAs) in a questionnaire adapted from standards of care for children with complex care needs. Particular attention was given to: management of the personalized plan, organization of the transition from the hospital to the child’s home, provision of general and preventive services and access to specialized services. Responses of the CAs were summarized using UML to capture: the professionals involved in each activity and their configuration in a multidisciplinary team (MDT) (Use case diagram); the flow of activities performed and the messages exchanged by the different actors/teams taking into account the location and the timeline of each activity (Activity diagram). Results: Twenty-three CAs responded to the questionnaire. Within a high variety of patterns of collaboration, primary care professionals are involved in the majority of countries providing general services, while specialists continue to be a reference point also when the child is discharged at home. Moreover, the presence of a social worker within a MDT indicates a trend of including the social component for the children and their families. The adoption of a personalized plan is one of the optimum features in the treatment of complex care, in particular considering that it should include the procedures to access care in case of medical crisis. Discussion: This approach provides important indications on the efficiency in performing and organizing health-related activities. The association of identified activities with data, such as number and cost of professionals, health outcomes and waiting times, could provide an in-depth analysis indicating best practices in the provision of care. Conclusions: The adoption of a business process analysis allowed us to identify different patterns of collaboration that may be distributed along a continuum of integration. Moreover, the use UML made it possible to represent the different organizational features in place in the MOCHA countries to manage children with LTV in a comparable way. Lessons learned: The adoption of a business process analysis contributed to the analysis of the integration of care among the primary, secondary and social level. It captured the patterns of care delivery in the highly dynamic, complex and multi-disciplinary nature of healthcare processes. Limitations: The description of the care process is provided by a single CA that describes the actual situation in his/her country. Further analysis can help to capture regional variations, differences in terms of services provided in urban and rural areas or changes depending on the severity. Suggestions for future research: Compare the results obtained for LTV with other complex care needs analysed in MOCHA such as, traumatic brain injury, intractable epilepsy.

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

The Lung session of the 2017 14th Banff Foundation for Allograft Pathology Conference, Barcelona focused on the multiple aspects of antibody-mediated rejection (AMR) in lung transplantation. Multidimensional approaches for AMR diagnosis, including classification, histological and immunohistochemical analysis, and donor- specific antibody (DSA) characterization with their current strengths and limitations were reviewed in view of recent research. The group also discussed the role of tissue gene expression analysis in the context of unmet needs in lung transplantation. The current best practice for monitoring of AMR and the therapeutic approach are summarized and highlighted in this report. The working group reached consensus of the major gaps in current knowledge and focused on the unanswered questions regarding pulmonary AMR. An important outcome of the meeting was agreement on the need for future collaborative research projects to address these gaps in the field of lung transplantation.

Neuropathology and symptoms of central nervous disease are late complications of HIV-1 infection. Before widespread use of antiretroviral therapy (ART), the most severe form, HIV-1-associated dementia (HAD), developed in 20–30% of patients [1,2]. Although HAD has virtually disappeared, up to 40% of HIV-infected individuals whose peripheral viral loads are effectively managed with antiretroviral drugs still develop HIV-1-associated neurocognitive impairment (HIV-NCI) [3,4] that can greatly affect daily life, notably disrupting adherence to their drug regimen. Current drugs, while able to suppress peripheral viral load for many years, do not protect against development of neurocognitive impairment [5]. Unless the cause of this impairment is determined and treatments identified, it may present a real barrier to further extension of therapeutic protection of infected individuals. Few studies have compared HIV-associated neuropathology pre and post-ART introduction [6–8]; however, a common feature is the presence of astrogliosis and microgliosis in the absence of detectable peripheral viral load. Triggers for this neuropathology and its cause remain unclear with possible causes including both direct/indirect effects of virus or antiretroviral drugs within the brain [5]. Effective control of viral replication within this organ is challenging because of difficulties transporting drugs across the blood–brain barrier (BBB) and potential neurotoxic effects of long-term ART exposure. Therefore, new treatment strategies targeting the specific lesion may be needed to manage these neurological complications. As relevant clinical material is difficult to obtain, we have investigated the value of simian models to investigate the pathogenesis of HIV-NCI. Previous reports of neuropathology in simian models relate to models of accelerated disease with high persisting peripheral viral loads. For modelling of patients on virus-suppressive ART, this would appear inappropriate. We have previously reported cynomolgus macaques (Macaca fascicularis) develop distinct neuropathology following extended infection with the Nef-disrupted, attenuated virus SIVmacC8 [9] with the lesion including both astrogliosis and microgliosis despite low chronic peripheral viral loads below 100 RNA copies/ml [10,11]. In this report, we characterize further the neuropathology arising from a 43-week infection with SIVmacC8. In particular, we use complementary techniques to assess BBB integrity. Furthermore, using brain samples collected from macaques used in the longitudinal analysis of virus kinetics and host responses following SIVmacC8 infection [11], we investigate the kinetics of virus entry into neurological tissues at very early time points after infection and associated neuropathological consequences. These data indicate attenuated SIVmacC8 enters neurological tissues within a few days of infection, coincidental with disruption of the BBB. Neuroinflammation that immediately responds to this invasion progresses 5–10 months following infection, despite the BBB now appearing intact. On-going neuropathological consequences of HIV, therefore, may not depend upon repeated central nervous system exposure to new waves of replicating virus entering from the blood. These data should be considered when developing new treatments to control, delay, or reverse HIV-NCI.

This cohort study explores the association between index hospitalization length of stay and hospital readmissions among children.

Instream biogeochemical process measurements are often short-term and localized. Here we use in situ sensors to quantify the net effects of biogeochemical processes on seasonal patterns in baseflow nitrate retention at the river-reach scale. Dual-station high-frequency in situ nitrate measurements, were coupled with high-frequency measurements of stream metabolism and dissolved inorganic carbon, in a tributary of the Buffalo National River, Arkansas. Nitrate assimilation was calculated from net primary production, and combined with mass-balance measurements, to estimate net nitrification and denitrification. The combined net effects of these instream processes (assimilation, denitrification, and nitrification) removed >30–90% of the baseflow nitrate load along a 6.5 km reach. Assimilation of nitrate by photoautotrophs during spring and early summer was buffered by net nitrification. Net nitrification peaked during the spring. After midsummer, there was a pronounced switch from assimilatory nitrate uptake to denitrification. There was clear synchronicity between the switch from nitrate assimilation to denitrification, a reduction in river baseflows, and a shift in stream metabolism from autotrophy to heterotrophy. The results show how instream nitrate retention and downstream delivery is driven by seasonal shifts in metabolic pathways; and how continuous in situ stream sensor networks offer new opportunities for quantifying the role of stream biota in the dynamics, fate, and transport of nitrogen in fluvial systems.

Introduction: Approaches to the management of care of children with complex care needs CCN is known to vary among countries. Conducted as part of Models of Child Health Appraised MOCHA, an ongoing EU Horizon 2020 funded project, the aim of this study was to provide a contemporary account of the approaches to the integration of care at the acute/community interface for children with CCN across 30 European countries. Methods: In this non-experimental descriptive study, utilising a mixed-methods design, 30 European countries were surveyed, using a local country agent who was an expert in child health. Each survey consisted of a vignette and open and closed-ended questions adapted from the Standards for Systems of Care for Children and Youth with Special Health Care Needs 1 and the Eurobarometer Survey 2. Vignettes were developed based on three clinical exemplars: Long-term Ventilation LTV, Intractable Epilepsy, and Traumatic Brain Injury TBI. Categorical data were analysed using descriptive statistics. Textual data were analysed using Attride-Stirling’s thematic network analysis 3. This abstract presents results pertaining to the qualitative analysis of the main barriers and facilitators to the integration of care for each exemplar. Results: Twenty-three countries 76.7% responded to the three surveys. Barriers to integration of care were similar across all exemplars and included; poor care coordination, lack of clinical expertise and training, insufficient funding, the absence of standards of care, lack of specialist clinical pathways, geographical variation in care, limited progress in the use electronic health, and inadequate access to psychological support. Training and retention of skilled healthcare staff were identified as a facilitator of integration of care across all exemplars. The need for a national database LTV & TBI, timely transfers to specialist services LTV & TBI and enhanced family and school support TBI & Intractable Epilepsy were identified for two of the three exemplar conditions. Discussions: Although commonalities exist across the results presented, there may be individual critical junctures in care delivery that will demand care provisions that are specific to particular cohorts of children with different complex conditions. Conclusions: The results suggest that there are a variety of processes and structures that act as barriers and facilitators to the integration of care for children with CNN across Europe. Lessons learned: This study was reliant on data from a large number of informants being collated by local country agents across the 30 MOCHA countries. The process was assisted by the development and utilisation of a glossary of terms in each survey, which ensured uniform comprehension of the included terms. Limitations: Previous research has posed concerns regarding the external validity of using clinical vignettes to elicit opinion 4,5. Nonetheless, the use of clinical vignettes in this study allowed for the creation of a variety of care delivery situations pertaining to complex care that could be utilised in a standardised manner in surveys developed for use across 30 European countries. Suggestions for future research: Future research should be considered to explore innovative ways of minimising the barriers to integration of care for children with CCN.

Sulfation of carbohydrate residues occurs on a variety of glycans destined for secretion, and this modification is essential for efficient matrix-based signal transduction. Heparan sulfate (HS) glycosaminoglycans control physiological functions ranging from blood coagulation to cell proliferation. HS biosynthesis involves membrane-bound Golgi sulfotransferases, including HS 2-O-sulfotransferase (HS2ST), which transfers sulfate from the cofactor PAPS (3′-phosphoadenosine 5′-phosphosulfate) to the 2-O position of α-l-iduronate in the maturing polysaccharide chain. The current lack of simple non-radioactive enzyme assays that can be used to quantify the levels of carbohydrate sulfation hampers kinetic analysis of this process and the discovery of HS2ST inhibitors. In the present paper, we describe a new procedure for thermal shift analysis of purified HS2ST. Using this approach, we quantify HS2ST-catalysed oligosaccharide sulfation using a novel synthetic fluorescent substrate and screen the Published Kinase Inhibitor Set, to evaluate compounds that inhibit catalysis. We report the susceptibility of HS2ST to a variety of cell-permeable compounds in vitro, including polyanionic polar molecules, the protein kinase inhibitor rottlerin and oxindole-based RAF kinase inhibitors. In a related study, published back-to-back with the present study, we demonstrated that tyrosyl protein sulfotranferases are also inhibited by a variety of protein kinase inhibitors. We propose that appropriately validated small-molecule compounds could become new tools for rapid inhibition of glycan (and protein) sulfation in cells, and that protein kinase inhibitors might be repurposed or redesigned for the specific inhibition of HS2ST.

This study is concerned with identifying features of 4-aminoquinoline scaffolds that can help pinpoint characteristics that enhance activity against chloroquine-resistant parasites. Statistically valid predictive models are reported for a series of 4-aminoquinoline analogues that are active against chloroquine-sensitive (NF54) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Quantitative structure activity relationship techniques, based on statistical and machine learning methods such as multiple linear regression and partial least squares, were used with a novel pruning method for the selection of descriptors to develop robust models for both strains. Inspection of the dominant descriptors supports the hypothesis that chemical features that enable accumulation in the food vacuole of the parasite are key determinants of activity against both strains. The hydrophilic properties of the compounds were found to be crucial in predicting activity against the chloroquine-sensitive NF54 parasite strain, but not in the case of the chloroquine-resistant K1 strain, in line with previous studies. Additionally, the models suggest that ‘softer’ compounds tend to have improved activity for both strains than do ‘harder’ ones. The internally and externally validated models reported here should also prove useful in the future screening of potential antimalarial compounds for targeting chloroquine-resistant strains. Graphical Abstract Predictive models reveal linear relationships for activity of 4-aminoquinoline analogues active against chloroquine-sensitive strains of Plasmodium falciparum Electronic supplementary material The online version of this article (10.1007/s00894-018-3755-z) contains supplementary material, which is available to authorized users.

Cyclometalation of [Cp*IrCl2]2 with methyl (S)-2-phenyl-4,5-dihydrooxazole-4-carboxylate in the presence of NaOAc selectively led to a N,C- or N,O-chelated Cp*Ir(III) complex, depending on whether ...