Mid-Arm Point in PAEDiatrics (MAPPAED): An effective procedural aid for safe pleural decompression in trauma.

OBJECTIVE: Life-threatening thoracic trauma requires emergency pleural decompression and thoracostomy and chest drain insertion are core trauma procedures. Reliably determining a safe site for pleural decompression in children can be challenging. We assessed whether the Mid-Arm Point (MAP) technique, a procedural aid proposed for use with injured adults, would also identify a safe site for pleural decompression in children. METHODS: Children (0-18 years) attending four EDs were prospectively recruited. The MAP technique was performed, and chest wall skin marked bilaterally at the level of the MAP; no pleural decompression was performed. Radio-opaque markers were placed over the MAP-determined skin marks and corresponding intercostal space (ICS) reported using chest X-ray. RESULTS: A total of 392 children participated, and 712 markers sited using the MAP technique were analysed. Eighty-three percentage of markers were sited within the 'safe zone' for pleural decompression (4th to 6th ICSs). When sited outside the 'safe zone', MAP-determined markers were typically too caudal. However, if the site for pleural decompression was transposed one ICS cranially in children ≥4 years, the MAP technique performance improved significantly with 91% within the 'safe zone'. CONCLUSIONS: The MAP technique reliably determines a safe site for pleural decompression in children, albeit with an age-based adjustment, the Mid-Arm Point in PAEDiatrics (MAPPAED) rule: 'in children aged ≥4 years, use the MAP and go up one ICS to hit the safe zone. In children <4 years, use the MAP.' When together with this rule, the MAP technique will identify a site within the 'safe zone' in 9 out of 10 children.

Executive function, repetitive behaviour and restricted interests in neurodevelopmental disorders.

BACKGROUND: Individuals with genetic syndromes show unique profiles of repetitive behaviours and restricted interests (RRBs). The executive dysfunction account of RRBs suggests that in autistic (AUT) individuals executive function impairments underpin RRBs, but not communication and social interaction autistic characteristics. AIMS: To 1) describe profiles of behavioural manifestations of executive function (EF behaviours) and 2) explore the relationship between EF behaviours and autistic traits across individuals with Cornelia de Lange (CdLS), fragile X (FXS) and Rubinstein-Taybi syndromes (RTS), and AUT individuals. METHOD: Carers completed the Behavior Rating Inventory of Executive Function - Preschool Version and the Social Communication Questionnaire. Data reporting on 25 individuals with CdLS (Mage = 18.60, SD = 8.94), 25 with FXS (Mage = 18.48, SD = 8.80), 25 with RTS (Mage = 18.60, SD = 8.65) and 25 AUT individuals (Mage = 18.52, SD = 8.65) matched on chronological age and adaptive ability were included in analyses. RESULTS: All groups showed impairments across EF behaviours compared to two-to-three-year-old typically developing normative samples with no differences between groups. Different EF behaviours predicted RRBs in the syndrome groups with no associations found in the AUT group. CONCLUSIONS: Syndrome related differences should be considered when developing targeted interventions that focus on EF behaviours and/or RRBs in these groups.

The Nonclinical Safety Profile of GalNAc-conjugated RNAi Therapeutics in Subacute Studies.

Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are the most clinically advanced oligonucleotide-based platforms. A number of N-acetylgalactosamine (GalNAc)-conjugated siRNAs (GalNAc-siRNAs), also referred to as RNA interference (RNAi) therapeutics, are currently in various stages of development, though none is yet approved. While the safety of ASOs has been the subject of extensive review, the nonclinical safety profiles of GalNAc-siRNAs have not been reported. With the exception of sequence differences that confer target RNA specificity, GalNAc-siRNAs are largely chemically uniform, containing limited number of phosphorothioate linkages, and 2'-O-methyl and 2'-deoxy-2'-fluoro ribose modifications. Here, we present the outcomes of short-term (3-5 week) rat and monkey weekly repeat-dose toxicology studies of six Enhanced Stabilization Chemistry GalNAc-siRNAs currently in clinical development. In nonclinical studies at supratherapeutic doses, these molecules share similar safety signals, with histologic findings in the organ of pharmacodynamic effect (liver), the organ of elimination (kidney), and the reticuloendothelial system (lymph nodes). The majority of these changes are nonadverse, partially to completely reversible, correlate well with pharmacokinetic parameters and tissue distribution, and often reflect drug accumulation. Furthermore, all GalNAc-siRNAs tested to date have been negative in genotoxicity and safety pharmacology studies.

IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung.

Allergic asthma is a chronic inflammatory disorder of the airway associated with bronchial obstruction, airway hyper-reactivity (AHR), and mucus production. The epithelium may direct and propagate asthmatic-like responses. Central to this theory is the observation that viruses, air pollution, and allergens promote epithelial damage and trigger the generation of IL-25, IL-33, and TSLP via innate pathways such as TLRs and purinergic receptors. Similarly, engineered nanomaterials promote a Th2-associated pathophysiology. In this study, we tested the hypothesis that instillation of multi-walled carbon nanotubes (MWCNT) impair pulmonary function in C57Bl/6 mice due to the development of IL-33-dependent Th2-associated inflammation. MWCNT exposure resulted in elevated levels of IL-33 in the lavage fluid (likely originating from airway epithelial cells), enhanced AHR, eosinophil recruitment, and production of Th2-associated cytokines and chemokines. Moreover, these events were dependent on IL-13 signaling and the IL-33/ST2 axis, but independent of T and B cells. Finally, MWCNT exposure resulted in the recruitment of innate lymphoid cells. Collectively, our data suggest that MWCNT induce epithelial damage that results in release of IL-33, which in turn promotes innate lymphoid cell recruitment and the development of IL-13-dependent inflammatory response.

Gene expression abnormalities in histologically normal breast epithelium of breast cancer patients.

Normal-appearing epithelium of cancer patients can harbor occult genetic abnormalities. Data comprehensively comparing gene expression between histologically normal breast epithelium of breast cancer patients and cancer-free controls are limited. The present study compares global gene expression between these groups. We performed microarrays using RNA from microdissected histologically normal terminal ductal-lobular units (TDLU) from 2 groups: (i) cancer normal (CN) (TDLUs adjacent to untreated ER+ breast cancers (n = 14)) and (ii) reduction mammoplasty (RM) (TDLUs of age-matched women without breast disease (n = 15)). Cyber-T identified differentially expressed genes. Quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC), and comparison to independent microarray data including 6 carcinomas in situ (CIS), validated the results. Gene ontology (GO), UniProt and published literature evaluated gene function. About 127 probesets, corresponding to 105 genes, were differentially expressed between CN and RM (p < 0.0009, corresponding to FDR <0.10). 104/127 (82%) probesets were also differentially expressed between CIS and RM, nearly always (102/104 (98%)) in the same direction as in CN vs. RM. Two-thirds of the 105 genes were implicated previously in carcinogenesis. Overrepresented functional groups included transcription, G-protein coupled and chemokine receptor activity, the MAPK cascade and immediate early genes. Most genes in these categories were under-expressed in CN vs. RM. We conclude that global gene expression abnormalities exist in normal epithelium of breast cancer patients and are also present in early cancers. Thus, cancer-related pathways may be perturbed in normal epithelium. These abnormalities could be markers of disease risk, occult disease, or the tissue's response to an existing tumor.