Prospective evaluation of the Whitt Neonatal Trigger Score in an 'at-risk' neonatal population.

AIM: The aim of this study was to prospectively evaluate the Whitt Neonatal Trigger Score (W-NTS), determining optimum threshold scores for consideration of medical intervention and intensive care unit admission. METHODS: All neonates on the postnatal ward (PNW) with a set of pre-defined risk factors were scored on the W-NTS. Neonates were divided into three groups: 'unwell' admitted to neonatal intensive care unit (NICU); 'well', who remained on the PNW receiving standard care; and 'intervention', who received antibiotics but did not require admission to NICU. RESULTS: A total of 3315 scores from 455 neonates were collected. The W-NTS area under the receiver operating characteristic curve (AUC ROC) was 0.968, with a score of 2 or more predicting NICU admission, with 82.5% sensitivity and 95.0% specificity. Adopting a cut-off score of 2 for admission would significantly improve speed to admission (11.6 vs. 6.9 h, P 0.037). A score of 0 was strongly predictive of being well enough to remain on the PNW without intervention (odds ratio 565.6, P < 0.001), and a score of 1 or more predicted the need for intravenous antibiotics with 100.0% sensitivity and 86.1% specificity (AUC ROC 0.977). CONCLUSION: The W-NTS observation chart, previously shown to outperform existing early warning scores, acts well as an adjunct to clinical assessment on the PNW, with its simplicity allowing for the successful and safe use by non-paediatric specialists. We recommend that neonates scoring 1 should be reviewed, with a septic screen and commencement of antibiotic therapy considered, while those scoring 2 or more should be strongly considered for NICU admission for further management.

Large-Scale Profiling of Kinase Dependencies in Cancer Cell Lines.

One approach to identifying cancer-specific vulnerabilities and therapeutic targets is to profile genetic dependencies in cancer cell lines. Here, we describe data from a series of siRNA screens that identify the kinase genetic dependencies in 117 cancer cell lines from ten cancer types. By integrating the siRNA screen data with molecular profiling data, including exome sequencing data, we show how vulnerabilities/genetic dependencies that are associated with mutations in specific cancer driver genes can be identified. By integrating additional data sets into this analysis, including protein-protein interaction data, we also demonstrate that the genetic dependencies associated with many cancer driver genes form dense connections on functional interaction networks. We demonstrate the utility of this resource by using it to predict the drug sensitivity of genetically or histologically defined subsets of tumor cell lines, including an increased sensitivity of osteosarcoma cell lines to FGFR inhibitors and SMAD4 mutant tumor cells to mitotic inhibitors.

Retrospective evaluation of a new neonatal trigger score.

OBJECTIVES: To design and validate an objective clinical scoring system to identify unwell neonates, by using routinely collected bedside observations. METHODS: A Neonatal Trigger Score (NTS) was designed by using local expert consensus and incorporated into a new observation chart. All neonates >35 weeks' gestation admitted to the NICU over an 18-month period, and an age-matched "well" cohort, were retrospectively scored by using the newly constructed NTS and all established pediatric early warning system (PEWS) scores. RESULTS: Scores were calculated for 485 neonates. The NTS score area under the receiver operating characteristic curve was 0.924 with a score of 2 or more predicting need for admission to the NICU with 77% sensitivity and 97% specificity. Neonates scoring ≥2 had increased odds of needing intensive care (odds ratio [OR] 48.7, 95% confidence interval [CI] 27.5-86.3), intravenous fluids (OR 48.1, 95% CI 23.9-96.9), and continuous positive airway pressure (OR 29.5, 95% CI 6.9-125.8). The NTS was more sensitive than currently established PEWS scores. CONCLUSIONS: The NTS observation chart acts as an adjunct to clinical assessment, highlighting unwell neonates. Its simplicity allows successful and safe use by nonpediatric specialists. NTS out-performed PEWS, with significantly better sensitivity, particularly in neonates who deteriorated within the first 12 hours after birth (P < .001) or in neonates with sepsis or respiratory symptoms (P < .001). Neonates with a score of 1 should be reviewed and those scoring ≥2 should be considered for NICU admission for further management.

Limbal stem cell deficiency in patients with inherited stem cell disorder of dyskeratosis congenita.

The aim of this study is to present the limbal stem cell deficiency (LSCD) cases with features resembling dyskeratosis congenita (DC), a heritable disease of stem cells principally caused by telomerase deficiency. The clinical, laboratory and molecular findings of four cases are presented. A complete systemic examination was performed in a standardized manner for each patient. Laboratory measurements included investigations of the tests used for screening DC. All eight known disease-causing genes in DC (DKC1, TERC, TERT, NOP10, NHP2, TINF2, C16orf57, and TCAB1) were screened for mutations. The family members of the cases were also assessed, when possible. In all four patients, multisystem involvement was present, along with the disorder affecting corneal LSCs. The affected tissues were mainly the skin and its adnexa, the oral cavity and the hematopoietic system, which are rapidly renewing tissues, consistent with the presence of a stem cell disorder. Similarly affected cases were seen in different generations in families, suggesting an underlying inherited disorder. No mutation was detected in any of the known disease-causing genes in these patients. Based on the presented cases and with the contribution of the review of previously reported DC cases available, we suggest that DC is one of the inherited causes of LSCD and that those cases presenting with LSCD might represent a subgroup of DC caused by mutations in an as yet undefined gene.

Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia.

The myelodysplastic syndromes (MDS) are heterogeneous and can evolve into acute myeloid leukaemia (AML). Rare familial cases are reported in which five disease genes have been identified to date (RUNX1, CEBPA, TERC, TERT and GATA2). Here we report the genetic categorization of 27 families with familial MDS/AML. All of these families were screened for RUNX1, CEBPA, TERC, TERT and GATA2 as well as TET2 and NPM1. Five of the 27 families had telomerase mutations; one had a RUNX1 mutation, while none were found to have TET2, CEBPA or NPM1 mutations. We identified four families with heterozygous GATA2 mutations, each associated with a different phenotype. While one of these mutations is novel, three have been previously reported: one has been described in dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and one is in a family that has been reported in a series with primary lymphoedema with a predisposition to AML (Emberger syndrome). In summary, genetic characterization was shown in 10 (four GATA2, three TERT, two TERC, one RUNX1) of these families; however 17 remain uncharacterized, highlighting marked genetic heterogeneity in familial MDS/AML and the scope for further functional pathways that could give rise to this group of disorders.

Successful use of daptomycin in Panton-Valentine leucocidin positive Staphylococcus aureus paediatric osteomyelitis.

INTRODUCTION: Efficacy of daptomycin has been recorded in adult Gram-positive bone and joint infections OAI (1) and daptomycin has been used as secondary or tertiary agent when primary agents have failed (1, 2) in the treatment of osteoarticular infections caused by Staphylococcus aureus. PRESENTATION OF CASE: We report a 16-year-old schoolboy with Panton-Valentine Leucocidin (PVL) positive methicillin susceptible S. aureus osteomyelitis, who was refractory to 9days of recognised antimicrobial chemotherapy with progressive multifocal haematogenous spread. Subsequent addition of daptomycin promptly cleared the bacteraemia and arrested the disease process within 9days. DISCUSSION: Although cases have been reported of daptomycin usage in children with invasive staphylococcus bacteraemia, endocarditis and OAI (2), we believe this to be the first case report describing the use of daptomycin in paediatric osteomyelitis caused by PVL positive S. aureus. CONCLUSION: Repercussions of osteomyelitis, in particular those caused by PVL S. aureus, and evolving resistance patterns internationally, highlight the need for further evaluation of daptomycin in the paediatric arena. The response seen with the addition of Daptomycin in this case suggests possible reduction in hospital stay and number of surgical procedures when compared to other published series using conventional antibiotic regimens.

Corynebacterium pseudodiphtheriticum septic arthritis secondary to intra-articular injection--a case report and literature review.

This is believed to be the first report of a case of septic arthritis, secondary to intra-articular injection, caused by Corynebacterium pseudodiphtheriticum - a skin commensal micro-organism. Review of the literature highlights the rarity of this pathogen in osteoarticular infections and a potential for delayed diagnosis and inadequate treatment due to subtle initial presentation.

Superior vena cava obstruction: dangers of a missed diagnosis.

We report the case of a 7 year old girl who presented to the Children's Emergency Department with a 6 week history of bilateral facial and neck swelling. She had felt generally unwell, tired, with a recent onset of dry cough, and had presented multiple times to her general practitioner (GP) who after initially unsuccessfully trying an antihistamine, had given her five courses of soluble Betamethasone (corticosteroid) over six weeks, for presumed allergy; this temporarily relieved her symptoms for a couple of days each time. On subsequent referral to Accident and Emergency she was found to have a superior mediastinal mass, with a left pleural effusion and mediastinal deviation to the right. Further investigation confirmed the diagnosis of a T-cell lymphoma causing superior vena cava obstruction of blood flow through the SVC to the right atrium and is a classical oncological emergency. This case report highlights the importance of recognizing superior vena cava obstruction and the need for awareness of malignancy as a differential diagnosis when initially presented with a child with non-specific respiratory findings. We highlight that acute tumour lysis syndrome, a life threatening metabolic emergency that results from massive cytolysis of malignant cells, may occur after a single dose of corticosteroids and one should be aware of this potentially life-threatening complication.

Paediatric presentation of familial cerebral cavernoma.

We report the case of a 13-year-old male who presented with headaches and was presumed to have a brain tumour. He was subsequently found to have multiple cerebral cavernomas with haemorrhage and positive family history. We review the literature on familial cavernomas. Cerebral cavernous malformations (CCMs) are characterized by abnormally enlarged capillary cavities without intervening brain parenchyma [Verlaan et al. Neurology 2005; 65:1982-1983] that may involve any part of the central nervous system. Focal neurologic deficit and haemorrhage occur in 45% of children, higher than in adults [Stoeter. Neurosurg Rev 2001; 24]. Paediatric patients with symptomatic cavernous malformations should be treated surgically because of the risk of haemorrhage [Lee et al. Child's Nervous Syst 2008; 24:321-327].