A hyperacute immune map of ischaemic stroke patients reveals alterations to circulating innate and adaptive cells.

Systemic immune changes following ischaemic stroke are associated with increased susceptibility to infection and poor patient outcome due to their role in exacerbating the ischaemic injury and long-term disability. Alterations to the abundance or function of almost all components of the immune system post-stroke have been identified, including lymphocytes, monocytes and granulocytes. However, subsequent infections have often confounded the identification of stroke-specific effects. Global understanding of very early changes to systemic immunity is critical to identify immune targets to improve clinical outcome. To this end, we performed a small, prospective, observational study in stroke patients with immunophenotyping at a hyperacute time point (< 3 h) to explore early changes to circulating immune cells. We report, for the first time, decreased frequencies of type 1 conventional dendritic cells (cDC1), haematopoietic stem and progenitor cells (HSPCs), unswitched memory B cells and terminally differentiated effector memory T cells re-expressing CD45RA (TEMRA). We also observed concomitant alterations to human leucocyte antigen D-related (HLA-DR), CD64 and CD14 expression in distinct myeloid subsets and a rapid activation of CD4+ T cells based on CD69 expression. The CD69+ CD4+ T cell phenotype inversely correlated with stroke severity and was associated with naive and central memory T (TCM) cells. Our findings highlight early changes in both the innate and adaptive immune compartments for further investigation as they could have implications the development of post-stroke infection and poorer patient outcomes.

Developing a national colorectal educational agenda: a survey of the Association of Coloproctology of Great Britain and Ireland.

AIM: In order to develop its education agenda, the Association of Coloproctology of Great Britain and Ireland (ACPGBI) sought the opinion of its members on current coloproctology training needs. The aims of this study were to canvass multidisciplinary needs and explore the perceived gaps and barriers to meeting them. METHOD: A learner-needs analysis was performed between July 2015 and October 2016. A bespoke electronic survey was sent to 1453 colorectal healthcare professionals [ACPGBI membership (1173), colorectal nurse specialists and allied health professionals (NAHPs) (261) and regional chapter-leads (19)] seeking their needs, experiences and barriers to training across the coloproctology disciplines. RESULTS: In all, 390 responses were received [26.8% overall; 180 consultants/trainees (15%); 196 NAHPs (75%); 14 (74%) chapter-leads]. Lack of funding and difficulties in obtaining study leave were the most frequently reported barriers to course and conference attendance. Transanal total mesorectal excision and laparoscopic training were the top educational needs for consultants and trainees respectively. 79% of NAHP respondents reported education gaps on a broad range of clinical and non-clinical topics. NAHPs lacked information on relevant training opportunities and 27% felt available courses were insufficient to meet their educational needs. Wide heterogeneity in ACPGBI chapter composition and activity was reported. All groups felt the ACPGBI should increase the number of courses offered with coloproctology knowledge updates commonly requested. CONCLUSION: A series of training needs across the coloproctology disciplines have been identified. These will underpin the development of the educational agenda for the ACPGBI.

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

Fifteen-minute consultation: investigation and management of an infant with stridor.

Stridor is an abnormal sound caused by turbulent airflow through the airway. In an infant under 3 months of age presenting with stridor, there are many different underlying aetiologies. Some key assessment points help to differentiate those patients who can be reassured and monitored versus those requiring referral to an ear, nose and throat (ENT) surgeon for further assessment or management. We present a structured approach to guide the clinician through initial assessment, examination and management, including referral to ENT surgery.

Quality of life Evaluation in patients receiving Steroids (the QuESt tool): initial development in children and young people with acute lymphoblastic leukaemia.

BACKGROUND: The powerful cytotoxic and immunomodulatory effects of corticosteroids are an important element of the success that has been achieved in the treatment of acute lymphoblastic leukaemia (ALL). In addition to physical side effects, corticosteroids can adversely influence behaviour, cognitive function and mood leading to significantly impaired quality of life (QoL). A number of tools exist for assessing QoL, but none of these specifically examines changes attributable to steroids. METHODS: Children and young adults aged 8-24 years and parents of children receiving maintenance therapy for ALL from four UK centres were invited to participate. The study comprised three stages carried out over 2 years: (1) focus groups and interviews where participants were asked to describe their experiences of dexamethasone; (2) analysis of questionnaires sent to healthcare professionals and patients to evaluate the importance and relevance of the questions; and (3) cognitive interviewing. RESULTS: Interpretative phenomenological analysis of focus group and interview transcripts identified that dexamethasone adversely influenced behaviour, appetite, body image, mood and family relationships. 157 electronic survey responses were analysed leading to further item development. Cognitive interviewing confirmed face validity and internal consistency. QuESt comprises 28 questions within four domains and has three age-specific versions. CONCLUSIONS: QuESt is the first treatment-specific QoL measure for children and young adults receiving corticosteroids. It can be completed in 10-15 min by children aged ≥8 years. Further validity and reliability testing will be undertaken. Although the initial application is for ALL, QuESt may also be a valuable tool for understanding the impact of corticosteroids in other paediatric conditions.

International cross-cultural validation study of the Canadian haemophilia outcomes: kids' life assessment tool.

Health-related quality of life (HRQoL) assessment is recognized as an important outcome in the evaluation of different therapeutic regimens for persons with haemophilia. The Canadian Haemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT) is a disease-specific measure of HRQoL for 4 to 18-year-old boys with haemophilia. The purpose of this study was to extend this disease-specific, child-centric, outcome measure for use in international clinical trials. We adapted the North American English CHO-KLAT version for use in five countries: France, Germany, the Netherlands, Spain and the United Kingdom (UK). The process included four stages: (i) translation; (ii) cognitive debriefing; (iii) validity assessment relative to the PedsQL (generic) and the Haemo-QoL (disease-specific) and (iv) assessment of inter and intra-rater reliability. Cognitive debriefing was performed in 57 boys (mean age 11.4 years), validation was performed in 144 boys (mean age 11.0 years) and reliability was assessed for a subgroup of 64 boys (mean age 12.0 years). Parents also participated. The mean scores reported by the boys were high: CHO-KLAT 77.0 (SD = 11.2); PedsQL 83.8 (SD = 11.9) and Haemo-QoL 79.6 (SD = 11.5). Correlations between the CHO-KLAT and PedsQL ranged from 0.63 in Germany to 0.39 in the Netherlands and Spain. Test-retest reliability (concordance) for child self-report was 0.67. Child-parent concordance was slightly lower at 0.57. The CHO-KLAT has been fully culturally adapted and validated for use in five different languages and cultures (in England, the Netherlands, France, Germany and Spain) where treatment is readily available either on demand or as prophylaxis.

Regulatory role of suppressive motifs from commensal DNA.

The microbiota contributes to the induction of both effector and regulatory responses in the gastrointestinal (GI) tract. However, the mechanisms controlling these distinct properties remain poorly understood. We previously showed that commensal DNA promotes intestinal immunity. Here, we find that the capacity of bacterial DNA to stimulate immune responses is species specific and correlated with the frequency of motifs known to exert immunosuppressive function. In particular, we show that the DNA of Lactobacillus species, including various probiotics, is enriched in suppressive motifs able to inhibit lamina propria dendritic cell activation. In addition, immunosuppressive oligonucleotides sustain T(reg) cell conversion during inflammation and limit pathogen-induced immunopathology and colitis. Altogether, our findings identify DNA-suppressive motifs as a molecular ligand expressed by commensals and support the idea that a balance between stimulatory and regulatory DNA motifs contributes to the induction of controlled immune responses in the GI tract and gut immune homeostasis. Further, our findings suggest that the endogenous regulatory capacity of DNA motifs enriched in some commensal bacteria could be exploited for therapeutic purposes.

MRI brain abnormalities in cochlear implant candidates: how common and how important are they?

OBJECTIVE: To investigate the incidence of abnormal findings on brain MRI in paediatric cochlear implantation candidates. METHODS: Retrospective review of brain MRI scans of cochlear implant patients between 2000 and 2009 who underwent MRI brain as part of their pre-operative work-up. RESULTS: MRI scans of 162 patients were reviewed (76 female patients and 86 male patients). The mean age at time of MRI scan was 3 years 8 months. Abnormalities were detected/ reported in 49 patients (30%). The total number of abnormalities detected was 51 (two patients had two separate abnormalities each). Of the abnormalities 82% could be related to known pre-existing conditions. 18% of the abnormalities were incidental/unexpected. Incidental/unexpected abnormalities were found in 9 patients (6%). Four of the patients with incidental abnormalities required referral and further investigations (2.5%). The most common abnormality detected was white matter changes (70%). All the white matter changes were related to pre-existing known medical conditions. CONCLUSION: At our institution abnormalities detected by pre-operative brain MRI scans on cochlear implant candidates are common (30%). The majority of abnormalities are related to known pre-existing medical conditions. Incidental findings are rare (4%) and approximately half of them required further investigation or referral.

The effectiveness of the '2-week wait' referral service for colorectal cancer.

INTRODUCTION: The UK government target expects all suspected cancer patients to be seen within 2 weeks of referral made by general practitioners. This has significant impact on the workload for colorectal surgeons. The aim of this study was to investigate the effectiveness of this colorectal service. METHOD: A retrospective study of all patients referred to a 2-week wait colorectal clinic over a 12-month period was assessed, documenting diagnosis and staging. Comparison of patients diagnosed with colorectal cancer (CRC) presenting via other routes in the same period was made. RESULTS: Over the 12-month period, all 1100 patients were seen in the 2-week wait clinic; 938 (85%) patients fulfilled the referral criteria, but only 81 (7.3%) were diagnosed with cancer. Conversely, 136 CRC patients presented to the surgeons via urgent referrals (n = 86), emergency (n = 13), routine colorectal clinic (n = 19) and bowel screening (n = 18). The 2-week cohort had more advanced staging than those referred by standard letter and pilot screening. Cancers in the symptomatic population are predominantly Dukes' B and Dukes' C whereas in pilot screening group predominantly Dukes' A. CONCLUSION: The effectiveness of 2-week wait referral was poor, confirming its lack of validity. Further work is required to offer primary care stricter inclusion and exclusion referral criteria.

An Adaptive Resonance Theory account of the implicit learning of orthographic word forms.

An Adaptive Resonance Theory (ART) network was trained to identify unique orthographic word forms. Each word input to the model was represented as an unordered set of ordered letter pairs (open bigrams) that implement a flexible prelexical orthographic code. The network learned to map this prelexical orthographic code onto unique word representations (orthographic word forms). The network was trained on a realistic corpus of reading textbooks used in French primary schools. The amount of training was strictly identical to children's exposure to reading material from grade 1 to grade 5. Network performance was examined at each grade level. Adjustment of the learning and vigilance parameters of the network allowed us to reproduce the developmental growth of word identification performance seen in children. The network exhibited a word frequency effect and was found to be sensitive to the order of presentation of word inputs, particularly with low frequency words. These words were better learned with a randomized presentation order compared with the order of presentation in the school books. These results open up interesting perspectives for the application of ART networks in the study of the dynamics of learning to read.

daf-7-related TGF-beta homologues from Trichostrongyloid nematodes show contrasting life-cycle expression patterns.

The transforming growth factor-beta (TGF-beta) gene family regulates critical processes in animal development, and plays a crucial role in regulating the mammalian immune response. We aimed to identify TGF-beta homologues from 2 laboratory model nematodes (Heligmosomoides polygyrus and Nippostrongylus brasiliensis) and 2 major parasites of ruminant livestock (Haemonchus contortus and Teladorsagia circumcincta). Parasite cDNA was used as a template for gene-specific PCR and RACE. Homologues of the TGH-2 subfamily were isolated, and found to differ in length (301, 152, 349 and 305 amino acids respectively), with variably truncated N-terminal pre-proteins. All contained conserved C-terminal active domains (>85% identical over 115 amino acids) containing 9 cysteine residues, as in C. elegans DAF-7, Brugia malayi TGH-2 and mammalian TGF-beta. Surprisingly, only the H. contortus homologue retained a conventional signal sequence, absent from shorter proteins of other species. RT-PCR assays of transcription showed that in H. contortus and N. brasiliensis expression was maximal in the infective larval stage, and very low in adult worms. In contrast, in H. polygyrus and T. circumcincta, tgh-2 transcription is higher in adults than infective larvae. The molecular evolution of this gene family in parasitic nematodes has diversified the pre-protein and life-cycle expression patterns of TGF-beta homologues while conserving the structure of the active domain.

A comparison of linear respiratory system models based on parameter estimates from PRN forced oscillation data.

The forced oscillation technique offers some advantages over spirometry for assessing pulmonary function. It requires only passive patient cooperation; it also provides data in a form, frequency-dependent impedance, which is very amenable to engineering analysis. In particular, the data can be used to obtain parameter estimates for electric circuit-based models of the respiratory system, which can in turn aid the detection and diagnosis of various diseases/pathologies. In this study, we compare the least-squares error performance of the RIC, extended RIC, augmented RIC, augmented RIC+I(p), DuBois, Nagels and Mead models in fitting 3 sets of impedance data. These data were obtained by pseudorandom noise forced oscillation of healthy subjects, mild asthmatics and more severe asthmatics. We found that the aRIC+I(p) and DuBois models yielded the lowest fitting errors (for the healthy subjects group and the 2 asthmatic patient groups, respectively) without also producing unphysiologically large component estimates.

Local anaesthetic for post-tonsillectomy pain: a systematic review and meta-analysis.

BACKGROUND: Tonsillectomy is one of the most commonly performed procedures in otolaryngology. Pain is a significant aspect of post-operative patient morbidity. The use of local anaesthetic, by infiltration or topical application, has been advocated as a way of reducing post-operative pain. OBJECTIVES: To review the current evidence for the use of local anaesthetic as a means of reducing post-tonsillectomy pain and reducing supplemental analgesic requirements. TYPE OF REVIEW: A systematic review of the literature pertaining to the use of local anaesthetic agents for post-tonsillectomy pain and meta-analysis of randomised control trials assessing pain scores. SEARCH STRATEGY: Systematic literature searches of MEDLINE (1952-2008), EMBASE (1974-2008) and the Cochrane Central Register of Controlled Trials. EVALUATION METHOD: Review of all randomised controlled trials by two authors and grading of articles for quality. RESULTS: Thirteen studies were included. Overall, local anaesthetic, applied topically or infiltrated, significantly reduces pain scores compared with controls at 4-6 h, -0.66 (95% CI: -0.82, -0.50); 20-24 h, -0.34 (95% CI: -0.51, -0.18) and on day 5, -0.97 (95% CI: -1.30, -0.63) (standardised mean differences). These changes approximate to a reduction in pain of between 7 and 19 mm on a 0-100 mm visual analogue scale. Most studies did not report a difference in supplemental analgesia or in adverse events. CONCLUSION: Local anaesthetic does seem to provide a modest reduction in post-tonsillectomy pain. Topical local anaesthetic on swabs appears to provide a similar level of analgesia to that of infiltration without the potential adverse effects and should be the method of choice for providing additional post-operative analgesia.

Montelukast in allergic rhinitis: a systematic review and meta-analysis.

Allergic rhinitis is common. This systematic review outlines the evidence regarding montelukast in allergic rhinitis and provides a meta-analysis of its efficacy. The evidence suggests that montelukast does reduce nasal symptom score by 3.4% (95% CI: 2.5% to 4.2%) when compared with placebo. Montelukast is not as effective as topical nasal steroids or antihistamines and should therefore be regarded as second line therapy. When used, montelukast should be used in combination with an antihistamine.