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Ticks are blood-feeding arthropods that can transmit pathogens to humans and animals, leading to serious infectious diseases such as Lyme disease. After single or multiple tick infestation, some animal species develop resistance to tick feeding, leading to reduced risk of pathogen transmission. In mice infested with larval ticks, both mast cells and basophils reportedly play key roles in the manifestation of acquired tick resistance (ATR), but it remains ill-defined how they contribute to it. Here, we investigated their products responsible for ATR. Treatment of mice with antihistamine abolished the ATR while histamine or histamine H1 receptor agonist reduced tick-feeding even in the first infestation. In accordance with these, mice deficient for histamine production showed little or no ATR, indicating the crucial role for histamine in the expression of ATR. Adoptive transfer of mast cells and basophils derived from histamine-sufficient or deficient mice to recipient mice lacking mast cells and basophils, respectively, revealed that histamine produced by basophils but not mast cells is essential for the manifestation of ATR, in contrast to the case of local and systemic anaphylaxis where mast cell-derived histamine is the major player. During the second but not first tick infestation, basophils accumulated and made a cluster, surrounding a tick mouthpart, in the epidermis whereas mast cells were scattered and localized mainly in the dermis, more distantly from a tick mouthpart. This appears to explain why basophil-derived histamine is much more effective than mast cell-derived one. Histamine-sufficient, but not -deficient mice showed the thickened epidermis at the second tick-feeding site. Taken together, histamine released from skin-infiltrating basophils rather than skin-resident mast cells plays a crucial role in the manifestation of ATR, perhaps through promotion of epidermal hyperplasia that may inhibit tick feeding.

AimsThe aim was to evaluate whether standardised exercise performance during the incremental shuttle walk test (ISWT) can be used to assess disease severity in children and young people (CYP) with chronic conditions, through (1) identifying the most appropriate paediatric normative reference equation for the ISWT, (2) assessing how well CYP with haemophilia and cystic fibrosis (CF) perform against the values predicted by the best fit reference equation and (3) evaluating the association between standardised ISWT performance and disease severity.MethodsA cross-sectional analysis was carried out using existing data from two independent studies (2018–2019) at paediatric hospitals in London,UK. CYP with haemophilia (n=35) and CF (n=134) aged 5–18 years were included. Published reference equations for standardising ISWT were evaluated through a comparison of populations, and Bland-Altman analysis was used to assess the level of agreement between distances predicted by each equation. Associations between ISWT and disease severity were assessed with linear regression.ResultsThree relevant reference equations were identified for the ISWT that standardised performance based on age, sex and body mass index (Vardhan, Lanza, Pinho). A systematic proportional bias of standardised ISWT was observed in all equations, most pronounced with Vardhan and Lanza; the male Pinho equation was identified as most appropriate. On average, CYP with CF and haemophilia performed worse than predicted by the Pihno equation, although the range was wide. Standardised ISWT, and not ISWT distance alone, was significantly associated with forced expiratory volume in 1 s in CYP with CF. Standardised ISWT in CYP with haemophilia was slightly associated with haemophilia joint health score, but this was not significant.ConclusionsISWT performance may be useful in a clinic to identify those with worsening disease, but only when performance is standardised against a healthy reference population. The development of validated global reference equations is necessary for more robust assessment.

Why did you do this work?The climate crisis is a global emergency that disproportionately affects children and young people. The RCPCH’s climate change action plan calls on paediatricians to be role models in mitigating climate change personally and professionally.1 Road transport is the largest contributor to UK CO2 emissions, with average car commuters (33km round-trip) directly emitting 1.1 metric tonnes of CO2 annually (MTCO2e).2 3 Understanding the environmental cost of commuting for paediatric training is crucial for exploring mitigation strategies. Given that rotational training placements are often outside trainees’ control and assigned on short notice—making green commuting options like carpooling challenging—this study aimed to estimate the CO2 emissions associated with commuting for paediatric rotational training in the East of England (EoE).What did you do?An anonymous electronic survey was distributed to all EoE paediatric trainees in June 2024, with reminders given at regional study days. The survey collected data on commuting modality currently and to furthest rotational placement, home outcodes, LTFT status, and concern for environment and ranked factors influencing commuting choices. Commute distances were calculated using RStudio’s ‘gmapsdistance’ package, and CO2 emissions were derived from UK government data.4 5 Annual emissions were based on 20 round trips per month, adjusted for full-time equivalent (FTE) status over 12 months. Total emissions for all trainees were calculated as a sum of mean emissions per trainee stratified by number of trainees per level of training.What did you find?Of 225 EoE Paediatric trainees, 34% (n=77) responded. Individual car use, mostly fossil-fuelled, is the dominant mode of commuting among trainees. Despite concerns about environmental impact, commute choices were primarily influenced by time, caring responsibilities, and cost and least by environmental concerns. The mean daily round-trip commute to current placements was 84.7km (UK average: 33km), and to furthest placements 141km. Annually, trainees averaged 8,968km commuting to current placements, equivalent to 1.94MTCO2e, and 14,641km to their furthest placements, equivalent to 3.4MTCO2e. Extrapolating these figures to all EoE paediatric trainees estimates 435.8MTCO2e attributable to paediatric training annually.What does it mean?Paediatric rotational training generates significant CO2 emissions, primarily from car commuting. Trainees are concerned about the environmental impact, but cost, time, and caring responsibilities primarily influence their commute choices. As paediatricians, we must reflect on the necessity of frequent rotations and their environmental impact. The RCPCH should consider strategies to alleviate this and lead by example: promoting remote training opportunities, improved longitudinal rota design and facilitating or incentivising green transport options including transition to electric vehicles. These initiatives would reflect the College’s commitment to sustainability, environmental responsibility, and trainee wellbeing.ReferencesThe impact of climate change on global child health – position statement RCPCH. Available from: https://www.rcpch.ac.uk/resources/impact-climate-change-global-child-health-position-statement#key-messages-for-health-professionalsOffice for National Statistics. Available from: https://www.ons.gov.uk/visualisations/dvc99999/covid-emissions-gh-pages/index.html?2020 UK Greenhouse Gas Emissions. Available from: https://www.ipcc-nggip.iges.or.jp/public/wetlands/index.html;UK Government – Department for Energy Security and Net Zero. Greenhouse gas reporting: conversion factors 2023. Available from: https://www.gov.uk/government/publications/greenhouse-gas-reporting-conversion-factors-2023Melo R, Zarruk D. Distance and travel time between two points from google maps. 2016.

Early vaccine trials are under way, but other strategies look more promising at present

Our previous studies have characterized Dexamethasone (Dex)-induced apoptotic signaling pathways in multiple myeloma (MM) cells; however, related transcriptional events are not fully defined. In the present study, gene expression profiles of Dex-treated MM cells were determined using oligonucleotide arrays. Dex triggers early transient induction of many genes involved in cell defense/repair-machinery. This is followed by induction of genes known to mediate cell death and repression of growth/survival-related genes. The molecular and genetic alterations associated with Dex resistance in MM cells are also unknown. We compared the gene expression profiles of Dex-sensitive and Dex-resistant MM cells and identified a number of genes which may confer Dex-resistance. Finally, gene profiling of freshly isolated MM patient cells validates our in vitro MM cell line data, confirming an in vivo relevance of these studies. Collectively, these findings provide insights into the basic mechanisms of Dex activity against MM, as well as mechanisms of Dex-resistance in MM cells. These studies may therefore allow improved therapeutic uses of Dex, based upon targeting genes that regulate MM cell growth and survival.

Background: Shoulder instability in the older patient traditionally has received less attention in the literature than in the younger patient population. However, when traumatic dislocation does occur, these patients often still have frequent pain, disability, and even continued instability. Purpose: To characterize the pathoanatomy of traumatic anterior shoulder instability in the older patient population and to discuss the correlating symptoms that ultimately led to operative treatment. Study Design: Case series; Level of evidence, 4. Methods: Patients with a history of an initial traumatic anterior shoulder instability event occurring after the age of 35 years who underwent arthroscopic surgical intervention were prospectively enrolled. Exclusion criteria included posterior instability, major fractures of the shoulder girdle, and multidirectional instability. All patients initially underwent a period of nonoperative rehabilitation. Operative treatment was performed if a patient continued to have pain and/or instability. Operative reports and arthroscopic pictures were reviewed for pathoanatomical findings. Results: A total of 27 patients (28 shoulders) met the inclusion criteria and were analyzed in this study (22 men and 5 women; mean age, 55 years; age range, 35-74 years). Surgical intervention was performed for recurrent instability in 7 patients, pain for 8 patients, and pain with instability for 13 patients. Arthroscopic findings demonstrated 18 rotator cuff tears (RCTs) (64.3%) and 18 Bankart lesions (64.3%). Nine patients had both an RCT combined with a Bankart lesion (32.1%). Three humeral avulsion of the glenohumeral ligament (HAGL) lesions (10.7%) and 2 anterior labral periosteal sleeve avulsion (ALPSA) lesions (7.1%) were found. All shoulders demonstrated Hill-Sachs lesions of various size and depth. Conclusion: Traumatic shoulder instability in the older patient may result in a wide array of pathologic findings as well as a diversity of clinical presentations. These findings suggest that the clinical diagnostician should maintain a high index of suspicion for RCT, Bankart lesions, and HAGL lesions in older patients who remain symptomatic after traumatic anterior shoulder instability.

Why did you do this work?A variety of immunological issues can be seen in patients with Trisomy 21 (T21), and they can require varying degrees of immunological support and intervention.We wanted to evaluate the immunophenotypes of the T21 patients we are caring for in our East of England Paediatric Immunology service order to understand our Immunology T21 cohort and future plan for optimisation of the care we provide to T21 patients from across the region.What did you do?The patients with T21 seen by our service are referred in from external clinicians, referred from an internal sub-specialty as an outpatient, or referred from an internal sub-specialty as an acutely unwell inpatient. There are no direct T21/Paediatric Immunology pathways and there is no sub-specialty T21 Paediatric Immunology Clinic.We looked back at the T21 patients seen in our Paediatric Immunology Clinic over a two-year period (September 2022 – September 2024) in order to better understand the immunology needs of our patient cohort.We looked at the demographics of the patients seen, their pathway into the service, their immunology test results, and type of input they required from us.What did you find?Patients with T21 can have a variety of immunological abnormalities, including decreased B cell numbers, decreased antibody responses, decreased T cell numbers, decreased T cell proliferation in response to mitogens, and impaired phagocyte function. We collated the immunological test results of our T21 patients to describe the immunophenotypes seen in our cohort.We described the pathways by which the patients reached our service and the amount of input (in particular, but not limited to, regarding medications) required by our service.What does it mean?To provide the highest quality care for this group of patients we want to continuously improve the service we deliver, we want to optimise their access to the immunological input they might need, and we want to avoid them receiving delayed care.We will use our evaluation of the current Paediatric Immunology T21 cohort to inform improvement of our service and our support of this patient group and their families.

AimsRespiratory Syncytial Virus (RSV) is the leading infectious cause of hospitalisation in infants. Neutrophilic infiltration of the airways has been observed in infants with severe infection clinically, but whether these neutrophils enhance recovery from disease or contribute to its pathology is unknown. Adults do not suffer the same clinical syndrome of bronchiolitis though are still susceptible to RSV infection. This study aims to examine differences in adult and neonatal neutrophil migration across RSV infected airway epithelial cells (AECs), using a novel sophisticated in vitro model, and measure neutrophil apoptosis, cellular markers and secreted markers of neutrophil activation key to clinical pathology.MethodsCord blood neutrophils were collected following uncomplicated term caesarean deliveries at University College Hospital, London. Adult neutrophils were collected from healthy donors at UCL Institute of Child Health. Full research ethics committee approval was provided by Bloomsbury Research Ethics committee (Project ID Number: 14/LO/0863) and UCL Research Ethics Committee (4735/002). Neutrophils were purified using negative immunoselection (StemCell).Neutrophil trans-epithelial migration was modelled using a novel in-vitro system1 (figure 1). Primary human airway epithelial cells (AECs) were grown at air liquid interface for 28 days then infected with RSV A2 for 72hrs. Uninfected AECs inoculated with sterile media (Mock) and uninfected AECs with RSV infected AEC supernatant apically (RSV Sup) were used as controls. Purified neutrophils were then added to the basolateral side of AECs and allowed to migrate for one hour.Neutrophils adhered to AECs, those basolaterally and apically were collected for analysis. Neutrophil numbers were determined by CD11b-APC positivity absolute count in a measured volume via flow cytometry. Viability, death and apoptosis were determined by co-staining with AnnexinV-FITC and Propidium Iodide. Statistical analysis was performed using RStudio v.1.2.5.ResultsSignificantly greater numbers of cord blood neutrophils (336,684 ±48129) (Mean ±SEM) migrated to the apical compartment in 1 hours migration, in comparison to adult neutrophils (56,586 ±16139) in the same conditions (p=<0.0001). Conversely, greater numbers of adult neutrophils (171,641 ±31632) remained basolaterally in comparison to cord blood neutrophils (23,870 ±3359) in the same conditions (p=<0.05). A greater proportion of apical and adherent cord blood neutrophils were apoptotic (43.3% ±10.68) in comparison to adult (9.49% ±2.7) (p=0.0024), although despite this higher proportion of apoptosis there were still greater numbers of viable cord blood neutrophils apical to RSV infected AECs in comparison to adult. Finally, we showed that although cord blood neutrophils displayed greater levels of CD11b, CD64, NE and MPO expression unstimulated, they did not upregulate expression in response to migration in the same order as adult neutrophils.Abstract 547 Figure 1Schematic of experimental protocol including neutrophil collection, neutrophil purification and the neutrophil trans-epithelial migration model1Abstract 547 Figure 2Numbers and viability of neutrophils after transpithelial migration across RSV infected ciliated AECsConclusionGreater numbers of neonatal neutrophils migrate across RSV infected AECs in comparison to adult, of which a greater proportion undergo apoptosis, and which show limited upregulation of activation markers in comparison to adult. These differences may facilitate a greater neutrophilic infiltrate to the lung in response to RSV infection in infants, compared with adults and suggests neutrophil modulating treatments could be beneficial as novel therapies for RSV infection.• β2 integrin LFA1 mediates airway damage following neutrophil trans-epithelial migration during RSV infection, Herbert et al

IntroductionRespiratory syncytial virus (RSV) causes a severe respiratory condition, bronchiolitis, in infants but not in adults. Bronchiolitis is characterised by neutrophilic infiltration in the airways, but whether neutrophils enhance recovery from infection or contribute to its pathology remains unknown.MethodsWe used a novel in-vitro model to compare term umbilical cord blood (infant) (n=17 donors) and adult neutrophils (n=15 donors) during migration across RSV-infected differentiated human nasal airway epithelial cells (AECs) in a basolateral to apical direction.ResultsGreater numbers of infant neutrophils (mean (95% CI)) (336 684 (242 352 to 431 015)) migrated across RSV-infected AECs to the apical compartment (equivalent to the airway lumen) compared with adult neutrophils (56 586 (24 954 to 88 218)) (p<0.0001). Having reached the apical compartment of infected AECs, much greater numbers of infant neutrophils (140 787 (103 117 to 178 456)) became apoptotic compared with adult (5853 (444 to 11 261)) (p=0.002). Infant neutrophils displayed much greater expression of CD11b, CD64, neutrophil elastase (NE) and myeloperoxidase (MPO) than adult neutrophils at baseline and at all points of migration. However, as adult neutrophils migrated, expression of CD11b, CD64, NE and MPO became greater than at baseline.DiscussionThe high proportion of infant neutrophils migrating across RSV-infected AECs correlates with the neutrophilic infiltrate seen in infants with severe RSV bronchiolitis, with large numbers undergoing apoptosis, which may represent a protective mechanism during infection. Compared with adult neutrophils, infant neutrophils already have high expression of surface markers before contact with AECs or migration, with less capacity to increase further in response to RSV infection or migration.

Why did you do this work?22q11.2 Deletion Syndrome is the most frequent chromosomal microdeletion syndrome and is the second most common cause of developmental delay and congenital heart disease.It has a wide range of phenotypic manifestations. For this reason, it has been established that multidisciplinary team (MDT) care is the best way to achieve optimal outcomes in 22q11 patients.We deliver a monthly 22q11 MDT clinic at Cambridge University Hospital (CUH). We wanted to evaluate the service provided, and areas of potential improvement.What did you do?We looked back at our CUH 22q11 MDT Clinic over a two-year period (September 2022 – September 2024) in order to better understand the needs of our patient cohort.We looked at the demographics of the patients seen, the level of input they required from the sub-specialities present at our clinic, and any input required from sub-specialities not currently represented in the clinic.In particular we looked at the distribution of problems identified in the clinic, if these were newly identified problems, and what support and management had already been put in place plus what needed to be introduced.We also looked for the gaps in services provided to aid with future planning and optimisation of the clinic.What did you find?22q11 patients can have cardiac, immune, endocrine, palatal, and gastrointestinal abnormalities. They can have developmental delay and learning difficulties. Throughout their childhoods they may require management from a number of sub-speciality teams, and which teams are most valuable for them will vary between different timepoints in their life.We identified the input, from the sub-specialities represented, needed over the two-year period evaluated. We looked at this in relation to what they needed at various ages and also what had to be provided by this tertiary service rather than by local secondary care providers. We also identified the potential areas for improvement in terms of both sub-specialities we ought to consider incorporating into our clinic, and how we can improve the care provided by the teams already a part of the clinic.What does it mean?To provide the highest quality care for this group of patients we want to continuously improve the service we deliver, we want to optimise their access to the sub-specialty input they need, and we want to avoid them receiving fragmented or incomplete care.We will use our evaluation of the current 22q11 MDT Clinic to inform expansion and improvement of the clinic, building on the foundation we have established.ReferencesJ Pediatr. 2011 Aug;159(2):332–9.e1.Anne S Bassett. Practical guidelines for managing patients with 22q11.2 deletion syndrome.