The application of advanced imaging techniques for the assessment of paediatric chest disease

Introduction – Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) both result in chronic suppurative lung disease with significant resulting morbidity and early mortality. Many clinical and academic groups advocate biennial or even annual CT surveillance from as early as 2 years of age, but new therapies and increasing life expectancy lead to concerns over the use of repeated CT imaging. There are many recent studies showing promise of MRI for structural lung imaging MRI based measures of lung function. Both CF and PCD result in multisystem disease and whilst much of the morbidity results from lung disease, monitoring of extrathoracic disease is likely also relevant. Aims and objectives – 1) To set up a clinically feasible, multisystem (lung, sinonasal and upper abdominal visceral) quantitative MRI examination for the investigation and follow up of CSLD 2) To evaluate novel imaging biomarkers of CF and PCD disease severity Hypotheses – 1) Combined structural and quantitative MRI assessment of the thorax can provide comparable information to CT such that follow up imaging via CT could be replaced with MRI. 2) Quantitative MR measures of ventilation correlate with established clinical measures of ventilation (LCI and FEV1) and provide additional spatial information. 3) A multisystem MRI assessment can provide new extra-thoracic imaging biomarkers of CF and PCD disease severity whilst being better tolerated by patients than current multimodality imaging follow up. Methods – People with CF or PCD referred for clinically indicated lung CT were prospectively recruited to undergo MR imaging of the lungs, liver and paranasal sinuses. Structural lung imaging was optimised for speed of acquisition using T2 BLADE imaging, in axial and coronal plane, during breath holds rather than more conventional respiratory triggering. Images were scored by two observers using the Eichinger scoring system and compared to CT structural scores using the CFCT scoring system. Lung T1 mapping was performed via free breathing IR-HASTE and T1 and T2 mapping performed via breath hold ufbSSFP imaging. Functional lung imaging was performed via pre and post hyperoxygenation ufbSSFP T1 mapping, free breathing dynamic oxygen enhanced IR-HASTE imaging (OE-MRI) and non-contrast ufbSSFP-based matrix pencil decomposition imaging of ventilation and pulmonary perfusion. Lung T1 maps included the superior portion of the liver enabling simultaneous liver T1 mapping. A multiparametric paranasal sinus protocol was devised containing structural (T1 and T2 TSE), susceptibility and diffusion weighted sequences for the calculation of sinus volume, mucus volume and mucosal volume, presence or absence of artefact associated with infective micro-organisms and calculation of mucus and mucosal diffusion. Participant tolerability of MR imaging assessed via a bespoke questionnaire, completed before and after both CT and MR imaging. Multiple breath wash-out testing was performed on the day of the MRI and spirometry, antibiotic usage, abdominal ultrasound and sheer wave elastography collected retrospectively from the electronic patient record. Results – 22 participants were recruited, all of whom completed the hour-long MRI protocol. The median age was 14 years (range 6 – 35). 2-plane structural lung imaging was acquired in a total of 2 minutes 4 seconds with only a single participant reporting difficulties with the required breath holds. Interclass Correlation Coefficients of interobserver variability in MRI scores were comparable to CT (0.877-0.965 compared to 0.877-0.989 respectively) suggesting good image quality with strong correlation between MR and CT component scores (bronchiectasis/bronchial wall thickening r=0.828,p<0.001; mucus plugging r=0.812, p<0.001; parenchymal score r=0.564 – 0.729, p<0.001 – 0.006). Median lung T1 did not correlate with clinical markers of disease severity, but median lung T2 demonstrated strong correlation with CT bronchial wall thickening (r=-0.655, p=0.001) and LCI2.5 (r=-0.540, p=0.046), most likely representing a surrogate of pulmonary perfusion (most pulmonary T2 signal likely originates from the pulmonary blood pool). Significant ufbSSFP enhancement was demonstrated post hyperoxygenation, but the degree of enhancement did not correlate significantly with clinical measures of disease severity. There was, however, very strong correlations between matrix pencil decomposition ventilation fraction and LCI2.5 (r=0.831, p=0.001) and CFCT scores (r= up to 0.731, p=<0.001). Significant correlation was also demonstrated between measures of ventilation heterogeneity (oxygen wash-out time skew and kurtosis) and both LCI2.5 (r=0.591, p=0.013) and CFCT component scores (r= up to 0.718, p<0.001). Liver T1 values did not correlate with evidence of liver disease on liver function tests or ultrasound imaging, but interpretation was severely limited by the very small number of recruits with CF liver disease. Sinus imaging was the last part of the protocol with failed analysis in only one patient from too much motion (a 6 year old). Association was demonstrated between exacerbation frequency and opacification of maxillary sinuses by mucusa (p=0.074), between CT hyperinflation score and increasing levels of mucus susceptibility artefact (0=0.028), between exacerbation frequency, CT bronchial wall thickening and mucus plugging and increased sinus mucus diffusion (r=0.581, p=0.048, r=0.744, p=0.006 and r=0.633, p=0.019 respectively) and between CT hyperinflation, bronchiectasis and bronchial wall thickening scores and increased sinus mucosal diffusion (r=-0.847, p=0.016; r=-0.542, p=0.017 and r=-0.427, p=0.069 respectively). A third of recruits stated that they would opt for MR imaging over CT imaging in the future and whilst 41% reported difficulties staying still for the MRI, respiratory image post processing was successful in all participants, with no parts of the MRI studies repeated. Conclusion – Multisystem lung, liver and sinus MRI is feasible, well tolerated by people with CF or PCD, down to the age of 6 years, and provides gross structural imaging of sufficient quality to replace CT for lung imaging surveillance. Furthermore, the addition of functional lung imaging provides quantitative outputs which correlate well with clinically established lung function tests with the benefit of spatially localised lung function and additional quantitative measures of relevant extrapulmonary disease, within a single ionising radiation free examination. The data from this study have supported funding for future work addressing short, medium and long-term repeatability and longitudinal trends both in times of disease stability and over the course of an infective exacerbation.Open Acces

Species delimitation in asexual insects of economic importance: The case of black scale (Parasaissetia nigra), a cosmopolitan parthenogenetic pest scale insect

Asexual lineages provide a challenge to species delimitation because species concepts either have little biological meaning for them or are arbitrary, since every individual is monophyletic and reproductively isolated from all other individuals. However, recognition and naming of asexual species is important to conservation and economic applications. Some scale insects are widespread and polyphagous pests of plants, and several species have been found to comprise cryptic species complexes. Parasaissetia nigra (Nietner, 1861) (Hemiptera: Coccidae) is a parthenogenetic, cosmopolitan and polyphagous pest that feeds on plant species from more than 80 families. Here, we implement multiple approaches to assess the species status of P. nigra, including coalescence-based analyses of mitochondrial and nuclear genes, and ecological niche modelling. Our results indicate that the sampled specimens of P. nigra should be considered to comprise at least two ecotypes (or "species") that are ecologically differentiated, particularly in relation to temperature and moisture. The presence of more than one ecotype under the current concept of P. nigra has implications for biosecurity because the geographic extent of each type is not fully known: some countries may currently have only one of the biotypes. Introduction of additional lineages could expand the geographic extent of damage by the pest in some countries.This project was supported, in part, by an Australian Research Council Discovery Projects grant (DP130101141) and funding from The University of Queensland, Australia to LGC, and the College of Life Science, Shanxi University, China to YPL (National Serial Number of Postdoctoral Fellowship: 140975)

Wheeze in the time of COVID-19: overcoming obstacles to an unusual diagnosis

This case is an example of a rare cause of a common clinical presentation (persistent lobar collapse with wheeze). We describe patient management from primary care through to a national thoracic referral centre. We highlight the importance of objective testing to support an asthma diagnosis and the need to consider alternative or additional diagnoses if a patient does not respond to treatment or the clinical course is unexpected. We highlight the importance of follow-up X-ray to determine whether atelectasis has resolved, which was significantly delayed in this case due to COVID-19 restrictions. Though rare, an endobronchial tumour should be considered if atelectasis persists and when planning endoscopy for a presumed foreign body, especially if the clinical history and patient factors make a foreign body less likely. Greater awareness of this as a differential may expedite diagnoses for patients in future. We show how virtual, multicentre, multidisciplinary meetings can aid rapid diagnosis, surgical planning and coordination of follow-up across centres

Genome-Wide Association Study of Non-Alcoholic Fatty Liver Disease using Electronic Health Records

Genome‐wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case‐control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co‐existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta‐analysis using available summary association statistics. Six risk loci were identified (P < 5*10(−8)) (apolipoprotein E [APOE], patatin‐like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co‐existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta‐analysis. Rs429358 (P = 2.17*10(−11)) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78‐0.90] and homozygotes 0.64 [0.50‐0.79]). Conclusion: This GWAS replicates six known NAFLD‐susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches

Improving quality of life through the routine use of the patient concerns inventory for head and neck cancer patients: main results of a cluster preference randomised controlled trial

Funding: UK National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0215-36047).Purpose The patient concerns inventory (PCI) is a prompt list allowing head and neck cancer (HNC) patients to discuss issues that otherwise might be overlooked. This trial evaluated the effectiveness of using the PCI at routine outpatient clinics for one year after treatment on health-related QOL (HRQOL). Methods   A pragmatic cluster preference randomised control trial with 15 consultants, 8 ‘using’ and 7 ‘not using’ the PCI intervention. Patients treated with curative intent (all sites, disease stages, treatments) were eligible. Results   Consultants saw a median (inter-quartile range) 16 (13–26) patients, with 140 PCI and 148 control patients. Of the pre-specified outcomes, the 12-month results for the mean University of Washington Quality of Life (UW-QOLv4) social-emotional subscale score suggested a small clinical effect of intervention of 4.6 units (95% CI 0.2, 9.0), p = 0.04 after full adjustment for pre-stated case-mix. Results for UW-QOLv4 overall quality of life being less than good at 12 months (primary outcome) also favoured the PCI with a risk ratio of 0.83 (95% CI 0.66, 1.06) and absolute risk 4.8% (− 2.9%, 12.9%) but without achieving statistical significance. Other non-a-priori analyses, including all 12 UWQOL domains and at consultant level also suggested better HRQOL with PCI. Consultation times were unaffected and the number of items selected decreased over time. Conclusion   This novel trial supports the integration of the PCI approach into routine consultations as a simple low-cost means of benefiting HNC patients. It adds to a growing body of evidence supporting the use of patient prompt lists more generally.Publisher PDFPeer reviewe

Improving quality of life through the routine use of the patient concerns inventory for head and neck cancer patients : baseline results in a cluster preference randomised controlled trial

Funding: RfPB on behalf of the NIHR (PB-PG-0215-36047). This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0215-36047).Purpose The main aim of this paper is to present baseline demographic and clinical characteristics and HRQOL in the two groups of the Patient Concerns Inventory (PCI) trial. The baseline PCI data will also be described. Methods This is a pragmatic cluster preference randomised control trial with 15 consultant clusters from two sites either ‘using' (n = 8) or ‘not using’ (n = 7) the PCI at a clinic for all of their trial patients. The PCI is a 56-item prompt list that helps patients raise concerns that otherwise might be missed. Eligibility was head and neck cancer patients treated with curative intent (all sites, stage of disease, treatments). Results From 511 patients first identified as eligible when screening for the multi-disciplinary tumour board meetings, 288 attended a first routine outpatient baseline study clinic after completion of their treatment, median (IQR) of 103 (71–162) days. At baseline, the two trial groups were similar in demographic and clinical characteristics as well as in HRQOL measures apart from differences in tumour location, tumour staging and mode of treatment. These exceptions were cluster (consultant) related to Maxillofacial and ENT consultants seeing different types of cases. Consultation times were similar, with PCI group times taking about 1 min longer on average (95% CL for the difference between means was from − 0.7 to + 2.2 min). Conclusion Using the PCI in routine post-treatment head and neck cancer clinics do not elongate consultations. Recruitment has finished but 12-month follow-up is still ongoing.Publisher PDFPeer reviewe

What is the recovery rate and risk of long-term consequences following a diagnosis of COVID-19?:A harmonised, global longitudinal observational study protocol

Introduction: Very little is known about possible clinical sequelae that may persist after resolution of acute COVID-19. A recent longitudinal cohort from Italy including 143 patients followed up after hospitalisation with COVID-19 reported that 87% had at least one ongoing symptom at 60-day follow-up. Early indications suggest that patients with COVID-19 may need even more psychological support than typical intensive care unit patients. The assessment of risk factors for longer term consequences requires a longitudinal study linked to data on pre-existing conditions and care received during the acute phase of illness. The primary aim of this study is to characterise physical and psychosocial sequelae in patients post-COVID-19 hospital discharge. Methods and analysis: This is an international open-access prospective, observational multisite study. This protocol is linked with the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) and the WHO’s Clinical Characterisation Protocol, which includes patients with suspected or confirmed COVID-19 during hospitalisation. This protocol will follow-up a subset of patients with confirmed COVID-19 using standardised surveys to measure longer term physical and psychosocial sequelae. The data will be linked with the acute phase data. Statistical analyses will be undertaken to characterise groups most likely to be affected by sequelae of COVID-19. The open-access follow-up survey can be used as a data collection tool by other follow-up studies, to facilitate data harmonisation and to identify subsets of patients for further in-depth follow-up. The outcomes of this study will inform strategies to prevent long-term consequences; inform clinical management, interventional studies, rehabilitation and public health management to reduce overall morbidity; and improve long-term outcomes of COVID-19. Ethics and dissemination: The protocol and survey are open access to enable low-resourced sites to join the study to facilitate global standardised, longitudinal data collection. Ethical approval has been given by sites in Colombia, Ghana, Italy, Norway, Russia, the UK and South Africa. New sites are welcome to join this collaborative study at any time. Sites interested in adopting the protocol as it is or in an adapted version are responsible for ensuring that local sponsorship and ethical approvals in place as appropriate. The tools are available on the ISARIC website (www.isaric.org)

X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins