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  • Mental Health Admissions to Paediatric Wards Study (MAPS): a protocol for the analysis of Hospital Episode Statistics (HES) data

    Roland, Damian (2024-01-29)
    Introduction: Children and young people (CYP) presenting with a mental health (MH) crisis are frequently admitted to general acute paediatric wards as a place of safety. Prior to the pandemic, a survey in England showed that CYP occupied 6% of general paediatric inpatient beds due to an MH crisis, and there have been longstanding concerns about the quality of care to support these patients in this setting. Mental Health Admissions to Paediatric Wards Study aims to generate a theory of change (ToC) model to improve the quality of care for CYP admitted to acute paediatric services after presenting in a MH crisis. Methods and analysis: We will undertake a national (England), sequential, mixed methods study to inform a ToC framework alongside a stakeholder group consisting of patients, families/carers and healthcare professionals (HCPs). Our study consists of four work packages (WP) undertaken over 30 months. WP1 is limited to using national routine administrative data to identify and characterise trends in MH admissions in acute paediatric wards in England between 2015- 2022. Ethics and dissemination: WP1 received ethical approval (Ref 23/NW/0192). We will publish the overall synthesis of data and the final ToC to improve care of CYP with MH crisis admitted to general acute paediatric settings. As coproducers of the ToC, we will work with our stakeholder group to ensure wide dissemination of findings. Potential impacts will be on service development, new models of care, training and workforce planning.
  • Mental Health Admissions to Paediatric Wards Study (MAPS): protocol of a prospective study of mental health admissions to paediatric wards in England using surveillance and qualitative methods

    Roland, Damian (2024-01-25)
    Introduction: Children and young people (CYP) presenting with a mental health (MH) crisis are frequently admitted to general acute paediatric wards as a place of safety. Prior to the pandemic, a survey in England showed that CYP occupied 6% of general paediatric inpatient beds due to an MH crisis, and there have been longstanding concerns about the quality of care to support these patients in this setting. MAPS aims to generate a Theory of Change (ToC) model to improve the quality of care for CYP admitted to acute paediatric services after presenting with an MH crisis. Here, we describe work packages (WPs) 2 and 3 of the study, which have been granted ethics approval. Methods and analysis: We will undertake a national (England), sequential, mixed-methods study to inform a ToC framework alongside a stakeholder group consisting of patients, families/carers and healthcare professionals (HCPs). Our study consists of four WPs undertaken over 30 months. WP2 is limited to working with stakeholders to develop a data collection instrument and then use this in a prospective study of MH admissions over 6 months in 15 purposively recruited acute paediatric wards across England. WP3 consists of gathering the views of CYP, their families/carers and HCPs during admissions using semistructured interviews. Ethics and dissemination: WP2 and WP3 received ethical approval (ref: 23/LO/0349). We will publish the overall synthesis of data and the final ToC to improve care of CYP with MH crisis admitted to general acute paediatric settings. As co-producers of the ToC, we will work with our stakeholder group to ensure wide dissemination of findings. Potential impacts will be upon service development, new models of care, training and workforce planning. Prospero registration number: CRD42022350655.
  • Are adenomyosis and endometriosis phenotypes of the same disease process?

    Habiba, Marwan (2023-12-25)
    In recent literature reviews, we concluded that the possibility that endometrial molecular aberrations are the sole or a necessary determinant of endometriosis and the Tissue Injury and Repair (TIAR) theory are yet to be convincingly proven. Here, we critically examine the theory that adenomyosis and endometriosis represent different phenotypes of a single disease. A common etiopathology for adenomyosis and endometriosis has been suggested because both conditions entail the presence of endometrial tissue at locations other than the lining of the uterus. There are wide differences in reported disease incidence and prevalence and, consequently, in estimates of the coexistence of both conditions. There are some similarities but also differences in their clinical features and predisposing factors. Each condition has a range of subtypes. These differences alone pose the question of whether subtypes of endometriosis and adenomyosis have different etiopathologies, and, in turn, this raises the question of whether they all share a common etiology. It is debatable whether the recognized differences between the eutopic endometrium in adenomyosis and endometriosis compared to those in unaffected women are the cause or the effect of the disease. The finding of common mutations, particularly of KRAS, lend support to the notion of shared predisposing factors, but this alone is insufficient evidence of causation.
  • PCSK6 and survival in idiopathic pulmonary fibrosis

    Tobin, Martin (2023-06-01)
    Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 × 10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 × 10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 × 10-9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression.
  • Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease

    Barwell, Julian; Gupta, Pankaj; Neal, Christopher P; Tobin, Martin D; Vemala, Vishwaray M (2023-04-23)
    Background & aims: Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods: Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. Results: We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. Conclusions: We have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and implications: A rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.
  • Interventions to increase vaccination against COVID-19, influenza and pertussis during pregnancy: a systematic review and meta-analysis

    Ravindram, Pahalavi (2023-12-28)
    Background: Pregnant women and their babies face significant risks from three vaccine-preventable diseases: COVID-19, influenza and pertussis. However, despite these vaccines' proven safety and effectiveness, uptake during pregnancy remains low. Methods: We conducted a systematic review (PROSPERO CRD42023399488; January 2012-December 2022 following PRISMA guidelines) of interventions to increase COVID-19/influenza/pertussis vaccination in pregnancy. We searched nine databases, including grey literature. Two independent investigators extracted data; discrepancies were resolved by consensus. Meta-analyses were conducted using random-effects models to estimate pooled effect sizes. Heterogeneity was assessed using the I2 statistics. Results: From 2681 articles, we identified 39 relevant studies (n = 168 262 participants) across nine countries. Fifteen studies (39%) were randomized controlled trials (RCTs); the remainder were observational cohort, quality-improvement or cross-sectional studies. The quality of 18% (7/39) was strong. Pooled results of interventions to increase influenza vaccine uptake (18 effect estimates from 12 RCTs) showed the interventions were effective but had a small effect (risk ratio = 1.07, 95% CI 1.03, 1.13). However, pooled results of interventions to increase pertussis vaccine uptake (10 effect estimates from six RCTs) showed no clear benefit (risk ratio = 0.98, 95% CI 0.94, 1.03). There were no relevant RCTs for COVID-19. Interventions addressed the 'three Ps': patient-, provider- and policy-level strategies. At the patient level, clear recommendations from healthcare professionals backed by text reminders/written information were strongly associated with increased vaccine uptake, especially tailored face-to-face interventions, which addressed women's concerns, dispelled myths and highlighted benefits. Provider-level interventions included educating healthcare professionals about vaccines' safety and effectiveness and reminders to offer vaccinations routinely. Policy-level interventions included financial incentives, mandatory vaccination data fields in electronic health records and ensuring easy availability of vaccinations. Conclusions: Interventions had a small effect on increasing influenza vaccination. Training healthcare providers to promote vaccinations during pregnancy is crucial and could be enhanced by utilizing mobile health technologies.
  • Attitudes and barriers to participation in window-of-opportunity trials reported by White and Asian/Asian British ethnicity patients who have undergone treatment for endometrial cancer

    Amirthanayagam, Anumithra; Moss, Esther (2023-11-23)
    Purpose: Window-of-opportunity trials (WOT) are a study design that have been used to investigate drug activity in endometrial cancer (EC). Recruitment to cancer clinical trials by patients from ethnic minority groups is reported to be lower than for patients of White ethnicity. Methods: A verbal questionnaire was conducted with White and Asian/Asian British ethnicity patients who had undergone treatment for EC. Strategic purposeful sampling was used to recruit patients from diverse social/educational backgrounds. Questions explored: background knowledge of clinical research, WOT study design, and views on medications that might be investigated. Thematic analysis was used to explore motivations for WOT participation and perceived barriers. Results: In total, 21 patients were recruited to the study (15 White and 6 Asian/Asian British). Views on optimum time to receive trial information differed, preferences ranging from 'at the time of diagnosis' to 'a few days after diagnosis'. The choice of medication under investigation had a strong influence on potential willingness to participate, with greater interest reported in medications derived from vitamins or food supplements rather than hormone-based drugs. Potential barriers to participation included concern over potential side-effects and the emotional/physical burden of a cancer diagnosis prior to major surgery. Discussion: This study provides important insights into patients' views on WOT participation in EC and raises issues that need to be considered for future trial design and participant recruitment materials. The timing and format of study information and type of substance under investigation were factors influencing potential participation. Future studies should consider using multi-lingual visual information videos to address information needs, as this may encourage participation by ethnic minority patients.
  • Apixaban for prevention of thromboembolism in pediatric heart disease

    Bu'Lock, Frances (2023-12-12)
    Background: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages. Objectives: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. Methods: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. Primary endpoint: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy. Results: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels. Conclusions: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472).
  • Prevalence of invasive bacterial infection in febrile infants ≤90 days with a COVID-19 positive test: a systematic review and meta-analysis

    Roland, Damian (2023-12-06)
    Background: Febrile infants with an infection by influenza or enterovirus are at low risk of invasive bacterial infection (IBI). Objective: To determine the prevalence of IBI among febrile infants ≤90 days old with a positive COVID-19 test. Methods: MEDLINE, Embase, Cochrane Central Register databases, Web of Science, and grey literature were searched for articles published from February 2020 to May 2023. Inclusion criteria: researches reporting on infants ≤90 days of age with fever and a positive test for SARS-CoV-2 (antigen test/PCR). Case reports with <3 patients, articles written in a language other than English, French or Spanish, editorials and other narrative studies were excluded. Preferred Reposting Items for Systematic Reviews and Meta-analysis guidelines were followed, and the National Institutes of Health Quality Assessment Tool was used to assess study quality. The main outcome was the prevalence of IBI (a pathogen bacterium identified in blood and/or cerebrospinal fluid (CSF)). Forest plots of prevalence estimates were constructed for each study. Heterogeneity was assessed and data were pooled by meta-analysis using a random effects model. A fixed continuity correction of 0.01 was added when a study had zero events. Results: From the 1023 studies and 3 databases provided by the literature search, 33 were included in the meta-analysis, reporting 3943 febrile infants with a COVID-19 positive test and blood or CSF culture obtained. The pooled prevalence of IBI was 0.14% (95% CI, 0.02% to 0.27%). By age, the prevalence of IBI was 0.56% (95% CI, 0.0% to 1.27%) in those 0-21 days old, 0.53% (95% CI, 0.0% to 1.22%) in those 22-28 days old and 0.11% (95% CI, 0.0% to 0.24%) in those 29-60 days old. Conclusion: COVID-19-positive febrile infants ≤90 days old are at low risk of IBI, especially infants >28 days old, suggesting this subgroup of patients can be managed without blood tests. Prospero registration number: CRD42022356507.
  • Complications of acute mastoiditis in a paediatric population at a UK tertiary centre: a retrospective review

    Chandarana, Karishma; Bowerman, Kathryn; Baruah, Paramita (2023-11-27)
    Objectives: Acute mastoiditis (AM) and its associated intra and extracranial complications are rare complications of acute otitis media. However, they are associated with a high morbidity. The management of AM with complications carries significant variations in approach. We aimed to evaluate the presentation of children with AM with complications to a tertiary referral centre in the United Kingdom and describe evolution of the treatment approaches. Methods: We undertook a retrospective chart review of all children admitted with AM to the University Hospitals of Leicester between 2013 and 2022. Results: Twenty-seven children were included in this study: 7 patients had sigmoid sinus thrombosis (SST), 4 had an intracranial collection, 3 had cranial nerve palsy and 16 had a subperiosteal abscess (SPA); some patients had more than 1 complication. In this study, treatment of SPA with incision and drainage (I&D) and grommet insertion was effective, as all patients treated with grommet insertion and I&D recovered well and did not require a subsequent cortical mastoidectomy. All patients with SST received anticoagulation and intravenous (IV) antibiotics; surgical input consisted of grommet insertion alone and cortical mastoidectomy was not routinely performed in these patients. Conclusion: In our series, management of SPA with grommet insertion and drainage had good outcomes. SST management mainly consisted of IV antibiotics, anticoagulation and grommet insertion with good recovery. The evidence to guide the management of complications of mastoiditis is of poor quality and further research is needed to clarify the optimal management of these complications.
  • The clinical impact of serious respiratory disease in children under the age of two years during the 2021-2022 bronchiolitis season in England, Scotland and Ireland

    Roland, Damian (2023-12-01)
    Background: Interventions introduced to reduce the spread of SARS-CoV-2 led to a widespread reduction in childhood infections. However, from spring 2021 onwards the United Kingdom and Ireland experienced an unusual out-of-season epidemic of respiratory disease. Methods: We conducted a prospective observational study (BronchStart), enrolling children 0-23 months of age presenting with bronchiolitis, lower respiratory tract infection or first episode of wheeze to 59 Emergency Departments across England, Scotland and Ireland from May 2021 to April 2022. We combined testing data with national admissions datasets to infer the impact of respiratory syncytial virus (RSV) disease. Results: The BronchStart study collected data on 17,899 presentations for 17,164 children. Risk factors for admission and escalation of care included prematurity and congenital heart disease, but most admissions were for previously healthy term-born children. Of those aged 0-11 months who were admitted and tested for RSV, 1,907/3,912 (48.7%) tested positive. We estimate that every year in England and Scotland 28,561 (95% confidence interval 27,637-29,486) infants are admitted with RSV infection. Conclusions: RSV infection was the main cause of hospitalisations in this cohort, but 51.3% of admissions in infants were not associated with the virus. The majority of admissions were in previously healthy term-born infants.
  • A systematic review of long-term complications of mechanical tubal occlusion

    Horne, Jonathan (2023-06)
    Objectives: To collate the available evidence of the rare but identified late complications of mechanical tubal occlusion. The primary objective is to describe the nature of these longer-term acute presentations. Secondary objectives are: 1) to delineate their aetiology, 2) characterise imaging findings and 3) identify successful management options. Study design: Literature search using National Institute of Clinical Excellence Healthcare Databases Advanced Search and terms (complicat* OR torsion OR infect* OR migrat* OR extru*) AND (tubal occlusion OR sterili*). Results reviewed by CM and JH for eligibility. Results: 33 published case reports of long-term complications of mechanical tubal occlusion. 30 demonstrated migration of the device. 16 had infective pathology. Multiple modalities of imaging used with no clear evidence that one was superior. Medical and surgical management was used with removal of device proving definitive treatment. Conclusions: Long-term complications of mechanical tubal occlusion are rare and show a varied clinical course. Clinicians should be mindful of this when evaluating patients in the acute setting, as there is no identified timeline as to when complications may occur. Imaging is almost always essential for diagnosis and the modality should be directed by the clinical presentation. Definitive management is by removal of the occlusive device, but this carries its own risks.
  • Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial

    Samanta, Rajib (2023-12)
    Background: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. Methods: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. Findings: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. Interpretation: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. Funding: National Institute for Health and Care Research.
  • Core outcomes and factors influencing the experience of care for children with severe acute exacerbations of asthma: a qualitative study

    Roland, Damian (2023-11)
    Objective: To identify the outcomes considered important, and factors influencing the patient experience, for parents and caregivers of children presenting to hospital with a severe acute exacerbation of asthma. This work contributes to the outcome-identification process in developing a core outcome set (COS) for future clinical trials in children with severe acute asthma. Design: A qualitative study involving semistructured interviews with parents and caregivers of children who presented to hospital with a severe acute exacerbation of asthma. Setting: Hospitals in 12 countries associated with the global Pediatric Emergency Research Networks, including high-income and middle-income countries. Interviews were conducted face-to-face, by teleconference/video-call, or by phone. Findings: Overall, there were 54 interviews with parents and caregivers; 2 interviews also involved the child. Hospital length of stay, intensive care unit or high-dependency unit (HDU) admission, and treatment costs were highlighted as important outcomes influencing the patient and family experience. Other potential clinical trial outcomes included work of breathing, speed of recovery and side effects. In addition, the patient and family experience was impacted by decision-making leading up to seeking hospital care, transit to hospital, waiting times and the use of intravenous treatment. Satisfaction of care was related to communication with clinicians and frequent reassessment. Conclusions: This study provides insight into the outcomes that parents and caregivers believe to be the most important to be considered in the process of developing a COS for the treatment of acute severe exacerbations of asthma.
  • Robotic-assisted surgery in high-risk surgical patients with endometrial cancer

    Moss, Esther (2023-11-04)
    Many patients diagnosed with an endometrial cancer are at high-risk for surgery due to factors such as advanced age, raised body mass index or frailty. Minimally-invasive surgery, in particular robotic-assisted, is increasingly used in the surgical management of endometrial cancer however, there are a lack of clinical trials investigating outcomes in high-risk patient populations. This article will review the current evidence and identify areas of uncertainty where future research is needed.
  • Standardized clinical annotation of digital histopathology slides at the point of diagnosis

    Hero, Emily (2023-11)
    As digital pathology replaces conventional glass slide microscopy as a means of reporting cellular pathology samples, the annotation of digital pathology whole slide images is rapidly becoming part of a pathologist's regular practice. Currently, there is no recognizable organization of these annotations, and as a result, pathologists adopt an arbitrary approach to defining regions of interest, leading to irregularity and inconsistency and limiting the downstream efficient use of this valuable effort. In this study, we propose a Standardized Annotation Reporting Style for digital whole slide images. We formed a list of 167 commonly annotated entities (under 12 specialty subcategories) based on review of Royal College of Pathologists and College of American Pathologists documents, feedback from reporting pathologists in our NHS department, and experience in developing annotation dictionaries for PathLAKE research projects. Each entity was assigned a suitable annotation shape, SNOMED CT (SNOMED International) code, and unique color. Additionally, as an example of how the approach could be expanded to specific tumor types, all lung tumors in the fifth World Health Organization of thoracic tumors 2021 were included. The proposed standardization of annotations increases their utility, making them identifiable at low power and searchable across and between cases. This would aid pathologists reporting and reviewing cases and enable annotations to be used for research. This structured approach could serve as the basis for an industry standard and be easily adopted to ensure maximum functionality and efficiency in the use of annotations made during routine clinical examination of digital slides.
  • A polygenic risk score for idiopathic pulmonary fibrosis and interstitial lung abnormalities

    Tobin, Martin (2023-10-01)
    Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.
  • PAEDIATRIC VASCULAR SURGERY: A review of cases from a dedicated paediatric vascular surgery clinic

    Kay, Mark (2023-11-06)
    Background: The experience in paediatric vascular diseases is limited in the UK and worldwide due to their rarity and variations in practice. We looked at types of cases presenting to a dedicated paediatric vascular clinic. Methods: Medical records of children seen in a dedicated paediatric vascular clinic at a tertiary referral service between 2016 and 2022 were reviewed. These patients were either seen for the first time in that clinic or had their appointments as a follow up after inpatient review or intervention while being under care of paediatric teams in local hospitals. Results: 55 patients (34 males) were seen aged between 4 months and 17 years (mean 9.5 years). Common presentations were limb length discrepancy secondary to iatrogenic arterial occlusion, follow up after bypass for trauma, lower limb swelling or discolouration and varicose veins. Operative procedures included lower limb bypass, angioplasty, ligation of aneurysms and varicose vein surgery. Conclusion: Paediatric vascular conditions are uncommon and therefore most vascular surgeons and trainees will have little exposure to such cases. Intervention is needed for arterial injury secondary to penetrating or iatrogenic trauma. National registry is required for these rare cases to gain prospective data that can help build up more evidence for educational purposes and to establish guidelines.
  • Extracorporeal membrane oxygenation in paediatric cardiac surgery: 5-year single centre experience

    Bezuska, Laurynas; Harvey, Chris; Omeje, Ikenna; Mimic, Branko (2023-11-10)
    Background: Extracorporeal membrane oxygenation (ECMO) has become an integral part of paediatric cardiac surgery. We report the experience of a well-established ECMO service over 5 years. Methods: This retrospective study analysed all paediatric patients who required ECMO support following cardiac surgery from April 2015 to March 2020. Inclusion criteria were age less than 18 years and post-operative ECMO support. Patients were analysed dividing into groups according to the urgency for ECMO support (extracorporeal cardiopulmonary resuscitation (ECPR) and cardiac ECMO) and according to age (neonatal and paediatric ECMO groups). They were followed for 30-day, 6-month mortality, long-term survival, postoperative morbidity and the need for reintervention. Results: Forty-six patients were included who had a total of venoarterial (VA) 8 ECMO runs. The 5-year incidence of the need for VA ECMO after cardiac surgery was 3.3% (48 of the overall 1441 cases recorded). The median follow-up period was 3.5 (interquartile ranges, 0.8-4.7) years. Thirty-day, 6-month and follow-up survival rate was 85%, 65% and 52% respectively. At the 6-month follow-up, the ECPR group showed a trend towards worse survival compared with the cardiac ECMO group (47% vs. 55%) but with no statistical significance (p = 0.35). Furthermore, the survival rates between paediatric (60%) and neonatal (46%) ECMO groups were similar, with no statistical significance (p = 0.45). The rate of acute neurological events was 27% (13/48). Conclusion: ECPR and neonatal ECMO groups had higher mortality. VA ECMO 30-day and 6-month survival rates were 85% and 65% respectively. Major neurological injury resulting in ECMO termination occurred in 3 patients. Accumulated experiences and protocols in ECMO management can improve mortality and morbidity.

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