Defining an Ageing-Related Pathology, Disease or Syndrome: International Consensus Statement.

Background: Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. Methods: The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19 th , 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥70% for approval. Results: The accepted criteria for an ageing-related pathology, disease or syndrome were: Develops and/or progresses with increasing chronological age.Should be associated with, or contribute to, functional decline, or an increased susceptibility to functional decline.Evidenced by studies in humans. Conclusions: Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

CD, or not CD, that is the question: a digital interobserver agreement study in coeliac disease.

OBJECTIVE: Coeliac disease (CD) diagnosis generally depends on histological examination of duodenal biopsies. We present the first study analysing the concordance in examination of duodenal biopsies using digitised whole-slide images (WSIs). We further investigate whether the inclusion of immunoglobulin A tissue transglutaminase (IgA tTG) and haemoglobin (Hb) data improves the interobserver agreement of diagnosis. DESIGN: We undertook a large study of the concordance in histological examination of duodenal biopsies using digitised WSIs in an entirely virtual reporting setting. Our study was organised in two phases: in phase 1, 13 pathologists independently classified 100 duodenal biopsies (40 normal; 40 CD; 20 indeterminate enteropathy) in the absence of any clinical or laboratory data. In phase 2, the same pathologists examined the (re-anonymised) WSIs with the inclusion of IgA tTG and Hb data. RESULTS: We found the mean probability of two observers agreeing in the absence of additional data to be 0.73 (±0.08) with a corresponding Cohen's kappa of 0.59 (±0.11). We further showed that the inclusion of additional data increased the concordance to 0.80 (±0.06) with a Cohen's kappa coefficient of 0.67 (±0.09). CONCLUSION: We showed that the addition of serological data significantly improves the quality of CD diagnosis. However, the limited interobserver agreement in CD diagnosis using digitised WSIs, even after the inclusion of IgA tTG and Hb data, indicates the importance of interpreting duodenal biopsy in the appropriate clinical context. It further highlights the unmet need for an objective means of reproducible duodenal biopsy diagnosis, such as the automated analysis of WSIs using artificial intelligence.

Are the recommendations in coronial prevention of future death (PFD) reports realistic and achievable?

Prevention is better than cure. Coroners are not often thought to have a role in prevention, even though they have a duty to produce prevention of future death reports. Such reports are supposed to stimulate changes to prevent further deaths from recognised problems, but we speculated that they do not achieve their purpose. The reports are categorised, published online and are publicly available. This study set out to analyse prevention of future death reports to understand how far they prompt change, in two healthcare-related categories. Reports dated in 2020 were reviewed and data were collated detailing the contents of each one and whether there was a response. Results showed that the prevention of future death reports are inconsistent with regard to the details they included and there is no evidence that concerns raised by Coroners stimulate significant, widespread change in the healthcare system.

Histopathology at autopsy: why bother?

AIMS: The frequency of histopathological sampling at autopsy varies, even though inadequate sampling may limit the value of autopsy reports. This study aims to investigate the contribution of histopathology at autopsy in a major teaching hospital. METHODS AND RESULTS: A total of 532 coronial autopsy reports from Manchester Royal Infirmary were analysed retrospectively. Gross and microscopic diagnoses were compared and classified as concordant, discordant, histology needed (i.e. indeterminate or unremarkable gross findings) or autolysed. Revisions made to the cause of death following histopathology were categorised as: altered direct cause of death, altered indirect cause of death, concordant with supportive information, irrelevant or inconclusive. The study was limited to brain, heart, kidney, liver, lung and spleen. Histopathology had been requested in 141 cases (27%), which were further analysed. The greatest discordance between gross and microscopic findings was observed in the lung (11.6%). The organs most frequently requiring histopathology to provide a diagnosis were the kidney and lung, at 52.8 and 28.2%, respectively. Alterations were made to the direct cause of death in 45% of cases where histopathology was taken; it provided additional or supportive information in a further 38%. Diagnoses of primary malignancy had a sensitivity of 74% [confidence interval (CI) = 0.59-0.86] and bronchopneumonia had a sensitivity of 45% (CI = 0.29-0.62). CONCLUSION: Histopathology has a major impact on the interpretation of organ pathology and determining a cause of death at autopsy.

Very Short Answer Questions: A Novel Approach To Summative Assessments In Pathology.

BACKGROUND: A solid understanding of the science underpinning treatment is essential for all doctors. Pathology teaching and assessment are fundamental components of the undergraduate medicine curriculum. Assessment drives learning and the choice of assessments influences students' learning behaviours. The use of multiple-choice questions is common but is associated with significant cueing and may promote "rote learning". Essay-type questions and Objective Structured Clinical Examinations (OSCEs) are resource-intensive in terms of delivery and marking and do not allow adequate sampling of the curriculum. To address these limitations, we used a novel online tool to administer Very Short Answer questions (VSAQs) and evaluated the utility of the VSAQs in an undergraduate summative pathology assessment. METHODS: A group of 285 medical students took the summative assessment, comprising 50 VSAQs, 50 single best answer questions (SBAQs), and 75 extended matching questions (EMQs). The VSAQs were machine-marked against pre-approved responses and subsequently reviewed by a panel of pathologists, with the software remembering all new marking judgements. RESULTS: The total time taken to mark all 50 VSAQs for all 285 students was 5 hours, compared to 70 hours required to manually mark an equivalent number of questions in a paper-based pathology exam. The median percentage score for the VSAQs test (72%) was significantly lower than that of the SBAQs (80%) and EMQs (84%), p <0.0001. VSAQs had a higher Cronbach alpha (0.86) than SBAQs (0.76), and EMQs (0.77). VSAQs, SBAQs and EMQs had a mean point-biserial of 0.35, 0.30 and 0.28, respectively. CONCLUSION: VSAQs are an acceptable, reliable and discriminatory method for assessing pathology, and may enhance students' understanding of how pathology supports clinical decision-making and clinical care by changing learning behaviour.

A randomised trial of the influence of racial stereotype bias on examiners' scores, feedback and recollections in undergraduate clinical exams.

BACKGROUND: Asian medical students and doctors receive lower scores on average than their white counterparts in examinations in the UK and internationally (a phenomenon known as "differential attainment"). This could be due to examiner bias or to social, psychological or cultural influences on learning or performance. We investigated whether students' scores or feedback show influence of ethnicity-related bias; whether examiners unconsciously bring to mind (activate) stereotypes when judging Asian students' performance; whether activation depends on the stereotypicality of students' performances; and whether stereotypes influence examiner memories of performances. METHODS: This is a randomised, double-blinded, controlled, Internet-based trial. We created near-identical videos of medical student performances on a simulated Objective Structured Clinical Exam using British Asian and white British actors. Examiners were randomly assigned to watch performances from white and Asian students that were either consistent or inconsistent with a previously described stereotype of Asian students' performance. We compared the two examiner groups in terms of the following: the scores and feedback they gave white and Asian students; how much the Asian stereotype was activated in their minds (response times to Asian-stereotypical vs neutral words in a lexical decision task); and whether the stereotype influenced memories of student performances (recognition rates for real vs invented stereotype-consistent vs stereotype-inconsistent phrases from one of the videos). RESULTS: Examiners responded to Asian-stereotypical words (716 ms, 95% confidence interval (CI) 702-731 ms) faster than neutral words (769 ms, 95% CI 753-786 ms, p < 0.001), suggesting Asian stereotypes were activated (or at least active) in examiners' minds. This occurred regardless of whether examiners observed stereotype-consistent or stereotype-inconsistent performances. Despite this stereotype activation, student ethnicity had no influence on examiners' scores; on the feedback examiners gave; or on examiners' memories for one performance. CONCLUSIONS: Examiner bias does not appear to explain the differential attainment of Asian students in UK medical schools. Efforts to ensure equality should focus on social, psychological and cultural factors that may disadvantage learning or performance in Asian and other minority ethnic students.

Kikuchi- Fujimoto disease of mesenteric lymph nodes mimicking acute appendicitis.

Kikuchi-Fujimoto disease, or histiocytic necrotising lymphadenopathy of unknown aetiology, is a rare, benign and self-limiting cause of lymphadenopathy often involving the cervical nodes, and rarely presenting with mesenteric lymphadenopathy. We present a 26-year-old Caucasian male, who presented with right iliac fossa pain and low grade pyrexia, mimicking acute appendicitis. He underwent a laparatomy and an extended right hemi-colectomy for a caecal mass. Histology of the specimen showed lymph nodes with extensive areas of necrosis, with abnormal architecture suggesting Kikuchi-Fujimoto lymphadenopathy. This was further confirmed by immunohistochemistry. In this context maintenance of a high index of suspicion of this condition can avoid major surgical interventions. We describe the management of our case of Kikuchi-Fujimoto's disease involving the mesenteric nodes and provide an up to date review of the pertinent literature on this subject.

Post-mortem imaging as an alternative to autopsy in the diagnosis of adult deaths: a validation study.

BACKGROUND: Public objection to autopsy has led to a search for minimally invasive alternatives. Imaging has potential, but its accuracy is unknown. We aimed to identify the accuracy of post-mortem CT and MRI compared with full autopsy in a large series of adult deaths. METHODS: This study was undertaken at two UK centres in Manchester and Oxford between April, 2006, and November, 2008. We used whole-body CT and MRI followed by full autopsy to investigate a series of adult deaths that were reported to the coroner. CT and MRI scans were reported independently, each by two radiologists who were masked to the autopsy findings. All four radiologists then produced a consensus report based on both techniques, recorded their confidence in cause of death, and identified whether autopsy was needed. FINDINGS: We assessed 182 unselected cases. The major discrepancy rate between cause of death identified by radiology and autopsy was 32% (95% CI 26-40) for CT, 43% (36-50) for MRI, and 30% (24-37) for the consensus radiology report; 10% (3-17) lower for CT than for MRI. Radiologists indicated that autopsy was not needed in 62 (34%; 95% CI 28-41) of 182 cases for CT reports, 76 (42%; 35-49) of 182 cases for MRI reports, and 88 (48%; 41-56) of 182 cases for consensus reports. Of these cases, the major discrepancy rate compared with autopsy was 16% (95% CI 9-27), 21% (13-32), and 16% (10-25), respectively, which is significantly lower (p<0·0001) than for cases with no definite cause of death. The most common imaging errors in identification of cause of death were ischaemic heart disease (n=27), pulmonary embolism (11), pneumonia (13), and intra-abdominal lesions (16). INTERPRETATION: We found that, compared with traditional autopsy, CT was a more accurate imaging technique than MRI for providing a cause of death. The error rate when radiologists provided a confident cause of death was similar to that for clinical death certificates, and could therefore be acceptable for medicolegal purposes. However, common causes of sudden death are frequently missed on CT and MRI, and, unless these weaknesses are addressed, systematic errors in mortality statistics would result if imaging were to replace conventional autopsy. FUNDING: Policy Research Programme, Department of Health, UK.

Mortality from pulmonary embolism is decreasing in hospital patients.

OBJECTIVES: Pulmonary embolism is believed to be a common cause of death of hospital inpatients. The aims of this study were to estimate the number of deaths caused by pulmonary embolism and the potential to reduce this by the use of caval filters according to accepted indications. DESIGN: Review of autopsy reports and death notification records from 2007 and 2008. When pulmonary embolism was given as cause of death (in the autopsy report or in section 1 a-c or part 2 of the Medical Certificate of the Cause of Death), hospital records were reviewed for evidence of pre-mortem diagnosis of pulmonary embolism or deep vein thrombosis (DVT) and for evidence of accepted indications for caval filter placement. SETTING: Large UK teaching hospital. PARTICIPANTS: Hospital inpatients whose deaths were attributed to pulmonary embolism. MAIN OUTCOME MEASURES: Proportion of deaths adjudged at autopsy to be due to pulmonary embolism; evidence of pre-mortem diagnosis of DVT or pulmonary embolism; total number of hospital admission and deaths. RESULTS: From a total of 186,517 adult inpatient admissions there were 2583 (1.4%) adult inpatient deaths of which 696 (27%) underwent autopsy. Of those undergoing autopsy, 14 (2.0%, 95% CI 1.2-3.3%) deaths were caused by pulmonary embolism. Pulmonary embolism was recorded as a cause of death in a further 12 (0.7%) of 1773 patients who did not undergo autopsy. Of these, five had a pre-mortem diagnosis of DVT or pulmonary embolism. CONCLUSIONS: The proportion of deaths caused by pulmonary embolism appears to be considerably lower than the widely published rate, and of this small number, few have a pre-mortem diagnosis of DVT or pulmonary embolism. There is little scope for further reduction of pulmonary embolism mortality through use of caval filters according to guidelines. Current policy on pulmonary embolism risk prevention appears to be based on an over-estimate of the level of risk.

Viral detection in hydrops fetalis, spontaneous abortion, and unexplained fetal death in utero.

This study was undertaken to investigate the occurrence of viral infection in fetal death by examining tissues for the presence of DNA of several viral agents. Tissue specimens including heart, kidney, liver, lung, and placenta of 73 cases of fetal death were examined with 27 cases of elective termination of pregnancy as a control group. DNA extracted from these samples was tested for the presence of HSV, CMV, EBV, VZV, HHV-6, HHV-7, and PVB19. Viral DNA was found in one or more tissue samples from 25/73 cases (34%): CMV in 20, HSV in 5, parvovirus B19 in 5, HHV-7 in 3, and HHV-6 in 2. The presence of HHV-6 in fetal tissue has been reported rarely. No study so far has reported the detection of HHV-7 in fetal tissues with normal or adverse outcomes. Viral DNA was not found in any of the termination of pregnancy samples. Among the positive cases, eight had dual infection. One further case was positive for three viruses: HSV, CMV, and HHV-7. HHV-6 was the sole infectious agent in two cases, HHV-7 in one case, PVB19 in three, and CMV in ten cases. The finding of multiple viral DNA in 12% of the cases suggests the involvement of complex risk factors in cases of fetal loss. Although the cause of fetal death often includes other factors (e.g., chromosomal abnormalities) these data suggest the incidence of viral infective etiology may be higher than considered previously. However, larger studies are required to establish this link.

Cystic adventitial disease of the femoral vein presenting as deep vein thrombosis: a case report and review of the literature.

Cystic adventitial disease of veins is a rare condition. We report the case of a 28-year-old man who presented with a swollen leg secondary to obstruction of the common femoral vein as a result of this disease. He underwent excision of the cyst and made a full recovery. The presentation, investigation, treatment and pathology of this condition is discussed.