Demographic bias in misdiagnosis by computational pathology models.

Despite increasing numbers of regulatory approvals, deep learning-based computational pathology systems often overlook the impact of demographic factors on performance, potentially leading to biases. This concern is all the more important as computational pathology has leveraged large public datasets that underrepresent certain demographic groups. Using publicly available data from The Cancer Genome Atlas and the EBRAINS brain tumor atlas, as well as internal patient data, we show that whole-slide image classification models display marked performance disparities across different demographic groups when used to subtype breast and lung carcinomas and to predict IDH1 mutations in gliomas. For example, when using common modeling approaches, we observed performance gaps (in area under the receiver operating characteristic curve) between white and Black patients of 3.0% for breast cancer subtyping, 10.9% for lung cancer subtyping and 16.0% for IDH1 mutation prediction in gliomas. We found that richer feature representations obtained from self-supervised vision foundation models reduce performance variations between groups. These representations provide improvements upon weaker models even when those weaker models are combined with state-of-the-art bias mitigation strategies and modeling choices. Nevertheless, self-supervised vision foundation models do not fully eliminate these discrepancies, highlighting the continuing need for bias mitigation efforts in computational pathology. Finally, we demonstrate that our results extend to other demographic factors beyond patient race. Given these findings, we encourage regulatory and policy agencies to integrate demographic-stratified evaluation into their assessment guidelines.

Slideflow: deep learning for digital histopathology with real-time whole-slide visualization.

Deep learning methods have emerged as powerful tools for analyzing histopathological images, but current methods are often specialized for specific domains and software environments, and few open-source options exist for deploying models in an interactive interface. Experimenting with different deep learning approaches typically requires switching software libraries and reprocessing data, reducing the feasibility and practicality of experimenting with new architectures. We developed a flexible deep learning library for histopathology called Slideflow, a package which supports a broad array of deep learning methods for digital pathology and includes a fast whole-slide interface for deploying trained models. Slideflow includes unique tools for whole-slide image data processing, efficient stain normalization and augmentation, weakly-supervised whole-slide classification, uncertainty quantification, feature generation, feature space analysis, and explainability. Whole-slide image processing is highly optimized, enabling whole-slide tile extraction at 40x magnification in 2.5 s per slide. The framework-agnostic data processing pipeline enables rapid experimentation with new methods built with either Tensorflow or PyTorch, and the graphical user interface supports real-time visualization of slides, predictions, heatmaps, and feature space characteristics on a variety of hardware devices, including ARM-based devices such as the Raspberry Pi.

Comparing scientific abstracts generated by ChatGPT to real abstracts with detectors and blinded human reviewers.

Large language models such as ChatGPT can produce increasingly realistic text, with unknown information on the accuracy and integrity of using these models in scientific writing. We gathered fifth research abstracts from five high-impact factor medical journals and asked ChatGPT to generate research abstracts based on their titles and journals. Most generated abstracts were detected using an AI output detector, 'GPT-2 Output Detector', with % 'fake' scores (higher meaning more likely to be generated) of median [interquartile range] of 99.98% 'fake' [12.73%, 99.98%] compared with median 0.02% [IQR 0.02%, 0.09%] for the original abstracts. The AUROC of the AI output detector was 0.94. Generated abstracts scored lower than original abstracts when run through a plagiarism detector website and iThenticate (higher scores meaning more matching text found). When given a mixture of original and general abstracts, blinded human reviewers correctly identified 68% of generated abstracts as being generated by ChatGPT, but incorrectly identified 14% of original abstracts as being generated. Reviewers indicated that it was surprisingly difficult to differentiate between the two, though abstracts they suspected were generated were vaguer and more formulaic. ChatGPT writes believable scientific abstracts, though with completely generated data. Depending on publisher-specific guidelines, AI output detectors may serve as an editorial tool to help maintain scientific standards. The boundaries of ethical and acceptable use of large language models to help scientific writing are still being discussed, and different journals and conferences are adopting varying policies.

Fifteen-minute consultation: Recognition and management of eating disorders presenting to the emergency department.

Eating disorder presentations in children and young people during the COVID-19 pandemic have increased, and this has become a common presentation to paediatric emergency departments (EDs). We cover a structured approach on identifying and managing these presentations within the ED including history taking, what to look for on examination, what investigations are needed and how to decide who requires admission to hospital.

Diagnostic and Management Considerations for the IPAA With Crohn's Disease-Like Features.

BACKGROUND: Patients with ulcerative colitis often develop medically refractory colonic inflammation or colorectal neoplasia, and approximately 10% to 15% of patients require surgery. The most common surgical procedure is a restorative proctocolectomy with IPAA. Even if the preoperative diagnosis is ulcerative colitis, approximately 10% of patients can develop inflammatory pouch conditions resembling a Crohn's disease phenotype. OBJECTIVE: This study aimed to review the diagnostic approach, prognosis, and management of IPAA with Crohn's disease-like features. DATA SOURCES: The data sources include search in electronic databases. STUDY SELECTION: This narrative review included studies focusing on pouches with Crohn's disease-like features. MAIN OUTCOME MEASURES: The main topics in this review included the pathogenesis, risk factors, diagnosis, phenotypes, prognosis, and medications of pouches with Crohn's disease-like features. RESULTS: A diagnostic approach for the pouch conditions resembling a Crohn's disease phenotype should be based on history-taking to evaluate its risk factors and endoscopic assessment of the pouch. Prior disease history and pathology, location of pouch complications, and timing of complications offer clues for the differential diagnosis of this phenotype. We advocate for the more descriptive term "pouch with Crohn's disease-like features" and reserve the term "Crohn's disease of the pouch" for patients who undergo IPAA and have a precolectomy diagnosis of Crohn's disease or whose colectomy pathology revealed Crohn's disease. Medications, which are often used for traditional Crohn's disease, show efficacy in pouches with Crohn's disease-like features as well. The poor prognosis associated with pouches with Crohn's disease-like features, particularly the fistulizing phenotype, underscores the importance of proactive monitoring and therapeutic intervention. LIMITATIONS: The limitations include no explicit criteria for article selection. CONCLUSIONS: This review suggests future research should seek to understand the natural history and meaningful shorter and longer term therapeutic targets for these types of pouch phenotypes. Long-term follow-up and prospective preoperative and postoperative interventional trials of treatments and prevention strategies are needed.

IL-23 Monoclonal Antibodies for IBD: So Many, So Different?

Interleukin [IL]-23 is a member of the IL-12 family of cytokines and has been implicated in multiple inflammatory disorders including psoriasis, psoriatic arthritis, and the inflammatory bowel diseases [IBDs]. Blockade of both IL-12 and IL-23 using an antibody that targets a shared subunit is highly effective in treating psoriasis, and recent data suggest similar efficacy in IBD with minimal adverse events. In this review, we summarise published data on the efficacy of anti-IL-12/23 therapies in IBD as well as emerging data on more selective anti-IL-23 specific therapies. Last, we discuss novel therapeutics under development which target the IL-23 pathway in unique ways and suggest that a biomarker-driven approach will soon guide clinicians to prescribe anti-IL-23 therapies to the patients most likely to respond to them.

Factors Associated With Fecal Calprotectin Sample Collection Compliance: An IBD Center Quality Improvement Project.

Background: Fecal calprotectin (Fcal) is a noninvasive, inexpensive biomarker of disease activity. However, patient compliance with this test is variable and incompletely described. We assessed compliance rates with Fcal tests and identified factors associated with noncompliance. Methods: A retrospective chart review of patients with inflammatory bowel disease (IBD) who had a Fcal test ordered through our center between August 2021 and December 2021 was conducted. Demographic, clinical, disease, and test-related information were recorded. Patients with incomplete Fcal orders were sent a survey to better understand their reasons for noncompliance. Simple statistical analysis and and multivariable logistic regression modeling were performed. Results: Of 303 patients, 165 (54.4%) had an order for Fcal. Of the Fcal tests ordered, 55 (33.3%) were not completed. Remission of IBD, no prior Fcal completion, and tests ordered at a distant site were all associated with test noncompletion. A multivariable logistic regression revealed that history of a prior completed Fcal test is associated with subsequent test completion (odds ratio = 2.1, 95% confidence interval 1.9-35.5, P = .004). Patients who did not complete the test described the pandemic and third-party testing center issues as the most common reasons for noncompliance. Conclusions: In this single center experience with Fcal testing in patients with IBD, we identified that a history of incomplete Fcal testing and distant location of lab testing were significantly associated with noncompletion of the test. We provide practical guidance for future utilization and compliance, including the impact of home-based testing.

FmhA and FmhC of Staphylococcus aureus incorporate serine residues into peptidoglycan cross-bridges.

Staphylococcal peptidoglycan is characterized by pentaglycine cross-bridges that are cross-linked between adjacent wall peptides by penicillin-binding proteins to confer robustness and flexibility. In Staphylococcus aureus, pentaglycine cross-bridges are synthesized by three proteins: FemX adds the first glycine, and the homodimers FemA and FemB sequentially add two Gly-Gly dipeptides. Occasionally, serine residues are also incorporated into the cross-bridges by enzymes that have heretofore not been identified. Here, we show that the FemA/FemB homologues FmhA and FmhC pair with FemA and FemB to incorporate Gly-Ser dipeptides into cross-bridges and to confer resistance to lysostaphin, a secreted bacteriocin that cleaves the pentaglycine cross-bridge. FmhA incorporates serine residues at positions 3 and 5 of the cross-bridge. In contrast, FmhC incorporates a single serine at position 5. Serine incorporation also lowers resistance toward oxacillin, an antibiotic that targets penicillin-binding proteins, in both methicillin-sensitive and methicillin-resistant strains of S. aureus FmhC is encoded by a gene immediately adjacent to lytN, which specifies a hydrolase that cleaves the bond between the fifth glycine of cross-bridges and the alanine of the adjacent stem peptide. In this manner, LytN facilitates the separation of daughter cells. Cell wall damage induced upon lytN overexpression can be alleviated by overexpression of fmhC. Together, these observations suggest that FmhA and FmhC generate peptidoglycan cross-bridges with unique serine patterns that provide protection from endogenous murein hydrolases governing cell division and from bacteriocins produced by microbial competitors.

Donor hearts in the Sydney Heart Bank: reliable control but is it 'normal' heart?

Human heart samples from the Sydney Heart Bank have become a de facto standard against which others can be measured. Crucially, the heart bank contains a lot of donor heart material: for most researchers this is the hardest to obtain and yet is necessary since we can only study the pathological human heart in comparison with a control, preferably a normal heart sample. It is not generally realised how important the control is for human heart studies. We review our studies on donor heart samples. We report the results obtained with 17 different donor samples collected from 1994 to 2011 and measured from 2005 to 2015 by our standard methodology for in vitro motility and troponin I phosphorylation measurements. The donor heart sample parameters are consistent between the hearts, over time and with different operators indicating that Sydney Heart Bank donor hearts are a valid baseline control for comparison with pathological heart samples. We also discuss to what extent donor heart samples are representative of the normal heart.

How to interpret urine toxicology tests.

A 13-year-old girl presents to the emergency department for the second time with an unresponsive episode. She has a GCS (Glasgow Coma Scale) score of 11 on arrival and all other observations are normal. The story is unclear, but there are ongoing safeguarding concerns and the family are known to social services. All investigations are normal. After a period of observation on the ward, her GCS returns to normal and she appears well. Both on the first presentation and this presentation ingestion of a toxin was suspected. However, this was denied by the patient and urine toxicology screen was negative. Does this rule out toxin ingestion? Will this change your management?

How to use C-reactive protein.

A 3-month-old baby is brought to the paediatric emergency department by their parents because of a fever. You decide to check their inflammatory markers. Their C-reactive protein (CRP) level comes back as 20 mg/L. Does this affect whether or not you start antibiotic therapy? Does it influence your decision to admit or discharge the patient? CRP is a commonly used biochemical test and yet its use is constantly debated and challenged. We look at the current evidence and suggest the best way to use this test in clinical practice.

Problem-solving in clinical practice: a baby who won't stop bleeding.

Spontaneous bleeding in the neonatal period is an unusual presentation, and yet one that can pose a challenge of both diagnosis and management to the general paediatrician. This case chronicles the diagnostic journey of an 8-day-old baby who presented with unrelenting bleeding from the umbilical cord and explores the clinical approach to bleeding in a neonate.

Fifteen-minute consultation: Monogenic forms of diabetes with onset after age 6 months.

Monogenic forms of diabetes (historically known as Maturity Onset Diabetes of the Young (MODY)) are caused by single gene mutations inherited in an autosomal dominant fashion that result in reduced pancreatic beta cell function. Children with these forms of diabetes may be misdiagnosed as having type 1 or 2 diabetes, which has important implications for treatment, genetic counselling, screening of family members and prognosis. Useful tools now exist to aid in their diagnosis and management. Here, we attempt to outline the clinical features that will help the physician make the differentiation from other diabetes subtypes.

How to interpret mast cell tests.

Mast cell tryptase (tryptase) is an enzyme produced almost exclusively by mast cells that is easy to measure using a widely available test. In this article we discuss the physiology of the mast cell and how that relates to IgE-mediated anaphylaxis and mastocytosis. We also describe the technical aspects of testing tryptase and the reported normal ranges in health. Finally we explore the diagnostic performance of serum mast cell tryptase measurements, when used to confirm anaphylaxis, estimate future anaphylaxis risk and in diagnosing/monitoring leukaemia.

How to interpret malaria tests.

There are over 300 new cases of imported paediatric malaria in the UK each year and this has been increasing over the last 20 years. Malaria in children is particularly difficult to diagnose because the initial presenting features are subtler than in adults and do not display the classical presenting features. However, they are also more likely to deteriorate rapidly and to develop severe malaria. The 'gold standard' for ruling out the diagnosis of malaria if clinically suspected is three negative thin and thick blood films, which require serial phlebotomy and the availability of trained technicians. There are now a range of other tests, including rapid diagnostic tests and PCR, as well as clinical features that make the diagnosis more or less likely. We explore the different tests available and whether these might replace the three negative blood films currently needed. We also look at whether we are able to use clinical features to aid the tests used for a diagnosis of imported malaria.

Molecular mechanism of the E99K mutation in cardiac actin (ACTC Gene) that causes apical hypertrophy in man and mouse.

We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca(2+) sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca(2+) sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to ß-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca(2+) sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.

Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome.

AIMS: The vascular type of Ehlers-Danlos syndrome (EDS IV) is an autosomal-dominant disorder characterized by thin translucent skin and extensive bruising. Patients with EDS IV have reduced life expectancy (median 45-50 years) due to spontaneous rupture of arteries (particularly large arteries) or bowel. EDS IV results from mutation of the COL3A1 gene, which encodes the pro-α(1) chains of type III collagen that is secreted into the extracellular matrix, e.g. by smooth muscle cells. A mouse model of EDS IV produced by targeted ablation of Col3a1 has been of limited use as only 10% of homozygous animals survive to adulthood, whereas heterozygous animals do not die from arterial rupture. We report a novel, exploitable model of EDS IV in a spontaneously generated mouse line. METHODS AND RESULTS: Mice were identified by predisposition to sudden, unexpected death from dissection of the thoracic aorta. Aortic dissection inheritance was autosomal-dominant, presented at an early age (median, 6 weeks) with incomplete penetrance, and had a similar sex ratio bias as EDS IV (2:1, male:female). Molecular genetic analysis demonstrated that the causal mutation is a spontaneous 185 kb deletion, including the promoter region and exons 1-39, of the Col3a1 gene. As in EDS IV, aortic dissection was not associated with elevated blood pressure, aneurysm formation, or infection, but may result from aberrant collagen fibrillogenesis within the aortic wall. CONCLUSION: This novel, exploitable mouse line that faithfully models the vascular aspects of human EDS IV provides an important new tool for advancing understanding of EDS IV and of aortic dissection in general.

Investigation of a transgenic mouse model of familial dilated cardiomyopathy.

We have investigated a transgenic mouse model of inherited dilated cardiomyopathy that stably expresses the ACTC E361G mutation at around 50% of total actin in the heart. F-actin isolated from ACTC E361G mouse hearts was incorporated into thin filaments with native human tropomyosin and troponin and compared with NTG mouse actin by in vitro motility assay. There was no significant difference in sliding speed, fraction of filaments motile or Ca(2+)-sensitivity (ratio EC(50) E361G/NTG=0.95+/-0.08). The Ca(2+)-sensitivity of force in skinned trabeculae from ACTC E361G mice was slightly higher than NTG (EC(50) E361G/NTG=0.78+/-0.04). The molecular phenotype was revealed when troponin was dephosphorylated; Ca(2+)-sensitivity of E361G-containing thin filaments was now lower than NTG (EC(50) E361G(dPTn)/NTG(dPTn)=2.15+/-0.09). We demonstrated that this was due to uncoupling of Ca(2+)-sensitivity from troponin I phosphorylation by comparing Ca(2+)-sensitivity of phosphorylated and dephosphorylated thin filaments. For NTG actin-containing thin filaments EC(50) native/dPTn=3.0+/-0.3 but for E361G-containing thin filaments EC(50) native/dPTn=1.04+/-0.07.We studied contractility in isolated myocytes and found no significant differences under basal conditions. We measured cardiac performance by cine-MRI, echocardiography and with a conductance catheter over a period of 4 to 18 months and found minimal systematic differences between NTG and ACTC E361G mice under basal conditions. However, the increase in septal thickening, ejection fraction, heart rate and cardiac output following dobutamine treatment was significantly less in ACTC E361G mice compared with NTG. We propose that the ACTC E361G mutation uncouples myofilament Ca(2+)-sensitivity from Troponin I phosphorylation and blunts the response to adrenergic stimulation, leading to a reduced cardiac reserve with consequent contractile dysfunction under stress, leading to dilated cardiomyopathy.

Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.

BACKGROUND: Familial dilated cardiomyopathy can be caused by mutations in the proteins of the muscle thin filament. In vitro, these mutations decrease Ca(2+) sensitivity and cross-bridge turnover rate, but the mutations have not been investigated in human tissue. We studied the Ca(2+)-regulatory properties of myocytes and troponin extracted from the explanted heart of a patient with inherited dilated cardiomyopathy due to the cTnC G159D mutation. METHODS AND RESULTS: Mass spectroscopy showed that the mutant cTnC was expressed approximately equimolar with wild-type cTnC. Contraction was compared in skinned ventricular myocytes from the cTnC G159D patient and nonfailing donor heart. Maximal Ca(2+)-activated force was similar in cTnC G159D and donor myocytes, but the Ca(2+) sensitivity of cTnC G159D myocytes was higher (EC(50) G159D/donor=0.60). Thin filaments reconstituted with skeletal muscle actin and human cardiac tropomyosin and troponin were studied by in vitro motility assay. Thin filaments containing the mutation had a higher Ca(2+) sensitivity (EC(50) G159D/donor=0.55 + or - 0.13), whereas the maximally activated sliding speed was unaltered. In addition, the cTnC G159D mutation blunted the change in Ca(2+) sensitivity when TnI was dephosphorylated. With wild-type troponin, Ca(2+) sensitivity was increased (EC(50) P/unP=4.7 + or - 1.9) but not with cTnC G159D troponin (EC(50) P/unP=1.2 + or - 0.1). CONCLUSIONS: We propose that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity could be the cause of the dilated cardiomyopathy phenotype. The differences between these data and previous in vitro results show that native phosphorylation of troponin I and troponin T and other posttranslational modifications of sarcomeric proteins strongly influence the functional effects of a mutation.