Diagnostic Challenge Research Articles

Acute pancreatitis as a manifestation of multisystem inflammatory syndrome among children (MIS-C): A rare case

A multisystem inflammatory syndrome among children (MIS-C) has been linked to COVID-19, and it affects multiple organ systems in the body, including the gastrointestinal system. In present case report, a 14-year-old girl presented with clinico-laboratory and imaging evidence of acute pancreatitis but did not respond to the standard line of management for pancreatitis. Later, the laboratory investigations pointed to the diagnosis of MIS-C. She responded well to a pulse doses of methylprednisolone therapy. Acute pancreatitis as a lone manifestation of MIS-C poses a diagnostic challenge for paediatricians, and one should suspect MIS-C in acute non-responding pancreatitis.

Motor polyradiculoneuropathy as an unusual presentation of neurobrucellosis: a case report and literature review

Brucellosis, a zoonotic disease caused by Brucella species, poses a significant global health concern. Among its diverse clinical manifestations, neurobrucellosis remains an infrequent yet debilitating complication. Here, we present a rare case of neurobrucellosis with unusual presentations in a 45-year-old woman. The patient’s clinical course included progressive lower extremity weakness, muscle wasting, and double vision, prompting a comprehensive diagnostic evaluation. Notable findings included polyneuropathy, elevated brucella agglutination titers in both cerebrospinal fluid and blood, abnormal EMG-NCV tests, and resolving symptoms with antibiotic therapy. The clinical presentation, diagnostic challenges, and differentiation from other neurological conditions are discussed. This case underscores the importance of considering neurobrucellosis in regions where brucellosis is prevalent and highlights this rare neurological complication’s distinctive clinical and radiological features. Early recognition and appropriate treatment are crucial to mitigate the significant morbidity associated with neurobrucellosis.

Approach to the Atypical Wound.

The heterogeneity of atypical wounds can present diagnostic and therapeutic challenges; however, as the prevalence of atypical wounds grows worldwide, prompt and accurate management is increasingly an essential skill for dermatologists. Addressing the underlying cause of an atypical wound is critical for successful outcomes. An integrated approach with a focus on pain management and patient engagement is recommended to facilitate enduring wound closure. Advances in treatment, in addition to further research and clinical training, are necessary to address the expanding burden of atypical wounds.

Metabolic dysfunction-associated steatotic liver disease: Navigating terminological evolution, diagnostic frontiers and therapeutic horizon-an editorial exploration

Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes. The redefinition of NAFLD in 2023 marked a significant reposition in terminology, emphasizing a broader understanding of liver steatosis and its associated risks. MASLD is now recognized as a major risk factor for liver cirrhosis, hepatocellular carcinoma, and systemic complications such as cardiovascular diseases or systemic inflammation. Diagnostic challenges arise, particularly in identifying MASLD in lean individuals, necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools. Therapeutically, there is an urgent need for effective treatments targeting MASLD, with emerging pharmacological options focusing on, among others, carbohydrate and lipid metabolism. Additionally, understanding the roles of bile acid metabolism, the microbiome, and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches. There is a strong need to emphasize the importance of collaborative efforts in understanding, diagnosing, and managing MASLD to improve physicians’ approaches and patient outcomes.

Diagnostic challenges in bilateral thalamic infarction: national series of cases

Diagnostic challenges in bilateral thalamic infarction: national series of cases

Diagnostic Biomarkers in Renal Cell Tumors According to the Latest WHO Classification: A Focus on Selected New Entities

The fifth edition of the World Health Organization (WHO) classification for urogenital tumors, released in 2022, introduces some novelties in the chapter on renal epithelial tumors compared to the previous 2016 classification. Significant changes include the recognition of new disease entities and adjustments in the nomenclature for certain pathologies. Notably, each tumor entity now includes minimum essential and desirable criteria for reliable diagnosis. This classification highlights the importance of biological and molecular characterization alongside traditional cytological and architectural features. In this view, immunophenotyping through immunohistochemistry (IHC) plays a crucial role in bridging morphology and genetics. This article aims to present and discuss the role of key immunohistochemical markers that support the diagnosis of new entities recognized in the WHO classification, focusing on critical topics associated with single markers, in the context of specific tumors, such as the clear cell capillary renal cell tumor (CCPRCT), eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), and so-called “other oncocytic tumors”, namely the eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT). Their distinctive characteristics and immunophenotypic profiles, along with insights regarding diagnostic challenges and the differential diagnosis of these tumors, are provided. This state-of-the-art review offers valuable insights in biomarkers associated with novel renal tumors, as well as a tool to implement diagnostic strategies in routine practice.

Integrated single-cell and bulk RNA-Seq analysis enhances prognostic accuracy of PD-1/PD-L1 immunotherapy response in lung adenocarcinoma through necroptotic anoikis gene signatures

In addition to presenting significant diagnostic and treatment challenges, lung adenocarcinoma (LUAD) is the most common form of lung cancer. Using scRNA-Seq and bulk RNA-Seq data, we identify three genes referred to as HMR, FAM83A, and KRT6A these genes are related to necroptotic anoikis-related gene expression. Initial validation, conducted on the GSE50081 dataset, demonstrated the model's ability to categorize LUAD patients into high-risk and low-risk groups with significant survival differences. This model was further applied to predict responses to PD-1/PD-L1 blockade therapies, utilizing the IMvigor210 and GSE78220 cohorts, and showed strong correlation with patient outcomes, highlighting its potential in personalized immunotherapy. Further, LUAD cell lines were analyzed using quantitative PCR (qPCR) and Western blot analysis to confirm their expression levels, further corroborating the model's relevance in LUAD pathophysiology. The mutation landscape of these genes was also explored, revealing their broad implication in various cancer types through a pan-cancer analysis. The study also delved into molecular subclustering, revealing distinct expression profiles and associations with different survival outcomes, emphasizing the model’s utility in precision oncology. Moreover, the diversity of immune cell infiltration, analyzed in relation to the necroptotic anoikis signature, suggested significant implications for immune evasion mechanisms in LUAD. While the findings present a promising stride towards personalized LUAD treatment, especially in immunotherapy, limitations such as the retrospective nature of the datasets and the need for larger sample sizes are acknowledged. Prospective clinical trials and further experimental research are essential to validate these findings and enhance the clinical applicability of our prognostic model.

Unraveling TAFRO Syndrome: An In-Depth Look at the Pathophysiology, Management, and Future Perspectives

TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman’s disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman’s disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

Diagnostic Challenges of Lyme Co-infections: Lessons From a Lyme and Herpes Simplex Virus-1 (HSV-1) Cocktail

Diagnostic Challenges of Lyme Co-infections: Lessons From a Lyme and Herpes Simplex Virus-1 (HSV-1) Cocktail

The significance of precise diabetes diagnosis: a case of euglycemic diabetic ketoacidosis induced by the introduction of empagliflozin with simultaneous reduction of insulin dosage

Euglycemic diabetic ketoacidosis (euDKA) is a rare but severe metabolic complication of diabetes mellitus characterised by elevated anion gap metabolic acidosis despite normal or mildly elevated blood glucose levels. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as effective antidiabetic medications, yet their use is associated with an increased risk of euDKA, especially when coupled with insulin dose reduction. We present the case of a 50-year-old male with a 20-year history of diabetes mellitus, initially managed with insulin and metformin, who developed euDKA following the introduction of empagliflozin and sitagliptin alongside a reduction in insulin therapy. Despite normoglycaemia the patient exhibited symptoms of ketoacidosis, including chronic fatigue, polydipsia, and polyuria. Diagnostic workup revealed metabolic acidosis, elevated inflammatory markers, acute kidney injury and ketonuria. Subsequent specialised laboratory tests confirmed type 1 diabetes mellitus (T1DM) with the presence of anti-glutamic acid decarboxylase (anti-GAD) antibodies and the absence of C-peptide secretion. Management involved fluid therapy, intravenous insulin and glucose administration. This case underscores the diagnostic challenges of euDKA and emphasises the importance of differentiating between T1DM and T2DM, as management strategies vary significantly. Patient education on insulin therapy and injection techniques is crucial to prevent complications such as improper insulin delivery and dose reduction, which can precipitate euDKA. In conclusion, clinicians should be vigilant for euDKA in patients on SGLT2 inhibitors, particularly when insulin dose reduction is involved. Comprehensive patient education and accurate differentiation between diabetes types are essential for timely diagnosis and optimal management, thereby reducing the risk of severe complications.

Overcoming Diagnostic Challenges: A Rare Presentation of Primary Hemophagocytic Lymphohistiocytosis (HLH) in a Young Female and the Importance of Timely Recognition

Overcoming Diagnostic Challenges: A Rare Presentation of Primary Hemophagocytic Lymphohistiocytosis (HLH) in a Young Female and the Importance of Timely Recognition

Genomic insights into inherited bone marrow failure syndromes in a Korean population.

Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next-generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field.

Introduction: A Practical Guide to Central Nervous System Malformations—From Genetics, to Diagnosis and Treatment

AbstractCentral nervous system (CNS) malformations encompass diverse congenital anomalies impacting brain and spinal cord development, profoundly affecting neurological function. They arise from disruptions in embryonic neural tube formation, neuronal migration, and cortical organization. This abstract provides a comprehensive overview of CNS malformations, covering classification, etiology, clinical manifestations, and diagnostic challenges. CNS malformations fall into distinct groups: neural tube defects (e.g., anencephaly, spina bifida), resulting from incomplete neural tube closure; malformations of cortical development (e.g., lissencephaly, polymicrogyria), featuring irregularities in cortical folding; and anomalies affecting structures like the corpus callosum, cerebellum, and CNS vasculature, alongside conditions such as hydrocephalus and Chiari malformations. Genetic factors, including mutations in LIS1, DCX, and RELN, contribute significantly, while environmental factors like maternal folic acid deficiency also play a role. Some malformations occur in genetic syndromes (e.g., tuberous sclerosis, neurofibromatosis). Clinical presentations vary, with neural tube defects typically presenting severe deficits at birth, while cortical malformations manifest as intellectual disabilities, seizures, and motor deficits. Hydrocephalus elevates intracranial pressure, and Chiari malformations cause headaches and neurological symptoms. Diagnosis necessitates a multidisciplinary approach involving clinical evaluation, neuroimaging, genetic testing, and histopathological analysis. Prenatal diagnosis via ultrasound and magnetic resonance imaging is crucial for planning interventions, while postnatal diagnosis relies on clinical and imaging findings.Understanding CNS malformations is vital for early detection, intervention, and comprehensive care provision. Advances in genetics and neuroimaging offer hope for improved outcomes and better quality of life for affected individuals.

Concurrent Craniosynostosis and Positional Plagiocephaly: A Scoping Review

Background: Craniosynostosis and positional plagiocephaly (PP) both lead to deformities of the infant skull. In some cases, patients may present with concurrent craniosynostosis and PP. The forces exerted on the skull by both conditions can complicate and delay correct diagnosis and require adjustments to surgical planning. Objective: The purpose of this scoping review was to identify and analyze the existing peer-reviewed literature covering the diagnosis and treatment of concurrent craniosynostosis and PP. Design: In accordance with PRISMA guidelines, PubMed, MEDLINE, and EMBASE were searched for articles discussing concurrent diagnoses of craniosynostosis and PP. Results: Out of 633 articles discovered, 7 met inclusion criteria and discussed a cumulative total of 10 patients. The average age of referral to a craniofacial team was 17 ± 22.2 months. The most common reason for referral was craniofacial asymmetry (90%, n = 9). 40% presented with unilateral coronal synostosis (n = 4), 40% with lambdoid synostosis (n = 4), 10% with sagittal synostosis (n = 1), and 10% with metopic synostosis (n = 1). The most commonly reported clinical features were occipital flattening (90%, n = 9), ear displacement (80%, n = 8), and frontal bossing (30%, n = 3). Delayed or incorrect initial diagnosis was noted in 70% (n = 7) of patients. CT scan was the most commonly employed diagnostic tool, utilized in 100% of patients. 70% of patients (n = 7) underwent surgery at an average age of 6.75 ± 3 months. Two studies, accounting for 2 patients reported, noted altering their surgical technique to account for PP in addition to the synostotic suture. Conclusions: Coincident craniosynostosis and PP can pose a complicated diagnostic and therapeutic challenge. An in-depth understanding of the most reliable physical exam findings associated with each type of craniosynostosis combined with PP will facilitate accurate diagnosis. Consideration of the concurrent forces on the skull created by craniosynostosis and PP aid in the design of a tailored surgical plan.

Glomangiopericytoma of the Nasal Sinus Mimicking Dacryocoele: A Case Report and Literature Review

Introduction: Glomangiopericytoma (GPC) of the nasal sinus is a rare mesenchymal tumor that can mimic various benign pathologies in this anatomical region. We report an unusual clinical case and describe the diagnostic and therapeutic challenges encountered. Case Presentation: A 62-year-old woman presented with swelling of the left inner eye angle, tearing, and ipsilateral nasal obstruction. Clinical examination and imaging initially suggested chronic dacryocystitis. A polypoid nasal sinus mass was detected on endoscopy and computed tomography. Complete excision was performed via endoscopic nasal sinus surgery. The histopathological analysis confirmed the definitive diagnosis of glomangiopericytoma. Discussion: Nasal sinus GPC is a rare tumor, typically benign, derived from perivascular cells. Its clinical presentation is nonspecific and can mimic more common pathologies. Diagnosis is based on imaging and histopathological analysis with immunohistochemistry. The treatment of choice is complete surgical excision, preferably via minimally invasive endoscopic approach. Long-term close monitoring is recommended due to the risk of local recurrence. Conclusion: This clinical case highlights the importance of considering glomangiopericytoma in the differential diagnosis of nasal sinus masses, even in cases of initial benign presentation. A multidisciplinary approach, involving imaging, surgery, and histopathological analysis, is essential for optimal management.

Multi-organ clinical ultrasound as a complement to the diagnostic process in an internal medicine consultation.

Evaluating outpatient cases in internal medicine consultations presents a significant diagnostic challenge. Ultrasound can be a highly useful tool in assessment and decision-making. A prospective observational study was conducted on a cohort of patients attending an internal medicine rapid assessment clinic. Eighty patients were prospectively recruited. A medical consultation was conducted as per usual clinical practice, followed by a POCUS evaluation; collecting pulmonary, cardiac, and abdominal data. All findings were analyzed and recorded, particularly those that were significant or altered the initial diagnosis, subsequent tests, or treatment. Significant ultrasound findings were found in 37.5% of the patients. Of all ultrasound scans, the most clinically relevant were in the heart region (31.9%), followed by the abdomen (26%). These findings led to a change in overall management in 27.5% of patients. Using logistic regression, a model was developed to estimate the presence of clinically relevant findings with an area under the curve (AUC) of 0.78 (95% CI 0.66-0.89; p < 0.001) with 80% Sensitivity and 66% Specificity. The systematic and standardized incorporation of clinical ultrasound in internal medicine consultations contributes to decision-making, can provide significant findings that allow for modifications in clinical suspicion and therapeutic management.

Towards XAI agnostic explainability to assess differential diagnosis for Meningitis diseases

Abstract Meningitis, characterized by meninges and cerebrospinal fluid (CSF) inflammation, poses diagnostic challenges due to diverse clinical manifestations. This work introduces an explainable AI automatic medical decision methodology that determines critical features and their relevant values for the differential diagnosis of various meningitis cases. We proceed with knowledge acquisition to define the rules for this research. Currently, we have established the etiological diagnosis of Meningococcaemia, Meningococcal Meningitis, Tuberculous Meningitis, Aseptic Meningitis, Haemophilus influenzae Meningitis, and Pneumococcal&amp;#xD;Meningitis. The data preprocessing was conducted after collecting data from samples with meningitis diseases at Setif Hospital in Algeria. Tree-based ensemble methods were then applied to assess the model’s performance. Finally, we implement an XAI agnostic explainability approach based on the SHapley Additive exPlanations technique to attribute each feature’s contribution to the model’s output. Experiments were conducted on the collected dataset and the SINAN database, obtained from the Brazilian Government’s Health Information System on Notifiable Diseases, which comprises 6729 patients aged over 18 years. The Extreme Gradient Boosting model was chosen for its superior performance metrics (Accuracy: 0.90, AUROC: 0.94, and F1-score: 0.98). Setif’s hospital data revealed notable performance metrics (Accuracy: 0.7143, F1-Score: 0.7857). This study's findings showcase each feature's contribution to the model’s predictions and diagnosis. It also reveals critical biomarker ranges associated with distinct types of Meningitis. Significant diagnostic effect was found for Meningococcal Meningitis with elevated neutrophil levels (&gt;40%) and balanced lymphocyte levels (40-60%). Tuberculous Meningitis demonstrated low neutrophil levels (&lt;60%) and elevated lymphocyte levels (&gt;60%). Haemophilus influenzae meningitis exhibited a predominance of neutrophils (&gt;80%), while Aseptic meningitis showed lower neutrophil levels (&lt;40%) and lymphocyte levels within the range of 50-60%. The majority of the AI automatic medical decision results are twinned with validation by our team of infectious disease experts, confirming the alignment of algorithmic diagnoses with clinical practices.

Development and Validation of the Bone Tumor Surgery Complexity Score

Bone tumors often manifest with non-specific symptoms such as pain and swelling, often posing diagnostic challenges. Optimal treatment requires centralized care in specialized centers, emphasizing the need for complete tumor removal and interdisciplinary collaboration. We developed the Bone Tumor Surgery Complexity Score (BT-SCS) based on a retrospective study of 501 patients. The BT-SCS, structured around patient demographics, tumor biology, and surgical parameters, categorizes surgical cases into four groups to comprehensively assess complexity. Application of the BT-SCS resulted in scores ranging from 3 to 33, with an average score of 14 ± 7.2. Patients with malignant tumors had higher scores (19.6 ± 5.2) compared to those with benign (10.0 ± 3.8) or intermediate malignant tumors (14.6 ± 7.1). Patients with pelvic tumors registered the highest scores (16.0), followed by extremities/trunk (14.3) and spinal tumors (13.6). The BT-SCS was validated against the Case Mix Index (CMI), using an independent cohort of bone and soft tissue cases. This validation process, utilizing Loess smoothing, illustrated the BT-SCS’s granular differentiation of surgical complexity, particularly in the lower-to-mid-range of case severities. The BT-SCS represents a significant shift from volume-based to complexity-based assessments in surgical care, aligning with evolving healthcare paradigms. It serves as a tool for strategic patient allocation to treatment centers, aiming to improve outcomes and benchmarking in sarcoma care. The score’s development and application in clinical practice align with the focus on patient-centered and value-based healthcare. Future enhancements, including machine learning integration and outcome data, will refine its categorization process, enhancing clinical utility.

Multiple sarcomatoid carcinomas in the small intestine with perforation: A case report and literature review.

Sarcomatoid carcinoma of the small intestine is an exceedingly rare and aggressive malignancy, often diagnosed at advanced stages with a poor prognosis. This study documents a detailed case of sarcomatoid carcinoma of the small intestine, highlighting the diagnostic challenges and treatment approaches, underscored by a comprehensive review of related literature. Given the rarity of this condition, our report aims to enrich the existing diagnostic and treatment frameworks for this malignancy, emphasizing the necessity for early detection and intervention strategies. By presenting this case in conjunction with a literature review, we seek to shed light on the elusive nature of sarcomatoid carcinoma in the small intestine and propose avenues for improving patient outcomes. Case presentation A 61-year-old male patient initially presented with recurrent abdominal pain and gastrointestinal symptoms. Initial abdominal computed tomography (CT) scans and gastrointestinal endoscopy revealed only inflammatory and hyperplastic changes in the duodenum and jejunum, with a diagnosis of intestinal obstruction. Two years later, due to gastrointestinal perforation, the patient was hospitalized again. CT scans and other examinations revealed small intestinal lesions. Four small intestinal lesions were surgically removed, and pathology and immunohistochemistry confirmed sarcomatoid carcinoma of the small intestine. A short time later, enhanced CT scans revealed metastatic lesions in the hepatic portal and adrenal glands. After surgery, the gastrointestinal function gradually recovered, and the patient was discharged from the hospital on a semiliquid diet. No further treatment such as radiotherapy or chemotherapy was administered postoperatively. Five months after the surgery, the patient died due to brain metastasis. The study outcomes reveal the aggressive nature of sarcomatoid carcinoma of the small intestine, characterized by rapid progression and poor prognosis despite surgical interventions. The patient condition rapidly deteriorated, leading to metastasis and death within 5 months postsurgery. These findings underscore the critical need for early detection and possibly innovative treatment approaches to improve survival rates. This case also highlights the potential for gastrointestinal sarcomatoid carcinoma to metastasize to distant organs, including the brain, suggesting a propensity for hematogenous spread.

Pyridine‐Bridged Covalent Organic Frameworks with Adjustable Band Gaps as Intelligent Artificial Enzymes for Light‐Augmented Biocatalytic Sensing

AbstractOne of the biggest challenges in biotechnology and medical diagnostics is finding extremely sensitive and adaptable biosensors. Since metal‐based enzyme‐mimetic biocatalysts may lead to biosafety concerns on accumulative toxicity, it is essential to synthesize metal‐free enzyme‐mimics with optimal biocatalytic activity and superior selectivity. Here, the pyridine‐bridged covalent organic frameworks (COFs) with specific oxidase‐like (OXD‐like) activities as intelligent artificial enzymes for light‐augmented biocatalytic sensing of biomarkers are disclosed. Because of the adjustable bandgaps of pyridine structures on the photocatalytic properties of the pristine COF structures, the pyridine‐bridged COF exhibit efficient, selective, and light‐responsive OXD‐like biocatalytic activity. Moreover, the pyridine‐bridged COF structures show tunable and light‐augmented biocatalytic detection capabilities, which outperform the recently reported state‐of‐the‐art OXD‐mimics regarding biosensing efficiency. Notably, the pyridine‐bridged COF exhibits efficient and multifaceted diagnostic activity, including the extremely low limit of detection (LOD), which enables visual assays for abundant reducibility biomarkers. It is believed that this design will offer unique metal‐free biocatalysts for high‐sensitive and low‐cost colorimetric detection and also provide new insights to create highly efficient enzyme‐like COF materials via linkage‐modulation strategies for future biocatalytic applications.