Evaluating the diagnostic performance of a large language model-powered chatbot for providing immunohistochemistry recommendations in dermatopathology.

BACKGROUND: Large language model (LLM)-powered chatbots such as ChatGPT have numerous applications. However, their effectiveness in dermatopathology has not been formally evaluated. Dermatopathological cases often require immunohistochemical workup. Here, we evaluate the performance of a chatbot in providing diagnostically useful information on immunohistochemistry relating to dermatological diseases. METHODS: We queried a commonly used chatbot for the immunophenotypes of 51 cutaneous diseases, including a diverse variety of epidermal, adnexal, hematolymphoid, and soft tissue entities. We requested it to provide references for each diagnosis. All tests were repeated, compiled, quantified, and then compared with established literature standards. RESULTS: Clustering analysis demonstrated that recommendations correlated with tumor type, suggesting chatbots can supply appropriate panels. However, a significant portion of recommendations were factually incorrect (13.9%). Citations were rarely clinically useful (24.5%). Many were confabulated (27.2%). Prompt responses for cutaneous adnexal lesions tended to be less accurate while literature references were less useful. Reference retrieval performance was associated with the number of PubMed entries per entity. CONCLUSIONS: This foundational study suggests that LLM-powered chatbots may be useful for generating immunohistochemical panels for dermatologic diagnoses. However, specific performance capabilities and biases must be considered. In addition, extreme caution is advised regarding the tendencies to fabricate material. Future models intentionally fine-tuned to augment diagnostic medicine may prove to be valuable.

Bi-Layer nanoimprinting lithography for metal-assisted chemical etching with application on silicon mold replication.

This paper reports a new type of nanoimprinting method called Bi-layer nanoimprinting lithography (BL-NIL), which can work along with metal-assisted chemical etching (MaCE) for fabricating nanostructures on silicon. In contrast to conventional nanoimprinting techniques, BL-NIL adds an interposing layer between the imprinting resist layer and silicon substrate. After the standard imprinting process, dry etching was used to etch away the residual imprinting layer and part of the interposing layer. Finally, the remaining interposing layer was wet-etched using its remover. This innovative approach can ensure cleanliness at the metal/silicon interface after metal lift-off processes, and therefore guarantees the success of MaCE. By combining BL-NIL and MaCE, expensive silicon molds with sub-micrometer/nanometer-scale feature sizes can be easily replicated and preserved. This is important for the application of nanoimprinting technologies in industrial manufacturing.

Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling.

Acquisition of planar cell polarity (PCP) in epithelia involves intercellular communication, during which cells align their polarity with that of their neighbors. The transmembrane proteins Frizzled (Fz) and Van Gogh (Vang) are essential components of the intercellular communication mechanism, as loss of either strongly perturbs the polarity of neighboring cells. How Fz and Vang communicate polarity information between neighboring cells is poorly understood. The atypical cadherin, Flamingo (Fmi), is implicated in this process, yet whether Fmi acts permissively as a scaffold or instructively as a signal is unclear. Here, we provide evidence that Fmi functions instructively to mediate Fz-Vang intercellular signal relay, recruiting Fz and Vang to opposite sides of cell boundaries. We propose that two functional forms of Fmi, one of which is induced by and physically interacts with Fz, bind each other to create cadherin homodimers that signal bidirectionally and asymmetrically, instructing unequal responses in adjacent cell membranes to establish molecular asymmetry.

Reflectance confocal microscopic visualization of melanocytic bodies in the stratum corneum overlying acral lentiginous melanoma.

BACKGROUND: We present a case of RCM evaluation of ALM surgical margins demonstrating intracorneal melanocytic bodies overlying subsequently confirmed melanoma in situ by histopathology. CASE PRESENTATION: A 73-year-old male with a history of acral lentiginous melanoma (ALM) of the right great toe presented to our clinic for evaluation of positive surgical margins. The positive margin was localized for examination and subsequent biopsy with reflectance confocal microscopy (RCM) which allowed targeted re-resection of the area of concern. Three punch biopsies were obtained in the area of concern, which confirmed residual melanoma in situ. Immunostains confirmed the cellular remnants in the stratum corneum were melanocytic. To correlate the intra stratum corneum findings seen with confocal to the histopathology, a 3D rendering of a stack of images was used to demonstrate the location. DISCUSSION: Typically, acral surfaces are challenging to examine with RCM due to the limited ability of light to penetrate thickened stratum corneum; however, we observed unique cellular features with confocal. Scattered hyper-reflective pleomorphic cells consistent with melanocytes were observed in the stratum corneum, although the visualized underlying epidermis appeared normal. Confocal microscopy may aid in diagnosis and management of ALM, especially in the context of positive surgical margins.

Foreign body reaction toward hydrophilic polymer at the site of endovascular procedure: A report of two cases.

Hydrophilic polymer-coated devices have been increasingly utilized for various endovascular procedures, however not been without adverse effects. We report two cases of subacute cutaneous lesions on the neck encountered in our dermatology clinic. Histopathologic findings were significant for a nodular aggregate of epithelioid histiocytes and lymphocytes with numerous foreign body giant cells in the dermis. The granulomatous infiltrate was associated with an amorphous basophilic non-polarizable material. Further chart review reveals both patients receiving a central venous procedure in the past, thus attributing the hydrophilic polymers as the likely source of the foreign material found at the insertion site. Our cases contrast to the more commonly reported distal embolization by these hydrophilic polymer layers. We suspect the incidence of retained hydrophilic polymer at the site of prior endovascular procedures may be underreported in the literature with the more inconspicuous presentations. Therefore, retained foreign material should be considered by both treating physicians and dermatopathologists in presenting cases of lesions that occur at common sites of endovascular procedures.

Histologic Patterns of Cutaneous Metastases of Breast Carcinoma: A Clinicopathologic Study of 232 Cases.

ABSTRACT: Cutaneous metastasis may be the initial sign of internal malignancy but more often represents a late manifestation of widely disseminated disease. Breast carcinoma is the most common malignancy to metastasize to the skin. Although several studies have detailed the histopathologic patterns of cutaneous metastasis from internal malignancies, very little has been published regarding metastases of breast carcinoma to the skin. Furthermore, the histopathologic and clinical features observed in the cases of breast carcinoma with local skin involvement as opposed to cases exhibiting distant cutaneous metastases have not been adequately investigated. We have reviewed 232 cases of breast carcinoma with cutaneous metastases from 2 large institutions. All cases of carcinoma of the breast with involvement of the skin of the anterior chest wall were compared with those with distant cutaneous metastases. Two hundred thirty-two cases in 199 patients were included, of which 126 had skin involvement exclusively involving the ipsilateral anterior chest, and 106 had biopsy-proven distant cutaneous metastases. Twelve patients had both local and distal spread. Distant cutaneous metastases showed a predilection for the contralateral anterior chest wall area, followed by the head and neck, back, and abdomen. Histologically, most of the tumors presented in this series showed features of infiltrating ductal carcinoma. In both ipsilateral and distant metastases, the tumors demonstrated little change in histologic features from the primary lesion; however, the distant metastases showed a tendency to display more poorly differentiated features. The mean patient survival when cutaneous involvement was localized to the skin of the anterior chest wall was 23 months as compared with 20.6 months when distant sites were affected. A comparison of the clinicopathologic features of the patients presented in this series suggests that alternate biological mechanisms may apply for local and distant skin metastases from breast carcinoma.

Limited value of serum neutrophil-to-lymphocyte ratio in the diagnosis of chronic periprosthetic joint infection.

BACKGROUND: Diagnosing chronic periprosthetic joint infection (PJI) is challenging. No single biomarker can accurately recognize PJI preoperatively in a timely manner. Therefore, the aim of the present study was to investigate the usefulness of the serum neutrophil-to-lymphocyte ratio (NLR) in aiding the diagnosis of chronic PJI. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 158 patients who had undergone revision arthroplasty (104 with aseptic mechanic failure and 54 with chronic PJI) from July 2011 to July 2020. Univariate analysis followed by multivariate logistic regression was applied to compare NLR, C-reactive protein (CRP), and erythrocyte sedimentation ratio (ESR) between the two groups. The receiver operating characteristic (ROC) curve was used to assess the diagnostic performance of NLR alone and in combination with CRP and ESR. RESULTS: NLR, CRP, and ESR were significantly higher in patients with chronic PJI than in the aseptic revision group (p < 0.05). ROC curve analysis revealed that NLR had a sensitivity of 57.41% and a specificity of 77.88% with an optimal threshold of 2.56. The optimal threshold for CRP and ESR was 7.00 mg/L (sensitivity 62.50% and specificity 83.12%) and 43 mm/h (sensitivity 59.38% and specificity 80.52%), respectively. The combined diagnostic value of NLR with CRP and ESR was shown to have no additional diagnostic value in predicting chronic PJI. CONCLUSION: Compared with traditional inflammatory biomarkers (ESR and CRP), the value of serum NLR alone or combined with CRP and ESR for diagnosing chronic PJI is limited. LEVEL OF EVIDENCE: Level 3.

BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus-like Melanoma.

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.

Suprabasal acantholytic dermatologic toxicities associated checkpoint inhibitor therapy: A spectrum of immune reactions from paraneoplastic pemphigus-like to Grover-like lesions.

Checkpoint inhibitors (CPIs) restore the function of effector immunocytes to target and destroy cancer cells. Immune-related adverse events (irAEs) are a consequence of immune reactivation, with unpredictable inflammatory response, loss of self-tolerance, and development of autoimmunity. Adverse events from CPIs that present as dermatologic toxicities have diverse clinical and histopathologic features. CPI-associated dermatologic toxicities may exhibit histopathologic features of lichenoid dermatitis, bullous pemphigoid, and granulomatous/sarcoid-like reactions. Suprabasal acantholytic dermatologic toxicities associated with CPIs are particularly rare but represent an emerging histopathologic pattern and include lichenoid dermatitis with suprabasal acantholysis/vesicle formation to Grover disease (transient acantholytic dermatosis). Here, we report two patients who developed suprabasal acantholytic dermatologic toxicities during CPI therapy. One patient exhibited a CPI-associated autoimmune blistering disease with paraneoplastic pemphigus (PNP)-like features restricted to histopathology and immunofluorescence, while the other patient had Grover-like lesions. A review of the literature revealed a spectrum of suprabasal acantholytic dermatologic toxicities associated CPIs that may present as lichenoid dermatitis with acantholysis/vesicle formation, Grover-like eruptions, and lesions with PNP-like features restricted to histopathology and immunofluorescence. It is important for clinicians and pathologists to recognize the types of dermatologic toxicities associated with CPIs to direct appropriate therapeutic strategies.

MicroRNA-455-3p modulates cartilage development and degeneration through modification of histone H3 acetylation.

Histone acetylation regulated by class I histone deacetylases (HDACs) plays a pivotal role in matrix-specific gene transcription and cartilage development. While we previously demonstrated that microRNA (miR)-455-3p is upregulated during chondrogenesis and can enhance early chondrogenesis, the mechanism underlying this process remains largely unclear. In this study, we characterized the effect of miR-455-3p on histone H3 acetylation and its role during cartilage development and degeneration. We observed that miR-455-3p was highly expressed in proliferating and pre-hypertrophic chondrocytes, while HDAC2 and HDAC8 were primarily expressed in hypertrophic chondrocytes. Meanwhile, miR-455-3p suppressed the activity of reporter constructs containing the 3'-untranslated regions of HDAC2/8, inhibited HDAC2/8 expression and promoted histone H3 acetylation at the collagen 2 (COL2A1) promoter in human SW1353 chondrocyte-like cells. Treatment with the HDAC inhibitor trichostatin A (TSA) resulted in increased expression of cartilage-specific genes and promoted glycosaminoglycan deposition. Moreover, TSA inhibited matrix metalloproteinase 13 (Mmp13) expression and promoted nuclear translocation of SOX9 in interleukin-1-treated primary mouse chondrocytes. Lastly, knockdown of HDAC2/3/8 increased SRY (sex-determining region Y)-box 9 (SOX9) and decreased Runt-related transcription factor 2 (RUNX2) expression. Taken together, these findings suggest that miR-455-3p plays a critical role during chondrogenesis by directly targeting HDAC2/8 and promoting histone H3 acetylation, which raises possibilities of using miR-455-3p to influence chondrogenesis and cartilage degeneration.

Identification and Characterization of Long Non-Coding RNAs in Osteogenic Differentiation of Human Adipose-Derived Stem Cells.

BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) play important roles in stem cell differentiation. However, their role in osteogenesis of human adipose-derived stem cells (ASCs), a promising cell source for bone regeneration, remains unknown. Here, we investigated the expression profile and potential roles of lncRNAs in osteogenic differentiation of human ASCs. METHODS: Human ASCs were induced to differentiate into osteoblasts in vitro, and the expression profiles of lncRNAs and mRNAs in undifferentiated and osteogenic differentiated ASCs were obtained by microarray. Bioinformatics analyses including subgroup analysis, gene ontology analysis, pathway analysis and co-expression network analysis were performed. The function of lncRNA H19 was determined by in vitro knockdown and overexpression. Quantitative reverse transcription polymerase chain reaction was utilized to examine the expression of selected genes. RESULTS: We identified 1,460 upregulated and 1,112 downregulated lncRNAs in osteogenic differentiated human ASCs as compared with those of undifferentiated cells (Fold change ≥ 2.0, P < 0.05). Among these, 94 antisense lncRNAs, 85 enhancer-like lncRNAs and 160 lincRNAs were further recognized. We used 12 lncRNAs and 157 mRNAs to comprise a coding-non-coding gene expression network. Additionally, silencing of H19 caused a significantly increase in expression of osteogenesis-related genes, including ALPL and RUNX2, while a decrease was observed after H19 overexpression. CONCLUSION: This study revealed for the first time the global expression profile of lncRNAs involved in osteogenic differentiation of human ASCs and provided a foundation for future investigations of lncRNA regulation of human ASC osteogenesis.

Advanced glycation end products biphasically modulate bone resorption in osteoclast-like cells.

Advanced glycation end products (AGEs) disturb bone remodeling during aging, and this process is accelerated in diabetes. However, their role in modulation of osteoclast-induced bone resorption is controversial, with some studies indicating that AGEs enhance bone resorption and others showing the opposite effect. We determined whether AGEs present at different stages of osteoclast differentiation affect bone resorption differently. Based on increased levels of tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CTSK), we identified day 4 of induction as the dividing time of cell fusion stage and mature stage in RAW264.7 cell-derived osteoclast-like cells (OCLs). AGE-modified BSA (50-400 µg/ml) or control BSA (100 µg/ml) was then added at the beginning of each stage. Results showed that the presence of AGEs at the cell fusion stage reduced pit numbers, resorption area, and CTSK expression. Moreover, expression of receptor activator of nuclear factor-κB (RANK) as well as the number of TRAP-positive cells, nuclei per OCL, actin rings, and podosomes also decreased. However, the presence of AGEs at the mature stage enlarged the resorption area markedly and increased pit numbers slightly. Intriguingly, only the number of nuclei per OCL and podosomes increased. These data indicate that AGEs biphasically modulate bone resorption activity of OCLs in a differentiation stage-dependent manner. AGEs at the cell fusion stage reduce bone resorption dramatically, mainly via suppression of RANK expression in osteoclast precursors, whereas AGEs at the mature stage enhance bone resorption slightly, most likely by increasing the number of podosomes in mature OCLs.

MicroRNA-381 Regulates Chondrocyte Hypertrophy by Inhibiting Histone Deacetylase 4 Expression.

Chondrocyte hypertrophy, regulated by Runt-related transcription factor 2 (RUNX2) and matrix metalloproteinase 13 (MMP13), is a crucial step in cartilage degeneration and osteoarthritis (OA) pathogenesis. We previously demonstrated that microRNA-381 (miR-381) promotes MMP13 expression during chondrogenesis and contributes to cartilage degeneration; however, the mechanism underlying this process remained unclear. In this study, we observed divergent expression of miR-381 and histone deacetylase 4 (HDAC4), an enzyme that directly inhibits RUNX2 and MMP13 expression, during late-stage chondrogenesis of ATDC5 cells, as well as in prehypertrophic and hypertrophic chondrocytes during long bone development in E16.5 mouse embryos. We therefore investigated whether this miRNA regulates HDAC4 expression during chondrogenesis. Notably, overexpression of miR-381 inhibited HDAC4 expression but promoted RUNX2 expression. Moreover, transfection of SW1353 cells with an miR-381 mimic suppressed the activity of a reporter construct containing the 3'-untranslated region (3'-UTR) of HDAC4. Conversely, treatment with a miR-381 inhibitor yielded increased HDAC4 expression and decreased RUNX2 expression. Lastly, knockdown of HDAC4 expression resulted in increased RUNX2 and MMP13 expression in SW1353 cells. Collectively, our results indicate that miR-381 epigenetically regulates MMP13 and RUNX2 expression via targeting of HDAC4, thereby suggesting the possibilities of inhibiting miR-381 to control chondrocyte hypertrophy and cartilage degeneration.

Wear particles promote reactive oxygen species-mediated inflammation via the nicotinamide adenine dinucleotide phosphate oxidase pathway in macrophages surrounding loosened implants.

BACKGROUND/AIMS: Prosthesis loosening is closely associated with chronic inflammatory cytokine secretion by macrophages, which are activated by wear particles or inflammatory stimulants such as lipopolysaccharide (LPS). Reactive oxygen species (ROS) are critical regulators of inflammation, but their enzymatic sources in response to wear particles and their effects on peri-implant LPS-tolerance remain unclear. METHODS: Three ROS-related enzymes-nicotinamide adenine dinucleotide phosphate oxidase (NOX)-1 and -2 and catalase-were investigated in interface membrane tissues and in titanium (Ti) particle-stimulated macrophages in vitro. The generation of ROS and downstream inflammatory effects were measured with or without pre-incubation with apocynin, an NOX inhibitor. RESULTS: Pre-exposure to Ti particles attenuated NF-κB activation in LPS-stimulated macrophages, indicating that wear particles suppress immune response, which may lead to chronic inflammation. NOX-1 and -2 were highly expressed in aseptically loosened interface membranes and in macrophages stimulated with Ti particles; the particles induced a moderate amount of ROS generation, NF-κB activation, and TNF-α secretion in macrophages, and these effects were suppressed by apocynin. CONCLUSION: Wear particles induce ROS generation through the NOX signaling pathway, resulting in persistent inflammation and delayed loosening. Thus, the suppression of NOX activity may be a useful strategy for preventing prosthesis loosening.

The Role of MicroRNA-381 in Chondrogenesis and Interleukin-1-ß Induced Chondrocyte Responses.

AIM: The molecular pathways regulating cartilage degradation are unclear. miR-381 was identified as a putative regulator of chondrogenesis related genes. Here, we examined its role in chondrogenesis and osteoarthritic cartilage degeneration. METHODS: miR-381 expression was assessed in vitro in response to IL-1ß stimulation in primary human (PHC) and mouse (PMC) chondrocytes, and ATDC5 derived chondrocytes; and in vivo in mouse embryos and human osteoarthritic cartilage. The effects of miR-381 on chondrogenesis and NF-kB signaling were assessed using a synthetic RNA mimic or inhibitor and luciferase assay, respectively. Upstream regulators of miR381 were probed using siRNA or overexpression plasmids for Sox9 and Runx2. RESULTS: miR-381 expression was elevated in chondrogenic and hypertrophic ATDC5 cells. miR-381 was induced in vitro by IL-1ß in ATDC5 cells, PMCs, and PHCs, and was expressed in areas of cartilage degradation or absorption in vivo. Overexpression of Runx2 or Sox9 increased miR-381 expression in ATDC5 cells. miR-381 suppressed expression of collagen, type II, alpha 1, and enhanced expression of metalloproteinase-13 (MMP-13), but did not regulate NFKBIA and NKRF activity. CONCLUSION: miR-381 was highly expressed during chondrogenesis and in arthritic cartilage. It may contribute to absorption of the cartilage matrix by repressing type II collagen and inducing MMP-13.

Growth-associated protein 43 in differentiating peripheral nerve sheath tumors from other non-neural spindle cell neoplasms.

The malignant peripheral nerve sheath tumor is a relatively uncommon type of soft tissue sarcoma arising from a peripheral nerve or extraneural soft tissues and showing nerve sheath differentiation. The diagnosis of malignant peripheral nerve sheath tumor is one of the most challenging tasks in surgical pathology because of its uncommon type (5-10% soft tissue sarcomas), morphologic resemblance to other spindle cell neoplasms and lack of sensitive and specific immunohistochemical markers. The pathologic diagnosis is more straightforward in the clinical setting of neurofibromatosis-1, but problems are mainly centered on the non-neurofibromatosis-1 malignant peripheral nerve sheath tumors. To date, S100 protein is the most widely applied marker in the case of a suspected malignant peripheral nerve sheath tumor, yet its suboptimal sensitivity and its expression in other spindle cell neoplasms, including spindle cell melanoma, clear-cell sarcoma, leiomyosarcoma and monophasic synovial sarcoma, add to the diagnostic conundrum. Growth-associated protein 43 (GAP43), a membrane-associated phosphoprotein expressed in neuronal growth cones and Schwann cell precursors during neural development and axonal regeneration, was applied to a set of nerve sheath and non-nerve sheath spindle cell neoplasms. The findings in this study indicate that GAP43 is expressed in malignant peripheral nerve sheath tumors (n=18/21; 86%) and demonstrates a sensitivity superior to S100 protein (n=13/21; 62%). GAP43 is also positive in neurofibromas (n=17/18; 94%), schwannomas (n=11/12; 92%) and desmoplastic melanomas (n=7/10; 70%). In contrast, it is negative in the non-desmoplastic spindle cell melanomas (n=20/22; 91%). Of the other non-neural soft tissue sarcomas, GAP43 is non-reactive in most leiomyosarcomas (n=14/16; 88%) and clear-cell sarcomas (n=8/8), and only focally positive in monophasic synovial sarcomas (n=3/7; 43%). GAP43 is seemingly a highly sensitive marker for peripheral nerve sheath tumors and may serve as a useful diagnostic adjunct in the diagnosis of malignant peripheral nerve sheath tumor from other spindle cell neoplasms, including spindle cell melanoma.

Analysis of pediatric outpatient visits uncovers disparities in molluscum contagiosum treatment across medical specialties in the United States.

Molluscum contagiosum (MC) is a common viral infection that affects the skin of children. In this study, treatment regimens and demographic information for MC patients across US medical specialties were compared. We discovered an average of 471,383 pediatric MC visits annually using the National Ambulatory Medical Care Survey database from 2000 to 2016. Non-Hispanics (82.9%) and Caucasians (91.0%) made up the majority of the visitors. The majority of cases were handled by pediatricians (46.5%), family medicine doctors (10.6%), and dermatologists (36.7%). Compared to pediatricians, dermatologists saw a higher percentage of Caucasian patients (95% vs.84%) and patients with private insurance (83% vs. 73%). Patients were more likely to see family medicine doctors (55.0%) in non-metropolitan areas than pediatricians (26.4%) or dermatologists (16.3%). Dermatologists were less likely than pediatricians (38%) to favor spontaneous resolution (70%). Dermatologists favored terpenoids (20%), imiquimod (12%), and curettage (10%), while pediatricians primarily used terpenoids (12%), steroids (4%), and imiquimod (4%). The majority of MC cases are managed by pediatricians; however, treatment approaches deviate markedly from recommended best practices.

Clinicopathologic correlation of dermatologic diseases in patients with darker pigmentation.

OBJECTIVES: Cutaneous diseases that disproportionately affect patients with darker pigmentation and their histologic features are historically understudied and undertreated. This review article aims to highlight the key clinical features, histopathology, and diagnostic pearls of several cutaneous diseases that commonly present in patients with darker pigmentation. METHODS: A literature search was conducted, and a list of cutaneous diseases that frequently affect patients with darker pigmentation was compiled. A group of experts expounded upon those that were most common or misdiagnosed according to scientific evidence and clinical practice. RESULTS: The diseases were divided into hypopigmented disorders, hyperpigmented disorders, scarring disorders, and alopecic disorders. Within each category, the etiology, clinical features, histopathology, and key histologic differential diagnoses are described and discussed. CONCLUSIONS: As many clinicians are taught that there are no effective treatment options or that these diseases are considered "cosmetic" in nature, patients often do not get a thorough medical workup or skin biopsy. This article aims to decrease the knowledge gap and serve as a resource for anyone involved in the care of patients with these cutaneous conditions.

A machine learning-based model for "In-time" prediction of periprosthetic joint infection.

Background: Previous criteria had limited value in early diagnosis of periprosthetic joint infection (PJI). Here, we constructed a novel machine learning (ML)-derived, "in-time" diagnostic system for PJI and proved its validity. Methods: We filtered "in-time" diagnostic indicators reported in the literature based on our continuous retrospective cohort of PJI and aseptic prosthetic loosening patients. With the indicators, we developed a two-level ML model with six base learners including Elastic Net, Linear Support Vector Machine, Kernel Support Vector Machine, Extra Trees, Light Gradient Boosting Machine and Multilayer Perceptron), and one meta-learner, Ensemble Learning of Weighted Voting. The prediction performance of this model was compared with those of previous diagnostic criteria (International Consensus Meeting in 2018 (ICM 2018), etc.). Another prospective cohort was used for internal validation. Based on our ML model, a user-friendly web tool was developed for swift PJI diagnosis in clinical practice. Results: A total of 254 patients (199 for development and 55 for validation cohort) were included in this study with 38.2% of them diagnosed as PJI. We included 21 widely accessible features including imaging indicators (X-ray and CT) in the model. The sensitivity and accuracy of our ML model were significantly higher than ICM 2018 in development cohort (90.6% vs. 76.1%, P = 0.032; 94.5% vs. 86.7%, P = 0.020), which was supported by internal validation cohort (84.2% vs. 78.6%; 94.6% vs. 81.8%). Conclusions: Our novel ML-derived PJI "in-time" diagnostic system demonstrated significantly improved diagnostic potency for surgical decision-making compared with the commonly used criteria. Moreover, our web-based tool greatly assisted surgeons in distinguishing PJI patients comprehensively. Level of evidence: Diagnostic Level III.

Deconvolution of synovial myeloid cell subsets across pathotypes and role of COL3A1+ macrophages in rheumatoid arthritis remission.

Background: Monocyte/macrophage (Mo/Mp) is a critical cell population involved in immune modulation of rheumatoid synovitis (RA) across different pathotypes. This study aims to investigate the contribution of Mo/Mp clusters to RA activity, and the biological function of particular subtypes in RA remission. Methods: We integrated single-cell RNA sequencing datasets from 4 published and 1 in-house studies using Liger selected by comparison. We estimated the abundance of Mo/Mp subtypes in bulk RNA-seq data from the 81 patients of the Pathobiology of Early Arthritis Cohort (PEAC) using deconvolution analysis. Correlations between Mo/Mp subtypes and RA clinical metrics were assessed. A particular cell type was identified using multicolor immunofluorescence and flow cytometry in vivo and successfully induced from a cell line in vitro. Potential immune modulation function of it was performed using immunohistochemical staining, adhesion assay, and RT-qPCR. Results: We identified 8 Mo/Mp clusters. As a particular subtype among them, COL3A1+ Mp (CD68+, COL3A1+, ACTA2-) enriched in myeloid pathotype and negatively correlated with RA severity metrics in all pathotypes. Flow cytometry and multicolor immunofluorescence evidenced the enrichment and M2-like phenotype of COL3A1+ Mp in the myeloid pathotype. Further assays suggested that COL3A1+ Mp potentially attenuates RA severity via expressing anti-inflammatory cytokines, enhancing Mp adhesion, and forming a physical barrier at the synovial lining. Conclusion: This study reported unexplored associations between different pathologies and myeloid cell subtypes. We also identified a fibroblast-and-M2-like cluster named COL3A1+ Mp, which potentially contributes to synovial immune homeostasis. Targeting the development of COL3A1+ Mp may hold promise for inducing RA remission.