The treatment of infantile giant café au lait spot using golden parameter therapy with a high fluence 1064-nm Q-switched Nd: YAG laser.

BACKGROUND: Infantile café au lait spot is a brown macule with various sizes (diameter: 0.5 cm-30 cm). Infantile giant café au lait spot (IGCALS) is a huge (diameter >20cm) irregular-shaped benign hyperpigmented skin disorder that arises in infants. There has been no clearly established laser treatment consensus for the treatment of IGCALS because infants are too fragile to receive laser treatment with long hours and broad areas along with the possibility of undesirable cosmetic results. OBJECTIVES: This study investigated the safety and efficacy of Golden Parameter Therapy (GPT) using a high fluence 1064-nm Q-switched Nd:YAG laser (QSNL) for IGCALS treatment. METHODS: This study included 24 Korean patients with IGCALS. Twenty-one patients who were treated with a 1064-nm QSNL weekly for 30-50 treatment sessions with GPT. The parameters included a spot size of 7 mm, a fluence of 2.2 J/cm2 and a pulse rate of 10 Hz with one pass using a sliding-stacking technique over the IGCALS. In control group, three patients were treated with a 532-nm picosecond laser monthly for three treatment sessions with a spot size of 3 mm, a fluence of 1 J/cm2 and a pulse rate of 2 Hz. RESULTS: After the last treatment, 21 patients with IGCALS reached the complete removal of pigmented lesions, which can be considered optimal cosmetic results without any side effects such as purpura, crust, post-inflammatory hyperpigmentation, iatrogenic punctate leukoderma, and scarring. There are no recurrences in any patients after 6-21 months' follow-up, but treatment failure occurred in three patients who were treated with 532 nm picosecond laser. CONCLUSIONS: Convincingly, we argue that early intervention before 12 months of age with GPT using a high fluence 1064 nm QSNL is a safe, applicable and effective treatment for IGCALS, minimizing side effects without any recurrences.

Communication: Evaluation of the Humasis COVID-19 Antigen Rapid Diagnostic Test for the Diagnosis of SARS-CoV-2 Infection.

OBJECTIVE: We assessed the performance of the Humasis COVID-19 AgHS Test (Humasis, Korea), a novel antigen rapid diagnostic test (Ag-RDT) based on lateral flow immunoassay. METHODS: 85 SARS-CoV-2-positive and 155 SARS-CoV-2-negative nasopharyngeal swab specimens confirmed by rRT-PCR were tested using the Humasis and PBCheck Ag-RDTs. The analytical specificity of the Humasis Ag-RDT was evaluated using 27 strains of human respiratory pathogens. RESULTS: The overall sensitivity and specificity were 72.9% and 99.4% for the Humasis Ag-RDT and 64.7% and 100% for the PBCheck Ag-RDT, respectively. The sensitivity for specimens with Ct≤25 was 100% for both Ag-RDTs. The Humasis Ag-RDT showed no cross-reactivity with other respiratory pathogens. CONCLUSION: Our data suggests that the Humasis Ag-RDT can be a useful diagnostic tool for the detection of SARS-CoV-2 infection.

Immunocytochemistry on frozen-embedded cell block for the diagnosis of hematolymphoid cytology specimen: a straightforward alternative to the conventional cell block.

Agarose-based cell block (CB) technique can be modified to be combined with the frozen section technique for the preparation of a high-quality frozen-embedded CB (F-CB) from an effusion or fine-needle aspiration (FNA) cytology sample. This combined technique can be effectively used for the immunocharacterization of the hematolymphoid cells on F-CB. To demonstrate the applicability of performing diagnostic ICC on F-CB, we have analyzed the immunophenotype of the hematolymphoid cells in a series of eight cases of effusions and eight cases of FNA cytology specimens by using CB-ICC on sections cut from frozen-embedded CBs. The SurePathTM residue or cytologic material scraped off from the FNA cytology smear that was diagnostic for or suspicious of hematolymphoid malignancy was pelleted and pre-embedded in agarose. Half of the agarose-embedded pellet was frozen-embedded in OCT compound for the preparation of F-CB, while the other half was processed for the preparation of paraffin-embedded CB. Sections cut from the F-CB and P-CB were used for CB-ICC. Panels of ICC on the F-CBs could enable the immunocytochemical differential diagnosis of large cell hematologic malignancies that encompass anaplastic large cell lymphoma and other forms of large-cell hematolymphoid malignancies such as large B-cell lymphomas, anaplastic plasma cell myeloma, myeloid sarcoma, and T-lymphoblastic lymphoma. It also appeared that the small B-cell lymphomas in the effusions or FNAs could be differentially diagnosed with the aid of CB-ICC on the F-CB. A modified agarose-based CB technique can be combined with the frozen-embedded CB method for the preparation of F-CB that can be directly used for the immunocytochemical differential diagnosis of hematolymphoid cytology samples.

Afterbirth oral fluid secretory leukocyte protease inhibitor decreased in acute histologic chorioamnionitis in preterm birth.

BACKGROUND: Secretory leukocyte protease inhibitor (SLPI) is an innate anti-inflammatory and anti-microbial peptide and produced in amnion of fetal membranes during pregnancy. However, studies on the association between SLPI levels in amniotic fluid and acute chorioamnionitis are limited. Afterbirth oral fluid (AOF) of the baby could be useful for representing the intra-amniotic environment precisely just before delivery. This study aimed to determine the relationship between SLPI levels in AOF and acute histologic chorioamnionitis (HC). METHODS: AOF of the baby was obtained during delivery from 24(0/7) to 36(6/7) weeks of gestational age (preterm group, n = 94) and from 37(0/7) to 41(6/7) weeks of gestational age (term group, n = 27) just after birth. SLPI expression levels among five classifications were compared to the intensity of acute HC as follows: no inflammation, acute subchorionitis, acute chorionitis, acute chorioamnionitis, and funisits. The SLPI and matrix metalloproteinase-8 (MMP-8) concentrations of AOF were determined using Enzyme Linked Immunosorbent Assay. Histologic examination of the placenta and membranes was performed after delivery. RESULTS: SLPI concentrations in AOF inversely decreased according to the intensity of acute HC (161.62 ng/mL in funisitis, 134.83 ng/mL in acute chorioamnionitis, 749.35 ng/mL in acute chorionitis, 953.05 ng/mL in acute subchorionitis, and 1126.77 ng/mL in no inflammation [p = .021]). The MMP-8 concentrations in AOF and maternal serum C-reactive protein were the highest in funisitis. The SLPI/ MMP-8 ratio was low in subgroup with acute chorioamnionitis and funisitis. CONCLUSION: Along with increased MMP-8 levels, decreased SLPI levels in AOF of the baby could be an additional factor in predicting acute HC immediately after birth.

The Relationship Between Matrix Metalloproteinase-8 in After Birth Oral Fluid and Acute Histologic Chorioamnionitis in Preterm Delivery.

Elevated concentration of matrix metalloproteinase-8 (MMP-8) in amniotic fluid is a known predictor of intra-amniotic inflammation and infection. The aim of this study was to determine the nature of the association between MMP-8 levels in oral fluid obtained immediately after birth and acute histologic chorioamnionitis (HCA) in preterm delivery. Oral fluid was collected from 93 consecutive preterm birth newborns between gestational weeks of 24 + 0 and 36 + 6. Concentrations of MMP-8 and interleukin-8 (IL-8) in after birth oral fluid were measured by ELISA. Acute HCA was defined as the presence of neutrophils infiltration into chorioamnionic membranes. Logistic regression analysis was used for the statistical analysis. MMP-8 concentrations in after birth oral fluid were significantly higher for women with acute HCA than for those without (median [range]; 68.3 ng/mL [0.06-12,479.6] vs. 10.2 ng/mL [0.06-1808.2], p = 0.002). A strong association was observed between MMP-8 and IL-8 levels (γ2 = 0.87, p < 0.01). The cutoff level of MMP-8 in after birth oral fluid for acute HCA was 39.7 ng/mL (sensitivity of 63.2%, specificity of 81.1%). Multivariable logistic regression analysis showed MMP-8 in after birth oral fluid had an odds ratio of 4.17 for acute HCA (95% confidence interval [CI] = 1.08-16.17, p = 0.03). An elevated MMP-8 level in after birth oral fluid is associated with acute HCA in preterm birth. Newborn oral fluid immediately after birth might provide another source for information of intra-amniotic condition just before birth.

[Undifferentiated Pleomorphic Sarcoma of the Small Intestine with Distant Endobronchial Metastasis Presenting as Intussusception: A Case Report]. / 장중첩증으로 발현된 기관지 내 ì „ì´ë¥¼ 동반한 소장의 미분화성 다형성 ìœ¡ì¢ : 증례 ë³´ê³ .

Undifferentiated pleomorphic sarcoma (UPS) is a high-grade soft tissue sarcoma that arises from mesenchymal tissue. Primary UPS of the small intestine is extremely rare, and only a few cases have been reported in the literature. Its presentation is usually nonspecific; however, it may occasionally present as intussusception with intermittent abdominal pain. It is a highly aggressive tumor with a propensity for early distant metastasis to the peritoneum, lymph nodes, other abdominal organs, lungs and brain. To our knowledge, there are no reported cases of endobronchial metastasis from small intestine UPS. We report a rare case of UPS of the small intestine with endobronchial metastasis presenting as intussusception.

Klatskin tumor diagnosed concurrently with IgG4 related sclerosing cholangitis: A case report.

RATIONALE: IgG4-related disease (IgG4-RD) is a systemic disease that can involve various organs and is characterized by the infiltrations of IgG4-positive plasma cells and lymphocytes, fibrosis, and elevated serum IgG4 levels. IgG4-related sclerosing cholangitis (IgG4-RSC) is a subtype of IgG4-RD. No certain relationship between IgG4-RSC and cholangiocarcinoma has been established as yet, and there have been few reports of the simultaneous diagnosis of IgG4-RSC and cholangiocarcinoma. PATIENT CONCERNS: A 76-year-old male visited our gastroenterology department due to the recent occurrence of pruritus and jaundice. DIAGNOSIS: Computed tomography (CT) scan showed ductal wall swelling and enhancement from both intrahepatic duct confluence to the common bile duct, upper biliary dilatation, and accompanying autoimmune pancreatitis (a sub type of IgG4-RD). Biopsy of the distal common bile duct by endoscopic retrograde cholangiopancreatography (ERCP) resulted in a diagnosis of IgG4-RSC. Subsequently, adenocarcinoma was identified by repeated cytology of bile juice. Finally, Klatskin tumor type IIIA and IgG4-RSC were concurrently diagnosed. INTERVENTIONS: IgG4-RSC was treated with steroid and Klatskin tumors by gemcitabine + cisplatin chemotherapy. OUTCOMES: The jaundice had improved and CT showed substantial improvement of the intrahepatic duct dilatation. LESSONS: IgG4-RSC and cholangiocarcinoma are easily confused, but their treatments are quite different, and thus, care must be taken during diagnosis. Furthermore, these 2 diseases may co-exist. Therefore, even if IgG4-RSC is diagnosed first, the possibility of accompanying cholangiocarcinoma should be thoroughly investigated.

A case of Henoch-Schönlein purpura associated with scrub typhus.

BACKGROUND: Henoch-Schönlein purpura (HSP) may be caused by several allergens. However, to date, HSP caused by Orientia tsutsugamushi has not been reported. Here, we report an unusual rash with features of HSP caused by Orientia tsutsugamushi. CASE PRESENTATION: A man visited a tertiary hospital with bilateral symmetrical purpura and fever. He presented with an eschar in the left popliteal fossa and proteinuria. He was diagnosed with tsutsugamushi disease by indirect fluorescent antibody and positive polymerase chain reaction tests. Purpura biopsy demonstrated a feature of leukocytoclastic vasculitis and IgA deposition in dermal vessels, indicative of HSP. CONCLUSIONS: When examining patients with unique rashes, such as in this case, we suggest investigating out-door activities and evidence of mite bites. Furthermore, differential diagnosis of tsutsugamushi disease should be considered when necessary.

Decreased expression of progesterone receptor membrane component 1 in fetal membranes with chorioamnionitis among women with preterm birth.

PURPOSE: Progesterone receptor membrane component 1 (PGRMC1) have anti-inflammatory and anti-apoptotic properties. This study aimed to determine the expression of PGRMC1 in fetal membranes among women with preterm labor (PTL), preterm premature rupture of membranes (PPROM), and acute histologic chorioamnionitis (HCA) during preterm birth. METHODS: Full thickness fetal membranes were obtained from women with gestational age-matched (32-34 weeks of gestational age), and categorized as PTL without HCA (PTL, n = 10), PPROM without HCA (PPROM, n = 10), PPROM with HCA (HCA, n = 10), and term without labor and HCA (term birth (TB), n = 9). The expression of PGRMC1 was assessed using western blot and Immunohistochemistry (IHC). As CD14 is a component of the innate immune system during inflammation, CD14 was used as inflammatory indicator. Nonparametric statistics were used for analysis. RESULTS: PGRMC1 expression for all of preterm birth was lower than in TB (P = 0.01). In HCA, PGRMC1 expression was significantly decreased compared to that in PTL and PPROM (P = 0.006. P = 0.001, respectively). PGRMC1 expression in PPROM was higher than that in PTL (P = 0.002). There was a negative correlation between PGRMC1 and CD 14/ß-actin ratio (r = - 0.518; P = 0.002). IHC showed that PGRMC1 was predominant in the cytoplasm of cells, these results were consistent with those of the western blot analysis. CONCLUSION: Preterm birth with PTL, PPROM, and especially HCA is associated with a decreased PGRMC1 in fetal membranes and inversely associated with increased CD 14.

Cytomorphologic features of small cell carcinoma of lung in effusion fluid using a liquid-based cytology technique.

BACKGROUND: Liquid-based cytology (LBC) testing induces morphologic changes due to the use of specific fixatives and preparation techniques, and the cytologies of effusions determined in this manner differ morphologically from those of conventional cytopreparation (CCP) smear methods. We compared the cytologic features of pulmonary small cell carcinoma in effusion fluid using CCP and LBC preparations. METHODS: Fifty-three malignant effusion specimens from 36 patients with small cell carcinoma were examined, including 41 LBCs from 27 patients and 12 CCPs from 9 patients. RESULTS: LBC and CCP preparations preserved the typical features of small cell carcinoma, that is, nuclear molding, very high nuclear to cytoplasmic ratio and granular chromatin. The architectural patterns involved small cohesive clusters and chains with nuclear molding, tight three-dimensional clusters, or single cell dispersion were preserved in both preparations. Oval nuclei (83.3% vs 26.8%, P < .001) and a discernable rim of cytoplasm (66.7% vs 26.8%, P = .043) were more frequently identified in CCPs, whereas cellular degeneration and dry artifact were more frequent in LBC preparations (73.2% vs 8.3%, P < .001). LBC had a tendency to show frequent nuclear size variation (51.2% vs 25.0%) than CCP. CONCLUSION: LBC tends to show more degeneration and dry artifact with exaggerated irregular nuclear shape and nuclear size variation and scanty cytoplasm than CCP. Cytopathologists should be familiar with the cytomorphologic spectrum of this tumor in CCP and LBC prepared effusions.

Comparative pathologic analysis of mediastinal B-cell lymphomas: selective expression of p63 but no GATA3 optimally differentiates primary mediastinal large B-cell lymphoma from classic Hodgkin lymphoma.

BACKGROUND: Interpretation of mediastinal biopsy is often challenging even for experienced pathologists especially when a hematolymphoid neoplasm is suspected. Primary mediastinal large B-cell lymphoma (PMLBCL) and classic Hodgkin lymphoma (CHL) represent two major types of mature B-cell lymphomas of the mediastinum. Although PMLBCL and mediastinal CHL share many clinicopathologic characteristics, their treatment strategies and responses are remarkably different. We therefore aimed to find distinctive histologic or protein markers to better differentiate these two lesions. METHODS: Search for primary mediastinal B-cell lymphomas found 52 consecutive cases from 3 university hospitals of Korea during 2005 to 2012. Among them, 32 cases that were available for additional immunohistochemistry (IHC) assessment were enrolled in this study. These cases consisted of the following: CHL (N = 13), PMLBCL (N = 16), and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL (gray zone lymphoma, N = 3). Along with the clinicopathologic findings, the expression of p63, GATA3 and cyclin E was investigated by IHC in the three categorized lesions mentioned above. RESULTS: Most clinical features overlapped between PMLBCL and CHL except for the increased disease progression and mortality found in PMLBCL. In the pathologic review, the presence of epithelioid granuloma favored a diagnosis of CHL, whereas reticulated or alveolar patterns of fibrosis were characteristic of PMLBCL. For protein markers, p63 was predominantly positive in PMLBCL (15/16) compared with CHL (2/13), which indicates that p63 is a marker of the highest diagnostic accuracy when calculated by the area under the ROC curve. GATA3 was expressed in the majority of CHL cases (10/13) compared with PMLBCL (0/16), while the expression of cyclin E was only rarely present in a minor population of PMLBCL. CONCLUSIONS: P63 expression in tumor cells, even focal expression, and no GATA3 is the most helpful feature in distinguishing PMLBCL from mediastinal CHL.

Effect of study-level factors on treatment-free remission rate in patients with chronic myeloid leukemia: a systematic review and meta-analysis.

As it is recommended that most assessments for treatment-free remission (TFR) in patients with chronic myeloid leukemia be conducted as prospective trials, we conducted a systematic review and meta-analysis to investigate which study-level factors affected the TFR rate. The MEDLINE, Embase, and Cochrane databases were systematically searched from inception to July 2018. A random effect model was used to estimate the overall mean TFR rate, subgroup differences, and regression coefficients with continuous variables. Overall, 12 tyrosine kinase inhibitor (TKI) stopping studies comprising 1699 chronic myeloid leukemia patients were included in this analysis. The overall mean TFR rate at 24 months after entering TFR phase was 55% [95% confidence interval (CI) 0.51-0.58]. Trials with molecular criteria of MR4.5 or better for stopping TKI reported higher TFR rates than those of MR4.0 (57.2% vs. 50.5%). Trials with eligible criteria for at least 24 months of deep molecular response (DMR) duration demonstrated higher TFR rates than those for 18 or 12 months (60.2% vs. 49.9%). Our results suggest that TKI stopping trials with sufficient duration of DMR and molecular criteria of MR4.5 or better may account for approximately 60% of the TFR rate at 24 months after stopping TKI.

Actinomycotic osteomyelitis of a long bone in an immunocompetent adult: a case report and literature review.

BACKGROUND: Actinomycosis is a rare, chronic granulomatous disease caused by Gram-positive anaerobic bacteria that colonize the oral cavity. Cervicofacial actinomycosis is the most frequent clinical presentation of actinomycosis, but hematogenous osteomyelitis at distant sites can occur in rare instance in immunocompromised or pediatric patients, only a few cases have been reported in healthy patients. Here we described a new case of distal femur osteomyelitis caused by Actinomyces in an adult patient who was immunocompetent and had no predisposing factors. CASE PRESENTATION: A woman aged 52 years with no history of trauma presented with severe pain, swelling, and increased local heat in the proximal area of the right knee 3 weeks after she first noticed discomfort. Magnetic resonance imaging showed persistent osteomyelitis of the distal metaphysis and diaphysis of the femur with a multifocal intraosseous abscess pocket. An incision and drainage of the abscess were conducted. The tissue culture, fungus culture, acid fast bacillus (AFB) culture, AFB smear, and tuberculosis polymerase chain reaction test results were negative. A pathologic examination confirmed the presence of actinomycosis. The patient was successfully treated with intravenous penicillin G for 8 weeks followed by oral amoxicillin-clavulanate for 6 weeks with repeated surgical debridement and drainage. After a 5-year follow up, the patient had no signs of recurring infection or complications and she had full range of movement in the affected knee. CONCLUSIONS: Although rare, actinomycotic osteomyelitis can occur in healthy people. Furthermore, actinomycotic osteomyelitis is easily misdiagnosed as tuberculosis in areas with a high prevalence of tuberculosis. To detect and identify the bacteria accurately, pathologic examination should be performed as well as culture tests, because the probability for culture confirmation of actinomycosis is quite low. The initial treatment is vital to a successful outcome without ostectomy or amputation.

Abundant expression of BMI1 in follicular lymphoma is associated with reduced overall survival.

Although generally indolent, follicular lymphoma (FL) sometimes pursues a more aggressive course leading to early death. B-cell-specific Mo-MLV insertion site-1 (BMI1) is a member of the polycomb group (PcG) proteins that confer stem cell properties through gene silencing. We used multi-channel immunofluorescence and automated image analysis to quantify BMI1 selectively in the nuclei of FL-derived B-cells in routine biopsy specimens. Applying this assay to 109 pretreatment FL biopsy samples demonstrates a significant association between abundant BMI1 and reduced overall survival (p = .001); the statistically significant association with mortality persists in a Cox proportional hazards model that includes Follicular Lymphoma International Prognostic Index (FLIPI) score, histological grade, and the presence of a component of diffuse large B-cell lymphoma in the biopsy sample. Ascertaining BMI1 over-expression may be useful in identifying patients who might benefit from novel therapies directed at reversing the chromatin-modifying functions of BMI1.

Platelet-derived growth factor receptor α in hepatocellular carcinoma is a prognostic marker independent of underlying liver cirrhosis.

BACKGROUND AND AIMS: Platelet-derived growth factor receptor alpha (PDGFRα) is suggested as a prognosis marker for hepatocellular carcinoma (HCC). Since PDGFRα is also known as a marker for activated hepatic stellate cells (HSCs), this study aimed to investigate whether PDGFRα expression in HCC was dependent on the background liver fibrous condition. RESULTS: Strong PDGFRα expression in the tumor lesions was associated with decreased survival after curative HCC resection. Expression of PDGFRα in the tumor correlated with increased collagen α1(I), lecithin retinol acyltransferase, and smooth muscle α-actin suggesting increased HSCs in tumor sites. The expression of PDGFRα in the tumor sites was associated neither with underlying liver fibrosis/cirrhosis nor with the expression of PDGFRα in adjacent non-tumor sites of the liver. MATERIALS AND METHODS: Patients with HCC who underwent liver resection as curative treatment were included in this study. Using liver samples of 95 patients, tissue microarray was constructed and immunohistochemical study of PDGFRα was conducted in both tumor and non-tumor sites. PDGFRα expression in tumor and matching non-tumor sites was compared. Freshly frozen liver tissue specimens of 16 HCC patients were used for gene expression analysis of PDGFRα and fibrosis related genes. CONCLUSIONS: Our results suggest that PDGFRα overexpression in HCC is a prognostic marker independent of adjacent non-tumor site liver fibrosis status.

Ciliated muconodular papillary tumor of the lung harboring BRAF V600E mutation and p16INK4a overexpression without proliferative activity may represent an example of oncogene-induced senescence.

Ciliated muconodular papillary tumor (CMPT) is a rare peripheral lung tumor that shows puzzling histologic features encompassing metaplastic and neoplastic nature. This type of tumor is occasionally misdiagnosed as lung adenocarcinoma clinically and pathologically, and its pathogenic mechanism has not been well characterized. We experienced a case of CMPT in a 73-year-old male and performed targeted deep sequencing to characterize its molecular features. The tumor was an ill-defined, subpleural, and non-endobronchial nodule showing glandular and papillary proliferation of mucous cells, ciliated columnar cells, and basal cells without any cytologic atypia. Abundant intra-alveolar mucin surrounded the main lesion. The patient was well without recurrence throughout 36 months of follow-up. Our case harbored BRAF V600E mutation and strongly expressed p16INK4a without proliferative activity, representing senescence and indolent biologic behavior. Overall, the results of this study indicate that BRAF V600E mutation might be the driver for tumorigenesis of CMPT and eventually leads to oncogene-induced senescence of this tumor.

The effect of neutral-surface iron oxide nanoparticles on cellular uptake and signaling pathways.

In recent years, iron oxide nanoparticles (IONPs) have been applied widely to biomedical fields. However, the relationship between the physicochemical properties of IONPs and their biological behavior is not fully understood yet. We prepared 3-methacryloxypropyltrimethoxysilane (MPS)-coated IONPs, which have a neutral hydrophobic surface, and compared their biological behavior to that of Resovist (ferucarbotran), a commercialized IONP formulation modified with carboxymethyl dextran. The rate of MPS-IONP uptake by human aortic endothelial cells (HAoECs) was higher than ferucarbotran uptake, indicating that the neutral hydrophobic nature of MPS-IONPs allowed them to be absorbed more readily through the plasma membrane. However, the signaling pathways activated by MPS-IONPs and ferucarbotran were comparable, suggesting that surface charge is not a key factor for inducing changes in HAoECs. In vivo fate analysis showed that MPS-IONPs accumulated for longer periods in tissues than hydrophilic ferucarbotran. These findings could enlarge our understanding of NP behavior for advanced applications in the biomedical field.