Bias in artificial intelligence in vascular surgery.

Application of artificial intelligence (AI) has revolutionized the utilization of big data, especially in patient care. The potential of deep learning models to learn without a priori assumption, or without prior learning, to connect seemingly unrelated information mixes excitement alongside hesitation to fully understand AI's limitations. Bias, ranging from data collection and input to algorithm development to finally human review of algorithm output affects AI's application to clinical patient presents unique challenges that differ significantly from biases in traditional analyses. Algorithm fairness, a new field of research within AI, aims to mitigate bias by evaluating the data at the preprocessing stage, optimizing during algorithm development, and evaluating algorithm output at the postprocessing stage. As the field continues to develop, being cognizant of the inherent biases and limitations related to black box decision making, biased data sets agnostic to patient-level disparities, wide variation of present methodologies, and lack of common reporting standards will require ongoing research to provide transparency to AI and its applications.

A potential treatment option for advanced non-small cell lung cancer: Three cases.

OBJECTIVE: Recent progress in targeted therapy and immunotherapy has reduced the mortality of advanced-stage patients with non-small cell lung cancer (NSCLC). However, despite advances in treatment, only some patients are eligible for and benefit from genome-targeted therapy, while few patients are ineligible for genome-driven therapy or have limited treatment options due to performance status, comorbidity, and adverse events or rejection of chemotherapy. CLINICAL FEATURES AND OUTCOMES: We report the cases of three patients with advanced NSCLC who were not available to continue conventional anticancer therapy, who were able to maintain progression-free survival (PFS) or disease-free survival (DFS), and who have shown symptom amelioration after treatment with herbal Medicine. Patients were managed only with herbal medicines according to their disease status and symptoms, without conventional anticancer therapy. Two patients with metastatic NSCLC maintained PFS for 19 and 20 months after the discontinuation of chemotherapy, respectively. A patient with locally advanced NSCLC showed no evidence of recurrence for more than 5 years despite an increase in squamous cell carcinoma antigens. These patients had considerable clinical outcomes to maintain relatively long PFS and DFS. CONCLUSION: This study demonstrates the potential treatment option of herbal medicine in inhibiting tumor progression and prolonging PFS and DFS in patients with advanced NSCLC.

Comprehensive analysis of cellular estrogen signaling in representative estrogen receptor ligands.

The estrogen receptor (ER)-mediated signaling pathway in physiological and biochemical aspects is very important in the environment, including food. The physiological action of estrogen is mediated by ER alpha (ERα) and beta (ERß), whose physiological action on estrogenic substances is complex because of the relatively low ligand-binding domain (LBD) similarity of the two ERs. In this study, the comprehensive activity of representative ER ligands was evaluated by using BRET-based ERα and ERß dimerization and ER transactivation assays to differentiate the specific binding and function of ERα and ERß from 12 representative natural and synthetic estrogenic substances. Results revealed that 11 chemicals mediated receptor ERα and ERß dimerization, 7 out of 12 chemicals were confirmed to be estrogen agonists, and 5 chemicals were antagonistic. Overall, this study demonstrated consistency between BRET dimerization and transactivation responses, supporting potential supplementary application of mechanism-based BRET assays as high-throughput screening methods for evaluation of potential endocrine-disrupting activity of environmental agents. This study also provided information about receptor specificity of ligand-mediated estrogenic activity via dimerization assays and elucidated cellular estrogen signaling pathways.

Life-Sustaining Treatment States in Korean Cancer Patients after Enforcement of Act on Decisions on Life-Sustaining Treatment for Patients at the End of Life.

PURPOSE: In Korea, the "Act on Hospice and Palliative Care and Decisions on Life-sustaining Treatment for Patients at the End of Life" was enacted on February 4, 2018. This study was conducted to analyze the current state of life-sustaining treatment decisions based on National Health Insurance Service (NHIS) data after the law came into force. MATERIALS AND METHODS: The data of 173,028 cancer deaths were extracted from NHIS qualification data between November 2015 and January 2019. RESULTS: The number of cancer deaths complied with the law process was 14,438 of 54,635 cases (26.4%). The rate of patient self-determination was 49.0%. The patients complying with the law process have used a hospice center more frequently (28% vs. 14%). However, the rate of intensive care unit (ICU) admission was similar between the patients who complied with and without the law process (ICU admission, 23% vs. 21%). There was no difference in the proportion of patients who had undergone mechanical ventilation and hemodialysis in the comparative analysis before and after the enforcement of the law and the analysis according to the compliance with the law. The patients who complied with the law process received cardiopulmonary resuscitation at a lower rate. CONCLUSION: The law has positive effects on the rate of life-sustaining treatment decision by patient's determination. However, there was no sufficient effect on the withholding or withdrawing of life-sustaining treatment, which could protect the patient from unnecessary or harmful interventions.

Preparation and Practice of the Necessary Documents in Hospital for the "Act on Decision of Life-Sustaining Treatment for Patients at the End-of-Life".

PURPOSE: Six forms relating to decisions on life-sustaining treatment (LST) for patients at the end-of-life (EOL) in hospital are required by the "Act on Decision of LST for Patients at the EOL." We investigated the preparation and creation status of these documents from the database of the National Agency for Management of LST. MATERIALS AND METHODS: We analyzed the contents and details of each document necessary for decisions on LST, and the creation status of forms. We defined patients completing form 1 as "self-determined" of LST, and those whose family members had completed form 11/12 as "family decision" of LST. According to the determination subject, we compared the four items of LST on form 13 (the paper of implementation of LST) and the documentation time interval between forms. RESULTS: The six forms require information about the patient, doctor, specialized doctor, family members, institution, decision for LST, and intention to use hospice services. Of 44,381 who had completed at least one document, 36,693 patients had form 13. Among them, 11,531, 10,976, and 12,551 people completed forms 1, 11, and 12, respectively. The documentation time interval from forms 1, 11, or 12 to form 13 was 8.6±13.6 days, 1.0±9.5 days, and 1.5±9.7 days, respectively. CONCLUSION: The self-determination rate of LST was 31% and the mean time interval from self-determination to implementation of LST was 8.6 days. The creation of these forms still takes place when the patients are close to death.

Current Status and Cardinal Features of Patient Autonomy after Enactment of the Life-Sustaining Treatment Decisions Act in Korea.

PURPOSE: The main purpose of the Life-Sustaining Treatment Decisions Act recently enacted in Korea is to respect the patient's self-determination. We aimed to investigate the current status and features of patient self-determination after implementation of the law. MATERIALS AND METHODS: Between February 2018 and January 2019, 54,635 cancer deaths were identified from the National Health Insurance Service (NHIS) database. We analyzed the characteristics of decedents who complied with the law process by self-determination compared with decedents with family determination and with decedents who did not comply with the law process. RESULTS: In multivariable analysis, patients with self-determination were younger, were less likely to live in rural areas, were less likely to belong to the highest income quintile, were less likely to be treated in general hospitals, and were more likely to show a longer time from cancer diagnosis compared with patients with family determination. Compared with patients who did not comply with the law process, patients with self-determination were younger, lived in Seoul or capital area, were less likely to belong to the highest income quintile, were treated in general hospitals, were less likely to have genitourinary or hematologic malignancies, scored higher on the Charlson comorbidity index, and showed a longer time from cancer diagnosis. Patients with self-determination were more likely to use hospice and less likely to use intensive care units (ICUs) at the end-of-life (EOL). CONCLUSION: Decedents with self-determination were more likely to be younger, reside in the Seoul or capital area, show a longer time from cancer diagnosis, and were less likely to belong to the highest income quintile. They utilized hospice more frequently, and received less ICU care at the EOL.

The Situation of Life-Sustaining Treatment One Year after Enforcement of the Act on Decisions on Life-Sustaining Treatment for Patients at the End-of-Life in Korea: Data of National Agency for Management of Life-Sustaining Treatment.

PURPOSE: The "Act on Hospice and Palliative Care and Decisions on Life-Sustaining Treatment for Patients at the End-of-Life" was enacted on February 3, 2016 and went into effect on February 4, 2018 in Korea. This study reviewed the first year of determination to life-sustaining treatment (LST) through data analysis of the National Agency for Management of Life-Sustaining Treatment. MATERIALS AND METHODS: The National Agency for Management of LST provided data between February 4, 2018 and January 31, 2019 anonymously from 33,549 patients. According to the forms patients were defined as either elf-determinants or family-determinants. RESULTS: The median age of the patient was 73 and the majority was male (59.9%). Cancer patients were 59% and self-determinants were 32.1%. Cancer patients had a higher rate of self-determinants than non-cancer (47.3% vs. 10.1%). Plan for hospice service was high in cancer patients among self-determinants (81.0% vs. 37.5%, p < 0.001). In comparison to family-determinants, self-determinants were younger (median age, 67 years vs. 75 years; p < 0.001) and had more cancer diagnosis (87.1% vs. 45.9%, p < 0.001). Decision of withholding or withdrawing of LSTs in cancer patients was higher than non-cancer patients in four items. CONCLUSION: Cancer patients had a higher rate in self-determination and withholding or withdrawing of LSTs than non-cancer patients. Continued revision of the law and education of the public will be able to promote withdrawing or withholding the futile LSTs in patients at end-of-life. Further study following the revision of the law should be evaluated to change of end-of-life care.

Preoperative plateletcrit is a Prognostic Biomarker for Survival in Patients with Non-Small Cell Lung Cancer.

Objectives: Several factors associated with the prognosis of patients with NSCLC have been reported in the literature; however, most of these factors cannot be examined preoperatively. In this study, the clinical utility of platelet parameters in patients with NSCLC who underwent curative resection was evaluated. Materials and Methods: A retrospective study on patients with NSCLC who underwent curative resection from July 2006 to September 2016 was conducted. The Cox proportional hazard regression model was applied to evaluate the variables that demonstrated effects on disease-free and overall survival (DFS and OS). Results: A total of 116 patients with NSCLC were analyzed. There were 15 patients with plateletcrit greater than 0.2755%, and 101 patients whose plateletcrit was 0.2755% or lower. Multivariate analysis identified plateletcrit higher than 0.2755% (hazard ratio [HR] = 4.18, 95% confidence interval [CI] = 1.54-11.34, P =0.004), patient age of 65 years or more (HR = 4.02, 95% CI = 1.67-9.66, P = 0.001), and stage II or IIIA disease (HR = 2.95, 95% CI = 1.26-6.87, P = 0.012) as independent factors for OS that predicted a poor prognosis. Multivariate analysis identified plateletcrit higher than 0.2755% (HR = 4.07, 95% CI = 1.52-10.94, P = 0.005), stage II or IIIA disease (HR = 5.38, 95% CI = 2.71-10.66, P < 0.001) and non-adenocarcinoma (HR = 1.92, 95% CI = 1.02-3.59, P = 0.040) as independent prognostic factors for DFS that predicted a poor prognosis. Conclusion: Our results suggest a potential role of preoperative plateletcrit as an independent prognostic marker for patients with resectable NSCLC.

A Randomized, Open-Label, Phase II Study Comparing Pemetrexed Plus Cisplatin Followed by Maintenance Pemetrexed versus Pemetrexed Alone in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer after Failure of First-Line EGFR Tyrosine Kinase Inhibitor: KCSG-LU12-13.

PURPOSE: The optimal cytotoxic regimens have not been established for patients with non-small cell lung cancer (NSCLC) who develop disease progression on first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). MATERIALS AND METHODS: We conducted a multi-center randomized phase II trial to compare the clinical outcomes between pemetrexed plus cisplatin combination therapy followed by maintenance pemetrexed (PC) and pemetrexed monotherapy (P) after failure of first-line EGFR-TKI. The primary objective was progression-free survival (PFS), and secondary objectives included overall response rate (ORR), overall survival (OS), health-related quality of life (HRQOL), and safety and toxicity profiles. RESULTS: A total of 96 patientswere randomized, and 91 patientswere treated at 14 centers in Korea. The ORR was 34.8% (16/46) for the PC arm and 17.8% (8/45) for the P arm (p=0.066). With 23.4 months of follow-up, the median PFS was 5.4 months in the PC arm and 6.4 months in the P arm (p=0.114). The median OS was 17.9 months and 15.7 months in PC and P arms, respectively (p=0.787). Adverse events ≥ grade 3 were reported in 12 patients (26.1%) in the PC arm and nine patients (20.0%) in the P arm (p=0.491). The overall time trends of HRQOL were not significantly different between the two arms. CONCLUSION: The outcomes of pemetrexed therapy in NSCLC patients with disease progression after firstline EGFR-TKI might not be improved by adding cisplatin.

Recurrent maxillary sinus cancer with only adrenal metastasis.

Maxillary sinus cancer is rare, and often presents as a locally advanced disease. Recurrence commonly occurs locoregionally, while fewer patients present with distant metastasis; the most common sites involved are the lung and bone. This report discusses the case of a 64-year-old male who presented with a mass in the left submandibular area. Biopsy was performed and histological analysis identified a poorly differentiated squamous cell carcinoma. After staging work up, it was concluded the patient had a maxillary sinus squamous cell carcinoma at clinical stage IVA. The patient received a left partial maxillectomy and left radical neck dissection followed by postoperative chemoradiotherapy. After three months of CRT, the patient developed a left adrenal gland metastasis without locoregional failure. The patient subsequently received a laparoscopic left adrenalectomy and the results of histological analysis revealed a poorly-differentiated squamous cell carcinoma. Within one month of surgery, the patient had developed multiple metastases at the left adrenalectomy site and succumbed to the disease four months later.

Different subtypes of epithelioid sarcoma and their clinical implication: long-term multi-institutional experience with a rare sarcoma.

Epithelioid sarcoma (ES) is a very rare soft-tissue sarcoma with a high tendency of recurrence and metastasis. We analyzed clinical features of ES and aimed to identify the potential role of radio- and chemotherapy in ES. Fifty-five patients diagnosed with ES between 1997 and 2014 were enrolled from seven tertiary hospitals in Korean Cancer Research Group. The clinical variables were retrospectively reviewed and analyzed. Forty-six (84%) patients underwent surgical resection of ES, and among them, 27 experienced recurrence. In these patients, resection margin status and adjuvant radiotherapy were independent prognostic factors for longer recurrence-free survival (RFS), while adjuvant chemotherapy did not influence RFS. Twenty-two (40%) patients received palliative chemotherapy for metastatic or recurrent ES, and in these patients, palliative chemotherapy was the only independent prognostic factor for longer overall survival. Intriguingly, the clinical benefit of radio- and chemotherapy was observable only in proximal ES, but not in extremity ES, indicating that subtypes of ES might respond to radio- or chemotherapy differently. Proximal ES seems to benefits more from active anticancer treatment than conventional extremity ES. The aggressive characteristics of proximal ES could be overcome with an optimal multimodal treatment.

Replacing the terminal piperidine in ceritinib with aliphatic amines confers activities against crizotinib-resistant mutants including G1202R.

The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound 10 shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC50 of 1.8 nM. Furthermore, pharmacokinetic profiles of 10 is apparently better than that of ceritinib. In murine xenograft studies, compound 10 turns out to be as active as ceritinib, suggesting that further optimization of 10 may lead to clinical candidates overcoming ALK mutant issues.

Assessment of Independent Risk Factors of Developing Pneumothorax During Percutaneous Core Needle Lung Biopsy: Focus on Lesion Depth.

BACKGROUND: Previous studies identifying risk factors for pneumothorax in percutaneous core needle lung biopsies reported inconsistent and contradictory results. OBJECTIVES: We aimed to identify independent risk factors for pneumothorax associated with computed tomography (CT)-guided percutaneous core needle lung biopsy (PCNB). PATIENTS AND METHODS: We retrospectively reviewed 591 biopsy procedures for focal lung lesions. Risk factors for pneumothorax as a complication after lung biopsy were determined by univariate and multivariate analyses of variables including the patient's age, gender, lesion depth from the pleural surface, lesion size, lesion location, presence or absence of fissure crossing by the needle, emphysema in the same lobe where the biopsy was performed, and the final diagnosis of the biopsy lesion. RESULTS: Pneumothorax occurred in 100 (16.9%) of 591 procedures. Based on univariate analyses, significant risk factors affecting the incidence of pneumothorax were patient gender (P = 0.039), lesion depth from the pleural surface (P < 0.001), fissure crossing by the needle (P = 0.002), and the presence of emphysema (P = 0.009). From the multivariate analysis, an increased rate of pneumothorax was strongly correlated with lesion depth from the pleural surface (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.50 - 1.96; P < 0.001) and the presence of emphysema (OR, 2.95; 95% CI, 1.73 - 5.04; P < 0.001). CONCLUSION: Lesion depth from the pleural surface and the presence of emphysema were strongly correlated with the increasing incidence of pneumothorax after CT-guided PCNB. Our results may be applicable for the risk management of PCNBs to reduce pneumothorax as a complication.

Factors Influencing Clinicians' Choice of Adjuvant S-1 versus Capecitabine plus Oxaliplatin after Curative Gastrectomy in Patients with Gastric Cancer.

Purpose: Two recent randomized, phase III trials in Asia (ACTS-GC and CLASSIC) documented the survival benefit of postoperative chemotherapy after D2 lymph node dissection in patients with gastric cancer. We sought to determine what factors influenced clinicians' choices of either S-1 or capecitabine plus oxaliplatin (CAPOX) as adjuvant therapy after curative D2 gastrectomy. Materials and Methods: We retrospectively reviewed the clinicopathologic factors and adjuvant treatments for 435 patients from nine centers in Korea who were treated with either S-1 or CAPOX adjuvant chemotherapy after undergoing curative D2 gastrectomy between January 2013 and July 2014. Results: Of the 435 patients, 204 (46.9%) were treated with S-1 and 231 (53.1%) were treated with CAPOX. The median age at diagnosis was 61 years (range, 30-88). CAPOX was prescribed more often for patients who were 65 years of age or younger than for patients who were age 65 or older (77.1% vs. 22.9%, P<0.0001). Of the patients in stage II, 121 (60.8%) were treated with S-1 and 78 (39.2%) were given CAPOX; however, of those in stage III, 83 (35.2%) received S-1 and 153 (64.8%) were treated with CAPOX (P<0.0001). Conclusions: Clinicians only preferred CAPOX for younger patients with stage III gastric cancer after curative D2 gastrectomy. However, for elderly patients, clinicians more chose S-1 regardless of the stage.

Inhibitory effect of 2-methyl-naphtho[1,2,3-de]quinolin-8-one on melanosome transport and skin pigmentation.

Melanosomes are lysosome-related organelles with specialized capabilities of melanin synthesis and movement mediated by the Rab27a-Melanophilin-MyosinVa protein complex. In this study, we found that 2-methyl-naphtho[1,2,3-de]quinolin-8-one (MNQO) induced melanosome aggregation around the nucleus in melan-a melanocytes and in melan-a melanocytes/SP-1 keratinocyte co-cultures without inducing toxicity or changing the melanin content. Western blot and real-time PCR analyses showed that MNQO decreased expression of the Rab27a, Melanophilin and MyosinVa proteins and mRNAs, respectively, in melan-a melanocytes. In a reconstituted human epidermis model, treatment with 0.001% MNQO reduced skin pigmentation. Also, MNQO reduced skin pigmentation in brown guinea pigs induced by UVB irradiation. These results indicated that regulation of melanosome transport may serve as a good target for new skin depigmenting agents and MNQO itself could be a candidate.

Angiosarcoma after excisional surgery for chronic lymphedema.

Angiosarcoma is a rare soft tissue sarcoma of endothelial cell origin. It can arise from the endothelium of lymphatics (lymphangiosarcoma) or blood vessels (hemangiosarcoma). Chronic lymphedema of any origin is associated with its development. Few cases have been reported after surgical procedures for lymphedema. Here, we report one case of angiosarcoma that developed 15 months after excisional surgery for lymphedema. In spite of radical surgery and adjuvant chemoradiotherapy, the patient died of multiple lung metastases and pleural effusion 13 months later.

Epidermal growth factor receptor (EGFR) exon 20 mutations in non-small-cell lung cancer and resistance to EGFR-tyrosine kinase inhibitors.

INTRODUCTION: In patients with non-small cell lung cancer (NSCLC), the predictive value of rare epidermal growth factor receptor (EGFR) exon 20 mutations in determining a patient's response to EGFR tyrosine kinase inhibitor (TKI) treatment is unclear. PATIENTS AND METHODS: We reviewed data for NSCLC patients harboring EGFR exon 20 mutations from two hospitals in Korea. EGFR mutations were analyzed using directional sequencing. RESULTS: We identified eight patients carrying EGFR exon 20 mutations, seven of whom had insertional mutations. Three patients carried previously unreported insertional mutations. Among six patients who were treated with EGFR TKI, one showed stable disease and three showed primary resistance. Response evaluations were not performed for the other two patients because of their clinical deterioration. CONCLUSIONS: EGFR exon 20 insertional mutations, including three that were previously unreported, were associated with the poor response of patients to TKI treatment.

miR-140-5p suppresses BMP2-mediated osteogenesis in undifferentiated human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) have self-renewal and differentiation capabilities but the regulatory mechanisms of MSC fate determination remain poorly understood. Here, we aimed to identify microRNAs enriched in hMSCs that modulate differentiation commitments. Microarray analysis revealed that miR-140-5p is commonly enriched in undifferentiated hMSCs from various tissue sources. Moreover, bioinformatic analysis and luciferase reporter assay validated that miR-140-5p directly represses bone morphogenic protein 2 (BMP2). Furthermore, blocking miR-140-5p in hMSCs increased the expression of BMP signaling components and critical regulators of osteogenic differentiation. We propose that miR-140-5p functionally inhibits osteogenic lineage commitment in undifferentiated hMSCs.

Hesperidin Suppresses Melanosome Transport by Blocking the Interaction of Rab27A-Melanophilin.

We investigated the inhibitory effects of hesperidin on melanogenesis. To find melanosome transport inhibitor from natural products, we collected the structural information of natural products from Korea Food and Drug Administration (KFDA) and performed pharmacophore-based in silico screening for Rab27A and melanophilin (MLPH). Hesperidin did not inhibit melanin production in B16F10 murine melanoma cells stimulated with α-melanocyte stimulating hormone (α-MSH), and also did not affect the catalytic activity of tyrosinase. But, hesperidin inhibited melanosome transport in melanocyte and showed skin lightening effect in pigmented reconstructed epidermis model. Therefore, we suggest that hesperidin is a useful inhibitor of melanosome transport and it might be applied to whitening agent.

Treatment of dexamethasone-induced hiccup in chemotherapy patients by methylprednisolone rotation.

Dexamethasone-induced hiccup (DIH) is an underrecognized symptom in patients with cancer, and little information is available about its treatment. The aims of this study were to investigate the feasibility of methylprednisolone rotation as treatment and to confirm the male predominance among those with cancer who experienced DIH during chemotherapy. Methods. Persons with cancer who experienced hiccups during chemotherapy treatment and who were receiving treatment with dexamethasone were presumed to have DIH. The following algorithmic practice was implemented for antiemetic corticosteroid use: rotation from dexamethasone to methylprednisolone in the next cycle and dexamethasone re-administration in the second cycle of chemotherapy after recognition of hiccups to confirm DIH. All other antiemetics except corticosteroid remained unchanged. Patients (n = 40) were recruited from eight cancer centers in Korea from September 2012 to April 2013. Data were collected retrospectively. Results. Hiccup intensity (numeric rating scale [NRS]: 5.38 vs. 0.53) and duration (68.44 minutes vs. 1.79 minutes) were significantly decreased after rotation to methylprednisolone, while intensity of emesis was not increased (NRS: 2.63 vs. 2.08). Median dose of dexamethasone and methylprednisolone were 10 mg and 50 mg, respectively. Thirty-four (85%) of 40 patients showed complete resolution of hiccups after methylprednisolone rotation in the next cycle. Of these 34 patients, 25 (73.5%) had recurrence of hiccups after dexamethasone re-administration. Compared with baseline values, hiccup intensity (NRS: 5.24 vs. 2.44) and duration (66.43 minutes vs. 22.00 minutes) were significantly attenuated after dexamethasone re-administration. Of the 40 eligible patients, 38 (95%) were male. Conclusion. DIH during chemotherapy could be controlled without losing antiemetic potential by replacing dexamethasone with methylprednisolone. We also identified a male predominance of DIH. Further prospective studies are warranted.