Search

PURPOSE: The proportion of patients with advanced cancer who receive outpatient specialty palliative care (OSPC) is as low as 2.0%. Improved understanding of the system-level factors influencing use of OSPC could inform adaptations to the delivery of palliative care to maximize access. We examined associations between OSPC use among patients with advanced solid tumors and oncology-OSPC clinic colocation and patient travel time to an OSPC clinic. PATIENTS AND METHODS: We conducted a retrospective cohort study of patients with advanced solid tumors receiving oncologic treatment between January 1 and December 31, 2016, within a comprehensive cancer center network with well-established, oncology-specific OSPC clinics. Multivariable logistic regression analysis was used to evaluate the associations of clinic colocation and geographic access with OSPC use. RESULTS: Of 9,485 patients with advanced solid tumors, 478 (5.0%) received OSPC services in 2016. After controlling for age, sex, marital status, cancer type, insurance, treatment intent, and illness severity, patients whose oncologist practices were colocated with OSPC clinics were more likely to use OSPC (odds ratio [OR], 19.2; 95% CI, 14.1 to 26.2). Compared with patients who lived > 90 minutes from an OSPC clinic, patients with travel times of < 30 minutes (OR, 3.2; 95% CI, 2.2 to 4.6) and 31 to 60 minutes (OR, 2.4; 95% CI, 1.6 to 3.6) were also more likely to use OSPC. CONCLUSION: Among patients with advanced solid tumors, colocation of oncology and OSPC clinics and shorter patient travel time were associated with greater odds of using OSPC. Future efforts to increase OSPC use in this population should consider clinic colocation and travel burden.

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a serious disease with a poor prognosis. Only a minority of patients undergo surgery due to the advanced stage of the disease, and patients with early-stage disease, who are expected to have a better prognosis, often experience recurrence. Thus, it is important to identify the risk factors for early recurrence and to develop an adequate treatment plan. AIM To evaluate the predictive factors associated with the early recurrence of early-stage PDAC. METHODS This study enrolled 407 patients with stage I PDAC undergoing upfront surgical resection between January 2000 and April 2016. Early recurrence was defined as a diagnosis of recurrence within 6 mo of surgery. The optimal cutoff values were determined by receiver operating characteristic (ROC) analyses. Univariate and multivariate analyses were performed to identify the risk factors for early recurrence. RESULTS Of the 407 patients, 98 patients (24.1%) experienced early disease recurrence: 26 (26.5%) local and 72 (73.5%) distant sites. In total, 253 (62.2%) patients received adjuvant chemotherapy. On ROC curve analysis, the optimal cutoff values for early recurrence were 70 U/mL and 2.85 cm for carbohydrate antigen 19-9 (CA 19-9) levels and tumor size, respectively. Of the 181 patients with CA 19-9 level > 70 U/mL, 59 (32.6%) had early recurrence, compared to 39 (17.4%) of 226 patients with CA 19-9 level ≤ 70 U/mL (P < 0.001). Multivariate analysis revealed that CA 19-9 level > 70 U/mL (P = 0.006), tumor size > 2.85 cm (P = 0.004), poor differentiation (P = 0.008), and non-adjuvant chemotherapy (P = 0.025) were significant risk factors for early recurrence in early-stage PDAC. CONCLUSION Elevated CA 19-9 level (cutoff value > 70 U/mL) can be a reliable predictive factor for early recurrence in early-stage PDAC. As adjuvant chemotherapy can prevent early recurrence, it should be recommended for patients susceptible to early recurrence.

The identification of viable tumor after stereotactic radiosurgery (SRS) is important for future targeted therapy. This study aimed to determine whether tumor habitat on structural and physiologic MRI can distinguish viable tumor from radiation necrosis of brain metastases after SRS. Multiparametric contrast-enhanced T1- and T2-weighted imaging, apparent diffusion coefficient (ADC), and cerebral blood volume (CBV) were obtained from 52 patients with 69 metastases, showing enlarging enhancing masses after SRS. Voxel-wise clustering identified three structural MRI habitats (enhancing, solid low-enhancing, and nonviable) and three physiologic MRI habitats (hypervascular cellular, hypovascular cellular, and nonviable). Habitat-based predictors for viable tumor or radiation necrosis were identified by logistic regression. Performance was validated using the area under the curve (AUC) of the receiver operating characteristics curve in an independent dataset with 24 patients. None of the physiologic MRI habitats was indicative of viable tumor. Viable tumor was predicted by a high-volume fraction of solid low-enhancing habitat (low T2-weighted and low CE-T1-weighted values; odds ratio [OR] 1.74, p

Severe pulmonary hypertension (PHT) is a contraindication to liver transplantation (LT); however, the prognostic implication of mild to moderate PHT in living-donor LT (LDLT) is unknown. The study cohort retrospectively included 1307 patients with liver cirrhosis who underwent LDLT. PHT was defined as a mean pulmonary artery pressure (PAP) of ≥25 mmHg, measured intraoperatively just before surgery. The primary endpoint was graft failure within 1 year after LDLT, including retransplantation or death from any cause. The secondary endpoints were in-hospital adverse events. In the overall cohort, the median Model for End-stage Liver Disease-Sodium (MELD-Na) score was 19, and 100 patients (7.7%) showed PHT. During 1-year follow-up, graft failure occurred in 94 patients (7.2%). Patients with PHT had lower 1-year graft survival (86% vs. 93.4%, P = 0.005) and survival rates (87% vs. 93.6%, P = 0.011). Mean PAP was associated with a high risk of in-hospital adverse events and 1-year graft failure. Adding the mean PAP to the clinical risk model improved the risk prediction. In conclusion, mild to moderate PHT was associated with higher risks of 1-year graft failure and in-hospital events, including mortality after LDLT in patients with liver cirrhosis. Intraoperative mean PAP can help predict the early clinical outcomes after LDLT.

Purpose Interest in unenhanced magnetic resonance imaging (MRI) screening for breast cancer is growing due to concerns about gadolinium deposition in the brain and the high cost of contrast-enhanced MRI. The purpose of this report is to describe the protocol of the Diffusion-Weighted Magnetic Resonance Imaging Screening Trial (DWIST), which is a prospective, multicenter, intraindividual comparative cohort study designed to compare the performance of mammography, ultrasonography, dynamic contrast-enhanced (DCE) MRI, and diffusion-weighted (DW) MRI screening in women at high risk of developing breast cancer. Methods A total of 890 women with BRCA mutation or family history of breast cancer and lifetime risk ≥ 20% are enrolled. The participants undergo 2 annual breast screenings with digital mammography, ultrasonography, DCE MRI, and DW MRI at 3.0 T. Images are independently interpreted by trained radiologists. The reference standard is a combination of pathology and 12-month follow-up. Each image modality and their combination will be compared in terms of sensitivity, specificity, accuracy, positive predictive value, rate of invasive cancer detection, abnormal interpretation rate, and characteristics of detected cancers. The first participant was enrolled in April 2019. At the time of manuscript submission, 5 academic medical centers in South Korea are actively enrolling eligible women and a total of 235 women have undergone the first round of screening. Completion of enrollment is expected in 2022 and the results of the study are expected to be published in 2026. Discussion DWIST is the first prospective multicenter study to compare the performance of DW MRI and conventional imaging modalities for breast cancer screening in high-risk women. DWIST is currently in the patient enrollment phase. Trial registration ClinicalTrials.gov Identifier: NCT03835897.

From May 2015 to June 2016, 296 patients undergoing 1.5-Tesla MRI for symptoms of acute ischemic stroke were retrospectively enrolled. Conventional, echo-planar imaging (EPI) and echo train length (ETL)-FLAIR were simultaneously obtained in 118 patients (1st group), and conventional, ETL-, and repetition time (TR)-FLAIR were simultaneously obtained in 178 patients (2nd group). A total of 595 radiomics features were extracted from one region-of-interest (ROI) reflecting the acute and chronic ischemic hyperintensity, and concordance correlation coefficients (CCC) of the radiomics features were calculated between the fast scanned and conventional FLAIR for paired patients (1st group and 2nd group). Stabilities of the radiomics features were compared with the proportions of features with a CCC higher than 0.85, which were considered to be stable in the fast scanned FLAIR. EPI-FLAIR showed higher proportions of stable features than ETL-FLAIR, and TR-FLAIR also showed higher proportions of stable features than ETL-FLAIR, both in acute and chronic ischemic hyperintensities of whole- and intersection masks (p Radiomics features in fast scanned FLAIR showed variable stabilities according to the sequences compared with conventional FLAIR. Therefore, radiomics features may be used cautiously in applications for feature analysis as their stability and robustness can be variable.

Background: Prediction of post-pancreaticoduodenectomy (PD) morbidity is difficult, especially in the early postoperative period when CT (Computed Tomography) scans are not available. Elevated serum amylase and lipase in postoperative day 0 or 1 may be used to define postoperative acute pancreatitis (POAP), but the existing literature does not agree on whether POAP is significantly associated with postoperative pancreatic fistula (POPF). Methods: We analyzed the data obtained from a previously published randomized controlled trial. POAP was defined as elevations in serum amylase above 110 U/L on postoperative day 0 or 1. Clinically relevant POAP (CR-POAP) was defined as elevations in C-reactive protein level (CRP) on postoperative day 2 in those with POAP. Postoperative complications including severe complications (Clavien–Dindo ≥ IIIa), POPF, and clinically relevant POPF (CR-POPF) were analyzed. Results: In 246 patients, POAP did not show significant associations with total postoperative complications (odds ratio (OR) 0.697, 95% CI, 0.360–1.313, p = 0.271), severe complications (OR 0.647, 95% CI, 0.258–1.747, p = 0.367), and CR-POPF (OR 0.998, 95% CI, 0.310–3.886, p = 0.998) in multivariable analysis. Conclusions: In patients undergoing PD, POAP was not significantly associated with postoperative complications including POPF. Caution should be taken when using POAP as a predictor of POPF.

Although surgery is the primary treatment for ampullary cancer (AC), the benefit of adjuvant chemotherapy (CTx) has not yet been confirmed.AC patients who were administered 5-fluorouracil(FU)/leucovorin(LV)-based CTx after curative intent surgery between 2011 and 2019 were included. Prognosis was compared between the observation (OB) and CTx groups after propensity score matching (PSM) using perioperative variables to control differences in patient characteristics.Before PSM, of 475 patients, those in the CTx group (n = 281) had worse 5-year overall survival (OS) (82.1% vs. 78.5%, p = 0.017) and worse 5-year recurrence-free survival (RFS) (54.9% vs. 75.7%, p 0.001) than those in the OB group (n = 194). In addition, the CTx group had a higher rate of poor prognostic factors such as a high T stage (p 0.001), node metastasis (p 0.001), and poor differentiation (p 0.001). After PSM, perioperative outcomes were comparable. In addition, there were no significant differences in OS (hazard ratio [HR], 1.085; 95% confidence interval [CI], 0.688-1.710; p = 0.726) or RFS (HR, 0.883; 95% CI, 0.613 1.272; p = 0.505) between the CTx (n = 123) and OB (n = 123) groups even after stratification by TNM stage. Intestinal subtype showed better 5-year OS (83.7% vs 33.2%, p = 0.015) and RFS (46.5% vs 24.9%, p = 0.035) rate compared with pancreatobiliary/mixed subtype.Patients who received adjuvant chemotherapy based on 5-FU/LV showed comparable oncologic outcomes to patients in the OB group even after stratification by tumor stage. The patients with intestinal subtype showed oncologic benefit for adjuvant 5-FU/LV CTx compared with pancreatobiliary or mixed subtypes.

BACKGROUND AND OBJECTIVES: The existing prediction formulas for in-hospital mortality of very low birth weight (VLBW) infants were mostly developed in the 1990s or 2000s and thus may not reflect the recently improved levels of neonatal care. We conducted this study to build a model for predicting the in-hospital mortality using perinatal factors available soon after birth. METHODS: We gathered data on VLBW infants from the Korean Neonatal Network, a nationwide, prospective, Web-based registry that enrolled patients from 2013 to 2017. Perinatal variables that were significantly associated with mortality in univariate logistic regression or those with apparent clinical importance were included in the multivariable logistic regression model. The final formula was constructed by considering the collinearity, parsimony, goodness of fit, and clinical interpretation. RESULTS: A total of 9248 VLBW infants were analyzed, including 1105 (11.9%) who died during hospitalization. The mean gestational age was 29.0 ± 2.9 weeks and the mean birth weight was 1096 ± 280 g. Significant variables used in the final equation included polyhydramnios, oligohydramnios, gestational age, Apgar score at 1 minute, intubation at birth, birth weight, and base excess. In internal validation, the area under the curve (AUC) for the prediction of in-hospital mortality was 0.870 and the optimism-corrected AUC was 0.867. The prediction equation revealed good discrimination and calibration in the external validation as well (AUC: 0.876). CONCLUSIONS: The newly developed Korean Neonatal Network prediction formula for in-hospital mortality could be a useful tool in counseling by providing a reliable prediction for the in-hospital mortality of VLBW infants.

The advent of Industry 4.0, partly characterized by the development of cyber-physical systems (CPSs), naturally entails the need for reliable security schemes. In particular, accurate detection of anomalies is of paramount importance, as even a small number of anomalous instances can trigger a catastrophic failure, often leading to a cascading one, throughout the CPS due to its interconnectivity. In this work, we aim to contribute to the body of literature on the application of anomaly detection techniques in CPSs. We propose novel Functional Data Analysis (FDA) and Autoencoder-based approaches for anomaly detection in the Secure Water Treatment (SWaT) dataset, which realistically represents a scaled-down industrial water treatment plant. We demonstrate that our methods can capture the underlying forecasting error patterns of the SWaT dataset generated by Mixture Density Networks (MDNs). We evaluate our detection performances using the \(F_1\) score and show that our methods empirically outperform the baseline approaches—cumulative sum (CUSUM) and static thresholding. We also provide a comparative analysis of our methods to discuss their abilities as well as limitations.

To determine reproducible MRI parameters predictive of molecular subtype and risk stratification in glioma and develop a structured reporting system. All study patients were initially diagnosed with glioma, 141 from the Cancer Genome Atlas and 131 from our tertiary institution, as training and validation sets, respectively. Images were analyzed by three neuroradiologists with 1–7 years of experience. MRI features including contrast enhancement pattern, necrosis, margin, edema, T2/FLAIR mismatch, internal cyst, and cerebral blood volume higher than normal cortex were reported using a structured reporting system. The pathology was stratified into five risk types: (1) oligodendroglioma, isocitrate dehydrogenase [IDH]-mutant, 1p19q co-deleted; (2) diffuse astrocytoma, IDH-mutant, grade II–III; (3) glioblastoma, IDH-mutant, grade IV; (4) diffuse astrocytoma, IDH-wild, grade II–III; and (5) glioblastoma, IDH-wild, grade IV. Significant predictors were selected using multivariate logistic regression, and diagnostic performance was tested using a validation set. Reproducible imaging parameters exhibiting > 50% agreement across readers included the presence of necrosis, T2/FLAIR mismatch, internal cyst, and predominant contrast enhancement. In the validation set, prediction of risk type 5 exhibited the highest diagnostic performance with AUCs of 0.92 (reader 1) and 0.93 (reader 2) with predominant enhancement, followed by risk type 2 with AUCs of 0.95 and 0.95 with T2/FLAIR mismatch sign and no necrosis, and risk type 1 with AUCs of 0.84 and 0.83 with internal cyst or necrosis. Risk types 3 and 4 were difficult to visually predict. Imaging parameters with high reproducibility enabling prediction of IDH-wild-type glioblastoma, IDH-mutant/1p19q co-deletion oligodendroglioma, and IDH-mutant diffuse astrocytoma were identified. • Reproducible MRI parameters for determining molecular subtypes of glioma included the presence of necrosis, T2/FLAIR mismatch, internal cyst, and predominant contrast enhancement. • IDH-wild type glioblastoma, IDH-mutant/1p19q co-deletion oligodendroglioma, and IDH-mutant low-grade astrocytoma were identified using MRI parameters with high inter-reader reproducibility. • Identification of IDH-wild type low-grade glioma and IDH-mutant glioblastoma was difficult by visual analysis.

Background Sarcopenia, known as physical frailty, is highly prevalent in older patients and is related to adverse outcomes post-cardiac surgery. However, whether sarcopenia assessment can reclassify an individual patients’ risk, which is estimated by Society of Thoracic Surgeons-predicted risk of mortality scores in patients who undergo surgical aortic valve replacement, is unclear. Methods This retrospective, single center, cohort study comprised 874 patients aged ≥65 years who underwent surgical aortic valve replacement between 2009 and 2016. Total skeletal muscle area was calculated using height-squared and was measured by preoperative computed tomography at the third lumbar vertebra inferior border using machine learning-based analysis. Sex-specific Z-scores were calculated and patients in the lowest Z-score tertile were considered to have sarcopenia. The primary endpoint was 30-day mortality, and secondary endpoints were in-hospital events, 1-year mortality, and long-term mortality. Results Thirty-day mortality, 30-day in-hospital events, and one-year mortality rates were 4.7%, 17.6%, and 8.0%, respectively. As the Z-score decreased, early adverse event odds showed a stepwise increase. Sarcopenia were independently associated with higher 30-day mortality, 30-day in-hospital events, and 1-year mortality. Reclassification analyses showed improvements in the ability to predict early adverse events after adding the Z-scores over and above the Society of Thoracic Surgeons-predicted risk of mortality scores (All, p Conclusions Sarcopenic patients had significantly higher risks of early adverse events and long-term mortality after undergoing surgical aortic valve replacement than non-sarcopenic patients. Sarcopenia determined by preoperative computed tomography can enhance the prediction of postoperative outcome risk.

Although inhaled corticosteroids (ICSs) are the recommended first-line therapy for asthma, determining whether to continue or discontinue ICS treatment in patients with mild asthma remains challenging for clinicians. Several studies have revealed that patients with mild-persistent asthma maintained a well-controlled state after ICS withdrawal. However, the long-term outcomes of ICS withdrawal have not yet been determined.To determine the possible clinical outcomes of the discontinuation of ICS in patients with well-controlled mild asthma.We investigated the clinical outcomes of discontinuing ICSs in patients with well-controlled mild asthma and compared the time to loss of control (LOC) between patients who stopped ICS treatment (ICS withdrawal group, IWG) and those who continued treatment for 3 years (continuous ICS group, CIG).A significant difference in the time to LOC was observed between the IWG and CIG (hazard ratio, 2.56; 95% confidence interval, 1.52-4.33; P.001). Increasing fractional exhaled nitric oxide levels (P = 0.008) and sputum eosinophil counts (%) (P = 0.015) revealed a weak but significant association with LOC risk in the CIG. The sputum eosinophil counts (P = 0.039) and serum total immunoglobulin E levels (P = 0.014) were significantly higher in the LOC group than in the non-LOC group of the CIG.Our results suggest that the maintenance of ICS treatment may help keep patients' asthma under control. Furthermore, patients with LOC had significantly higher sputum eosinophil counts in the CIG than those in the non-LOC group. Therefore, continuous ICS use by patients with mild, well-controlled asthma could be associated with good clinical outcomes.ClinicalTrials.gov Identifier: KCT0002234.

The reduction in the oxygenation dynamics in the prefrontal cortex (PFC) during cognitive tasks is a well-known occurrence in major depressive disorders (MDD). Studies focusing on oxygenation changes in the PFC in individuals with suicidal ideation are limited. Therefore, this study investigated and confirmed the presence of prefrontal dysfunction depending on the intensity of suicidal ideation among 77 young adults (45 patients with MDD and 32 healthy controls) using near-infrared spectroscopy (NIRS). All participants underwent assessment with the Beck Depression Inventory-II, Beck Anxiety Inventory, and Beck Scale for Suicidal ideation. NIRS revealed relative hypofunction in the left dorsolateral PFC, left ventrolateral PFC (LVLPFC), and both orbitofrontal cortices in young adults with MDD compared to that in the healthy controls during verbal fluency tasks. Furthermore, the oxyhaemoglobin changes in the LVLPFC mediated the indirect effect of depression severity on suicidal ideation intensity. Our results confirmed that functional NIRS is a useful auxiliary tool for objectively assessing the risk of suicidal ideation.

Background Achieving high-spatial-resolution pituitary MRI is challenging because of the trade-off between image noise and spatial resolution. Deep learning-based MRI reconstruction enables image denoising with sharp edges and reduced artifacts, which improves the image quality of thin-slice MRI. Purpose To assess the diagnostic performance of 1-mm slice thickness MRI with deep learning-based reconstruction (DLR) (hereafter, 1-mm MRI+DLR) compared with 3-mm slice thickness MRI (hereafter, 3-mm MRI) for identifying residual tumor and cavernous sinus invasion in the evaluation of postoperative pituitary adenoma. Materials and Methods This single-institution retrospective study included 65 patients (mean age ± standard deviation, 54 years ± 10; 26 women) who underwent a combined imaging protocol including 3-mm MRI and 1-mm MRI+DLR for postoperative evaluation of pituitary adenoma between August and October 2019. Reference standards for correct diagnosis were established by using all available imaging resources, clinical histories, laboratory findings, surgical records, and pathology reports. The diagnostic performances of 3-mm MRI, 1-mm slice thickness MRI without DLR (hereafter, 1-mm MRI), and 1-mm MRI+DLR for identifying residual tumor and cavernous sinus invasion were evaluated by two readers and compared between the protocols. Results The performance of 1-mm MRI+DLR in the identification of residual tumor was comparable to that of 3-mm MRI (area under the receiver operating characteristic curve [AUC], 0.89-0.92 vs 0.85-0.89, respectively; P ≥ .09). In the identification of cavernous sinus invasion, the diagnostic performance of 1-mm MRI+DLR was higher than that of 3-mm MRI (AUC, 0.95-0.98 vs 0.83-0.87, respectively; P ≤ .02). Conventional 1-mm MRI (AUC, 0.82-0.83) showed comparable diagnostic performance to 3-mm MRI (AUC, 0.83-0.87) (P ≥ .38). With 1-mm MRI+DLR, residual tumor was diagnosed in 20 patients and cavernous sinus invasion was diagnosed in 14 patients, in whom these diagnoses were not made with 3-mm MRI. Conclusion In the postoperative evaluation of pituitary adenoma, 1-mm slice thickness MRI with deep learning-based reconstruction showed higher diagnostic performance than 3-mm slice thickness MRI in the identification of cavernous sinus invasion and comparable diagnostic performance to 3-mm slice thickness MRI in the identification of residual tumor. © RSNA, 2020 Online supplemental material is available for this article.

Objectives: The clinical benefit of conventional disease-modifying antirheumatic drugs (cDMARDs) for treating ankylosing spondylitis (AS) is generally limited to improvements in peripheral arthritis. However, cDMARDs could be conditionally considered as alternatives to established drugs for improving axial manifestations in exceptional circumstances. However, there are few studies of the impact of cDMARDs on radiographic progression outcomes. Therefore, we investigated the effectiveness of cDMARDs on radiographic progression in AS. Methods: Among 1280 AS patients at a single hospital from 2000 to 2018, 301 who had been treated with sulfasalazine (SSZ) or methotrexate (MTX) were enrolled. For each patient, the entire follow-up period was split into 1-year intervals. Each interval was classified as either an “on-cDMARD” interval, which was a period of treatment with SSZ alone, MTX alone, or a combination of SSZ and MTX, or an “off-cDMARD” interval, which was a period without cDMARD treatment. Radiographic progression was scored using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The relationship between cDMARD use and radiographic progression within the intervals, defined as the rate of mSASSS progression, was investigated using linear models with adjustment for potential confounding covariates and for clustering among observations from the same patient. Results: The 732 on-cDMARD intervals and 1027 off-cDMARD intervals were obtained from enrolled patients. In multivariable regression analysis, there was no significant association between cDMARDs and the rate of mSASSS progression (β = −0.081, p = 0.418). The mean adjusted mSASSS change per year was 0.610 from on-cDMARD intervals and 0.691 from off-cDMARD intervals. Conclusion: Treatment with cDMARDs may not reduce radiographic progression in AS patients.

We aimed to develop multiparametric physiologic MRI-based spatial habitats and to evaluate whether temporal changes in these habitats help to distinguish tumor progression from treatment-related change in post-treatment glioblastoma. This retrospective, single-institution study included patients with glioblastoma treated by concurrent chemoradiotherapy who had newly developed or enlarging, measurable contrast-enhancing mass. Contrast-enhancing mass was divided into three spatial habitats by K-means clustering of voxel-wise ADC and CBV values. Temporal changes of these habitats between two consecutive examinations prior to the diagnosis of tumor progression or treatment-related change were assessed. Predictors were selected using logistic regression and the performance was measured with an area under the receiver operating characteristics curve (AUC). Spatiotemporal habitats were further analyzed for correlation with the site of tumor progression. There were 75 patients (mean, 58 years; range, 26−81 years; 43 men) with 48 cases of tumor progression and 39 cases of treatment-related change including 12 patient overlaps at different time points. Three spatial habitats of hypervascular cellular, hypovascular cellular, and nonviable tissue were identified. Increase in the hypervascular cellular (OR 4.55, p = .002) and hypovascular cellular habitat (OR 1.22, p < .001) was predictive of tumor progression. Combination of spatiotemporal habitats yielded a high diagnostic performance with an AUC of 0.89 (95% CI, 0.87–0.92). An increase in hypovascular cellular habitat predicted the site of tumor progression in 84% [21/25] of cases with tumor progression. Temporal changes in spatial habitats derived from multiparametric physiologic MRI provided diagnostic value in distinguishing tumor progression from treatment-related change and predicted site of tumor progression in post-treatment glioblastoma. • In post-treatment glioblastoma, three spatial habitats of hypervascular cellular, hypovascular cellular, and nonviable tissue were identified, and an increase in the hypervascular cellular (OR 4.55, p = .002) and hypovascular cellular habitat (OR 1.22, p < .001) was predictive of tumor progression. • Combination of spatiotemporal habitats yielded a high diagnostic performance with an AUC of 0.89 (95% CI, 0.87–0.92). • An increase in hypovascular cellular habitat predicted the site of tumor progression in 84% (21/25) of cases with tumor progression.

To investigate the impact of acceleration factors on reproducibility of radiomic features in sensitivity encoding (SENSE) and compressed SENSE (CS), compare between SENSE and CS, and identify reproducible radiomic features.Three-dimensional turbo spin echo T1-weighted imaging was performed in 14 healthy volunteers (mean age, 57 years; range, 33-67 years; 7 men) under SENSE and CS with accelerator factors of 5.5, 6.8, and 9.7. Eight anatomical locations (brain parenchyma, salivary glands, masseter muscle, tongue, pharyngeal mucosal space, eyeballs) were evaluated. Reproducibility of radiomic features was evaluated by calculating concordance correlation coefficient (CCC) in reference to the original image (SENSE with acceleration factor of 3.5). Reproducibility of radiomic features among acceleration factors and between SENSE and CS was compared.Proportion of radiomic features with CCC0.85 in reference to the original image was lower with higher acceleration factors in both SENSE and CS across all anatomical locations (p.001). Proportion of radiomic features with CCC0.85 in reference to the original image was higher in SENSE compared with CS (SENSE, 6.7-7.3% vs CS, 4.4-5.0%; p.001). Run percentage of gray-level run-length matrix (GLRLM) with wavelet D showed CCC0.85 in reference to the original image in both SENSE and CS at acceleration factor of 9.7 in the highest number of anatomical locations.Higher acceleration factors resulted in lower reproducibility of radiomic features in both SENSE and CS, and SENSE showed higher reproducibility of radiomic features than CS in reference to the original image. Run percentage of GLRLM with wavelet D was identified as the most reproducible feature.• Reproducibility of radiomic features in reference to the original image was lower with higher acceleration factors in both sensitivity encoding (SENSE) and compressed SENSE (CS) across all anatomical locations (p.001). • SENSE showed higher proportions of radiomic features with CCC0.85 in reference to the original image (SENSE, 6.7-7.3% vs CS, 4.4-5.0%; p.001) compared with CS. • Run percentage of gray-level run-length matrix (GLRLM) with wavelet D showed CCC0.85 in reference to the original image in both SENSE and CS with the highest acceleration factor.

Objective: To propose a decision tool considering both malignancy probability and surgical risk for intraductal papillary mucinous neoplasm (IPMN). Background Data Summary: Surgical risk and malignancy probability are both critical factors in making decisions about surgical resection of IPMN. Methods: We included 800 patients who underwent pancreatic resection for branch duct and mixed-type IPMN (April 1995 to June 2018). A nomogram was used to obtain the malignancy probability (MP-N). The surgical risks were estimated as the postoperative complication rate and serious complication from the ACS NSQIP surgical risk calculator (SC-ACS NSQIP). The risk&ndash, benefit analysis was conducted in two ways: calculation of the cutoff value of MP-N using the complication rate and directly comparing the MP-N and SC-ACS NSQIP results. Results: The optimal cutoff value of MP-N was 32% and 21% in the pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) groups, respectively, when using the major complication rate (Clavien grades III over). When we applied the optimal cutoff value to the two surgical methods, surgery was reduced by 51.7% in the PD group and 56% in the DP group, and the AUC value of the malignant predictions were 0.7126 and 0.7615, respectively. According to the direct comparison of MP-N and SC-ACS NSQIP, surgery was reduced by 31.7%, and the AUC value of malignant prediction was 0.6588. Conclusion: Our risk&ndash, benefit analysis model considering both malignancy probability and surgical risk is relatively acceptable, and it may help surgeons and patients make treatment decisions for a disease with a broad spectrum of malignancy rates.

The gut microbiota and its metabolites play critical roles in human health and disease. Advances in high-throughput sequencing, mass spectrometry, and other omics assay platforms have improved our ability to generate large volumes of data exploring the temporal variations in the compositions and functions of microbial communities. To elucidate mechanisms, methods and tools are needed that can rigorously model the dependencies within time-series data. Longitudinal data are often sparse and unevenly sampled, and nontrivial challenges remain in determining statistical significance, normalization across different data types, and model validation. In this review, we highlight recent developments in models and software tools for the analysis of time series microbiome and metabolome data, as well as integration of these data.

Deep learning-based automatic segmentation (DLAS) helps the reproducibility of radiomics features, but its effect on radiomics modeling is unknown. We therefore evaluated whether DLAS can robustly extract anatomical and physiological MRI features, thereby assisting in the accurate assessment of treatment response in glioblastoma patients. A DLAS model was trained on 238 glioblastomas and validated on an independent set of 98 pre- and 86 post-treatment glioblastomas from two tertiary hospitals. A total of 1618 radiomics features from contrast-enhanced T1-weighted images (CE-T1w) and histogram features from apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) mapping were extracted. The diagnostic performance of radiomics features and ADC and CBV parameters for identifying treatment response was tested using area under the curve (AUC) from receiver operating characteristics analysis. Feature reproducibility was tested using a 0.80 cutoff for concordance correlation coefficients. Reproducibility was excellent for ADC and CBV features (ICC, 0.82–0.99) and first-order features (pre- and post-treatment, 100% and 94.1% remained), but lower for texture (79.0% and 69.1% remained) and wavelet-transformed (81.8% and 74.9% remained) features of CE-T1w. DLAS-based radiomics showed similar performance to human-performed segmentations in internal validation (AUC, 0.81 [95% CI, 0.64–0.99] vs. AUC, 0.81 [0.60–1.00], p = 0.80), but slightly lower performance in external validation (AUC, 0.78 [0.61–0.95] vs. AUC, 0.65 [0.46–0.84], p = 0.23). DLAS-based feature extraction showed high reproducibility for first-order features from anatomical and physiological MRI, and comparable diagnostic performance to human manual segmentations in the identification of pseudoprogression, supporting the utility of DLAS in quantitative MRI analysis. • Deep learning-based automatic segmentation (DLAS) enables fast and robust feature extraction from diffusion- and perfusion-weighted MRI. • DLAS showed high reproducibility in first-order feature extraction from anatomical, diffusion, and perfusion MRI across two centers. • DLAS-based radiomics features showed comparable diagnostic accuracy to manual segmentations in post-treatment glioblastoma.

Purpose: Heterogeneity in glioblastomas is associated with poorer outcomes, and physiologic heterogeneity can be quantified with noninvasive imaging. We developed spatial habitats based on multiparametric physiologic MRI and evaluated associations between temporal changes in these habitats and progression-free survival (PFS) after concurrent chemoradiotherapy (CCRT) in patients with glioblastoma. Experimental Design: Ninety-seven patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma were enrolled and two serial MRI examinations after CCRT were analyzed. Cerebral blood volumes and apparent diffusion coefficients were grouped using k-means clustering into three spatial habitats. Associations between temporal changes in spatial habitats and PFS were investigated using Cox proportional hazard modeling. The performance of significant predictors for PFS and overall survival (OS) was measured using a discrete increase of habitat (habitat risk score) in a temporal validation set from a prospective registry (n = 53, ClinicalTrials.gov NCT02619890). The site of progression was matched with the spatiotemporal habitats. Results: Three spatial habitats of hypervascular cellular, hypovascular cellular, and nonviable tissue were identified. A short-term increase in the hypervascular cellular habitat (HR, 40.0; P = 0.001) and hypovascular cellular habitat was significantly associated with shorter PFS (HR, 3.78; P < 0.001) after CCRT. Combined with clinical predictors, the habitat risk score showed a C-index of 0.79 for PFS and 0.74 for OS and stratified patients with short, intermediate, and long PFS (P = 0.016). An increase in the hypovascular cellular habitat predicted tumor progression sites. Conclusions: Hypovascular cellular habitats derived from multiparametric physiologic MRIs may be useful predictors of clinical outcomes in patients with posttreatment glioblastoma.

Recent advances in metabolite quantification and identification have enabled new research into the detection and control of titer inhibitors and promoters. This paper presents a bigdata analytics study to identify both inhibitors and promoters using multivariate data analysis of metabolomics data. By applying multi-way partial least squares (PLS) model to metabolite data from four fed-batch bioreactor conditions where feed formulation and selection agent concentrations varied, metabolites which exhibited the most significant impact on titer during cultivation were ranked from highest to lowest. The model outputs were then constrained to reduce the number of statistically relevant inhibitors or promoters to the top ten, which were used to conduct metabolic pathway analysis. Furthermore, a method is presented for identifying amino acids that prevent the accumulation of the inhibitors and/or enhance the formation of promoters during production. Finally, the metabolomics and pathway analysis results were integrated and validated with transcriptomics data to characterize metabolic changes occurring among different growth conditions. From these results, new feeding strategies were implemented which resulted in increased fed-batch production titer. Methodology from this work could be applied to future process optimization strategies for biotherapeutic production.

Background: The association between optimal carbohydrate antigen (CA) 19-9 concentration after neoadjuvant chemotherapy (NACT) and prognosis has not been confirmed in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). Methods: This retrospective study included 122 patients with BRPC and 103 with LAPC who underwent surgery after NACT between 2012 and 2019 in a tertiary referral center. Prognostic models were established based on relative difference of the CA 19-9 (RDC), with their prognostic performance compared using C-index and Akaike information criterion (AIC). Results: CA 19-9 concentrations of 37&ndash, 1000 U/mL before NACT showed prognostic significance in patients with BRPC and LAPC (hazard ratio [HR]: 0.262, 95% confidence interval [CI]: 0.092&ndash, 0.748, p = 0.012). Prognostic models in this subgroup showed that RDC was independently prognostic of better overall survival (HR: 0.262, 95% CI: 0.093&ndash, 0.739, p = 0.011) and recurrence free survival (HR: 0.299, 95% CI: 0.140&ndash, 0.642, p = 0.002). The prognostic performances of RDC (C-index: 0.653, AIC: 227.243), normalization of CA 19-9 after NACT (C-index: 0.625, AIC: 230.897) and surgery (C-index: 0.613, AIC: 233.114) showed no significant differences. Conclusion: RDC was independently associated with better prognosis after NACT in patients with BRPC or LAPC. Decreased CA19-9 after NACT was a prognostic indicator of better survival and recurrence, as was normalization of CA 19-9 after both NACT and surgery.

Background Current guidelines for the treatment of asthma and chronic obstructive pulmonary disease overlap (ACO) recommend initial treatment using inhaled corticosteroids (ICSs) plus 1 or more bronchodilators. Objective To clarify which therapeutic effect is better between the ICS + long-acting β2 agonist (LABA) and ICS + LABA + long-acting muscarinic antagonist (LAMA) treatment in patients with ACO. Methods We conducted a multicenter, 48-week, randomized, noninferiority trial. Patients with ACO were enrolled if they were treated with a moderate to high dose of ICS + LABA. In total, 303 patients were involved in the present trial, with 149 receiving ICS + LABA + LAMA. The primary end point was the time to first exacerbation. Secondary outcomes included changes in FEV1, forced vital capacity, FEV1/forced vital capacity ratio, asthma control, blood eosinophil count, and fractional exhaled nitric oxide. Results In the ICS + LABA treatment group, 29 of 154 patients (18.83%) experienced exacerbation, whereas 28 of 149 patients (18.79%) experienced exacerbation in the ICS + LABA + LAMA treatment group. The results of this noninferiority study were ultimately inconclusive (hazard ratio, 1.1; 95% CI, 0.66-1.84). However, the patients treated with the addition of LAMA showed significant improvements in FEV1 and forced vital capacity (P Conclusions Although this study was unable to conclude that ICS + LABA treatment is not inferior to ICS + LABA + LAMA in terms of exacerbation, it is obvious that the ICS + LABA + LAMA treatment group had improved lung function in ACO.

Background Data are still limited regarding whether there are differential long‐term outcomes after percutaneous coronary intervention versus coronary artery bypass grafting ( CABG ) for left main coronary artery disease with or without diabetes mellitus ( DM ). Methods and Results Using the 10‐year data from the MAIN ‐ COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry, we sought to examine the effect of DM on comparative outcomes after percutaneous coronary intervention or CABG in patients with unprotected left main coronary artery disease. The outcomes of interest were all‐cause mortality; a composite of death, Q‐wave myocardial infarction, or stroke; and target‐vessel revascularization. The primary adjusted analyses were performed with the use of propensity scores and inverse‐probability weighting. Of 2240 patients with left main coronary artery revascularization, 722 (32%) had DM . In the overall population, the adjusted 10‐year risks of death and composite outcome were similar between percutaneous coronary intervention and CABG , irrespective of DM status ( P interaction : 0.41, mortality; 0.40, composite outcome). However, in the cohort of bare‐metal stents and concurrent CABG , we observed differential outcomes after stenting and CABG by DM status ( P interaction : 0.09, mortality; 0.04, composite outcome), favoring CABG in patients with DM. In the cohort of drug‐eluting stents and concurrent CABG , the better effect of CABG over stenting was narrowed in patients with DM without a significant interaction ( P interaction : 0.63, mortality; 0.47, composite outcome). Conclusions In this cohort of patients with longest follow‐up who underwent left main coronary artery revascularization, the clinical impact of DM favoring CABG over percutaneous coronary intervention has diminished over time from the bare‐metal stent to the drug‐eluting stent era. Registration URL : http://www.clini​caltr​ials.gov . Unique identifier: NCT 02791412.

Background In surgery for perihilar cholangiocarcinoma (PHCC), it is still controversial as to whether additional resection of the bile duct is needed on high grade (HG) biliary intraepithelial neoplasia (BilIN) margin. Methods Patients who underwent surgery for PHCC with curative intent between 2001 and 2015 were stratified by resection margin, and were analyzed comparing the clinical outcomes. Results Of the 306 study participants, 217 patients had negative margins (R0), 18 patients had HG BilIN, and 71 patients had positive margins (R1). The median overall survival was 36.0 months in the R0 group, 41.0 months in the HG BilIN group, and 25.0 months in the R1 group while overall survival rates at 5 years were 34.5% in the R0 group, 44.4% in the HG BilIN group, and 21.0% in the R1 group. The median disease-free survival was 15.0 months in the R0 group, 16.5 months in the HG BilIN group, and 12.0 months in the R1 group. Conclusions Although the HG BilIN group had neoplasia with malignant potential, survival and recurrence outcomes were comparable to those of the R0 group, which suggests that no additional resection is needed when the maximal bile duct margin in PHCC surgery contains HG BilIN.

Objectives The optimal duration of fasting after endoscopic hemostasis in patients with peptic ulcer bleeding has not yet been determined. We investigated the appropriate timing of feeding after endoscopic hemostasis in patients with high-risk peptic ulcer bleeding. Methods This study was a randomized, single center, noninferiority trial. Between February 2014 and March 2019, consecutive patients with peptic ulcer bleeding were randomized to resume feeding either 24 or 48 hours after successful endoscopic hemostasis. A total of 209 eligible patients were included in the intention-to-treat analysis and 200 in the per-protocol (PP) analysis. The primary outcome measure was recurrent bleeding within 7 days of hemostasis. Noninferiority testing was performed in the PP population, and the noninferiority margin was set at 10%. Secondary outcomes included 30-day rebleeding and mortality, transfusion requirements, and length of hospital stay. Results Recurrent bleeding rates at 7 days were 7.9% in the 24-hour group and 4.0% in the 48-hour group in the PP analysis; tests for noninferiority did not reach statistical significance (difference: 3.9%, 95% confidence interval [CI]: -2.7 to 10.5, P value for noninferiority = 0.034). The recurrent bleeding rates within 30 days were 10.9% and 4.0% in the 24- and 48-hour groups (difference: 6.9%, 95% CI: -0.5 to 14.2), and the 30-day mortality rates were 5.9% and 14.1%, respectively (difference: -8.2%, 95% CI: -16.5 to 0.1) in the PP analysis. The transfusion requirement and the length of hospital stay were similar between the 2 groups. Discussion Early refeeding at 24 hours after endoscopic hemostasis is not noninferior to later refeeding at 48 hours for rebleeding in patients with high-risk peptic ulcer bleeding. Our results do not allow a recommendation of refeeding at 24 hours, rather than later refeeding in this population.

Background The incidence of inappropriate shocks remains high at 30% in patients with implantable cardioverter-defibrillators (ICDs). This retrospective study sought to examine the efficacy of strategic programming (ICD programming with a long detection interval and high-rate cutoff) in reducing electrical storm, inappropriate shocks, and unexpected hospital visits in patients with ICDs with/without cardiac resynchronization therapy with defibrillator (CRT-Ds). Methods This was a single tertiary center retrospective study, evaluating the clinical outcomes, especially regarding inappropriate therapies in patients with ICDs or CRT-Ds. Enrolled patients underwent ICD or CRT-D implantations from January 2008 to May 2016. Clinical information was attained by a thorough chart review. Results We analyzed 155 defibrillator patients from January 2008 to May 2016 (124 patients had ICDs and 31 had CRT-Ds). Since we adopted this strategic programming as a default programming from 2015 implanted ICDs and CRT-Ds, we divided the patients into two groups: devices implanted before 2015 (group A, n = 94) versus implanted after 2015 (group B, n = 61). During a median of 1289 days of follow-up, electrical storms occurred in three patients (eight events) in group B versus 11 (28 events) in group A (P = 0.18); appropriate therapies were delivered in 27 patients (56 events) in group A versus 7 (15 events) in group B (P = 0.72); inappropriate therapies were delivered in 15 patients (21 events) in group A versus 1 with 1 episode in group B (P = 0.03); and 5 unexpected hospitalizations occurred in four patients in group B versus 36 in 24 patients in group A (P = 0.02). Conclusion The clinical application of strategic programming reduced inappropriate shocks and unexpected hospitalizations in ICD and CRT-D patients.

Background To evaluate radiomics analysis in neuro-oncologic studies according to a radiomics quality score (RQS) system to find room for improvement in clinical use. Methods Pubmed and Embase were searched up the terms radiomics or radiogenomics and gliomas or glioblastomas until February 2019. From 189 articles, 51 original research articles reporting the diagnostic, prognostic, or predictive utility were selected. The quality of the methodology was evaluated according to the RQS. The adherence rates for the six key domains were evaluated: image protocol and reproducibility, feature reduction and validation, biologic/clinical utility, performance index, a high level of evidence, and open science. Subgroup analyses for journal type (imaging vs. clinical) and biomarker (diagnostic vs. prognostic/predictive) were performed. Results The median RQS was 11 out of 36 and adherence rate was 37.1%. Only 29.4% performed external validation. The adherence rate was high for reporting imaging protocol (100%), feature reduction (94.1%), and discrimination statistics (96.1%), but low for conducting test-retest analysis (2%), prospective study (3.9%), demonstrating potential clinical utility (2%), and open science (5.9%). None of the studies conducted a phantom study or cost-effectiveness analysis. Prognostic/predictive studies received higher score than diagnostic studies in comparison to gold standard (P P = .02), and cut-off analysis (P = .001). Conclusions The quality of reporting of radiomics studies in neuro-oncology is currently insufficient. Validation is necessary using external dataset, and improvements need to be made to feature reproducibility, demonstrating clinical utility, pursuits of a higher level of evidence, and open science.

593 Background: Extranodal extension (ENE) is an established prognostic factor of several gastrointestinal cancers; furthermore, ENE is already included as one component of nodal category of oral cavity, penis, and vulvar cancers. However, the prognostic impact of ENE in pancreatic cancer remains unclear. In this study, we aimed to investigate prognostic implication of ENE in patients with surgically resected pancreatic cancer. Methods: We retrospectively reviewed electronic medical records and pathologic slides of 503 surgically resected pancreatic head cancer patients, who consecutively underwent pancreaticoduodenectomy for pathologically confirmed pancreatic ductal adenocarcinoma between January 2009 and December 2013. Patients were categorized into subgroups according to ENE status and AJCC 8th pancreatic cancer staging system. We compared the disease-free survival rates of the patients according to ENE status. Cox proportional hazard analysis was performed to evaluate prognostic factors for the disease-free survival of pancreatic head cancer. Results: ENE-positive patient group showed a larger tumor size, a higher rate of lymph node metastasis, and a tendency to be positive for lymphovascular invasion, perineural invasion, and resection margin (p < 0.001). Patients with ENE had lower overall survival (OS) and disease-free survival (DFS) rates compared with those without ENE (N0, 30 months; LN+/ENE-, 20 months; LN+/ENE+, 16 months; p < 0.001), (N0, 13 months; LN+/ENE-, 8 months; LN+/ENE+, 5 months; p < 0.001). Patients with higher N categories had lower OS and DFS rates. In addition, even in the same N stage, patients with ENE showed lower OS and DFS rates than those without ENE (p < 0.001). However, there was no significant difference in survival rates between patients in the N1/ENE+ group and the N2/ENE- group. Additionally, ENE was an independent prognostic factor for pancreatic cancer. Conclusions: ENE significantly influenced adverse prognosis among patients with pancreatic head cancer especially for those with nodal metastasis. Therefore, ENE should be considered as a prognostic factor in the future editions of the AJCC staging system.

Background Next-generation sequencing (NGS) enables highly sensitive cancer genomics analysis, but its clinical implications for therapeutic options from imaging-based prediction have been limited. Purpose To predict core signaling pathways in isocitrate dehydrogenase (IDH) wild-type glioblastoma by using diffusion and perfusion MRI radiomics and NGS. Materials and Methods The radiogenomics model was developed by using retrospective patients with glioma who underwent NGS and anatomic, diffusion-, and perfusion-weighted imaging between March 2017 and February 2019. For testing model performance in predicting core signaling pathway, patients with IDH wild-type glioblastoma from a retrospective analysis from a registry (

Roller compaction is a dry granulation process for manufacturing solid drug formulations. A flowing powder is continuously fed into the counter-rotating rolls and compacted into dense ribbons. These ribbons are subsequently broken into granules by milling. In this study, an integrated flowsheet model of the dry granulation process was developed for unit operations of powder feeding, roller compaction and milling with gSOLIDS (PSE Enterprise, UK) and tested against experimental data. The effect of roll force and roll speed on ribbon density and granule size was assessed with the flowsheet model and validated with experimental data. The experimentation was conducted with microcrystalline cellulose with magnesium stearate (1%, w/w) in a Fitzpatrick CCS220/M3B with serrated rollers. Experimental design on roll force, roll speed and different screen sizes and mill speeds were conducted to investigate their impacts on the quality attributes of granule size, ribbon density, and roll gap. Parameters in each unit were estimated and the sensitivity of the model outputs to the material property based parameter values was also investigated. The predictions of the ribbon density and roll gap at various operating conditions were assessed. The roll force has a more significant effect on ribbon density than the roll speed, while the roll speed has a more significant effect on the roll gap. Higher roll force and narrower roll gap lead to dense ribbon. The ribbon density is much less sensitive to the roll speed compared with the roll force. The roll gap has a considerable influence on ribbon quality. The developed flowsheet model for the continuous dry granulation process can be directly used for process optimization, risk assessment and control strategy determination.

ObjectiveABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI.MethodsDNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r2>0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs.ResultsWild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=−2.91, p=0.001; β=−2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2–15 of the 39-exon gene.ConclusionsThis study identifies four ABCC8 tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials.

Amino acids and glucose consumption, cell growth and monoclonal antibody (mAb) production in mammalian cell culture are key considerations during upstream process and particularly media optimization. Understanding the interrelations and the relevant cellular physiology will provide insight for setting strategy of robust and effective mAb production. The aim of this study was to further our understanding of nutrient consumption metabolism, since this could have significant impact on enhancing mAb titer, cell proliferation, designing feeding strategies, and development of feed media. The nutrient consumption pattern, mAb concentration, and cell growth were analyzed in three sets of cell cultures with media supplementation of glucose, methionine, threonine, tryptophan, and tyrosine. The amino acids metabolism and its impact on cell growth and mAb production during the batch and fed-batch culture were closely analyzed. It was shown that the phenylalanine, tyrosine and tryptophan biosynthesis pathways were significantly altered under different culture conditions with different media. These changes were more apparent in the fed-batch process in which higher mAb titer was observed due to the metabolic changes than mAb titer in the batch process. The pathway analysis approach was well utilized for evaluating the impact on the relevant pathways involved under different cell culture conditions to improve cell growth and mAb titer. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:793-805, 2018.

Objectives To evaluate Hepatitis C virus (HCV) knowledge and awareness among pregnant women with opioid use disorder (OUD). Methods From May through November 2015, a one-time survey was distributed to a convenience sample of pregnant women with OUD to assess their knowledge and awareness of (a) risk factors for HCV infection, (b) HCV transmission prevention strategies, (c) hepatotoxic risk reduction and (d) perinatal transmission and neonatal implications of HCV infection. Chi square and Fisher's exact tests were used to compare demographic characteristics and HCV knowledge between participants who were HCV positive and negative. Results Of 179 pregnant women with OUD approached, 169 (94%) completed the survey. Of these, 153 (90.5%) reported at least one risk factor for HCV infection, 85 (50.3%) were HCV positive and 38 (44.7%) of HCV positive women were diagnosed with HCV for the first time during pregnancy. When HCV knowledge was evaluated, 114 (66.7%) responded that sharing eating utensils could transmit HCV, 69 (55.0%) responded that there is a vaccine to prevent HCV and 56 (32.7%) did not identify intranasal drug use as a risk factor for HCV transmission. Among HCV positive women, 61 (71.8%) associated breastfeeding with an increased risk for HCV transmission, 33 (38.1%) failed to identify the importance of pediatric follow-up for HCV-exposed children and 16 (18.8%) perceived the risk of HCV vertical transmission as "likely" or "very likely." Conclusions for Practice Gaps in HCV knowledge exist among a rapidly growing population of pregnant women with OUD. Healthcare providers have a unique opportunity to provide HCV education and counseling during pregnancy.

Context: Intervention fidelity is a critical component of behavioral research that has received inadequate attention in palliative care studies. With increasing focus on the need for palliative care models that can be widely disseminated and delivered by non-specialists, rigorous yet pragmatic strategies for training interventionists and maintaining intervention fidelity are needed. Objectives: (1) Describe components of a plan for interventionist training and monitoring and maintaining intervention fidelity as part of a primary palliative care trial (CONNECT) and (2) present data about perceived training effectiveness and delivery of key intervention content. Methods: Post-training evaluations, visit checklists, and visit audio-recordings. Results: Data were collected from June, 2016 through April, 2017. We include procedures for (1) identification, training and certification of oncology nurses as CONNECT interventionists; (2) monitoring intervention delivery; and (3) maintaining intervention quality. All nurses (N = 14) felt prepared to deliver key competencies after a 3-day in-person training. As assessed via visit checklists, interventionists delivered an average of 94% (SD 13%) of key content for first intervention visits and 85% (SD 14%) for subsequent visits. As assessed via audio-recordings, interventionists delivered an average of 85% (SD 8%) of key content for initial visits and 85% (SD 12%) for subsequent visits. Conclusion: We present a 3-part strategy for training interventionists and monitoring and maintaining intervention delivery in a primary palliative care trial. Training was effective in having nurses feel prepared to deliver primary palliative care skills. As assessed via nursing checklists and visit audio-recordings, intervention fidelity was high. Keywords: Oncology nursing, Primary palliative care, Intervention fidelity, CONNECT

In clinical trials evaluating HIV-1 prevention products, ex vivo exposure of mucosal tissue to HIV-1 is performed to inform drug levels needed to suppress viral infection. Understanding assay and participant variables that influence HIV-1 replication will help with assay implementation. Demographic and behavioral data were obtained from 61 healthy women aged 21–45. Paired cervical tissue (CT) and vaginal tissue (VT) biopsies were collected and treated with HIV-1(BaL) or HIV-1(JR-CSF), washed, and cultured. On days 3, 7, and/or 11, culture supernatant was collected, and viral replication was monitored by p24 ELISA. Tissue was extracted at study end, and HIV-1 relative RNA copies were determined by polymerase chain reaction. Cumulative p24 and RNA were log-transformed and analyzed using a linear mixed model, t-test, and an intraclass correlation coefficient (ICC). HIV replication was similar between CT and VT for each virus, but HIV-1(BaL) had 1.5 log(10) and 0.9 log(10) higher levels of p24 than HIV-1(JR-CSF) in CT and VT, respectively (p

In this study, a novel three-compartmental population balance model (PBM) for a continuous twin screw wet granulation process is developed, combining the techniques of PBM and regression process modeling. The developed model links screw configuration, screw speed, and blend throughput with granule properties to predict the granule size distribution (GSD) and volume-average granule diameter. The granulator screw barrel was divided into three compartments along barrel length: wetting compartment, mixing compartment, and steady growth compartment. Different granulation mechanisms are assumed in each compartment. The proposed model therefore considers spatial heterogeneity, improving model prediction accuracy. An industrial data set containing 14 experiments is applied for model development. Three validation experiments show that the three-compartmental PBM can accurately predict granule diameter and size distribution at randomly selected operating conditions. Sixteen combinations of aggregation and breakage kernels are investigated in predicting the experimental GSD to best judge the granulation mechanism. The three-compartmental model is compared with a one-compartmental model in predicting granule diameter at different experimental conditions to demonstrate its advantage. The influence of the screw configuration, screw speed and blend throughput on the volume-average granule diameter is analyzed based on the developed model.

Today’s biomanufacturing processes are still operated based on experience, and thus can hardly cope with increasing bioprocess complexity. Recently, there is a growing interest in industrial applications of the digital twins (DT) which integrate physical and virtual systems via real-time data monitoring, thus enabling their interactive communications for the enhanced operational efficiency towards advanced biomanufacturing. We suggest that bioprocess DT of cell cultures can be developed by incorporating in-line monitoring, advanced data analytics with machine and deep learning, and mechanistic models representing the mammalian cells and bioreactor for virtually mirroring their behaviors under adjustable process conditions. In this review, we summarize and highlight recent advances in the key components within bioprocess DT platform and discuss the current challenges with future research direction.

Background Although inhaled corticosteroids (ICSs) are the recommended first-line therapy for asthma, determining whether to continue or discontinue ICS treatment in patients with mild asthma remains challenging for clinicians. Several studies have revealed that patients with mild-persistent asthma maintained a well-controlled state after ICS withdrawal. However, the long-term outcomes of ICS withdrawal have not yet been determined. Objective To determine the possible clinical outcomes of the discontinuation of ICS in patients with well-controlled mild asthma. Methods We investigated the clinical outcomes of discontinuing ICSs in patients with well-controlled mild asthma and compared the time to loss of control (LOC) between patients who stopped ICS treatment (ICS withdrawal group, IWG) and those who continued treatment for 3 years (continuous ICS group, CIG). Results A significant difference in the time to LOC was observed between the IWG and CIG (hazard ratio, 2.56; 95% confidence interval, 1.52-4.33; P Conclusion Our results suggest that the maintenance of ICS treatment may help keep patients’ asthma under control. Furthermore, patients with LOC had significantly higher sputum eosinophil counts in the CIG than those in the non-LOC group. Therefore, continuous ICS use by patients with mild, well-controlled asthma could be associated with good clinical outcomes. Trial Registration ClinicalTrials.gov Identifier: KCT0002234.

Introduction Although minimally invasive pancreaticoduodenectomy (MIPD) is expanded from benign to malignant disease, oncologic outcome of MIPD for common bile duct cancer (CBDC) were not confirmed yet. Methods The patients who underwent PD for CBDC were identified from 2015 to 2019 in a tertiary referral center. They were divided into open PD (OPD) (n = 342) and MIPD (n = 87) and perioperative and oncologic outcomes were compared between two groups after propensity score matched (PSM) analysis including patients` characteristics, pathology and adjuvant therapy. Results OPD group showed higher T stage (p < 0.001) and frequent adjuvant chemotherapy (p = 0.017) compared with MIPD before PSM and discordance between OPD (n = 78) and MIPD (n = 78) groups were matched with standardized mean difference

The addition of specialty palliative care to standard oncology care improves outcomes for patients with advanced cancer and their caregivers, but many lack access to specialty care services. Primary palliative care-meaning basic palliative care services provided by clinicians who are not palliative care specialists-is an alternative approach that has not been rigorously evaluated.A cluster randomized, controlled trial of the CONNECT (Care management by Oncology Nurses to address supportive care needs) intervention, an oncology nurse-led care management approach to providing primary palliative care for patients with advanced cancer and their family caregivers, is currently underway at 16 oncology practices in Western Pennsylvania. Existing oncology nurses are trained to provide symptom management and emotional support, engage patients and families in advance care planning, and coordinate appropriate care using evidence-based care management strategies. The trial will assess the impact of CONNECT versus standard oncology care on patient quality of life (primary outcome), symptom burden, and mood; caregiver burden and mood; and healthcare resource use.This trial addresses the need for more accessible models of palliative care by evaluating an intervention led by oncology nurses that can be widely disseminated in community oncology settings. The design confronts potential biases in palliative care research by randomizing at the practice level to avoid contamination, enrolling patients prior to informing them of group allocation, and conducting blinded outcome assessments. By collecting patient, caregiver, and healthcare utilization outcomes, the trial will enable understanding of the full range of a primary palliative care intervention's impact.