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BACKGROUND: Early recognition of severe COVID-19 is essential for timely patient triage. AIMS: We aim to report clinical and laboratory findings and patient outcomes at a tertiary hospital in Melbourne, Australia. METHODS: This is a retrospective study of adult inpatients with COVID-19 admitted to Northern Health from March to September 2020. Data were extracted from electronic medical records. RESULTS: Key admission data was available for 182 patients (median age 67.0 years (interquartile range, 47.9-83.1; 51.1% female). 56 (30.8%) were from residential care. 117 (64.3%) patients were assigned Goals-of-Patient-Care (GOPC) A or B and 65 (35.7%) GOPC C or D. Comorbidities were present in 135 patients (74.2%). 63.2% of patients received antibiotics, 6.6% had antivirals, 45.6% received systemic glucocorticoid and 3.3% had tocilizumab. 56 (30.8%) developed clinical deterioration (24 requiring ventilation, 21 receiving critical care, 34 died). Overall, in-hospital clinical deterioration was significantly associated with older age (p

Although the most recent guidance from the International Society for the Study of Hypertension in Pregnancy (ISSHP) has highlighted the role of angiogenic marker assessment in the diagnosis of pre-eclampsia (PE) in women with chronic hypertension, the ISSHP has withheld recommending its implementation due to the limited available evidence in this group of women. Therefore, we aimed to investigate the value of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) assessment in women with chronic hypertension and suspected superimposed PE.This was a retrospective analysis of prospectively collected data recorded in an electronic database between January 2013 and October 2019. Women with chronic hypertension and singleton pregnancy who had suspected superimposed PE were included. Superimposed PE was suspected in women presenting with worsening hypertension, epigastric pain, new-onset edema, dyspnea or neurological symptoms. The exclusion criteria were delivery within 1 week after assessment for reasons other than PE, chronic kidney disease, history of cardiac disease, fetal aneuploidy, genetic syndrome or major structural anomaly and missing pregnancy outcome. Maternal serum angiogenic markers (sFlt-1, PlGF and sFlt-1/PlGF ratio) were measured. The primary outcome was the utility of angiogenic markers in the prediction of superimposed PE. Predictive accuracy was assessed for superimposed PE diagnosed at different timepoints, including within 1 week after assessment and any time before birth. The secondary outcome was comparison of adverse maternal and perinatal outcomes between women with superimposed PE diagnosed according to the traditional ISSHP criteria and those diagnosed according to extended criteria including angiogenic markers. The predictive accuracy of each angiogenic marker was assessed using receiver-operating-characteristics-curve analysis. Area under the curve (AUC) values were compared using De Long's test. A sensitivity analysis was planned for gestational age at assessment. The association of various variables with composite adverse maternal and perinatal outcomes was assessed using binomial regression.The study included 142 pregnant women with chronic hypertension and suspected superimposed PE, of whom 25 (17.6%) developed PE within 1 week after assessment, 52 (36.6%) developed PE at any timepoint before birth and 90 (63.4%) delivered without PE. Maternal serum angiogenic imbalance was associated significantly with superimposed PE diagnosed according to the ISSHP criteria within 1 week or at any time after assessment (P 0.001 for both). The predictive accuracy of maternal serum sFlt-1/PlGF ratio for superimposed PE diagnosed within 1 week after assessment was superior to that of maternal serum PlGF level (AUC, 0.91 vs 0.86; P = 0.032). The addition of angiogenic imbalance to the traditional ISSHP diagnostic criteria was associated with an increase in the detection rate (35.1% increase; 95% credible interval (CrI), 16.6-53.6%) and positive (9.6% increase; 95% CrI, 0.0-20.6%) and negative (3.1% increase; 95% CrI, 1.3-4.9%) predictive values for composite adverse maternal outcome, with high posterior probabilities of an increase in each predictive accuracy parameter ( 99.9%, 95.6% and 99.9%, respectively), without a meaningful decrease in specificity. The addition of angiogenic imbalance improved the detection rate for composite adverse perinatal outcome (20.6% increase; 95% CrI, 0.0-42.2%), with a high posterior probability (96.9%). There was a corresponding drop in specificity (5.7% decrease; 95% CrI, -2.3% to 13.6%), with a posterior probability of 91.8%.In women with chronic hypertension and suspected superimposed PE, addition of maternal serum angiogenic markers to the traditional diagnostic criteria for superimposed PE improved significantly the sensitivity for the prediction of both maternal and perinatal adverse outcomes. Implementation of angiogenic marker assessment in the evaluation of pregnant women with chronic hypertension should therefore be considered. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Background Anal squamous cell carcinoma (ASCC) is the main subtype of anal cancer and has great heterogeneity in prognosis. We aimed to construct a nomogram for predicting their 1‐, 3‐, and 5‐year overall survival (OS) rates. Methods Patients with ASCC, enrolled between January 1, 2010 and December 31, 2017, were identified from the SEER database. They were divided into a training group and a validation group in a ratio of 7:3. Univariate and multivariate Cox analyses were used to identify the prognostic factors for OS. Then a prognostic nomogram was established and validated by Harrell consistency index (C‐index), area under the curve (AUC) of the receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Results We identified 761 patients in training group and 326 patients in validation group. Four prognostic factors including age, sex, AJCC stage, and radiotherapy were identified and integrated to construct a prognostic nomogram. The C‐index and AUC values proved the model's effectiveness and calibration plots manifested its excellent discrimination. Furthermore, in comparison to the AJCC stage, the C‐index, AUC, and DCA proved the nomogram to be of good predictive value. Finally, we constructed a risk stratification model for dividing patients into low‐risk, medium‐risk, and high‐risk groups, and there were obvious differences in OS. Conclusions A prognostic nomogram was firstly established for predicting the survival probability of ASCC patients and helping clinicians improve their risk management., First, from the SEER database, we identified the prognostic factors for anal squamous cell carcinoma (ASCC) patients and develop a nomogram to better predict the prognosis of ASCC patients. Secondly, through comparison, our predictive model is a further improvement of traditional AJCC staging system based on patient’s demographic and clinicopathological features not only in survival prediction, but also in clinical utility.

High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFRcys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

Although blood DNA methylation (DNAm) profiles are reported to be associated with breast cancer incidence, they have not been widely used in breast cancer risk assessment. Among a breast cancer case–cohort of 2774 women (1551 cases) in the Sister Study, we used candidate CpGs and DNAm estimators of physiologic characteristics to derive a methylation‐based breast cancer risk score, mBCRS. Overall, 19 CpGs and five DNAm estimators were selected using elastic net regularization to comprise mBCRS. In a test set, higher mBCRS was positively associated with breast cancer incidence, showing similar strength to the polygenic risk score (PRS) based on 313 single nucleotide polymorphisms (313 SNPs). Area under the curve for breast cancer prediction was 0.60 for self‐reported risk factors (RFs), 0.63 for PRS, and 0.63 for mBCRS. Adding mBCRS to PRS and RFs improved breast cancer prediction from 0.66 to 0.71. mBCRS findings were replicated in a nested case–control study within the EPIC‐Italy cohort. These results suggest that mBCRS, a risk score derived using blood DNAm, can be used to enhance breast cancer prediction., Blood samples were collected between 2003 and 2009 from a prospective cohort of 50 844 cancer‐free women. Among a case–cohort subsample (2774 women; 1551 incident breast cancers) selected in 2014, DNA methylation was profiled using HumanMethylation450 BeadChips. Elastic net regularization derived a methylation‐based breast cancer risk score (mBCRS). In a validation sample, mBCRS values were higher among cases and improved breast cancer prediction.

Osteoporosis is a common, but silent disease until it is complicated by fractures that are associated with morbidity and mortality. Over the past few years, although deep learning-based disease diagnosis on chest radiographs has yielded promising results, osteoporosis screening remains unexplored. Paired data with 13,026 chest radiographs and dual-energy X-ray absorptiometry (DXA) results from the Health Screening and Promotion Center of Asan Medical Center, between 2012 and 2019, were used as the primary dataset in this study. For the external test, we additionally used the Asan osteoporosis cohort dataset (1089 chest radiographs, 2010 and 2017). Using a well-performed deep learning model, we trained the OsPor-screen model with labels defined by DXA based diagnosis of osteoporosis (lumbar spine, femoral neck, or total hip T-score ≤ -2.5) in a supervised learning manner. The OsPor-screen model was assessed in the internal and external test sets. We performed substudies for evaluating the effect of various anatomical subregions and image sizes of input images. OsPor-screen model performances including sensitivity, specificity, and area under the curve (AUC) were measured in the internal and external test sets. In addition, visual explanations of the model to predict each class were expressed in gradient-weighted class activation maps (Grad-CAMs). The OsPor-screen model showed promising performances. Osteoporosis screening with the OsPor-screen model achieved an AUC of 0.91 (95% confidence interval [CI], 0.90-0.92) and an AUC of 0.88 (95% CI, 0.85-0.90) in the internal and external test set, respectively. Even though the medical relevance of these average Grad-CAMs is unclear, these results suggest that a deep learning-based model using chest radiographs could have the potential to be used for opportunistic automated screening of patients with osteoporosis in clinical settings. © 2021 American Society for Bone and Mineral Research (ASBMR).

Objective: Dual-specificity phosphatase 6 (Dusp6) was proposed as a predictive marker of response of atypical endometrial hyperplasia (AEH) and early endometrial cancer (EEC) to conservative treatment. However, its predictive accuracy has never been calculated. We aimed to define it in conservatively treated AEH and EEC. Methods: All patients

Background Hyperadrenocorticism (HAC) is a common endocrine disorder in dogs; however, there are no reports on the use of the corticotropin‐releasing hormone test (CRHT) to differentiate between pituitary‐dependent hyperadrenocorticism (PDH) and cortisol‐producing adrenal tumors (CPATs), both causative of HAC. Objectives To evaluate the usefulness of CRHT as a tool to differentiate between PDH and CPAT in dogs and to determine the reference intervals for CRHT in healthy, PDH, and CPAT dogs. Animals Dogs diagnosed with PDH (n = 21), CPAT (n = 6), and healthy beagle dogs (n = 33). Methods This prospective study included dogs with a definitive diagnosis of PDH and CPAT and healthy beagle dogs, in which CRHT was performed, were prospectively evaluated. We investigated the correlations of CRHT (endogenous adrenocorticotropic hormone [ACTH] concentration, endogenous ACTH concentration [EAC], and poststimulation ACTH concentration [PAC]) with pituitary‐to‐brain ratio (PBR) (in PDH) and with indices of adrenal ultrasonography (smaller and larger adrenal gland dorsoventral thickness in PDH and CPAT). Results For EAC, the area under the curve (AUC) was 0.95, with a cutoff value of 26.3 pg/mL (sensitivity: 90.62%, specificity: 87.50%). The AUC for PAC was 0.96 with a cutoff value of 54.5 pg/mL (sensitivity: 100.00%, specificity: 66.67%). The 95% reference interval for CRHT in healthy (control) dogs ranged 5.00 to 79.8 pg/mL (1.10‐17.57 pmol/L) for EAC, and 1.92 to 153.42 pg/mL (0.42‐33.78 pmol/L) for PAC. There was no significant correlation between PBR and CRHT, nor adrenal size and CRHT. Conclusions and Clinical Importance CRHT appears to be a rapid and reliable test for differentiating PDH from CPAT in dogs.

OBJECTIVES The aim of this study was to investigate the role of quantitative values obtained by superb microvascular imaging (SMI) and shearwave elastography (SWE) in the prediction of malignancy in intraductal papilloma-like lesions (IDPL). METHODS In the study, 61 patients between the ages of 14 to 73 years (mean age 44) diagnosed with IDPL on ultrasound (US) examination between the years 2020 and 2021 were included. The B-Mode US findings (shape, margins, size, echo pattern, and accompanying ductal dilatation), SMI vascular index (SMIvi), E-mean, and SWE-ratio values were recorded. RESULTS There was a statistically significant difference between malignant (n = 14) and benign (n = 47) groups in terms of symptoms (P = .005), size (P = .042), shape (P = .002), margins (P = .001), echogenicity (P = .023), microcalcifications (P = .009), SMIvi (P = .031), E-mean (P

Progesterone is an important natural hormone regulating ovulation and menstruation. The present study aimed to investigate the pharmacokinetics and safety of two formulations of progesterone in Chinese postmenopausal females under fasting and fed conditions. The study adopted a single-dose, open-label, randomized, three-period bioequivalence design. A total of 96 subjects were enrolled and randomly assigned to the fasting cohort or fed cohort. A high-fat meal (890 kcal) was used in the fed study. The reference-scaled average bioequivalence method was used for bioequivalence evaluation. A high-fat meal led to a 22-fold higher peak concentration (Cmax ) and a 7-fold higher area under the curve (AUC) while time to reach Cmax and half-life was not significantly affected. The concentration-time curve displayed double peaks suggesting the existence of enterohepatic circulation. The test/reference geometric mean ratios for Cmax and AUC under fasting and fed conditions are all within the range of 80% to 125%. All adverse events (AEs) that occurred during the trial were mild and did not cause drop-out, though these AEs occurred more frequently under fed state. In conclusion, the two formulations of progesterone are bioequivalent in Chinese subjects under fasting and fed conditions. Drug label modification regarding food effects needs further discussion.

Background One of the primary treatment for resectable advanced esophageal squamous cell cancer (ESCC) is neoadjuvant chemotherapy (NAC) followed by minimally invasive esophagectomy (MIE). Because the neutrophil-to-lymphocyte ratio (NLR) is a widely reported prognostic factor in several cancers, we investigated whether the preoperative NLR is a biomarker in ESCC patients treated with NAC and MIE. Methods In this study, we investigated 174 ESCC patients who underwent MIE from January 2010 to December 2015, including 121 patients who received NAC. The cutoff value of the NLR was analyzed using the receiver operating characteristic curve. Multivariate analyses were performed to clarify independent prognostic factors for overall survival (OS). Results The cutoff value of the NLR for OS in 121 patients who received NAC was 2.5 ng/ml, and the area under the curve was 0.63026 (p = 0.0127). The 5-year OS rate was 64% in those with an NLR 415 ml were independent poor prognostic factors. Conclusions NLR is a biomarker of prognosis in ESCC patients who undergo MIE after NAC.

BACKGROUND Drain fluid amylase is commonly used as a predictor of pancreatic fistula after pancreaticoduodenectomy (PD). This study aimed to determine the ideal cut-off value of drain fluid amylase on postoperative day 1 (DFA1) for predicting pancreatic fistula after pancreaticogastrostomy (PG). METHODS Prospective data of 272 consecutive patients undergoing PG between 2010 and 2020 was collected and analysed to determine the postoperative pancreatic fistula (POPF) risk factors. RESULTS The incidence of POPF was 143 cases (52.6%). The median DFA1 in patients with POPF was significantly higher than that of patients with NO-POPF (5483 versus 311, P

BACKGROUND Normal right ventricular (RV) function has been traditionally assessed from the apical window. However, in several patients the subcostal window is the only available acoustic. METHODS Given the intricate functional and mechanical inter-dependence between longitudinal tricuspid annular (TA) displacement and RV free wall contractility (RVFW), we studied the utility of RVFW inward motion using both M-mode and velocity with tissue Doppler imaging (TDI) from the subcostal transthoracic view. RESULTS If a TAPSE value ≥ 2 cm is used to identify normal RV function, an RVFW M-mode value > .8 cm, TA TDI s' velocity > .06 cm/s and TA TDI e' velocity value > .05 cm/s identify normal RV systolic function. Furthermore, ROC curve analysis for the RVFW M-mode showed an area under the curve (AUC) of .753 (95% CI: .604-.868) with a cut-off value > .8, sensitivity 75% and specificity 73%; for TA TDI s' AUC at .822 (95% CI: .681-.919) with a cut-off value > .06, sensitivity 75% and specificity 77% and for TA TDI e' the AUC was .771 (95% CI: .624-.882) with a cut-off value > .05, sensitivity 90% and specificity 46%. Reproducibility of repeat RVFW M-mode, TDI s' and e' measurements was good with strong inter-rater agreement (Kappa > .8). CONCLUSIONS The subcostal window appears useful for assessing RV systolic function. Additional studies are now required to prospectively use these measures in the routine evaluation of RV systolic function particularly in patients with suboptimal apical windows.

Key points Vascular dysfunction has been demonstrated in lowlanders at high-altitude (>4,000 m), however the extent of impairment and the delineation of contributing mechanisms have remained unclear. Using the gold-standard isolated perfused forearm model, we determined the extent of vasodilatory dysfunction and oxidative stress as a contributing mechanism in healthy lowlanders before and 4-6 days after rapid ascent to 4,300 m. The total forearm blood flow response to acetylcholine at high-altitude was decreased by ∼30%. Co-infusion of acetylcholine with the antioxidant vitamin C partially restored the total forearm blood flow by ∼20%. The magnitude of forearm blood flow reduction, as well as the impact of oxidative stress, was positively associated with the individual severity of hypoxemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourn, with important implications for understanding the etiology of high-altitude related changes in endothelial-mediated vasodilatory function. Abstract High-altitude induced hypoxemia is often associated with peripheral vascular dysfunction; however, the basic mechanism(s) underlying high-altitude vascular impairments remains unclear. This study tested the hypothesis that oxidative stress contributes to the impairments in endothelial function during early acclimatization to high-altitude. Ten young healthy lowlanders were tested at sea-level (344 m) and following 4-6 days at high-altitude (4,300 m). Vascular endothelial function was determined using the isolated perfused forearm technique with forearm blood flow (FBF) measured by strain-gauge venous occlusion plethysmography. FBF was quantified in response to acetylcholine (ACh), sodium nitroprusside (SNP), and co-infusion of ACh with the antioxidant vitamin C (ACh+VitC). The total FBF response to ACh (area under the curve) was ∼30% lower at high-altitude compared to sea-level (P = 0.048). There was no difference in the response to SNP at high-altitude (P = 0.860). At sea-level, co-infusion of ACh+VitC had no influence on the FBF dose response (P = 0.268); however, at high-altitude ACh+VitC resulted in an average increase in the FBF dose response by ∼20% (P = 0.019). At high-altitude, the decreased FBF response to ACh, and the increase in FBF in response to ACh+VitC, were associated with the magnitude of arterial hypoxemia (R2 = 0.60, P = 0.008 and R2 = 0.63, P = 0.006, respectively). Collectively, these data support the hypothesis that impairments in vascular endothelial function at high-altitude are in part attributable to oxidative stress, consequent of the magnitude of hypoxemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourn, with important implications for understanding the etiology of high-altitude related vascular dysfunction. This article is protected by copyright. All rights reserved.

OBJECTIVE This study aimed to investigate the correlation between contrast-enhanced ultrasound (CEUS) features and molecular subtypes of breast cancer (BC). METHODS A total of 116 patients (116 lesions) with pathologically diagnosed BC who received conventional ultrasound and CEUS before surgery were enrolled in this study. BC molecular subtypes were identified by postoperative pathological and immunohistochemical analysis as Luminal A (LA), Luminal B (LB), HER2 (H2) over-expression, and triple-negative (TN). Qualitative and quantitative CEUS characteristics were analyzed by one-way analysis of variance (continuous variables) or Pearson's χ2 test or Fisher's exact probability method (categorical variables). RESULTS There were significant differences in enhancement speed and enhancement degree among the four subtypes (P

Patients with cerebral malaria with polymorphic Cytochrome P450 2C19 (CYP2C19) genotypes who receive concurrent treatment with quinine are at risk of inadequate or toxic therapeutic drug concentrations due to metabolic drug interactions. The study aimed to predict the potential dose regimens of quinine when coadministered with phenobarbital in adult patients with cerebral malaria and complications (e.g., lactic acidosis and acute renal failure) and concurrent with seizures and acute renal failure who carry wild‐type and polymorphic CYP2C19. The whole‐body physiologically based pharmacokinetic (PBPK) models for quinine, phenobarbital, and quinine–phenobarbital coadministration were constructed based on the previously published information using Simbiology®. Four published articles were used for model validation. A total of 100 virtual patients were simulated based on the 14‐day and 3‐day courses of treatment. using the drug–drug interaction approach. The predicted results were within 15% of the observed values. Standard phenobarbital dose, when administered with quinine, is suitable for all groups with single or continuous seizures regardless of CYP2C19 genotype, renal failure, and lactic acidosis. Dose adjustment based on area under the curve ratio provided inappropriate quinine concentrations. The recommended dose of quinine when coadministered with phenobarbital based on the PBPK model for all groups is a loading dose of 2000 mg intravenous (i.v.) infusion rate 250 mg/h followed by 1200 mg i.v. rate 150 mg/h. The developed PBPK models are credible for further simulations. Because the predicted quinine doses in all groups were similar regardless of the CYP2C19 genotype, genotyping may not be required.

OBJECTIVE To identify serum protein biomarkers that might distinguish patients with early inflammatory arthritis (IA) with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) and may be used to support appropriate early intervention. METHODS The serum proteome of patients with PsA and patients with RA was interrogated using nano-liquid chromatography mass spectrometry (nano-LC-MS/MS) (n = 64 patients), an aptamer-based assay (SomaScan) targeting 1,129 proteins (n = 36 patients), and a multiplexed antibody assay (Luminex) for 48 proteins (n = 64 patients). Multiple reaction monitoring (MRM) assays were developed to evaluate the performance of putative markers using the discovery cohort (n = 60 patients) and subsequently an independent cohort of PsA and RA patients (n = 167). RESULTS Multivariate machine learning analysis of the protein discovery data from the 3 platforms revealed that it was possible to differentiate PsA patients from RA patients with an area under the curve (AUC) of 0.94 for nano-LC-MS/MS, 0.69 for bead-based immunoassay measurements, and 0.73 for aptamer-based analysis. Subsequently, in the separate verification and evaluation studies, random forest models revealed that a subset of proteins measured by MRM could differentiate PsA and RA patients with AUCs of 0.79 and 0.85, respectively. CONCLUSION We present a serum protein biomarker panel that can separate patients with early-onset IA with PsA from those with RA. With continued evaluation and refinement using additional and larger patient cohorts, including those with other arthropathies, we suggest that the panel identified here could contribute to improved clinical decision making.

The pharmacokinetic profiling of active compounds is necessary for drug development and application. Approaches to a pharmacokinetic study based on biological markers are alternatives to traditional approaches based on chromatographic methods. The aim of the study was to compare two analytical approaches to pharmacokinetics investigation for an example of sitagliptin in rabbits after one dose oral administration. The method for sitagliptin quantification in rabbit plasma samples based on a correlation between its concentration and dipeptidyl peptidase IV activity was proposed, validated, and applied. The high-performance liquid chromatography (HPLC)-ultraviolet (UV) method was also validated and applied for the same sample analysis. The plasma pharmacokinetics of sitagliptin after oral administration to the rabbits in one dose was characterized after two analytical assays. The close values of the main pharmacokinetic parameters were obtained after two approaches. The nontraditional approach based on correlation of special marker activity and active substance concentration appears to be more sensitive than HPLC-UV. Thus, the sitagliptin concentrations determined by biomarker assay were higher than the lower limit of quantification (LLOQ) for a longer period (more timepoints) than after the HPLC-UV assay. This feature may influence the values of some calculated concentration-dependent (area under the curve [AUC]0-t , etc.) and time-dependent parameters (mean residence time [MRT], T1/2 , etc.). The values of Tmax obtained by the two approaches were similar and adequate for oral drug administration that confirms the correctness of biomarker selection for pharmacokinetics assessment. The obtained results on the example of sitagliptin confirms that the biomarker approach is adequate and applicable for a pharmacokinetics study. Similar approaches may be effective for individual compounds and complex mixtures when it is difficult or impossible to analyze them traditionally by chromatographic methods.

BACKGROUND Clinical tumor staging is essential information for making a therapeutic decision in cancer. This study aimed to identify the optimal tumor classification system for predicting resectability and survival probability in perihilar cholangiocarcinoma. METHODS Patients who were treated for perihilar cholangiocarcinoma between 2009 and 2018 were enrolled. Local tumor extension was staged radiologically according to a diameter-based classification system in addition to the AJCC, Blumgart, and Bismuth systems. Survival and resectability were compared between T subgroups, and the discriminability of the four systems was assessed with Harrell's concordance index (C-index). RESULTS Among 702 study patients, 559 (80.0%) underwent laparotomy, 489 (70.0%) of whom underwent resection. The resectability significantly decreased for more advanced tumors in all systems (P

Aims Left atrial strain (LAS) and skeletal muscle endurance demonstrate a linear relationship to peak VO2. Less is known about the relationship between central (cardiac) and peripheral (muscle endurance) limitations of exercise capacity in patients with heart failure (HF). We investigated this relationship using novel cardiac markers such as LAS and left atrial ejection fraction (LAEF). Methods We analysed echocardiographic measurements, cardiopulmonary exercise testing, and isokinetic muscle function in 55 subjects with HF and controls (17 heart failure with preserved ejection fraction -HFpEF, 18 heart failure with reduced ejection fraction-HFrEF and 20 healthy controls). Results Patients with reduced LAEF showed reduced peak VO2: 14.3±3.5 vs. 18.5±3.5 ml/min/kg, p=0.003 and reduced muscle endurance (RME): 64.3±23.9 vs. 88.5±32.3 Nm/kg, p=0.028. Patients with reduced LAS showed similar results. Neither left ventricular global longitudinal strain (LVGLS) nor left atrial volume index (LAVI) were associated with RME. The area under the curve of LAS and LAEF in patients with HF in association with RME were (0.76 vs. 0.80) with 95% confidence interval (CI) (0.59–0.96, p=0.012 vs. 0.63–0.98, p=0.006, respectively). Peak torque of the left leg was associated with E/LAS (E: early diastolic) in patients with HFpEF (r=−0.6, p=0.020). Endurance of the left leg was associated with LAEF (r=0.79, p=0.001) in patients with HFrEF. Conclusion LAS/LAEF are potential cardiac markers in demonstrating the link between cardiac and peripheral limitations of exercise capacity. Thus, integrating LAS/LAEF in the evaluation of exercise intolerance in patients with HF could be useful. Funding Acknowledgement Type of funding sources: None.

OBJECTIVE To examine whether serum procalcitonin (PCT) is useful for differentiating acute pyelonephritis (APN) from asymptomatic bacteriuria and acute cystitis during pregnancy. METHODS A multicenter prospective observational study was conducted to compare serum white blood cell (WBC) counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and PCT level among pregnant women with asymptomatic bacteriuria, acute cystitis, and APN and healthy pregnant women (controls). Utility of WBC count, ESR, CRP, and PCT biomarkers for the prediction of APN during pregnancy were measured. RESULTS Area under the curve (AUC) values of PCT, CRP, ESR, and WBC count for predicting asymptomatic bacteriuria were 0.576, 0.628, 0.542, and 0.532, respectively; those for predicting acute cystitis were 0.766, 0.735, 0.681, and 0.597, respectively; and those for predicting acute pyelonephritis 0.859, 0.763, 0.711, and 0.732, respectively. Compared with the other inflammatory markers used to predict APN, PCT exhibited the highest AUC (0.859 [95% confidence interval (CI) 0.711-0.935]). A cutoff value of >0.25 ng/ml had a sensitivity of 87% and a specificity of 79%. CONCLUSION Serum PCT can be a valuable addition to existing methods of differentiating asymptomatic bacteriuria, acute cystitis, and APN during pregnancy and can facilitate the early identification of APN during pregnancy.

Background Malignant pleural effusion (MPE) is common in malignant pleural mesothelioma (MPM). The survival of patients with MPM and MPE is heterogeneous. The LENT and BRIMS scores using routine clinical parameters were developed to predict the survival of patients with unselected MPE and MPM, respectively. This study aimed to stratify the survival of selected MPM patients with MPE. Methods Data were collected from subjects diagnosed with MPM and MPE. The LENT and BRIMS scores were applied using a combination of clinical variables to stratify subjects and compare survival characteristics. Results In total, 101 patients with MPM complicated by MPE were included in the study. The median follow‐up time was 71 months (interquartile range: 24–121 months). Overall median survival was 24 (interquartile range: 12–52 months). Based on the LENT score, the low‐, moderate‐, and high‐risk groups accounted for 65.3% (66 cases), 34.7% (35 cases), and 0%, respectively. The cumulative survival rates of the two groups were statistically significant (p = 0.031). The area under the curve (AUC) of the LENT score was 0.662. Based on the BRIMS score, the first, second, third, and fourth risk groups accounted for 1.0% (1 case), 42.9% (35 cases), 28.7% (29 cases), and 19.4% (36 cases), respectively. Survival was significantly higher in patients in the risk groups 1 and 2 than in patients in the risk groups 3 and 4 (p = 0.037). The AUC of the BRIMS score was 0.605. Conclusions Using routinely available clinical variables, both LENT and BRIMS scores could stratify selected MPM and MPE patients into risk groups with statistically different survival., The individual survival of patients with MPM combined with MPE varied greatly in this study. Both LENT and BRIMS scores could help stratify the survival risk of patients with MPM complicated by MPE with fair‐to‐good performance. More effective predictive models should be established in adequately designed prospective studies.

International audience; Introduction/aims: Respiratory status is a key determinant of prognosis in patients with Duchenne muscular dystrophy (DMD). We aimed to evaluate the determinants of diaphragm ultrasound and its performance in predicting restrictive respiratory patterns in DMD.Methods: This was a retrospective study of DMD patients followed in our center and admitted for an annual checkup from 2015 to 2018. We included DMD patients who underwent diaphragm ultrasound and pulmonary functional tests.Results: This study included 74 patients with DMD. The right diaphragm thickening fraction (TF) was significantly associated with age (P = .001), Walton score (P = .012), inspiratory capacity (IC) (P = .004), upright forced vital capacity (FVC) (P < .0001), supine FVC (P = .038), and maximal inspiratory pressure (MIP) (P = .002). Right diaphragm excursion was significantly associated with age (P < .0001), steroid use (P = .008), history of spinal fusion (P < .0001), body mass index (BMI) (P = .002), Walton score (P < .0001), IC (P < .0001), upright FVC (P < .0001), supine FVC (P < .0001), and MIP (P < .0001). A right diaphragm TF >28% and a right diaphragm excursion>25.4 mm were associated with an FVC >50% with, respectively, an area under the curve (AUC) of 0.95 (P = .001) and 0.93 (P < .001). A left diaphragm TF >26.8% and a left diaphragm excursion >21.5 mm were associated with an FVC >50% with, respectively, an AUC of 0.95 (P = .011) and 0.97 (P < .001).Discussion: Diaphragm excursion and diaphragm TF can predict restrictive pulmonary insufficiency in DMD.

OBJECTIVES To compare the diagnostic accuracy in detecting early non-vital bone changes between orthopantomography (OPT) and cone-beam computed tomography (CBCT) in correlation with histopathological findings before tooth extractions in patients with antiresorptive (AR) intake. SUBJECTS Patients with an indication tooth extraction who had received OPT and CBCT preoperatively while or after undergoing AR treatment were prospectively enrolled over a 24-month period in the progesterone in spontaneous miscarriage (PRISM) trial. Imaging studies were randomly analyzed by three examiners for early non-vital bone changes using specific predefined characteristics and a 5-level scale (1 definite absence of criteria to 5 definite presence of criteria). Sensitivity and specificity values were calculated in correlation with the histopathologically evaluated bone samples at the time point of tooth extraction. RESULTS One hundred thirty patients with 237 treated extraction sites met the inclusion criteria. For all images evaluated by all examiners, CBCT (430/492; 87.4%; receiver operating characteristic [ROC]: area under the curve [AUC] = 0.88; p

Aim Tenofovir and para-aminosalicylic acid (PAS) may be co-prescribed to treat patients with concomitant infections of human immunodeficiency virus and Mycobacterium tuberculosis bacteria. Both drugs are known to have remarkable renal uptake transporter-mediated clearance. Owing to the lack of clinical studies on drug-drug interaction between the two drugs, we conducted a translational clinical study to investigate the effect of PAS on tenofovir pharmacokinetics. Methods Initially, we studied in vitro renal uptake transporter-mediated drug-drug interactions using stably transfected cells with human organic anion transporters (organic anion transporter 1 and 3 [OAT1 and OAT3]). Later, we estimated clinical drug interactions using static and physiologically based pharmacokinetic (PBPK) modeling. Finally, we investigated the effects of PAS-calcium formulation (PAS-Ca) on tenofovir disoproxil fumarate pharmacokinetics in healthy male Korean subjects. Results PAS inhibited OAT1- and OAT3-mediated tenofovir uptake in vitro. The PBPK drug-drug interaction model suggested a 1.26-fold increase in tenofovir peak plasma concentration when co-administered with PAS. By contrast, an open-label, randomized, crossover clinical trial evaluating the effects of PAS-Ca on tenofovir pharmacokinetics showed significantly altered geometric mean ratio (90% confidence intervals) of maximum plasma concentration (Cmax ) and area under the curve (AUC0-inf ) by 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively. Conclusions Our study findings suggest that the PAS-Ca formulation significantly reduced systemic exposure to tenofovir through an unexplained mechanism, which was contrary to the initial prediction. Caution should be exercised while predicting in vivo PK profiles from in vitro data, particularly when there are potential confounders such as pharmaceutical interactions.

BACKGROUND Indeterminate thyroid nodules (Bethesda III) are challenging to characterize without diagnostic surgery. Auxiliary strategies including molecular analysis, machine learning models, and ultrasound grading with Thyroid Imaging, Reporting and Data System (TI-RADS) can help to triage accordingly, but further refinement is needed to prevent unnecessary surgeries and increase positive predictive values. DESIGN Retrospective review of 88 patients with Bethesda III nodules who had diagnostic surgery with final pathological diagnosis. MEASUREMENTS Each nodule was retrospectively scored through TI-RADS. Two deep learning models were tested, one previously developed and trained on another data set, mainly containing determinate cases and then validated on our data set while the other one trained and tested on our data set (indeterminate cases). RESULTS The mean TI-RADS score was 3 for benign and 4 for malignant nodules (p = .0022). Radiological high risk (TI-RADS 4,5) and low risk (TI-RADS 2,3) categories were established. The PPV for the high radiological risk category in those with >10 mm nodules was 85% (CI: 70%-93%). The NPV for low radiological risk in patients >60 years (mean age was 100% (CI: 83%-100%). The area under the curve (AUC) value of our novel classifier was 0.75 (CI: 0.62-0.84) and differed significantly from the chance-level (p

OBJECTIVE To create a risk scoring system comprised of clinical and radiological characteristics that can predict the likelihood of antibiotic treatment failure of tubo-ovarian abscesses. The score should guide clinicians in identifying patients to whom early intervention should be offered instead of a prolonged trial of antibiotics. METHODS A multicenter, retrospective cohort study carried out between January 1, 2013 and September 30, 2019, identified consecutive patients with tubo-ovarian abscess. Using a chronological split, patients were allocated to two groups for the development and subsequent validation of the postulated scoring system. Univariate and bivariate analyses were performed to identify statistically significant variables for the failure of intravenous antibiotic treatment. RESULTS In total, 214 consecutive patients with tubo-ovarian abscesses were identified. Data from the first 150 patients were used for the development of the postulated scoring system; data from the subsequent 64 patients were used for validation. Statistically significant clinical features between those having successful and unsuccessful management were: temperature (median = 37.1℃ vs 38.2℃, P = 0.0001), C-reactive protein (151 mg/L vs 243 mg/L, P = 0.0001), and tubo-ovarian abscess diameter (6.0 cm vs 8.0 cm, P = 0.0001). These parameters were used to create a risk prediction score. A score of four or more was predictive of requiring surgical/radiological intervention of tubo-ovarian abscess (P

AIM To validate an appropriate spleen size measurement technique for the prediction of high-risk esophagogastric varices. METHODS This retrospective cross-sectional study included 369 patients who underwent ultrasonography and computed tomography (CT) of the spleen and esophagogastroduodenoscopy between January 2018 and December 2020. Maximum spleen length, width, and craniocaudal length were measured in a longitudinal view. The two-dimensional (2D) spleen index (maximum length × maximum width in the longitudinal view) was calculated. A three-dimensional (3D) spleen index was then defined as follows: 2D spleen index × maximum length in the transverse view. The similarity in spleen volume measured by CT and ultrasonography (spleen index) was assessed by the correlation coefficient. The diagnostic accuracies of the spleen index, platelet/spleen length, and platelet/spleen index were calculated to determine the overall diagnostic accuracy. RESULTS Compared to the other spleen indices, our 3D spleen index was significantly better correlated with spleen volume on CT (r = 0.91, 95% confidence interval 0.89-0.92, p

Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration of treatment. The purpose of this study was to demonstrate utility of a physiologically‐based pharmacokinetic modeling approach to predict plasma and lung concentrations of 11 compounds used or under development as TB therapies (bedaquiline [and N‐desmethyl bedaquiline], clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, pyrazinamide, rifampicin, and rifapentine). Model accuracy was assessed by comparison of simulated plasma pharmacokinetic parameters with healthy volunteer data for compounds administered alone or in combination. Eighty‐four percent (area under the curve [AUC]) and 91% (maximum concentration [C max]) of simulated mean values were within 1.5‐fold of the observed data and the simulated drug‐drug interaction ratios were within 1.5‐fold (AUC) and twofold (C max) of the observed data for nine (AUC) and eight (C max) of the 10 cases. Following satisfactory recovery of plasma concentrations in healthy volunteers, model accuracy was assessed further (where patients’ with TB data were available) by comparing clinical data with simulated lung concentrations (9 compounds) and simulated lung: plasma concentration ratios (7 compounds). The 5th–95th percentiles for the simulated lung concentration data recovered between 13% (isoniazid and pyrazinamide) and 88% (pyrazinamide) of the observed data points (Am J Respir Crit Care Med, 198, 2018, 1208; Nat Med, 21, 2015, 1223; PLoS Med, 16, 2019, e1002773). The impact of uncertain model parameters, such as the fraction of drug unbound in lung tissue mass (fumass), is discussed. Additionally, the variability associated with the patient lung concentration data, which was sparse and included extensive within‐subject, interlaboratory, and experimental variability (as well interindividual variability) is reviewed. All presented models are transparently documented and are available as open‐source to aid further research.

INTRODUCTION: Microstructural abnormalities at the epicardium of the right ventricular outflow tract (RVOT) may provide the arrhythmia substrate in Brugada syndrome (BrS). Endocardial unipolar electroanatomical mapping allows the identification of epicardial abnormalities. We evaluated the clinical implications of an abnormal endocardial substrate as perceived by high-density electroanatomical mapping (HDEAM) in patients with BrS. METHODS: Fourteen high-risk BrS patients with aborted sudden cardiac death (SCD) (12 males, mean age: 41.9 ± 11.8 years) underwent combined endocardial-epicardial HDEAM of the right ventricle/RVOT, while 40 asymptomatic patients (33 males, mean age: 42 ± 10.7 years) underwent endocardial HDEAM. Based on combined endocardial-epicardial procedures, endocardial HDEAM was considered abnormal in the presence of low voltage areas (LVAs) more than 1 cm2 with bipolar signals less than 1 mV and unipolar signals less than 5.3 mV. Programmed ventricular stimulation (PVS) was performed in all patients. RESULTS: The endocardial unipolar LVAs were colocalized with epicardial bipolar LVAs (p = .0027). Patients with aborted SCD exhibited significantly wider endocardial unipolar (p

OBJECTIVES The aim of this study is to systematically evaluate the diagnostic ability of the contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI-RADS) in hepatocellular carcinoma (HCC). METHODS We searched relevant studies from PubMed, Medline, and Embase database. After literature search, duplicate removal, and data extraction, we calculated and analyzed the pooled sensitivity, pooled specificity, pooled odds ratios of diagnostic, pooled likelihood ratio (LR) of positive and negative, and area under the curve (AUC), accuracy, and F1 score to evaluate the diagnostic value of CEUS LI-RADS for HCC. RESULTS Thirteen studies and 6491 patients were included in this analysis. The pooled sensitivity and pooled specificity were 0.72 (95% confidence interval [CI], 0.70-0.73) and 0.92 (95% CI, 0.91-0.93), respectively. The positive LR was 8.02 (95% CI, 4.93-13.06) and the negative LR was 0.31 (95% CI, 0.27-0.37). The pooled diagnostic odds ratio was 27.91 (95% CI, 15.39-50.63). The overall AUC was 0.8406 and the accuracy was 0.77. CONCLUSIONS CEUS LI-RADS is an effective and promising method to diagnose HCC.

BACKGROUND Our aims were to evaluate the ultrasound scan (USS) criteria in diagnosing hypertrophic pyloric stenosis (HPS), determine the best diagnostic threshold values for pyloric muscle thickness (PMT) and pyloric canal length (PCL), and assess the accuracy of flow through the pylorus. METHODS All patients who underwent pyloromyotomy at our tertiary paediatric surgery centre between July 2013 and June 2019 were identified (Group 1). All patients undergoing an USS to investigate for a possible HPS and did not undergo pyloromyotomy were also identified (Group 2). Accuracy was determined by Youden's Index (J) with the highest J determining the ideal cut-off value. RESULTS Two hundred and eighty-four patients (142 patients in each group) were included in the analysis. Using only the last USS before surgery, PMT provided an area under the curve (AUC) of 0.987 (n = 275), and PCL an AUC of 0.977 (n = 267). Ideal threshold values were 3.0 mm for PMT (J = 0.92), and 14.5 mm for PCL (J = 0.87). Combining PMT ≥3.0 mm with a PCL ≥14.5 mm resulted in a sensitivity of 95% and specificity of 99% (J = 0.94). The absence of flow through the pylorus on dynamic USS provided a sensitivity of 99% and specificity of 91% (J = 0.91; n = 277). CONCLUSION Combining threshold values of 3.0 mm for PMT and 14.5 mm PCL provides the highest accuracy for diagnosing pyloric stenosis on an ultrasound scan. These combined values were more accurate than observing for the absence of flow through the pylorus.

Background To investigate the diagnostic efficacy of sentinel lymph nodes (SLN) in breast cancer by percutaneous contrast‐enhanced ultrasound (CEUS) through pooled analysis of relevant studies published before June 2021. Methods We conducted a systematic review and meta‐analysis of relevant studies by searching the electronic databases of PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang and VIP and the studies were screened according to their inclusion and exclusion criteria. Sensitivity (SEN), specificity (SPE), positive likelihood ratio (+LR), negative likelihood ratio (−LR) and diagnostic odds ratio (DOR) were calculated by Meta‐disc 1.4 software and the summary receiver operating characteristic (SROC) curve and area under the curve of ROC (AUC) were constructed. Results Twenty‐two publications evaluating the diagnostic efficacy of SLN in breast cancer under percutaneous CEUS were included in the meta‐analysis. The diagnostic sensitivity, specificity were 0.86 (95% CI: 0.83–0.88) and 0.89 (95% CI: 0.87–0.91) for SLN in breast cancer detected by percutaneous CEUS respectively using a random effect model. The +LR and –LR were combined in a random effect model due to significant statistical heterogeneity (p, The SROC was constructed by using the Moses' Model. The area under the ROC (AUC) was 0.94, which indicated that CEUS had high diagnostic efficacy of sentinel lymph node metastasis in patients with breast cancer.

Background and Aim Biliary tract infection (BTI) is an inflammatory disease and commonly associated with bacteremia. Delays in diagnosis or treatment of BTI cause high morbidity and mortality. However, an early diagnosis depends on appropriate clinical investigations. Appropriate biomarkers are urgently needed to improve the BTI diagnostic rate. We hypothesized that intestinal fatty acid‐binding protein (I‐FABP) might be a potential biomarker for BTI diagnosis. Methods We examined data from subjects aged ≥18 years diagnosed with BTI, including cholangitis and cholecystitis, whose blood samples were adequate for I‐FABP and zonulin assessment. We also collected blood samples from healthy volunteers as the control group. We excluded subjects in both groups who received steroids, antibiotics, or probiotics within 1 month before hospital admission (BTI cohort) or participation in this research (controls). The main study endpoint was to compare the diagnostic ability of I‐FABP to detect BTI in comparison with high‐sensitivity C‐reactive protein (hs‐CRP) and zonulin. Results The study collected the data of 51 patients with BTI and 35 healthy subjects. The receiver operating characteristic (ROC) area under the curve (AUC) for I‐FABP was 0.884 (95% confidence interval [CI]: 0.814–0.954), numerically higher than that for hs‐CRP (0.880; 0.785–0.976) and zonulin (0.570; 0.444–0.697). We estimated that the optimal cutoff value of I‐FABP was 2.1 ng/mL (sensitivity: 0.804; specificity: 0.829) for the diagnosis of BTI. Conclusions In summary, this study suggests that I‐FABP may be a potential alternative biomarker to hs‐CRP for diagnosing BTI. Further research should verify the use of I‐FABP as a marker for BTI diagnosis, but also for other inflammatory diseases., Our study revealed the diagnostic performance of intestinal fatty acid‐binding protein (I‐FABP) was comparable to that of C‐reactive protein (CRP) and superior to zonulin for detecting biliary tract infection (BTI).

PURPOSE Persistent acute kidney injury (AKI) has been shown to be closely associated with poor prognosis in critical patients. Recent studies have shown that procalcitonin (PCT) is valuable for the early prediction of AKI in critically patients. Our aim was to determine whether PCT and its kinetic changes could predict the occurrence of persistent AKI in critical patients. METHODS This is a prospective observational study. The definition of AKI was based on the Kidney Disease: Improving Global Outcomes criteria. Persistent AKI was defined as renal function that does not return to baseline serum creatinine levels within 48 h. Blood samples were obtained at the onset of AKI and two subsequent days of hospital stay. 24-h PCT change (ΔPCT-24 h) was defined as 24 h PCT minus baseline PCT (day 0). RESULTS A total of 91 critical patients with AKI were included in this study. The persistent AKI group had a stepwise increase in PCT concentration. ΔPCT-24 h was higher in the persistent AKI group (p

OBJECTIVES Fetal 2D and 3D fractional limb volume (FLV) measurements by ultrasound can detect fetal lean and subcutaneous mass and possibly percent body fat. Our objectives were to 1) compare FLV measurements in fetuses with fetal growth restriction (FGR) versus small for gestational age (SGA) defined by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG)-supported international Delphi consensus and 2) correlate FLV findings with birth metrics. We hypothesize that FLV measurements will be significantly smaller in FGR versus SGA fetuses and will correlate closer with Ponderal index (PIx) in the neonate than abdominal circumference (AC). METHODS Patients were categorized as FGR or SGA as defined by ISUOG. Total thigh volume (TTV), volumes of lean mass (LMV), and fat mass volume (FMV) were calculated from 3D acquisitions. Measurements were compared between groups and correlated with birthweight (BW) and PIx (BW/crown-heal length). RESULTS The FGR group (n = 37) delivered earlier (37/2 versus 38/0; P = .0847), were lighter (2.2 kg versus 2.6 kg; P = .0003) and had lower PIx (0.023 versus 0.025; P = .0013) than SGAs (n = 22). FGRs had reduced TTV (40.6 versus 48.4 cm3 ; P = .0164), FMV (20.8 versus 25.3 cm3 ; P = .0413), and LMV (19.8 versus 23.1 cm3 ; P = .0387). AC had the highest area under the curve (0.69) for FGR. FMV was more strongly associated with PIx than the AC (P = .0032). CONCLUSIONS The AC and FLV measurements were significantly reduced in FGR fetuses compared to SGAs. While the AC outperformed FLV in predicting FGR, the FLV correlated best with PIx, which holds investigative promise.

Aim To verify the role of maternal serum levels of alpha-1-antitrypsin (AAT), an acute-phase inflammatory protein, as a marker for distinguishing between fetal growth restriction (FGR) and normal birth weight in pre-eclamptic women. We correlate serum AAT levels to the essential feto-maternal parameters for an earlier and cost-benefit diagnostic method, thus distinguishing between FGR and normal birth weight in pre-eclamptic women. Methods An observational study conducted at the University hospital recruited 100 pregnant women in 32/34 weeks of a singleton single tone pregnancy; all were pre-eclampsia cases. All were tested by laboratory and ultrasound examination. Two sets of data were collected; one is maternal parameters such as blood pressure (BP), maternal serum AAT mean platelet volume (MPV), platelet distribution width (PDW), and serum uric acid levels, and the other is fetal parameters such as amniotic fluid index (AFI), fetal weight centile and estimated fetal weight. Results A strong negative correlation proved between serum levels of AAT and all study variables except fetal weight (systolic BP, diastolic BP, MPV, PDW, serum uric acid, fetal weight percentile, and AFI) with a correlation coefficient of; -0.95, -0.95, -0.85, -0.93, -0.91, -0.94, and -0.93 respectively. The cut-off value for AAT 0.013 mg/ml showed the highest sensitivity and specificity as a diagnostic marker for FGR. Area under the curve was 0.99. Conclusions Negative correlations between maternal serum AAT and fetal parameters used to assess FGR were confirmed, suggesting that AAT is closely related to the pathophysiology of FGR among pre-eclamptic patients and may serve as a helpful tool in distinguishing between FGR and normal birth weight babies, pending further validation in feto-maternal outcomes.

Filgotinib, a preferential Janus Kinase‐1 inhibitor, is approved in Europe and Japan for treatment of rheumatoid arthritis and is being developed for treatment of other chronic inflammatory diseases. Three drug‐drug interactions studies were conducted in healthy subjects to evaluate the effect of P‐glycoprotein (P‐gp) modulation (study 1: P‐gp inhibition by itraconazole and study 2: P‐gp induction by rifampin) on filgotinib pharmacokinetics and the potential of filgotinib to impact exposure of metformin, an organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2K substrate (study 3). Co‐administration of filgotinib with itraconazole increased filgotinib exposure (maximum concentration [Cmax] by 64% and area under the curve to infinity [AUCinf] by 45%) but had no effect on the exposure of GS‐829845, filgotinib’s primary metabolite. Rifampin moderately reduced exposures of filgotinib and GS‐829845 (Cmax by 26% and AUCinf by 27% for filgotinib; Cmax by 19% and AUCinf by 38% for GS‐829845). The data confirmed that filgotinib is a P‐gp substrate. However, the magnitude of change in filgotinib/GS‐829845 exposure by P‐gp modulators is not deemed to be clinically relevant based on filgotinib exposure‐response analyses in subjects with rheumatoid arthritis. Filgotinib did not alter metformin exposures, indicating that filgotinib and GS‐829845 do not inhibit OCT2 and MATE1/2K at the clinical doses. Filgotinib was generally well‐tolerated when administered alone or with the co‐administered drugs in the studies. Results from these studies were the basis to enable the use of P‐gp modulators and substrates of OCT2, MATE1, and MATE2K with filgotinib without the need for dose modifications in the current approved rheumatoid arthritis population.

To evaluate the clinical importance of endometrial polyp size measured using saline infusion sonohysterography (SIS) before performing a hysteroscopic resection in predicting premalignant/malignant lesions.A retrospective observational study analysis was conducted of 365 patients, who underwent SIS, in a reference hospital. The longest plane of the polyp size was taken as base. Polyps were classified as benign, premalignant, or malignant.The rates of premalignant and malignant lesions were 7.4% and 0.9%, respectively. The mean polyp size was 17.7 ± 0.5 mm in benign patients and 23.7 ± 1.8 mm in premalignant/malignant individuals (P 0.001). In the group of polyps that were 0-10, 10-20, 20-30, and30 mm, premalignancy/malignancy rates were 0.0%, 4.8%, 13.3%, and 18.8%, respectively. The cut-off value for polyp size to be able to predict lesions was calculated as 22.5 mm (sensitivity: 63%, specificity: 80%) on receiver operating characteristics curve analysis (P = 0.001, area under the curve 0.732). The power of the study was calculated as 90.86%.During the female reproductive years, endometrial polyps smaller than 10 mm, as measured in SIS, can be followed. However, when the polyp size is 22.5 mm or more, especially in postmenopausal women, treatment should be planned.

Introduction Glucose-dependent insulinotropic polypeptide (GIP) contributes importantly to glucose and lipid metabolism. We investigated the effects of exogenous GIP on lipid metabolism during stable insulin levels. Methods Ten male patients with type 1 diabetes without endogenous insulin secretion (C-peptide negative) (age [mean ± SD: 26 ± 4 years; BMI: 24 ± 2 kg/m2; HbA1c 7.3 ± 0.856 ± 8 mmol/mol]) were studied in a randomized, double-blind, placebo-controlled, crossover study with continuous intravenous infusions of GIP (4 pmol/kg/min) or placebo (saline), during two separate 90-minute hyperglycemic (12 mmol/L) clamps with basal insulin substitution (0.1–0.2 mU/kg/min). Results Plasma glycerol concentrations increased from baseline during GIP infusion and decreased during placebo infusion (baseline-subtracted area under the curve [bsAUC]: 703 ± 407 vs. −262 ± 240 μmol/L × min, respectively, p textless 0.001). Free fatty acids (FFA) increased during GIP infusions (bsAUC: 5505 ± 2170 μEq/L × min) and remained unchanged during placebo infusion (bsAUC: −74 ± 2363 μEq/L × min) resulting in a significant difference between GIP and placebo infusions (p textless 0.001). Plasma concentrations of glucose, insulin, GLP-1 and glucagon were similar during GIP and placebo infusions. Conclusions GIP increased plasma glycerol and FFA in patients with type 1 diabetes during hyperglycemia and stable basal insulin levels. This supports a direct lipolytic effect of GIP at high glucose and low levels of plasma insulin. Trial registration ClinicalTrials.gov NCT03195257 None.

Background To investigate the clinical value of acoustic cardiography in the diagnosis of coronary artery disease (CAD) and post‐percutaneous coronary intervention (PCI) early asymptomatic left ventricular systolic dysfunction. Methods Inpatients in the department of cardiology were included in the research (n = 315); including 180 patients with angina pectoris and 135 patients with acute anterior wall myocardial infarction after emergency PCI did not present with signs and symptoms of heart failure. Color Doppler echocardiography, brain natriuretic peptide, acoustic cardiography examination were performed. The patients were divided into four groups: non‐CAD group (n = 60), CAD group (n = 120), MIREF group (EF%

Background At present, lobectomy is still the standard treatment for lung cancer. Judging whether a lesion is invasive adenocarcinoma (IA) has important guiding significance for determining the scope of surgical resection. The commonly used methods are intraoperative frozen sections and computed tomography (CT) signs. There is still controversy about the accuracy of both in judging the invasiveness of ground‐glass nodules (GGNs). Methods The clinical data of patients with GGNs who underwent surgery were collected. According to the results of univariate analysis, the variables with statistical differences were selected and included in logistic regression multivariate analysis. The predictive variables were determined and the receiver operating characteristic (ROC) curve was drawn in order to achieve the area under the curve (AUC) value. Results According to the results of logistic regression analysis, the longest diameter and maximum CT value of nodules were independent risk factors for IA. The mathematical prediction model of CT signs was determined, and the ROC curves of CT signs and intraoperative frozen sections (FS) were drawn, respectively. The AUC values under the curves were calculated to be 0.873 and 0.807, respectively. The mathematical prediction model of intraoperative frozen section combined with CT signs was established. A ROC curve was drawn and the AUC was calculated to be 0.925. Conclusions The diagnostic accuracy of CT signs in judging whether nonbenign GGNs were IA was higher than that of intraoperative FS. Combined with CT signs and intraoperative FS to establish a mathematical prediction model, the diagnostic accuracy of judging whether nonbenign GGNs are IA is significantly improved., The receiver operating characteristic (ROC) curves for the mathematical prediction model (not included in the intraoperative frozen section). The area under the curve (AUC) value using the prediction model was 0.873.

Background The composition of the population of immune‐related long non‐coding ribonucleic acid (irlncRNA) generates a signature, irrespective of expression level, with potential value in predicting the survival status of patients with invasive breast carcinoma. Methods The current study uses univariate analysis to identify differentially expressed irlncRNA (DEirlncRNA) pairs from RNA‐Seq data from The Cancer Genome Atlas (TCGA). 36 pairs of DEirlncRNA pairs were identified. Using various algorithms to construct a model, we have compared the area under the curve and calculated the 5‐year curve of Akaike information criterion (AIC) values, which allows determination of the threshold indicating the maximum value for differentiation. Through cut‐off point to establish the optimal model for distinguishing high‐risk or low‐risk groups among breast cancer patients. We assigned individual patients with invasive breast cancer to either high risk or low risk groups depending on the cut‐off point, re‐evaluated the tumor immune cell infiltration, the effectiveness of chemotherapy, immunosuppressive biomarkers, and immunotherapy. Results After re‐assessing patients according to the threshold, we demonstrated an effective means of distinguish the severity of the disease, and identified patients with different clinicopathological characteristics, specific tumor immune infiltration states, high sensitivity to chemotherapy,wellpredicted response to immunotherapy and thus a more favorable survival outcome. Conclusions The current study presents novel findings regarding the use of irlncRNA without the need to predict precise expression levels in the prognosis of breast cancer patients and to indicate their suitability for anti‐tumor immunotherapy., The manuscript is an immune‐related lncRNA pairing strategy to construct a risk assessment model. We did not use precise expression levels of the target lncRNAs in the signature.

Background There are few effective drugs for treatment of seizures in avian species. Objectives To investigate the pharmacokinetics and safety of zonisamide in chickens. Methods Phase 1: chickens (n = 4) received a single oral dose of zonisamide at 20 mg/kg. Blood samples were collected intermittently for 36 hr after dosing. Phase 2: chickens (n = 8) received zonisamide in a dose escalation protocol (20, 30, 60 and 80 mg/kg orally every 12 hr). The dose was increased weekly, and peak and trough blood samples were collected on Days 1, 3, and 7 each week. Two birds were randomly euthanized at the end of each week. Plasma zonisamide concentrations were analysed using a commercial immunoassay. Drug concentration vs. time data were subjected to non‐compartmental pharmacokinetic analysis. Results For Phase 1, peak plasma zonisamide (Cmax) was 15 ± 3 µg/ml at 2 ± 1 hr (Tmax). The disappearance half‐life was 6.5 ± 1 hr. Mean plasma concentrations remained within the (human) therapeutic range (10–40 µg/ml) for 6 hr. For Phase 2 of the study, plasma concentrations of zonisamide remained within or close to the recommended mammalian therapeutic range for birds in the 20 and 30 mg/kg dose. Area under the curve (AUC) and Cmax were dose dependent. Two birds developed immune‐mediated haemolytic anaemia. Conclusions Zonisamide appears to be a viable drug for use in chickens at a dose of 20 mg/kg orally every 12 hr., The pharmacokinetics and safety of zonisamide were investigated in chickens in single and repeated dose trials. Zonisamide appears to be a viable drug for use in chickens at a dose of 20mg/kg orally every 12 hr.

Background Frailty is a state of increased vulnerability to stressors, and predicts risk of adverse outcomes, such as mortality. Frailty can be defined by a frailty index (FI) using an accumulation of deficits approach. An FI comprised of 20 items derived from our previously studied test‐based frailty index (TBFI) and an additional 33 survey‐based elements sourced from the standard CGA was developed to evaluate if predictive validity of survival was improved. Methods One hundred eighty‐nine cancer patients during acute hospitalization were consented between September 2018 and May 2019. Frailty scores were calculated, and patients were categorized into four groups: non‐frail (0–0.2), mildly frail (0.2–0.3), moderately frail (0.3–0.4), and severely frail (>0.4). Patients were followed for 1‐year to assess FI and TBFI prediction of survival. Area under the curve (AUC) statistics from ROC analyses were compared for the FI versus TBFI. Results Increasing frailty was similarly associated with increased risk of mortality (HR, 4.5 [95% CI, 2.519–8.075] and HR, 4.1 [95%CI, 1.692–9.942]) and the likelihood of death at 6 months was about 11‐fold (odds ratio, 10.9 [95% CI, 3.97–33.24]) and 9.73‐fold (95% CI, 2.85–38.50) higher for severely frail patients compared to non‐frail patients for FI and TBFI, respectively. This association was independent of age and type of cancer. The FI and TBFI were predictive of survival for older and younger cancer patients with no significant differences between models in discriminating survival (FI AUC, 0.747 [95% CI, 0.6772–0.8157] and TBFI AUC, 0.724 [95% CI, 0.6513–0.7957]). Conclusions The TBFI was predictive of survival, and the addition of an in‐person assessment (FI) did not greatly improve predictive validity. Increasing frailty, as measured by a TBFI, resulted in a meaningfully increased risk of mortality and may be well‐suited for screening of hospitalized cancer patients., A simplified test based frailty index (TBFI) is similarly predictive of survival as a more comprehensive CGA based frailty index in the hospitalized cancer patient. This index may be useful as a screening tool in the acute cancer patient.