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ABSTRACT This study aimed to evaluate the effects of the concomitant administration of TPN171 and alcohol on hemodynamic and pharmacokinetic characteristics in healthy Chinese male subjects. Fifteen eligible subjects were randomly assigned to one of three sequences, each comprising three treatments: Treatment A (placebo +0.5 g/kg alcohol), Treatment B (TPN171 + 0.5 g/kg alcohol), and Treatment C (TPN171 + placebo). Enrolled subjects were administered with 10 mg TPN171 and/or 0.5 g/kg alcohol in fasting state in a randomized crossover design. Blood pressure, pulse rate (PR), blood samples, and breath alcohol test were measured at designated time points for hemodynamic and pharmacokinetic analyses. Compared with 10 mg TPN171 alone, administration of 10 mg TPN171 + 0.5 g/kg alcohol significantly lowered the area under the effect–time curve from 0 to 4 h (AUEC0‐4h) of systolic blood pressure (95% confidence interval [CI]: −29.75 to −0.83, p = 0.039) and significantly increased AUEC0–4h of PR (95% CI: 7.47–28.92, p = 0.003). Compared with 0.5 g/kg alcohol alone, administration of 10 mg TPN171 + 0.5 g/kg alcohol contributed to significantly higher maximal increase of PR (95% CI: 2.78–9.44, p = 0.002) and AUEC0‐4h of PR (95% CI: 1.08–24.52, p = 0.035). Alcohol had no influence on the pharmacokinetics of TPN171, and vice versa. Though the concomitant administration of TPN171 and alcohol induced a more pronounced increase in PR, this did not result in clinical symptoms or heart rate increase‐related adverse events, indicating that the combined use was generally safe and well‐tolerated.

Objective It was shown that microRNAs (miRNAs) play an important role in milk protein synthesis. However, the post-transcriptional regulation of casein expression by exogenous miRNA (xeno-miRNAs) in ruminants remains unclear. This study explores the regulatory roles of alfalfa xeno-miR162 on casein synthesis in bovine mammary epithelial cells (bMECs). Methods The effects of alfalfa xenomiR-162 and G protein subunit gamma 11 (GNG11) on proliferation and milk protein metabolism of bMECs were detected by 5-Ethynyl-2′-Deoxyuridine (EdU) staining, flow cytometry, cell counting kit-8 (CCK-8), enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. Dual-luciferase reporter assay was used to verify the targeting relationship between GNG11 and xenomiR-162. Results Results showed that over-expression of xenomiR-162 inhibited cell proliferation but promoted apoptosis, which also up-regulated the expression of several casein coding genes, including CSN1S1, CSN1S2, and CSN3, while decreasing the expression of CSN2. Furthermore, the targeting relationship between GNG11 and xenomiR-162 was determined, and it was confirmed that GNG11 silencing also inhibited cell proliferation but promoted apoptosis and reduced the expression of casein coding genes and genes related to the mammalian target of rapamycin (mTOR) pathway. Conclusion Alfalfa xenomiR-162 appears to regulate bMECs proliferation and milk protein synthesis via GNG11 in the mTOR pathway, suggesting that this xeno-miRNA could be harnessed to modulate CSN3 expression in dairy cows, and increase κ-casein contents in milk.

Abstract This study aimed to evaluate the pharmacokinetic (PK) similarity of the proposed biosimilar HS628 compared with the reference tocilizumab (Actemra®) and also to demonstrate similar safety and immunogenicity profiles in healthy Chinese male subjects. Eighty eligible subjects were randomized into two treatment groups in a 1:1 ratio to receive a single intravenous infusion of HS628 or tocilizumab at 4 mg/kg over 60 min. Blood samples were collected at the scheduled time points for PK and immunogenicity analysis. PK biosimilarity was determined using the standard bioequivalence criteria 80%–125%. A total of 77 subjects received the study drug and completed the study. The main PK parameters were similar for the test and reference groups. The ratio of geometric least‐squares means (GMR) and its 90% CIs for AUC0–t, AUC0–∞, and Cmax between the test group and reference group were 1.06 (1.00–1.12), 1.07 (1.00–1.14), and 1.04 (0.99–1.10), respectively, which were fully within the predefined bioequivalent range of 80%–125%. The incidence of treatment‐emergent adverse events (TEAEs) was similar for HS628 and tocilizumab (p > 0.05). The most common TEAEs were decreased fibrinogen, decreased neutrophils, pharyngalgia, oral ulcer, decreased leukocytes, and increased erythrocyte sedimentation rate. The results of the present study provide strong evidence to support the PK similarity and bioequivalence of HS628 and tocilizumab. The safety and immunogenicity profiles of HS628 were also shown to be similar to those of the reference tocilizumab.

Abstract This study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects (FE) of SC0062, a highly active endothelin‐A (ETA) receptor antagonist, in healthy subjects. The primary objectives of this first‐in‐human phase I study, comprised of single‐ascending‐dose, multiple‐ascending‐dose, and FE parts, were to characterize the safety and tolerability of SC0062, and FE. The secondary objectives were to determine the PK behavior of SC0062 and its major active metabolite M18, whereas exploratory objectives focused on PD effects, principally effects on endothelin‐1 (ET‐1) and total bile acids (TBA). Single doses of 10 to 100 mg and multiple daily doses of 20 and 50 mg for 6 days were well tolerated. SC0062 was rapidly absorbed and plasma exposure of SC0062 and M18 increased disproportionately with dose, achieving steady state by day 3, with accumulation ratios of 1.22 and 1.89 on day 6 for SC0062 and M18, respectively. The geometric mean (geometric standard deviation) terminal elimination half‐life (t1/2) values of SC0062 and M18 were 7.25 (1.70) h and 13.73 (1.32) h, respectively. Plasma ET‐1 concentrations were dose‐proportional, whereas plasma TBA concentrations behaved erratically. Following a single 50 mg dose of SC0062 after a high‐fat meal, Cmax values for SC0062 and M18 increased by 41% and 32%, respectively, and median Tmax values for SC0062 were 3 h longer than fasting values; exposure was unaffected. These favorable safety, PK, and PD results provide a foundation for further studies of SC0062 in pulmonary arterial hypertension, chronic kidney disease, and other relevant indications.

Purpose: HSK16149 is a novel, potent gamma-aminobutyric acid (GABA) analog for the treatment of neuropathic pain. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of HSK16149 after single and multiple doses in healthy Chinese subjects.Methods: The randomized, double-blind, placebo-controlled study comprised two parts: SAD (single ascending-dose study) and MAD (multiple ascending-dose study). A total of 122 healthy subjects were enrolled in this study. HSK16149 capsule or placebo was administered as the protocol required. The safety of the drug was evaluated through clinical examinations and adverse events. Blood and urine samples were collected at the designated time intervals for pharmacokinetic analysis.Results: Subjects were generally well tolerated after HSK16149 administration and the most common treatment-emergent adverse event (TEAEs) was dizziness, which was expected based on the mechanism of action of HSK16149. In SAD, AUC and Cmax were shown to have a dose-proportional relationship in the dose range of 5-120 mg. The t1/2 of HSK16149 is 3.7-6.4 h. In MAD, after a single and multiple administration of 15-80 mg, AUC and Cmax are proportional to the increased dose of HSK16149, and the accumulative ratios of AUC and Cmax at steady-state were 1.05–1.44 and 1.07–1.36, respectively, indicating that HSK16149 only accumulated slightly after repeated administration.Conclusion: HSK16149 was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 80 mg twice daily (BID) was suggested as the highest target dose for further clinical development.Clinical Trial Registration:http://www.chinadrugtrials.org.cn, identifier CTR20182535 and CTR20191317

Abstract Baloxavir marboxil is an endonuclease inhibitor indicated for the treatment of influenza in patients ≥12 years. No data exist for Chinese patients in global studies. This randomized, open‐label, phase I study evaluated the pharmacokinetics (PK) and safety of baloxavir marboxil in healthy Chinese volunteers and was used to anticipate efficacy in Chinese patients. Patients received a single oral dose of baloxavir marboxil (40 or 80 mg [1:1]). Serial blood samples were collected predose and at various timepoints up to 14 days postdose. Baloxavir marboxil and acid plasma concentrations were determined by liquid chromatography tandem mass spectrometry. PK parameters of baloxavir acid were estimated by noncompartmental analysis. Adverse events (AEs) were recorded. Time to alleviation of symptoms (TTAS) was simulated for otherwise healthy (OwH) and high‐risk (HR) Chinese and Asian patients. Thirty‐two male patients received baloxavir marboxil. Baloxavir acid plasma concentration peaked 4 h postdose. Mean maximum concentration (Cmax) was 107.6 and 206.9 ng/ml, and mean area under the plasma concentration‐time curve from zero to infinity (AUC0–inf) was 6955 and 9643 ng·h/ml in the 40 and 80 mg cohorts, respectively. AEs were mild and transient; no new safety signals were identified. Simulated median TTAS for OwH and HR Chinese patients agreed with simulated values in Asian patients. PK parameters were similar to Asian populations in other studies. The globally adopted baloxavir marboxil dosing strategy was consistent with the established safety profile of baloxavir marboxil in this population. Simulated efficacy indicated Chinese patients could benefit from similar efficacy to Asian patients.

Abstract HSK16149 is a novel, potent gamma‐aminobutyric acid (GABA) analog for the treatment of neuropathic pain. The purpose of this study was to assess the effect of a high‐fat and high‐calorie meal on the pharmacokinetics of HSK16149 in healthy Chinese subjects. An open‐label, two‐period crossover design was applied in this study. Twenty‐six subjects were enrolled and were randomly divided into two groups: a fasted‐fed group and a fed‐fasted group, with 13 subjects in each group. Subjects took a single oral dose of 45 mg of HSK16149 under fasted or fed conditions on Day 1 and Day 4. A series of blood samples were collected for PK analysis. Safety was evaluated throughout the study by physical examinations, clinical laboratory tests, 12‐lead ECGs, vital signs, and adverse events (AEs). The parameters AUC0‐∞, AUC0‐t, and Cmax of HSK16149 were compared to assess the bioequivalence of HSK16149 under fasted and fed conditions. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) of AUC0‐t and AUC0‐∞ under the fed condition compared with the fasted condition were 95.84% (91.94–99.90%) and 95.79% (91.89–99.84%), respectively, which were all within the bioequivalent interval (80.00–125.00%). The GMR (90% CI) of Cmax under the fed condition compared with the fasted condition was 66.04% (59.45–73.36%), which was not within the bioequivalent range (80.00–125.00%). All adverse events were transient and resolved. This study demonstrated that HSK16149 can be administered with or without food.

ObjectivesTo compare the rate and extent of absorption of a launched generic calcium dobesilate capsule versus the branded reference formulation under fasting and fed conditions in healthy Chinese subjects, and to assess their bioequivalence and tolerability.MethodsThis single-dose, open-label, randomized-sequence, 2-period crossover bioequivalence study was conducted on healthy Chinese volunteers aged 18 to 45 years. Subjects received a single 0.5 g dose of calcium dobesilate capsule under fasting or fed conditions, with a 3-day washout period between doses of the test (T) and reference (R) formulations. Blood samples were collected before and up to 24 hours after administration. The plasma concentration of calcium dobesilate was determined by a validated Liquid chromatography-tandem mass spectrometry method. Non-compartmental analysis was applied to identify the pharmacokinetic (PK) properties. The primary PK parameters including the maximal plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), and the AUC extrapolated to infinity (AUC0-inf) were used for bioequivalence evaluation.ResultsThe mean of PK parameters for T and R capsules under fasting (fed) condition were: Cmax, 13.57 (6.71) and 12.59 (7.25) μg/mL; AUC0-t, 97.32 (79.74) and 96.97 (80.71) h*μg/mL; AUC0-inf, 101.68 (88.01) and 101.64 (87.81) h*μg/mL. The 90% confidence intervals (CIs) of GMRs under fasting (fed) condition were: Cmax, 97.91%-116.62% (88.63%-96.53%); AUC0-t, 97.15%-104.00% (96.58%-101.39%); and AUC0-inf, 97.19%-102.89% (98.67%-103.99%). These 90% CIs were all within the bioequivalence range of 80%-125%. All adverse events were mild.ConclusionIn this study, the T calcium dobesilate 0.5 g capsule was bioequivalent to the reference product under both fasting and fed conditions. Taking food would slow down its rate and reduce its amount of absorption. Both formulations were generally well tolerated.

Abstract Therapeutic drug monitoring (TDM) is necessary for the optimal administration of anti-arrhythmic drugs in the treatment of heart arrhythmia. The present study aimed to develop and validate a direct analysis in real time tandem mass spectrometry (DART–MS/MS) method for the rapid and simultaneous determination of five anti-arrhythmic drugs (metoprolol, diltiazem, amiodarone, propafenone, and verapamil) and one metabolite (5-hydroxy(OH)-propafenone) in human serum. After the addition of isotope-labeled internal standards and protein precipitation with acetonitrile, anti-arrhythmic drugs were ionized by DART in positive mode followed by multiple reaction monitoring (MRM) detection. The use of DART–MS/MS avoided the need for chromatographic separation and allowed rapid and ultrahigh throughput analysis of anti-arrhythmic drugs in a total run time of 30 s per sample. The DART–MS/MS method yielded satisfactory linearity (R2 ≥ 0.9906), accuracy (86.1–109.9%), and precision (≤ 14.3%) with minimal effect of biological matrixes. The method was successfully applied to analyzing 30 clinical TDM samples. The relative error (RE) of the concentrations obtained by DART–MS/MS and liquid chromatography-tandem mass spectrometry (LC–MS/MS) was within ± 13%. This work highlights the potential usefulness of DART for the rapid quantitative analysis of anti-arrhythmic drugs in human serum and gives rapid feedback in the clinical TDM practices.

It was shown that microRNAs (miRNAs) play an important role in the synthesis of milk fat; thus, this manuscript evaluated whether exogenous miRNA (xeno-miRNAs) from alfalfa could influence the milk fat content in dairy cows. At first, mtr-miR168b was screened from dairy cow milk and blood. Then, EdU staining, flow cytometry, Oil Red O staining, qRT-PCR, and WB were applied to explore the effect of xeno-miR168b on the proliferation, apoptosis, and lipid metabolism of bovine mammary epithelial cells (BMECs). Finally, in order to clarify the pathway that regulated the lipid metabolism of BMECs using xeno-miR168b, a double-luciferase reporter assay was used to verify the target gene related to milk fat. These results showed that overexpression of xeno-miR168b inhibited cell proliferation but promoted apoptosis, which also decreased the expression of several lipid metabolism genes, including PPARγ, SCD1, C/EBPβ, and SREBP1, significantly inhibited lipid droplet formation, and reduced triglyceride content in BMECs. Furthermore, the targeting relationship between CPT1A and xeno-miR168b was determined and it was confirmed that CPT1A silencing reduced the expression of lipid metabolism genes and inhibited fat accumulation in BMECs. These findings identified xeno-miR168b from alfalfa as a cross-kingdom regulatory element that could influence milk fat content in dairy cows by modulating CPT1A expression.

Objective To investigate the associations between interleukin (IL) gene polymorphisms and susceptibility to gastric cancer in the Qinghai population, China. Methods Patients with gastric cancer and cancer-free controls were enrolled into the study from Qinghai Provincial People’s Hospital between September 2016 and September 2018. Single nucleotide polymorphisms (SNPs) were genotyped with the Sequenom MassARRAY® SNP genotype system. The Hardy–Weinberg equilibrium in allele and genotype frequencies, and general characteristics between patients with gastric cancer and cancer-free controls, were evaluated using χ 2 -test. Potential associations between interleukin gene variants and the risk of gastric cancer were analysed by logistic regression. Results Among eight candidate SNPs, the allele and genotype frequency distribution of IL-1B rs1143634 polymorphism was significantly different between patients with gastric cancer ( n = 190) and cancer-free controls ( n = 186). The IL-1B rs1143634 GA genotype and IL-1B rs1143634 GA + AA genotype were associated with a reduced risk of gastric cancer, however, the remaining SNPs were not statistically associated with gastric cancer risk in the Qinghai population. Conclusion The IL-1B rs1143634 polymorphism might be associated with a decreased risk of gastric cancer, and may be a protective factor against gastric cancer.

Ulinastatin, is a broad-spectrum protease inhibitor purified from human urine, inhibits endogenous proteases such as trypsin, α-chymotrypsin, hyaluronidase, and plasmin. It is widely being used at increasingly higher doses for the treatment of acute or chronic pancreatitis, severe infection, and acute organ failure. We aimed to evaluate the safety and tolerability of high-dose ulinastatin in healthy volunteers in our single center, randomized, double-blind, placebo-controlled, single-dose escalation study. Fifty-one healthy Chinese subjects were enrolled in 9 dose cohorts (3×105 U, 6×105 U, 12×105 U, 20×105 U, 30×105 U, 45×105 U, 60×105 U, 70×105 U, or 80×105 U of ulinastatin) and randomized to UTI or matching placebo (n = 1). Each dose cohort was composed of 3-7 subjects. All subjects were required to have 2 h of intravenous infusion. Safety and tolerability were assessed throughout the study via monitoring of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and interviews with the subjects about adverse events. Fifty-one subjects (35 men and 16 women) completed the study. A total of 13 AEs were reported by 10 subjects: 11 adverse events in the ulinastatin groups and 2 adverse events in the placebo group. Twelve of the adverse events were possibly related to the study drug. The most common drug-related adverse events included dizziness, pain at injection site, and a decrease in white blood cell count. All adverse events were of mild severity; none were serious. In conclusion, 2 hours of intravenous infusion of ulinastatin (3×105 to 80×105 U) was well tolerated by healthy Chinese subjects.

Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 μg (delivering 55/22 μg) and UMEC/VI 125/25 μg (delivering 113/22 μg) compared with their monotherapy components (UMEC 62.5 μg, UMEC 125 μg and, VI 25 μg [delivering 55, 113, and 22 μg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2–4 h for UMEC and 1–2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11–34% based on Cmax and 19–59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25–66% based on Cmax and 17–43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies.Clinicaltrials.gov NCT01899638 NCT01899638.

Accurate quantification of creatinine (Cre) is important to estimate glomerular filtration rate (GFR). Differences among various methods of Cre quantification were previously noted. This study aims to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for serum Cre and compare this method with clinical routine methods. LC-MS/MS analysis was performed on API 4000 triple quadrupole mass spectrometer coupled with an Agilent 1200 liquid chromatography system. After adding isotope-labeled Cre-d3 as internal standard, serum samples were prepared via a one-step protein precipitation with methanol. The LC-MS/MS method was compared with frequently used enzymatic method and Jaffe method. This developed method, with a total run time of 3 min, had a lower limit of quantification of 4.4 μmol/L, a total imprecision of 1.15%-3.84%, and an average bias of 1.06%. No significant matrix effect, carryover, and interference were observed for the LC-MS/MS method. The reference intervals of serum Cre measured by LC-MS/MS assay were 41-79 μmol/L for adult women, and 46-101 μmol/L for adult men. Using LC-MS/MS as a reference, the enzymatic method showed an average bias of -2.1% and the Jaffe method showed a substantial average bias of 11.7%. Compared with the LC-MS/MS method, significant negative bias was observed for the enzymatic and Jaffe methods in hemolytic and lipimic samples. We developed a simple, specific, and accurate LC-MS/MS method to analyze serum Cre. Discordance existed among different methods.

ABSTRACT Background and Aims To investigate the infection status and outcomes of biliary atresia (BA) patients during the coronavirus disease 2019 (COVID‐19) pandemic in Chinese population. Methods This retrospective study involved Kasai‐postoperative BA patients who had achieved jaundice‐free during the SARS‐CoV‐2 outbreak from December 1, 2022 to February 28, 2023. Children without hepatobiliary diseases hospitalized during the same period were as control group. Data collected included nutritional status, comorbidities, epidemiologic characteristics, fever symptoms (duration, max), respiratory symptoms (cough, runny nose and shortness of breath), and gastrointestinal symptoms (diarrhea and vomiting). All cases infected with SARS‐CoV‐2 were followed up for 3 months. Results A total of 128 BA patients were enrolled, ranged in age from 6 months to 12 years old (median age: 1.8 years). A total of 51 (39.8%) and 49 BA patients (38.3%) were classified as confirmed and suspected COVID‐19 cases, respectively. Only two confirmed cases presented with moderate symptoms, while the rest developed asymptomatic or mild cases. Compared to the 115 control groups, the proportion of symptomatic cases in BA was slightly higher (78.1% vs. 67.8%) without significant difference (p = 0.07). Similarly, no differences were found in proportion of fever, respiratory tract symptoms and gastrointestinal symptoms between BA and control groups. However, it is worth noting that 7 BA patients developed symptoms of cholangitis during SARS‐CoV‐2 infection, who experienced pale stool and elevated bilirubin levels. After hospitalization, six patients achieved jaundice‐free survival, but one child finally had to undergo liver transplantation due to hepatic failure. Conclusions The symptoms and course of COVID‐19 in BA patients were similar to those in healthy population. The vast majority of BA patients made a good recovery from COVID‐19.

Abstract Background Prompt and precise differential diagnosis of biliary atresia (BA) among cholestatic patients is of great importance. Matrix metalloproteinase-7 (MMP-7) holds great promise as a diagnostic marker for BA. This study aimed to investigate the accuracy of age-specific serum MMP-7 for discriminating BA from other cholestatic pediatric patients. Methods This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases (n = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients (n = 318, with 172 BA) and validated in a prospective cohort (n = 687, including 395 BA). Results The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946–0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5–97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0–90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9–93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6–96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0–30 days, which was 86.4% (95% CI: 75.0–94.0%), 95.5% (95% CI: 77.2–99.9%), 98.1% (95% CI: 89.7–100%), and 72.4% (95% CI: 52.8–87.3%), respectively. Conclusions The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.

Abstract Increased pulmonary vascular permeability is a characteristic feature of lung injury. However, there are no established methods that allow the three‐dimensional visualization and quantification of pulmonary vascular permeability in vivo. Evans blue extravasation test and total protein test of bronchoalveolar lavage fluid (BALF) are permeability assays commonly used in research settings. However, they lack the ability to identify the spatial and temporal heterogeneity of endothelial barrier disruption, which is typical in lung injuries. Magnetic resonance (MR) and near‐infrared (NIR) imaging have been proposed to image pulmonary permeability, but suffer from limited sensitivity and penetration depth, respectively. In this study, we report the first use of magnetic particle imaging (MPI) to assess pulmonary vascular leakage noninvasively in vivo in mice. A dextran‐coated superparamagnetic iron oxide (SPIO), synomag®, was employed as the imaging tracer, and pulmonary SPIO extravasation was imaged and quantified to evaluate the vascular leakage. Animal models of acute lung injury and pulmonary fibrosis (PF) were used to validate the proposed method. MPI sensitively detected the SPIO extravasation in both acutely injured and fibrotic lungs in vivo, which was confirmed by ex vivo imaging and Prussian blue staining. Moreover, 3D MPI illustrated the spatial heterogeneity of vascular leakage, which correlated well with CT findings. Based on the in vivo 3D MPI images, we defined the SPIO extravasation index (SEI) to quantify the vascular leakage. A significant increase in SEI was observed in the injured lungs, in consistent with the results obtained via ex vivo permeability assays. Overall, our results demonstrate that 3D quantitative MPI serves as a useful tool to examine pulmonary vascular integrity in vivo, which shows promise for future clinical translation.

Abstract Purpose To develop and validate a deep learning‐based pathological risk score (RS) with an aim of predicting patients' prognosis to investigate the potential association between the information within the whole slide image (WSI) and cervical cancer prognosis. Methods A total of 251 patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IA1–IIA2 cervical cancer who underwent surgery without any preoperative treatment were enrolled in this study. Both the clinical characteristics and WSI of each patient were collected. To construct a prognosis‐associate RS, high‐dimensional pathological features were extracted using a convolutional neural network with an autoencoder. With the score threshold selected by X‐tile, Kaplan–Meier survival analysis was applied to verify the prediction performance of RS in overall survival (OS) and disease‐free survival (DFS) in both the training and testing datasets, as well as different clinical subgroups. Results For the OS and DFS prediction in the testing cohort, RS showed a Harrell's concordance index of higher than 0.700, while the areas under the curve (AUC) achieved up to 0.800 in the same cohort. Furthermore, Kaplan–Meier survival analysis demonstrated that RS was a potential prognostic factor, even in different datasets or subgroups. It could further distinguish the survival differences after clinicopathological risk stratification. Conclusion In the present study, we developed an effective signature in cervical cancer for prognosis prediction and patients' stratification in OS and DFS.

PurposeSerum matrix metalloproteinase-7 (MMP-7) is significant in differentiating biliary atresia (BA). This study aims to develop a new peripheral blood quantitative collection device to detect MMP-7 levels via dried blood spot (DBS).MethodsThis is a diagnostic accuracy test. Serum and DBS MMP-7 concentrations were measured using an ELISA kit. Intraoperative cholangiography and subsequent histological examinations were used to confirm BA diagnoses.ResultsA total of 241 infants with obstructive jaundice were enrolled, among whom 168 were BA. Linear regression showed DBS MMP-7 correlated well with serum MMP-7 (R = 0.93, P

ObjectiveTo investigate the clinical features and prognosis of biliary atresia (BA) with normal or minimally elevated gamma-glutamyl transpeptidase (GGT).MethodsThe clinical data of patients with BA in our hospital between 2012 and 2017 were retrospectively studied. The patients were divided into a low-GGT group (GGT ≤ 300 IU/L) and a high-GGT group (GGT > 300 IU/L) according to the preoperative GGT level. The perioperative clinical parameters, the postoperative jaundice clearance within 6 months, and the 2-year native liver survival were compared among the groups.ResultsA total of 1,998 children were included in this study, namely, 496 in the low-GGT group and 1,502 in the high-GGT group. The ages and weights at the surgery in the low-GGT group were significantly lower than those in the high-GGT group (64.71 ± 21.35 vs. 68.64 ± 22.42 days, P = 0.001; 4.67 ± 1.03 vs. 4.89 ± 0.98 kg, P < 0.001). The levels of serum ALP, ALT, and AST in the low-GGT group were significantly higher than those in the high-GGT group before and 2 weeks after the surgery (ALP: 647.52 ± 244.10 vs. 594.14 ± 228.33 U/L, P < 0.001; ALT: 119.62 ± 97.14 vs. 96.01 ± 66.28 U/L, P < 0.001; AST: 218.00 ± 173.82 vs. 160.71 ± 96.32 U/L; P < 0.001). The INR of the low-GGT group was higher than that of the high-GGT group (1.05 ± 0.34 vs. 0.98 ± 0.20, P < 0.001), while FIB was lower than the high-GGT group (2.54 ± 0.67 vs. 2.73 ± 1.44 g/L; P = 0.006). The decreasing amplitude of TB and DB within 2 weeks after surgery in the low-GGT group was smaller than those in the high-GGT group (TB: 51.62 ± 71.22 vs. 61.67 ± 53.99 μmol/L, P = 0.003; DB: 33.22 ± 35.57 vs. 40.20 ± 35.93 μmol/L, P < 0.001). The jaundice clearance rate in the low-GGT group was significantly lower than that in the high-GGT group at 1, 3, and 6 months after surgery (17.70 vs. 26.05%; 35.17 vs. 48.58%; 38.62 vs. 54.64%, P < 0.001). In addition, the 2-year native liver survival rate in the low-GGT group was significantly lower than that of the high-GGT group (52.5 vs. 66.3%, P < 0.001 HR 1.80, 95% CI 1.38–2.33).ConclusionCompared to patients with high GGT, patients with normal or minimally elevated pre-operative GGT in BA were found to have poorer pre-operative liver function parameters, and post-operatively had lower jaundice clearance rates and worse 2-year native liver survival. This suggests a lower GGT at presentation in biliary atresia could be a sign of more severe liver injury.

Introduction: The Federally Qualified Health Center (FQHC) setting poses unique challenges to reimbursement of services provided by ambulatory care pharmacists; however, recent changes to telemedicine reimbursement have created new opportunities to help overcome these challenges. This article describes the experience and outcomes of the implementation of a novel, pharmacist-physician split-shared telehealth model at AltaMed Medical Group, a large, multi-site FQHC in Los Angeles and Orange counties. Program Development and Implementation: A pilot program for pharmacist-physician split shared tele-visits was launched at one clinic site with one clinical pharmacist and has since been expanded to a total of 6 sites and 5 clinical pharmacists. Prior to this program, clinical pharmacists saw patients for diabetes mellitus (DM) video-conference disease management appointments. With the launch of the pilot program, additional steps were added to pre-existing workflows to create a model in which visits with the clinical pharmacists were followed by an “enhanced visit” with an eligible, billable clinic provider. Outcomes: Average A1c change for all patients in the split-shared model was -1.5%, and average A1c change for program graduates from enrollment through graduation was -3.8%. Evidence from similar services have also been associated with significant increases in revenue from a split-shared model, indicating this design can be a viable option for financial justification of ambulatory care pharmacy services. Conclusion: In the setting of current limitations, we advocate for increased utilization of shared visits and split-shared visits as a viable method to generate revenue and aid in the justification of clinical pharmacy services.

Introduction Biliary atresia is a severe liver disease in neonates, and the prognosis partially depends on the age at which infants undergo the Kasai procedure. Matrix metalloproteinase-7 (MMP-7) was confirmed to have significant value in the diagnosis of biliary atresia. However, so far, the reference range and its cut-off value for diagnosing biliary atresia have not been established yet.Methods and analysis DIagnosis Algorithm for Biliary Atresia (DIABA-7) is a prospective diagnostic test. Cholestatic infants and normal controls within 150 days of age are recruiting from the Chinese Biliary Atresia Collaborative Network. The serum samples and dried blood spot (DBS) samples are obtained to detect MMP-7 concentrations using an ELISA kit. The reference standard is the intraoperative exploration and subsequent histological examination of liver biopsies. Lambda-Mu-Sigma (LMS) method is used to calculate the normal range of serum MMP-7 of each age group. Receiver operating characteristics (ROC) curves are constructed to calculate the best cut-off point and area under the curve for the index test. The sensitivity, specificity, positive predictive value and negative predictive value are used to show the diagnostic accuracy. Pearson correlation coefficient test is applied to assess the correlation of serum MMP-7 and DBS MMP-7.Ethics and dissemination This study was reviewed and approved by the Ethics Committee of Children’s Hospital of Fudan University (Number 2020–296). Dissemination will be guided by investigators and patients. The aim is to publish the study results in a high-quality peer-reviewed journal and present the findings at international academic meetings.Trial registration number ChiCTR2000032983.

Objectives: Breast cancers show different regression patterns after neoadjuvant chemotherapy. Certain regression patterns are associated with more reliable margins in breast-conserving surgery. Our study aims to establish a nomogram based on radiomic features and clinicopathological factors to predict regression patterns in breast cancer patients. Methods: We retrospectively reviewed 144 breast cancer patients who received neoadjuvant chemotherapy and underwent definitive surgery in our center from January 2016 to December 2019. Tumor regression patterns were categorized as type 1 (concentric regression + pCR) and type 2 (multifocal residues + SD + PD) based on pathological results. We extracted 1158 multidimensional features from 2 sequences of MRI images. After feature selection, machine learning was applied to construct a radiomic signature. Clinical characteristics were selected by backward stepwise selection. The combined prediction model was built based on both the radiomic signature and clinical factors. The predictive performance of the combined prediction model was evaluated. Results: Two radiomic features were selected for constructing the radiomic signature. Combined with two significant clinical characteristics, the combined prediction model showed excellent prediction performance, with an area under the receiver operating characteristic curve of 0.902 (95% confidence interval 0.8343–0.9701) in the primary cohort and 0.826 (95% confidence interval 0.6774–0.9753) in the validation cohort. Conclusions: Our study established a unique model combining a radiomic signature and clinicopathological factors to predict tumor regression patterns prior to the initiation of NAC. The early prediction of type 2 regression offers the opportunity to modify preoperative treatments or aids in determining surgical options.

Purpose: To analyze the influence of perioperative complications in the management of biliary atresia (BA).Methods: A retrospective study was performed using a total of 422 BA patients who underwent Kasai portoenterostomy (KPE) in a single institution between February 2016 and May 2017. Data on patients' clinical characteristics, laboratory examinations, perioperative complications, and outcomes were collected. Unpaired two-tailed t-test and χ2 test were employed for the comparison between BA patients with and without perioperative complications. Cox regression analysis was used to screen the risk factors for 2-years NLS in BA, and their influence on the 2-years NLS was analyzed using Kaplan–Meier survival analysis as well as the log-rank test.Results: The incidence of perioperative complications, 6-months jaundice clearance (JC) and 2-years native liver survival (NLS) rate were 60.4, 59.5, and 56.6%, respectively. Patients with perioperative complications had lower serum albumin (ALB) level, but higher aspartate aminotransferase-to-platelet ratio index (APRI) and international normalized ratio (INR) levels when compared with those without perioperative complications (ALB, P < 0.05; APRI, P < 0.01; INR, P < 0.05). Moreover, perioperative complications were correlated with glucocorticoid administration (P = 0.002). Univariate Cox regression analysis showed no relationship between perioperative complications and 2-years NLS (P > 0.05). However, multivariate Cox regression analysis indicated 6-months JC was an independent protective factor for 2-years NLS [P < 0.0001, hazard ratio (HR) = 0.074, 95% confidence interval = 0.05–0.11], and concordance index of this prediction model including age, weight, APRI, glucocorticoid, and 6-months JC was 0.811.Conclusion: Although perioperative complication is common during and after KPE, it had no influence on the prognosis of BA. However, assessment of the serum level of total bilirubin after KPE may serve as an important predictor for the outcome in BA.

Objectives: Biliary atresia (BA) is a devastating pediatric liver disease. Early diagnosis is important for timely intervention and better prognosis. Using clinical parameters for non-invasive and efficient BA diagnosis, we aimed to establish an artificial neural network (ANN).Methods: A total of 2,384 obstructive jaundice patients from 2012 to 2017 and their 137 clinical parameters were screened for eligibility. A standard binary classification feed-forward ANN was employed. The network was trained and validated for accuracy. Gamma-glutamyl transpeptidase (GGT) level was used as an independent predictor and a comparison to assess the network effectiveness.Results: We included 46 parameters and 1,452 patients for ANN modeling. Total bilirubin, direct bilirubin, and GGT were the most significant indicators. The network consisted of an input layer, 3 hidden layers with 12 neurons each, and an output layer. The network showed good predictive property with a high area under curve (AUC) (0.967, sensitivity 97.2% and specificity 91.0%). Five-fold cross validation showed the mean accuracy for training data of 93.2% and for validation data of 88.6%.Conclusions: The high accuracy and efficiency demonstrated by the ANN model is promising in the noninvasive diagnosis of BA and could be considered as in a low-cost and independent expert diagnosis system.

Background & aims: The overlapping features of biliary atresia (BA) and the other forms of neonatal cholestasis (NC) with different causes (non-BA) has posed challenges for the diagnosis of BA. This study aimed at developing new and better diagnostic models for BA. Methods: We retrospectively analyzed data from 1728 newborn infants with neonatal obstructive jaundice (NOJ). New prediction models, including decision tree (DT), random forest (RF), and multivariate logistic regression-based nomogram for BA were created and externally validated in an independent set of 508 infant patients. Results: Fiver predictors, including gender, weight, direct bilirubin (DB), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT) were significantly different between the BA and non-BA groups (P

Previous results show that the floating reference theory (FRT) is an effective tool to reduce the influence of interference factors on noninvasive blood glucose sensing by near-infrared spectroscopy (NIRS). It is the key to measure the floating reference point (FRP) precisely for the application of FRT. Monte Carlo (MC) simulation has been introduced to quantitatively investigate the effects of positioning errors and light source drifts on measuring FRP. In this article, thinning and calculating method (TCM) is proposed to quantify the positioning error. Meanwhile, the normalization process (NP) is developed to significantly reduce the error induced by light source drift. The results according to TCM show that 7μm deviations in positioning can generate about 10.63% relative error in FRP. It is more noticeable that 1% fluctuation in light source intensity may lead to 12.21% relative errors. Gratifyingly, the proposed NP model can effectively reduce the error caused by light source drift. Therefore, the measurement system for FRPs must meet that the positioning error is less than 7μm, and the light source drift is kept within 1%. Furthermore, an improvement for measurement system is proposed in order to take advantage of the NP model.