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International Myeloma Working Group (IMWG) response criteria require refrigerated 24-hour urine specimens for most patients. However, given that serum free light chain testing has been shown to outperform 24-hour urine immunofixation as a prognostic marker, the importance of maintaining urine testing options or requirements within each level of IMWG response criteria has not been investigated. We analyzed responses to induction therapy for all transplant-eligible patients with multiple myeloma at our institution over a 3-year period using traditional versus 'urine-free' IMWG response criteria (where references to urine were removed from the descriptions for every depth of response). Of 281 evaluable patients, responses changed for only 4% of patients (95% confidence interval 2-7%) using urine-free criteria. Our results call into question the continued requirement for 24-hour urine measurements as part of IMWG response assessments for all patients. Research into the prognostic performance of urine-free IMWG criteria is ongoing.

Background: GATA4 (GATA-binding protein 4), a zinc finger–containing, DNA-binding transcription factor, is essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Defects in alternative splicing are associated with many heart diseases, yet relatively little is known about how cell type– or cell state–specific alternative splicing is achieved in the heart. Here, we show that GATA4 regulates cell type–specific splicing through direct interaction with RNA and the spliceosome in human induced pluripotent stem cell–derived cardiac progenitors. Methods: We leveraged a combination of unbiased approaches including affinity purification of GATA4 and mass spectrometry, enhanced cross-linking with immunoprecipitation, electrophoretic mobility shift assays, in vitro splicing assays, and unbiased transcriptomic analysis to uncover GATA4’s novel function as a splicing regulator in human induced pluripotent stem cell–derived cardiac progenitors. Results: We found that GATA4 interacts with many members of the spliceosome complex in human induced pluripotent stem cell–derived cardiac progenitors. Enhanced cross-linking with immunoprecipitation demonstrated that GATA4 also directly binds to a large number of mRNAs through defined RNA motifs in a sequence-specific manner. In vitro splicing assays indicated that GATA4 regulates alternative splicing through direct RNA binding, resulting in functionally distinct protein products. Correspondingly, knockdown of GATA4 in human induced pluripotent stem cell–derived cardiac progenitors resulted in differential alternative splicing of genes involved in cytoskeleton organization and calcium ion import, with functional consequences associated with the protein isoforms. Conclusions: This study shows that in addition to its well described transcriptional function, GATA4 interacts with members of the spliceosome complex and regulates cell type–specific alternative splicing via sequence-specific interactions with RNA. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.

Background: Retinal parameters could reflect systemic vascular changes. With the advances of deep learning technology, we have recently developed an algorithm to predict retinal age based on fundus images, which could be a novel biomarker for aging and mortality. Therefore, we aim to investigate associations of retinal age gap with arterial stiffness index and incident cardiovascular disease (CVD). Methods: A deep learning model was trained based on 19 200 fundus images of 11 052 participants without any medical history at baseline to predict the retinal age. Retinal age gap (retinal age predicted minus chronological age) was generated for the remaining 35 917 participants. Regression models were used to assess the association between retinal age gap and arterial stiffness index. Cox proportional hazards regression models and restricted cubic splines were used to explore the association between retinal age gap and incident CVD. Results: We found each 1-year increase in retinal age gap was associated with increased arterial stiffness index (β=0.002 [95% CI, 0.001–0.003]; P P =0.014). In the restricted cubic splines analysis, the risk of incident CVD increased significantly when retinal age gap reached 1.21 (hazard ratio=1.05 [95% CI, 1.00–1.10]; P -overall P -nonlinear=0.0681). Conclusions: We found that retinal age gap was significantly associated with arterial stiffness index and incident CVD events, supporting the potential of this novel biomarker in identifying individuals at high risk of future CVD events.

Ambient air pollution aggravates the process of Alzheimer's disease (AD) pathology. Currently, the exact inflammatory mechanisms underlying these links from clinical research remain largely unclear.This study included 1,131 cognitively intact individuals from the Chinese Alzheimer's Biomarker and LifestylE database with data provided on cerebrospinal fluid (CSF) AD biomarkers (amyloid beta-peptide 42 [Aβ42], total tau [t-tau], and phosphorylated tau [p-tau]), neuroinflammatory (CSF sTREM2), and systemic inflammatory markers (high sensitivity C-reactive protein and peripheral immune cells). The 2-year averaged levels of ambient fine particulate matter with diameter 2.5 μm (PMAmbient 2-year averaged exposure of PMThese findings demonstrated a strong link between PM

Pain management following cesarean section remains a challenge, with many puerpera suffering from severe acute postoperative pain. And for a second cesarean section the degree of uterine contraction pain is more severe and frequent than that of a primipara. This study investigated the effect of different doses of nalbuphine combined with sufentanil for postoperative analgesia in patients undergoing a second cesarean section.We prospectively recruited 168 women with a scarred uterus undergoing elective second cesarean section and they were randomly divided into 4 groups by random number extraction. A single intravenous injection of different doses of nalbuphine was given before the intravenous drip of oxytocin, and visual analogue scale (VAS) scores of uterine contraction pain were recorded 10 minutes before intravenous infusion of oxytocin (T1) and 10 minutes (T2), 30 minutes (T3), and 60 minutes (T4) after intravenous infusion of oxytocin. At 4, 8, 12, 24, and 48 hours after patient-controlled intravenous analgesia (PCIA), pain intensity was reassessed using the VAS score.One hundred and sixty patients underwent elective second cesarean section in between December 2020 and May 2021 completed the study. The VAS scores of uterine contractions at T1 and T4 were 3 (1.0), while the VAS scores at T2 and T3 were 7 (1.0), 6 (1.0), 5 (1.0), 5 (1.0) and 8 (1.0), 5 (2.0), 3 (1.0), 3 (0.75). The VAS scores at 12 hours after surgery of nalbuphine10mg and sufentanil (NS1), nalbuphine 10 mg and sufentanil 20 mg (NS2) and nalbuphine 30 mg and sufentanil 20 mg (NS3) were lower than sufentanil (S) group (P0.001). Compared with the S group, total amount of sufentanil and PCIA compression numbers in the NS1, NS2, and NS3 groups at 4-8 and 8-12 hours after surgery decreased (P0.001), with a more significant decrease in the NS2 and NS3 groups than in the NS1 group (P0.001). The NS3 group had a significantly higher incidence of dizziness and sleepiness (P=0.02, P=0.001). Compared with the NS2 and NS3 groups, the incidence of respiratory depression in the S group was significantly higher (P=0.001).A single intravenous injection of nalbuphine 20 mg 10 minutes before the infusion of oxytocin combined with sufentanil 2 µg/kg could be safely used for postoperative analgesia in patients undergoing a second cesarean section and could effectively inhibit uterine contractions induced by oxytocin and reduce adverse reactions.Clinical Trial Registry ChiCTR2100042382.

Neutrophil extracellular traps (NETs) play important roles in sepsis and deep-seated infections, but whether NET formation correlates with clinical outcomes of patients with streptococcal bloodstream infections (BSIs) is unclear.We analyzed serum levels of complexes of myeloperoxidase and DNA (MPO-DNA) in patients with streptococcal-BSIs. In vitro assay of NET induction by serum from BSI patients was performed.MPO-DNA values for the Streptococci-BSI group (n = 59) were significantly higher than those for healthy controls (p 0.00001) and matched control groups (n = 59, p = 0.004). The rate of higher MPO-DNA levels (1.87 μg/mL) were higher in abscess-prone streptococcal groups (streptococcus milleri group) (72.2% vs. 52.5%, p = 0.02). For patients with BSIs due to highly infective endocarditis (IE)-prone pathogens, the values of serum MPO-DNA were also higher in patients diagnosed of IE compared to their counterparts (p = 0.009). Notably, serum from patients with leukopenia could induce higher amounts of in vitro NET formation, despite having low MPO-DNA levels, suggesting that NET formation could be influenced by WBC counts. Therefore, we combined WBC counts with MPO-DNA to predict all-cause 30-day mortality in patients with commensal streptococcal-BSIs. The mortality risk was lowest among patients who had neither high MPO-DNA levels nor abnormal WBC counts (p = 0.058). Furthermore, this group of patients also had a favorable composite outcome consisting of major adverse cardiovascular events (MACE) and all-cause mortality (p = 0.026).Together, these study data suggested that serum MPO-DNA can be a biomarker for predicting a composite outcome consisting of MACE and all-cause mortality in patients with commensal streptococcal-BSIs.

Immune checkpoint inhibitors (ICIs) are widely used for first-line cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC). However, whether to use ICIs as monotherapy or in combination with chemotherapy is still uncertain. We retrospectively analyzed cisplatin-ineligible patients with mUC who underwent first-line ICI monotherapy or ICI plus chemotherapy at 2 medical centers in Taiwan from 2016 to 2021. We calculated the objective response rate, progression-free survival, and overall survival (OS) using the Kaplan-Meier method and Cox regression model for multivariable analysis. In total, 130 patients were enrolled and categorized into 2 groups: an ICI monotherapy group [immunotherapy (IO), n=101] and an ICI plus noncisplatin chemotherapy group [immunotherapy and chemotherapy (IC), n=29]. The median OS of patients in the IO and IC groups was 19.5 and 9.7 months ( P =0.33). Among patients with high programmed cell death ligand-1-expressing tumors, the median OS was significantly prolonged in the IO group compared with the IC group (not reached vs. 6.3 mo, P =0.02). First-line ICI monotherapy demonstrated robust antitumor activity in cisplatin-ineligible patients with mUC. Combining noncisplatin chemotherapy with ICI did not improve clinical outcomes.

In this study, we investigated various pubertal presentations and progressions before and after estrogen induction therapy and the correlations with Turner syndrome karyotypes.We reviewed the medical records of patients with Turner syndrome diagnosed before the age of 18 years between 2000 and 2019. Sixty-six patients were enrolled and distributed into 45,X monosomy group, X chromosome structural abnormalities group and X mosaicism group. The pubertal presentations were classified into spontaneous puberty, arrested puberty and no spontaneous puberty. All patients' karyotypes, pubertal progressions and laboratory data were collected and analyzed.The karyotypes were highly correlated with pubertal presentations. No spontaneous puberty was noticed in 58.3% 45,X monosomy patients, 50% patients with X chromosome structural abnormalities had arrested puberty, whereas 70% patients with X mosaicism had spontaneous puberty. Estrogen induction therapy in patients with no spontaneous puberty could induce puberty and the tempo of puberty may approximate to the spontaneous puberty group (median, 2.3 vs. 2.2 years, P = 0.95). In both interventional groups, the FSH level was distinguishable before treatment (median, 65.1 vs. 100.4 mIU/mL, P = 0.02). After long term estrogen therapy, the FSH could be suppressed to similar level in both interventional groups (median, 37.5 vs 34.5 mIU/mL, P = 0.84). Neither LH nor E2 level provided valuable information before and after treatment.The karyotypes were highly correlated with pubertal presentations at Turner syndrome patients. The integrity of 2nd X chromosome plays an important role. Low dose estrogen could mimic the tempo of puberty even delay induction age at Taiwan. The FSH data could provide predictive information of pubertal induction for both interventional groups.

"Sarcopenic obesity" refers to a condition of low muscle mass in the context of obesity, though may be difficult to assess in patients with cirrhosis who are acutely ill. We aimed to define sarcopenic visceral obesity (SVO) using CT-based skeletal muscle index (SMI) and visceral-to-subcutaneous adipose tissue ratio (VSR) to examine its association with post-transplant mortality. We analyzed 116 adult inpatients with cirrhosis who were urgently listed and transplanted between 1/2005 and 12/2017 at 4 North American transplant centers. SVO was defined as patients with sarcopenia (SMI50 cm

Anastomotic leakage is a serious complication in laparoscopic colorectal surgeries. To resolve this problem, a new stapling technology (Tri-staple) is developed. In this study, we aim to compare the short-term outcomes of Tri-staple versus Universal staple in laparoscopic anterior resection of rectal and distal sigmoid colonic cancer.A total of 446 patients were admitted to our hospital and received laparoscopic anterior resection for rectal and distal sigmoid colonic cancer between January 2016 and December 2020. Among them, Tri-staples were used in 202 patients, and the Universal staples were used in 244 patients. Propensity score matching was performed, followed by a comparison between the two groups (Tri-staple vs. Universal staple) in the incidences of anastomotic leakage, bleeding, and reoperation.In total, 270 patients were included in this retrospective cohort study by the propensity score matching, with each group having 135 patients. Tri-staple group had a significant lower incidence of anastomotic leakage compared with the Universal staple group (4.44% vs. 11.11%, P lt; 0.05). The reoperation rate was also lower in Tri-staple group than the Universal staple group (3.70% vs. 8.15%, P lt; 0.05). The anastomotic bleeding rates, average postoperative hospital stay, average drain indwelling period, and average fasting period had no statistical differences between the two groups.The usage of Tri-staple in laparoscopic anterior resection of rectal and distal sigmoid colonic cancer is associated with lower postoperative complications compared with Universal staple. Future high-quality randomized controlled trials are needed to confirm our findings.

The clinical outcomes of surgical treatments for vocal cord paralysis and tracheal stenosis, such as medialization laryngoplasty and laryngotracheal reconstruction, vary owing to the complex anatomy and physiology of the human upper airway. However, advances in three-dimensional (3D) simulation and printing ushered its use on an office-based workstation to aid in several surgical areas.The preoperation neck computed tomography image was loaded into the InVesalius 3.0 software for manual segmentation of airway and nearby important anatomic landmarks including hyoid bone, thyroid cartilage, and cricoid cartilage. The 3D model of the desired anatomy structure was manufactured and used for presurgical planning and rehearsal of the surgery.We review cases of four patients: two cases of unilateral vocal palsy undergoing medialization laryngoplasty and two cases of tracheal stenosis patients who used the air-cartilage combined model.Preoperation planning of the medialization thyroplasty could be more precise by prevision of the paralyzed vocal cord plane. Tracheal surgery could benefit from a preoperative design of segmented length. The novel airway-cartilage combined model offers new insight into vocal cord and trachea surgery.

The purpose of this study was to examine the in vivo activity of rosmarinic acid (RA) - a phytochemical with antioxidant, anti-inflammatory, and antiviral properties - against influenza virus (IAV). An antibody-based kinase array and different in vitro functional assays were also applied to identify the mechanistic underpinnings by which RA may exert its anti-IAV activity.We initially examined the potential efficacy of RA using an in vivo mouse model. A time-of-addition assay and an antibody-based kinase array were subsequently applied to investigate mechanism-of-action targets for RA. The hemagglutination inhibition assay, neuraminidase inhibition assay, and cellular entry assay were also performed.RA increased survival and prevented body weight loss in IAV-infected mice. In vitro experiments revealed that RA inhibited different IAV viruses - including oseltamivir-resistant strains. From a mechanistic point of view, RA downregulated the GSK3β and Akt signaling pathways - which are known to facilitate IAV entry and replication into host cells.RA has promising preclinical efficacy against IAV, primarily by interfering with the GSK3β and Akt signaling pathways.

This study aimed to develop and validate a machine learning-based short measure to assess 5 functions (the ML-5F) (activities of daily living [ADL], balance, upper extremity [UE] and lower extremity [LE] motor function, and mobility) in patients with stroke.Secondary data from a previous study. A follow-up study assessed patients with stroke using the Barthel Index (BI), Postural Assessment Scale for Stroke (PASS), and Stroke Rehabilitation Assessment of Movement (STREAM) at hospital admission and discharge.A rehabilitation unit in a medical center.Patients (N=307) with stroke.Not applicable.The BI, PASS, and STREAM.A machine learning algorithm, Extreme Gradient Boosting, was used to select 15 items from the BI, PASS, and STREAM, and transformed the raw scores of the selected items into the scores of the ML-5F. The ML-5F demonstrated good concurrent validity (Pearson's r, 0.88-0.98) and responsiveness (standardized response mean, 0.28-1.01).The ML-5F comprises only 15 items but demonstrates sufficient concurrent validity and responsiveness to assess ADL, balance, UE and LE functions, and mobility in patients with stroke. The ML-5F shows great potential as an efficient outcome measure in clinical settings.

Background/Purpose The intergenic SNP rs10865331 at 2p15 was identified as a major risk factor for ankylosing spondylitis (AS) susceptibility in genome-wide association studies (GWAS). B3GNT2 gene regulates polylactosamine synthesis is potentially functionally relevant to AS disease development. We investigated whether SNP rs10865331 and two B3GNT2 SNPs (rs11900673 and rs1136151) are associated with AS susceptibility and disease severity in Taiwanese. Methods Distributions of genotypes, alleles, and haplotypes of three SNPs were compared between 1,472 AS patients and 2,117 healthy blood donors and among AS patients stratified by clinical characteristics. Results The intergenic SNP rs10865331 was significantly associated with AS (PFDR = 1.02E-05) in Taiwanese. In AS patients stratified by positivity of HLA-B27 and syndesmophyte formation, all three B3GNT2 locus SNPs (rs11900673, rs1136151, and rs10865331) were significantly associated with syndesmophyte formation among HLA-B27 positive AS patients. Haplotype analyses revealed that the “CTA” (rs11900673C/rs1136151T/rs10865331A) haplotype was significantly associated with AS susceptibility (Padj = 0.0177) and syndesmophyte formation (Padj = 0.016) in HLA-B27 positive patients. In contrast, “TCG” (rs11900673T/rs1136151C/rs10865331G) haplotype showed protection against AS development (Padj = 0.0005 for HLA-B27 positive and Padj = 0.004 for HLA-B27 negative, respectively) and syndesmophyte formation (Padj = 0.0017) in HLA-B27 positive patients. Furthermore, B3GNT2 mRNA expressions were negatively associated with erythrocyte sedimentation rate (ESR, P = 0.0103), C-reactive protein (CRP, P = 0.0353), Bath ankylosing spondylitis functional index (BASFI, P = 0.0171), and syndesmophyte formation (P = 0.0148). Conclusion Our data suggest that B3GNT2 gene may contribute to AS development and affect AS severity by interacting with HLA-B27 in Taiwanese.

This cohort study of data from 39 patients assesses whether the presence of a dominant T-cell receptor clone in peripheral blood is associated with time to systemic treatment in patients with stage IB mycosis fungoides.

Programmed cell death protein 1 (PD-1) blockade plus radiotherapy may be a promising strategy to improve the prognosis of patients with metastatic non-small cell lung cancer (NSCLC). However, the optimum combined scheme, treatment time of radiotherapy, and irradiated lesion have not been fully determined.A total of 321 metastatic NSCLC patients treated with immunotherapy were identified. Among them, 107 patients received PD-1/PD-ligand 1 (PD-L1) inhibitors with radiotherapy, while the remaining cases did not receive radiotherapy. Data on overall survival (OS), progression-free survival (PFS), treatment response and adverse events were collected. Comparisons based on type of radiation, timing of radiotherapy and number of irradiated lesions were performed.The median OS in PD-1/PD-L1 inhibitors plus radiotherapy was longer than in nonradiotherapy (22.8 vs. 16.6 months, p = 0.022). The median PFS showed a similar trend in this study (9.4 vs. 6.2 months, p = 0.042). Moreover, the combined strategy demonstrated a superior disease control rate and abscopal control rate versus without radiotherapy (both p ≤ 0.001). Further multivariate analysis in the immunotherapy and radiotherapy groups revealed that age below 65 (p = 0.004), Eastern Cooperative Oncology Group performance scores of 0-1 (p = 0.001), oligometastasis (p = 0.006), concurrent combination (p = 0.002), and treated with SRT (p = 0.013) were associated with longer OS. There was a similar incidence of adverse events between the two groups (both p ≥ 0.05).The combination of PD-1/PD-L1 inhibitors plus palliative radiotherapy demonstrated favorable survival and good tolerability in metastatic NSCLC patients.

Semen analysis (SA) plays a key role in guiding treatments of male reproductive diseases and infertility due to male factors; however, it remains challenging to conduct an accurate SA due to lack of standardization, highly subjective assessments, and problems with automated procedures. Therefore, quality assurance (QA) and teaching courses are essential for making the laboratory results more consistent.The external quality assurance (EQA) scheme was organized by national human sperm bank technology training bases in Guangdong province in China between 2009 and 2020. Until 2020, 124 laboratories from China participated in the EQA program. The EQA scheme per year has been organized involving two semen aliquots for sperm concentration, two video recordings for motility, and two smears for sperm morphology. All samples used in the EQA scheme were obtained from different healthy donors or patients.We estimated that the median coefficient of variation (CV) of sperm concentration, ignoring the method used, was 26.6%. Using a 100 µm deep counting chamber led to a decreasing CV of 13.6%. For sperm motility, the median CV of nonprogressive motility was high (50.8%), but the CV of progressive motility (13.2%), immotile sperm (14.3%), and total motility (11.8%) were acceptable. The morphology assessment revealed large variability (44.4%) irrespective of the classification criteria.The reduction of interlaboratory variability is still a challenge during SA in China. Therefore, it is critical to increase awareness of joining EQA schemes and establish standardized training centers to follow WHO-recommended procedures toward Chinese standards.

Bisphosphonates are considered an effective inhibitor of glutamine synthetase and thus can be used for treating tuberculosis (TB). However, its clinical benefit in TB remains unknown. We conducted a population-based cohort study by using the Taiwan National Health Insurance Research Database and TB databases of the Taiwan Centers for Disease Control. Patients with osteoporosis and a history of bone fracture from 2007 to 2014 were identified. Among them, bisphosphonate users and propensity score-matched nonusers were selected. A stratified multivariable Cox proportional hazard regression model was employed to investigate the independent predictors of TB. Among 218 908 patients with osteoporosis and bone fracture, 46 842 bisphosphonate users and 46 842 propensity score-matched nonusers were selected. Within the 2-year follow-up, 723 patients-348 in the user group and 375 in the nonuser group-developed TB. Bisphosphonate use was not an independent predictor of TB in the multivariable Cox proportional hazard model (adjusted hazard ratio, 0.86; 95%CI, 0.71-1.04); however, male sex, older age, being bedridden, and steroid use were independent risk factors. The real-world data revealed that bisphosphonate use did not protect patients with osteoporosis against TB.

Liver disease has emerged as a healthcare burden because of high hospitalization rates attributed both to steatohepatitis and to severe hepatic toxicity associated with changes of drug exposure. Early detection of hepatic insufficiency is critical to preventing long-term liver damage. The galactose single-point test is recommended by the US FDA as a sensitive means to quantify liver function, yet the conventional method used for quantitation of circulating galactose still relies on the standard colorimetric method, requiring time-consuming and labor-intensive processes, and is confined to the medical laboratory, thus limiting prevalence. To facilitate time- and cost-effective disease management particularly during a pandemic, a pocket-sized rapid quantitative device consisting of a biosensor and electrochemical detection has been developed. An in vitro validation study demonstrated that the coefficient of variation was less than 15% and deviations were between -4 and 14% in the range of 100-1500 μg/mL. The device presented good linear fit (correlation coefficient, r = 0.9750) over the range of 150-1150 µg/mL. Moreover, the device was found to be free from interference of common endogenous and exogenous substances, and deviated hematocrit, enabling a direct measurement of galactose in the whole blood without sample pre-treatment steps. The clinical validation comprising 118 subjects showed high concordance (r = 0.953) between the device and the conventional colorimetric assay. Thus, this novel miniaturized device is reliable and robust for routine assessment of quantitative liver function intended for follow-up of hepatectomy, drug dose adjustment, and screening for galactosemia, allowing timely and cost-effective clinical management of patients.

Not all the susceptibility-guided therapies for Helicobacter pylori (H. pylori) infection achieve excellent eradication rates. The aim of this study was to perform a systematic review and meta-analysis to identify the optimal regimen for H. pylori treatment based on antibiotic susceptibility.A systematic search was performed in multiple databases. Studies reporting eradication rates of H. pylori with susceptibility-guided therapies were selected. Meta-analysis was conducted to calculate the pooled eradication rate among the treatment regimens.Forty-eight eligible studies with 101 susceptibility-guided treatment arms were included. The overall eradication rate in patients harboring susceptible strains was 95.0% (95% CI, 94.1-95.9%), but only 63.4% of treatment arms (64/101) achieved good eradication rates (≥ 90%). Pooled eradication rates in patients with susceptible strains were: 93.4% (95% CI, 92.0-94.8%) for clarithromycin, 99.0% (95% CI, 98.1-100%) for nitroimidazoles and 95.4% (95% CI, 93.6-97.2%) for fluoroquinolones. Among the arms using a triple therapy, 66.7% (28/42) using clarithromycin, 84.2% (16/19) using nitroimidazoles and 70.8% (17/24) using fluoroquinolones achieved good (≥ 90%) eradication rates. Of 13 arms using sequential therapy, ≥ 90% eradication was achieved in 14.3% (1/7) using clarithromycin, 25.0% (1/4) using nitroimidazoles and both arms (2/2) using fluoroquinolones.Susceptibility testing alone seemed insufficient to reliably attain high H. pylori cure rates. The eradication rate in patients with nitroimidazoles susceptible strains was higher than those of fluoroquinolones and clarithromycin.

To evaluate the correlation between structural parameters and visual acuity (VA) in advanced glaucoma.Prospective, cross-sectional study.A total of 238 eyes from 238 patients (82 were men and mean ± SD age was 59.9 ± 13.8 years) from a tertiary center were divided into an advanced (mean deviation of 24-2 visual field tests from -12.01 to -20.0 dB) and severe (-20 dB) glaucoma group. Structural parameters were obtained by RTVue (Optovue Inc) optical coherence tomography and angiography. Pearson correlation, partial correlation adjusted for age and axial length, and receiver operating characteristic curves to detect decreased VA (20/25) were performed.In the advanced glaucoma group (133 eyes), superficial (Pearson correlation coefficient, r = -0.46, P.001; partial correlation coefficient, r' = -0.30, P.001) and deep macular vessel densities (VDs) (r = -0.47, P.001; r' = -0.30, P.001) showed highest correlation with VA. The area under the receiver operating characteristic curves of the superficial parafoveal/macular VDs were 0.816 (95% CI, 0.735-0.897) and 0.808 (95% CI, 0.725-0.891), respectively. In the severe glaucoma group (105 eyes), deep nasal grid VD (r = -0.31, P = 0.002; r' = -0.35, P.001) showed highest correlation with VA. Deep macular VD showed better correlation with VA than other structural parameters. The area under the receiver operating characteristic curves of deep macular VD and deep nasal grid VD were 0.740 (95% CI, 0.632-0.849) and 0.748 (95% CI, 0.640-0.857), respectively.Macular VD showed better correlation with VA in advanced glaucoma. Deep macular VD, especially nasal grid, may be a promising structural parameter in severe glaucoma.

BackgroundWomen systematically experience lower rates of liver transplantation (LT) and higher rates of waitlist mortality than men. Self-rated health has been associated with patient outcomes in the global population. We, therefore, assessed gender differences in self-rated and clinician-rated health among LT candidates.MethodsAmbulatory LT candidates without hepatocellular carcinoma were enrolled from 2012 to 2018. Participants and their hepatologists were asked separately to rate the participant's overall general health on a 6-point scale (0="excellent" to 5="very poor"). Logistic regression was used to assess the associations between covariates and superior self-assessment, defined as 1 SD above the mean self-assessment score.ResultsOf 855 participants, the median (interquartile range) self-rated health score was 2 (1-3); 156 (18%) were categorized as superior self-rated health. The correlation between self-rated and clinician-rated health was positive (Spearman's rho 0.3, P

Metabolic syndrome (MetS) is a clustering of cardiometabolic components, posing tremendous burdens in the aging society. Retinal age gap has been proposed as a robust biomarker associated with mortality and Parkinson's disease. Although MetS and chronic inflammation could accelerate the aging process and increase the risk of mortality, the association of the retinal age gap with MetS and inflammation has not been examined yet.Retinal age gap (retina-predicted age minus chronological age) was calculated using a deep learning model. MetS was defined as the presence of three or more of the following: central obesity, hypertension, dyslipidemia, hypertriglyceridemia, and hyperglycemia. Inflammation index was defined as a high-sensitivity C-reactive protein level above 3.0 mg/L. Logistic regression models were used to examine the associations of retinal age gaps with MetS and inflammation.We found that retinal age gap was significantly associated with MetS and inflammation. Specifically, compared to participants with retinal age gaps in the lowest quartile, the risk of MetS was significantly increased by 10% and 14% for participants with retinal age gaps in the third and fourth quartile (odds ratio [OR]:1.10; 95% confidence interval [CI], 1.01,1.21;, p = .030; OR: 1.14, 95% CI, 1.03,1.26; p = .012, respectively). Similar trends were identified for the risk of inflammation and combined MetS and inflammation.We found that retinal age gaps were significantly associated with MetS as well as inflammation. Given the noninvasive and cost-effective nature and the efficacy of the retinal age gap, it has great potential to be used as a screening tool for MetS in large populations.

B-cell maturation antigen-targeted chimeric antigen receptor T-cell therapy (BCMA CAR-T) is an effective treatment of relapsed refractory multiple myeloma (MM). However, the pattern of infectious complications is not well elucidated. We performed a single-center retrospective analysis of infection outcomes up to 1 year after BCMA CAR-T for MM from 2018 to 2020. Fifty-five patients with MM were treated with BCMA CAR-T. Before lymphodepletion (LD), 35% of patients had severe hypogammaglobulinemia and 18% had severe lymphopenia. Most patients (68%) received bridging chemotherapy (BC) before LD. In the first month after CAR-T, 98% patients had grade 3 to 4 neutropenia. At 1 year after infusion, 76% patients had hypogammaglobulinemia. With a median follow-up of 6.0 months (95% confidence interval, 4.7-7.4), there were a total of 47 infection events in 29 (53%) patients: 40% bacterial, 53% viral, and 6% fungal. Most (92%) were mild-moderate and of the lower/upper respiratory tract system (68%). Half of the infections (53%) occurred in the first 100 days after CAR-T infusion. Although no statistically significant risk factors for infection were identified, prior lines of therapy, use of BC, recent infections, and post–CAR-T lymphopenia were identified as possible risk factors that need to be further explored. This is the largest study to date to assess infectious complications after BCMA CAR-T. Despite multiple risk factors for severe immunosuppression in this cohort, relatively few life-threatening or severe infections occurred. Further larger studies are needed to better characterize the risk factors for and occurrence of infections after BCMA CAR-T.

Maternal infection during pregnancy may affect fetal brain development and increase the risk of developing neurological and mental disorders later in life in offspring. In this study, we used low-dose lipopolysaccharide (LPS) injection to mimic mild maternal infection at a critical time window for fetal dopamine (DA) and serotonin (5-HT) neuron development. The affected offspring exhibited reduction of dopaminergic and serotonergic neurons and anxiety- and depression-related behaviors in adulthood. In the current study, we evaluated whether dextromethorphan (DM, 30 mg/kg), an over-the-counter antitussive drug with anti-inflammatory and neuroprotective properties, could reduce the adverse effects of maternal infection mimicked by LPS exposure. We discovered that DM application did not change the baseline serum interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) levels in the LPS-exposed offspring. However, DM treatment could reduce the heightened immune responses induced by a postnatal LPS challenge test in prenatal LPS-exposed offspring. The neuroprotective effect of DM was only seen in DA neurons but not in 5-HT neurons. We concluded that DM treatment can partially protect the offspring against the adverse effects of LPS-induced maternal immune activation. The reduction in heightened immune responses and dopaminergic neuronal loss in LPS-exposed offspring could potentially reduce the risk of DA-related neurological and psychiatric disorders later in life.

Purpose. Urinary tract infections (UTIs) are the most common infections among hospitalized patients. Cystoscopy is a minimally invasive procedure to check bladder disease, among the patients receiving procedure, approximately 10% of patients may experience UTI. In this study, a neural network model with high accuracy, sensitivity, and specificity was developed to predict the probability of UTIs caused by cystoscopic procedures. To reduce antibiotic overuse during cystoscopic procedures, the model can provide clinicians with a rapid assessment of whether patients require prophylactic antibiotics. Materials and Methods. Patients who underwent cystoscopic procedures at China Medical University Beigang Hospital from 2016 to 2019 were retrospectively reviewed. A total of 1647 patients were enrolled, and 147 cases of urinary tract infection occurred. An artificial neural network (ANN) and logistic regression analysis were used to develop the prediction models, and the two models were compared. Results. The logistic regression analysis model had an accuracy of 91%, sensitivity of 2%, and specificity of 99%, indicating that the logistic regression model predicted that most patients had a low risk of infection. The neural network model had a high accuracy of 85%, sensitivity of 80%, and specificity of 88%. Conclusions. Because the logistic regression model had low sensitivity and missed most cases of UTI, the logistic regression model is inappropriate for clinical application. The neural network model has superior predictive ability and can be considered a tool in clinical practice.

Kimura disease (KD) is a rare, chronic inflammatory disorder presenting with solitary or multiple masses. Treatment options include surgical excision, corticosteroids, and radiotherapy; however, optimal therapy remains to be established. Moreover, efficacy of a humanized monoclonal antibody, dupilumab (Dupixent), requires to be demonstrated. Here, we present a 36-year-old male patient with an enlarging mass in the left medial thigh and chronic eczema over the abdomen and lower legs. Kimura disease was diagnosed after surgical excision. Postoperative treatment with dupilumab was applied with an initial dose of 600 mg followed by 300 mg every 2 weeks for 8 months. No recurrence of KD was observed in the 1-year follow-up. The eczematous lesions improved greatly. To our knowledge, this is the first report of using dupilumab for treating KD.

To better understand the pain requirements of urologic patients in the post-operative outpatient setting. Healthcare providers are one of the leading contributors to the current opioid epidemic. Understanding opioid prescribing practices and patients' narcotic requirements while not over-prescribing opioids is a public health priority.We conducted a prospective study to examine opioid consumption among adult patients who presented for outpatient urologic surgery at the University of California San Francisco (UCSF) and Zuckerberg San Francisco General (ZSFG) hospitals. We administered a Pre-Operative Pain Requirement Assessment Tool (POPRAT) electronically via text message 3 days prior to surgery to identify objective factors that may predict post-operative pain and opioid requirements. Patients were followed for 7 days post-operatively, in a similar fashion, to assess daily pain, and opioid use.Two hundred and sixty-four participants were eligible for the study and 211 completed the study. Urology patients undergoing outpatient elective procedures used a mean of 5 morphine milligram equivalents (MME) (SD = 14.9) in a 7-day period. Women and patients less than 45 years of age had the highest opioid use. Based on the POPRAT, major predictors of post-operative pain were pre-operative anxiety (0.34 estimate, P value.001) and anticipated pain (0.34 estimate, P value.001). Anticipated opioid use, however, did not predict actual opioid use.Urologic outpatient surgeries require minimal opioids for pain management. The POPRAT may help identify which patients may experience more pain after surgery. Certain factors such as age and gender may need to be considered when prescribing opioids.

Purpose : The association between visual impairment (VI) and the risk of dementia has been poorly understood. We sought to investigate the VI-dementia relationship in the UK Biobank Study. Design : Prospective cohort study Methods : A total of 117,187 volunteers (aged 40-69 years) deemed free of dementia at baseline were included. Habitual distance visual acuity worse than 0.3 logMAR units in the better-seeing eye was used to define VI. The incident dementia was based on electronically linked hospital inpatient and death records. Results : During a median follow up of 5.96 years, the presence of VI was significantly associated with incident dementia (HR=1.78, 95% CI: 1.18-2.68, P=0.006). There was a clear trend between the severity of VI and the risk of dementia (P for trend=0.002). Conclusions : We found VI was associated with increased risk of dementia, with a progressively greater risk among those with worse visual acuity. Our findings suggested that visual impairment might be a modifiable risk factor for dementia and highlighted the potential value of VI elimination to delay the manifestation of dementia.

Clinically, the renin-angiotensin-aldosterone system is activated intensely in patients with moderate to severe traumatic brain injury (TBI). Increased angiotensin II in circulatory blood after TBI can enter the brain through the disrupted blood-brain barrier. Angiotensin-converting enzyme 2 (ACE2) is an enzyme that metabolizes angiotensin II into angiotensin (1-7), which has been shown to have neuroprotective results. The expression and role of ACE2 in the brain after TBI remains elusive, however. We found that ACE2 protein abundance was downregulated around the contusional area in the brains of both humans and mice. Endogenous ACE2 was expressed in neurons, astrocytes, and microglia in the cortex of the mouse brain. Administration of recombinant human ACE2 intracerebroventricularly alleviated neurological defects after TBI in mice. Treatment of recombinant human ACE2 suppressed TBI-induced increase of angiotensin II and the decrease of angiotensin (1-7) in the brain, mitigated neural cell death, reduced the activation of NLRP3 and caspase3, decreased phosphorylation of mitogen-activated protein kinases, and nuclear factor kappa B, and reduced inflammatory cytokines tumor necrosis factor alpha and interleukin-1β. Administration of ACE2 enzyme activator diminazene aceturate intraperitoneally rescued downregulation of ACE2 enzymatic activity and protein abundance in the brain. Diminazene aceturate treatment once per day in the acute stage after TBI alleviated long-term cognitive defects and neuronal loss in mice. Collectively, these results indicated that restoration of ACE2 alleviated neurological deficits after TBI by mitigation of pyroptosis and apoptosis.

The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders., Graphical abstract Unlabelled Image

Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. In this study, ORP4L was expressed in ATL cells but not in normal T-cells. ORP4L ablation completely blocked T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice, whereas engineering ORP4L expression in T-cells resulted in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L promote the initiation of T-cell leukemogenesis. For molecular insight, we found that loss of miR-31 caused by HTLV-1 induced ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation; NF-κB–dependent, p53 inactivation-induced pro-oncogene expression; and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cell deterioration by HTLV-1 that can be therapeutically targeted.

Pleckstrin homology-like domain family A, member 3 (PHLDA3), is emerging as a critical regulator for multiple cancers. Nevertheless, the expression and role of PHLDA3 in osteosarcoma remain unknown. Herein, we purposed to elucidate the role of PHLDA3 in the progression and chemoresistance of osteosarcoma. According to the bioinformatics analysis, PHLDA3 expression was low in osteosarcoma patients, and low content was linked to poor prognosis. Additionally, activation of PHLDA3 suppressed osteosarcoma cell proliferation, migration, and chemoresistance, whereas PHLDA3 inhibition caused the opposite effects. Mechanistically, our data revealed that PHLDA3 negatively regulates the Akt/GSK3β signaling cascade in osteosarcoma. Furthermore, we found that miR-19a-3p might exert its oncogenic function by inhibiting PHLDA3 expression in osteosarcoma. These results demonstrated miR-19a-3p/ PHLDA3/ Akt/GSK3β axis has a pivotal role in osteosarcoma, and PHLDA3 is a prospective therapeutic target for treating osteosarcoma.

The incidence of colorectal cancer (CRC) has increased significantly in the past decade. Early diagnosis and new therapeutics are still urgently needed for CRC in clinical practice. Human α-defensin 6 (HD6) plays a defense role against microbes in the gastrointestinal tract. However, the role and mechanism of HD6 in CRC is still unresolved. Specimens from CRC patients with higher HD6 showed better outcomes. Overexpressed HD6 in CRC cells caused a reduction of cell proliferative, migratory, and invasive ability in vitro and in vivo. HD6-overexpressed caused S phase arrest through changes in cyclin-A and B and CDK2 levels. In addition, serpine-1 may be negatively regulated by HD6 altering the translocation of c-Jun N-terminal kinases (JNK), extracellular regulated protein kinases (ERK), and p38. Higher HD6 and lower serpine-1 levels in CRC patients reflected better outcomes. Finally, we found that HD6 interacts directly with epidermal growth factor receptor (EGFR) by co-immunoprecipitated assay. EGF treatment caused an increase of the level of serpine-1 and pEGFR levels and then increased growth activity in HD6 overexpressing cells. Together, our study shows that HD6 may compete with EGF to bind to EGFR and interrupt cancer progression in CRC. We believe these findings may give new insights for HD6 in CRC therapy.

Background/purpose: Three first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely available to treat advanced lung adenocarcinoma harboring EGFR mutation. However, studies comparing efficacy or effectiveness of these EGFR TKIs came out with inconclusive results. Methods: In this real-world data analysis with a nationwide retrospective cohort design, adult patients with newly diagnosed advanced lung adenocarcinoma with EGFR mutation between 2011 and 2016, who received a first-line EGFR TKI, were included. Overall survival (OS) and time to next treatment (TTNT) were compared between patients receiving different EGFR TKIs after overlap weighting. Results: We enrolled 10,431 patients, including 6,230, 2,359, and 1842 in gefitinib, erlotinib, and afatinib groups, respectively. The median (95% confidence interval [CI]) OS were 24.2 (22.9–26.2), 25.7 (24.0–27.9), and 29.1 (25.8–32.1) months for those receiving gefitinib, erlotinib, and afatinib, respectively (p = 0.001). The hazard ratios (95% CI) for the afatinib group were 0.85 (0.74–0.98) and 0.91 (0.79–1.05) comparing with the gefitinib and erlotinib groups, respectively. The median (95% CI) TTNT were 10.9 (10.4–11.2), 11.7 (11.3–12.1), 13.4 (12.5–14.3) months for those receiving gefitinib, erlotinib, and afatinib, respectively (p

Background Immersive virtual reality (VR)-based motor control training (VRT) is an innovative approach to improve motor function in patients with stroke. Currently, outcome measures for immersive VRT mainly focus on motor function. However, serum biomarkers help detect precise and subtle physiological changes. Therefore, this study aimed to identify the effects of immersive VRT on inflammation, oxidative stress, neuroplasticity and upper limb motor function in stroke patients. Methods Thirty patients with chronic stroke were randomized to the VRT or conventional occupational therapy (COT) groups. Serum biomarkers including interleukin 6 (IL-6), intracellular adhesion molecule 1 (ICAM-1), heme oxygenase 1 (HO-1), 8-hydroxy-2-deoxyguanosine (8-OHdG), and brain-derived neurotrophic factor (BDNF) were assessed to reflect inflammation, oxidative stress and neuroplasticity. Clinical assessments including active range of motion of the upper limb and the Fugl-Meyer Assessment for upper extremity (FMA-UE) were also used. Two-way mixed analyses of variance (ANOVAs) were used to examine the effects of the intervention (VRT and COT) and time on serum biomarkers and upper limb motor function. Results We found significant time effects in serum IL-6 (p = 0.010), HO-1 (p = 0.002), 8-OHdG (p = 0.045), and all items/subscales of the clinical assessments (ps p = 0.055). However, significant group effects existed only in items of the AROM-Elbow Extension (p = 0.007) and AROM-Forearm Pronation (p = 0.048). Moreover, significant interactions between time and group existed in item/subscales of FMA-UE-Shoulder/Elbow/Forearm (p = 0.004), FMA-UE-Total score (p = 0.008), and AROM-Shoulder Flexion (p = 0.001). Conclusion This was the first study to combine the effectiveness of immersive VRT using serum biomarkers as outcome measures. Our study demonstrated promising results that support the further application of commercial and immersive VR technologies in patients with chronic stroke.

Genomic changes in Mycoplasma pneumoniae caused by adaptation to environmental or ecologic pressures are poorly understood. We collected M. pneumoniae from children who had confirmed pneumonia in Taiwan during 2017–2020. We used whole-genome sequencing to compare these isolates with a worldwide collection of current and historical clinical strains for characterizing population structures. A phylogenetic tree for 284 strains showed that all sequenced strains consisted of 5 clades: T1–1 (sequence type [ST]1), T1–2 (mainly ST3), T1–3 (ST17), T2–1 (mainly ST2), and T2–2 (mainly ST14). We identified a putative recombination block containing 6 genes (MPN366‒371). Macrolide resistance involving 23S rRNA mutations was detected for each clade. Clonal expansion of macrolide resistance occurred mostly within subtype 1 strains, of which clade T1–2 showed the highest recombination rate and genome diversity. Functional characterization of recombined regions provided clarification of the biologic role of these recombination events in the evolution of M. pneumoniae.

Introduction Chimeric antigen receptor (CAR) T-cells can induce a rapid disease response but are frequently associated with immunologic toxicities. In addition to cytokine release syndrome (CRS), macrophage activation syndrome-like manifestations (MAS-L), characterized by uncontrolled immune activation, have been described (Shah et al, 2020). Traditional MAS definitions are challenging to apply in patients receiving CAR T cells, due to overlapping signs and symptoms with lymphodepletion and CRS. Therefore, we sought to develop novel criteria to characterize MAS-L following CAR T cells and used these criteria to identify risk factors for developing MAS-L. Methods We conducted a retrospective review of 55 patients who received B cell maturation antigen-directed CAR T cells for multiple myeloma from 11/1/17 - 5/1/20. Based on the labs readily available in our patient population, we defined MAS-L using the following criteria: 1) rate of ferritin rise ³ 100 mg/L/hour within a 24 hour period and 2) minimum fibrinogen 2 times the upper limit of normal. In developing these simplified criteria, we considered multiple laboratory markers of inflammation (ferritin, LDH, soluble interleukin receptor-2, natural killer cell activity) and end organ damage. Infection was defined as any culture positivity, febrile neutropenia, or clinical suspicion such that a new antimicrobial was started in the 30 days prior to CAR T cells. Wilcoxon rank-sums and Fisher’s exact test were used to compare continuous and categorical variables, respectively. Overall (OS) and progression-free survival (PFS) were compared using log-rank tests. Results Of the 55 patients, 12 (21.8%) met the above criteria for MAS-L with similar disease trajectories. Following CAR T cells, all 12 patients first developed CRS, characterized by an elevated C-reactive protein (CRP) and administration of tocilizumab, and subsequently developed MAS-L, characterized by decrease in fibrinogen and rapid rise of ferritin and LDH (Figure 1). Compared to the 45 patients who did not develop MAS-L, patients with MAS-L had similar baseline patient and disease characteristics (Table 1); however, a significantly higher proportion of patients with MAS-L had an infection prior to receiving CAR T cells (75% vs 9.3%, p Compared to patients who did not develop MAS-L, a similar proportion of MAS-L patients developed any CRS (100% vs 84%, p = 0.33) and ³ grade 2 CRS (50% vs 50%, p = 1). Neurotoxicity was more common in patients with MAS-L (42% vs 14%, p = 0.05). A greater proportion of patients with MAS-L received tocilizumab (100% vs 70%, p = 0.05), systemic steroids (92% vs 27%, p Following CAR T cell therapy, patients with MAS-L had longer hospitalizations (21 vs 19 days, p = 0.009) and a greater proportion required ICU-level care (27% vs 2%, p = 0.02). OS and PFS between the two groups were similar (p = 0.15 and 0.63, respectively), with a 1-year OS of 65.2% vs 90.6% and PFS of 35.4% vs 54.7% for patients with vs without MAS-L, respectively. In univariate logistic regression of baseline patient factors, disease characteristics, and ferritin, CRP, and D-dimer prior to receiving CAR T cells, only a history of documented infection in the 30 days prior to CAR T cells predicted MAS-L development (Hazard Ratio 29.2, 95% CI 5.54 - 154, p Conclusions In this analysis, we developed novel criteria for defining MAS-L following CAR T cell therapy and used these criteria to define the unique laboratory profile and clinical trajectory of patients with MAS-L. We also identify pre-existing infection as a strong risk factor for MAS-L development. Although patients with MAS-L frequently require prolonged monitoring, this immunologic toxicity can be mitigated with steroids, anakinra, and supportive care, and patients ultimately have similar survival compared to patients without MAS-L. Larger studies are needed to prospectively validate these novel criteria. Download : Download high-res image (447KB) Download : Download full-size image Disclosures Wolf: Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martin: Sanofi, Amgen, Seattle Genetics, JNJ - Janssen: Research Funding; Legend Biotech: Consultancy. Shah: BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Wong: Bristol Myers Squibb: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding; GSK: Research Funding.

As a result of ongoing regional disparities, the United Network for Organ Sharing (UNOS) implemented policy in May 2019 limiting exception points for waitlisted patients with hepatocellular carcinoma (HCC) to median Model for End-Stage Liver Disease at transplant in the area surrounding a transplant center minus 3 points (MMAT-3). The impact of this policy change remains unknown. We included adult patients with HCC (n = 4567) and without HCC (n = 19,773) in the UNOS database added to the waiting list before this policy change (May 7, 2017-May 18, 2019) and after (May 19, 2019-March 7, 2020). Cumulative incidence analysis estimated the probability of dropout within 1 year of listing decreased from 12.9% before the policy to 11.1% after the policy in candidates without HCC and from 14% to 10.7% in candidates with HCC. Incidence rates of liver transplantation (LT) and waitlist dropout varied significantly before the policy in patients with HCC and without HCC but nearly equalized in the postpolicy era. These effects were observed in both shorter and longer wait regions. With policy change being modeled as a time-dependent covariate, competing risk regression analyses estimated a decreased risk of dropout after policy change in the non-HCC group (cause-specific hazard ratio, 0.91; P = 0.02) after adjusting for demographic variables. These results suggest that the MMAT-3 policy has successfully reduced disparities in access to LT including across UNOS wait regions, although certain patients with HCC are now disadvantaged.

Background From the perspective of information processing, an integrated understanding of the structural and functional connectomes in depression patients is important, a multimodal meta-analysis is required to detect the robust alterations in graph metrics across studies. Methods Following a systematic search, 952 depression patients and 1447 controls in nine diffusion magnetic resonance imaging (dMRI) and twelve rest state functional MRI (rs-fMRI) studies with high methodological quality met the inclusion criteria and were included in the meta-analysis. Results Regarding the dMRI results, no significant differences of meta-analytic metrics were found; regarding the rs-fMRI results, the modularity and local efficiency were found to be significantly lower in the depression group than in the controls (Hedge's g = -0.330 and -0.349, respectively). Conclusion Our findings suggested a lower modularity and network efficiency in the rs-fMRI network in depression patients, indicating that the pathological imbalances in brain connectomes needs further exploration. Limitations: Included number of trials was low and heterogeneity should be noted.

Purpose: To investigate the influence of benzalkonium chloride (BAK) on ocular surface disease (OSD) in glaucoma patients receiving ocular-hypotensive agent. Methods: Patients were randomized to re...

Objectives/hypothesis To examine the pathogenic bacterial spectra and prognosis of deep neck infection (DNI) in end-stage renal disease (ESRD) patients. Study design Retrospective study. Methods Patients diagnosed with DNI between 2004 and 2015 in Chang Gung Memorial Hospital were enrolled and divided into three groups, namely ESRD-DNI, chronic kidney disease (CKD)-DNI, and non-CKD-DNI. Differences in pathogenic bacteria, treatment, and prognosis were compared across the three groups. Results The bacterial spectra differed among the three groups. The main three facultative anaerobic or aerobic bacteria causing ESRD-DNIs were methicillin-resistant Staphylococcus aureus (MRSA; 25.4%), methicillin-susceptible S. aureus (MSSA; 14.1%), and Klebsiella pneumoniae (KP; 12.7%). For CKD-DNIs, they were KP (23.5%), Viridans streptococci (VS; 23.5%), and MSSA (14.7%). For non-CKD-DNIs, they were VS (31.7%), KP (17.2%), and coagulase-negative staphylococci (8.0%). Compared with the other groups, the ESRD-DNI group had higher white blood cell and C-reactive protein levels, longer hospital stays, more frequent admissions to the intensive care unit, more mediastinal complications, and a significantly higher mortality rate. Conclusions The ESRD-DNI group exhibited more severe disease activity and higher mortality compared with those of the CKD-DNI and non-CKD-DNI groups. MRSA was the leading pathogen for patients with ESRD-DNI. Physicians must implement strategies for the early detection of MRSA to accurately prescribe antibiotics and prevent nosocomial transmission. Level of evidence 4 Laryngoscope, 2021.

Objective To analyze the duration of gonadotropin hyperstimulation's impacts on oocyte quality and clinical outcomes in aged in vitro fertilization (IVF) patients. Materials and methods This retrospective study was carried out using IVF records of the Chang Gung Memorial Hospital IVF center from January 2017 to December 2019. A total of 308 IVF cycles with patients aged 40–44 years were included. Clinical characteristics of patients who received a short controlled ovarian hyperstimulation (COH) (i.e., 6–7 days; s-COH group) or a long COH treatment (i.e., 9–10 days; l-COH group) were compared. In addition, analysis was conducted using data within two age subgroups: 40–42 years and 42–44 years subgroups. Results The s-COH group received significantly lower total doses of gonadotropin and had smaller leading follicles at the time of ovulation trigger when compared to the l-COH group. The s-COH group also produced a significantly lower number of oocytes, mature metaphase II (MII) oocytes, and 2 PN zygotes compared to the l-COH group. However, there was no significant difference in the number of transferable and good-quality embryos between the two treatment groups. Likewise, the pregnancy rate and live birth rate were comparable in the s-COH and l-COH groups. Similar results were obtained when the analysis was limited to select age subgroups (i.e., 40–42 and 42–44 years subgroups). Conclusion While a long COH generates more oocytes per cycle, a 6–7 days COH treatment, which is at the lower end of the recommended window of stimulation, could achieve a pregnancy outcome comparable to that applied 9–10 days of COH in aged patients.

Chronic kidney disease (CKD) increases the risk of arrhythmia. The right ventricular outflow tract (RVOT) is a crucial site of ventricular tachycardia (VT) origination. We hypothesize that CKD increases RVOT arrhythmogenesis through its effects on calcium dysregulation. We analysed measurements obtained using conventional microelectrodes, patch clamp, confocal microscopy, western blotting, immunohistochemical examination and lipid peroxidation for both control and CKD (induced by 150 mg/kg neomycin and 500 mg/kg cefazolin daily) rabbit RVOT tissues or cardiomyocytes. The RVOT of CKD rabbits exhibited a short action potential duration, high incidence of tachypacing (20 Hz)‐induced sustained VT, and long duration of isoproterenol and tachypacing‐induced sustained and non‐sustained VT. Tachypacing‐induced sustained and non‐sustained VT in isoproterenol‐treated CKD RVOT tissues were attenuated by KB‐R7943 and partially inhibited by KN93 and H89. The CKD RVOT myocytes had high levels of phosphorylated CaMKII and PKA, and an increased expression of tyrosine hydroxylase‐positive neural density. The CKD RVOT myocytes exhibited large levels of I to, I Kr, NCX and L‐type calcium currents, calcium leak and malondialdehyde but low sodium current, SERCA2a activity and SR calcium content. The RVOT in CKD with oxidative stress and autonomic neuron hyperactivity exhibited calcium handling abnormalities, which contributed to the induction of VT.

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.

Objective To assess whether lifelong higher circulating 25-hydroxyvitamin D [25(OH)D] levels increase serum calcium levels and kidney stone disease (KSD) risk. Methods Summary data for KSD were obtained from the UK biobank genome-wide association study (6536 cases and 388 508 controls). We acquired summary data for 25(OH)D from 120 618 Europeans and another large-scale analysis (443 734 Europeans) for primary and secondary analysis. Random-effect inverse-variance weighted (IVW) and 7 additional sensitivity analyses were applied. Next, multivariable Mendelian randomization (MVMR) was performed by introducing data for serum calcium levels. Results Genetic predisposition for a 1-SD higher 25(OH)D level was associated with increased serum calcium levels (IVW; beta, 0.014; 95% CI, 0.010-0.018; P = 7.64E-10). Genetically predicted higher circulating 25(OH)D levels were associated with increased the risk of KSD, with per 1-SD odds ratios (ORs) of 1.47 (95% CI, 1.22-1.77; P = 5.49E-05) and 1.36 (95% CI, 1.03-1.80; P = 0.029) using the IVW and MVMR-Egger methods, respectively. In secondary analysis, similar results were found: 25(OH)D was associated with an increased risk of KSD in univariate Mendelian randomization (IVW; OR 1.71; 95% CI, 1.26-2.32; P = 0.001) and MVMR (OR 1.43; 95% CI, 1.16-1.76; P < 0.001) analyses. Most sensitivity analyses were consistent with the primary results, both for the primary and secondary analyses. Conclusions Our study supports that higher genetically predicted lifelong circulating 25(OH)D levels are associated with higher calcium levels and KSD risk. The effects of 25(OH)D on KSD were partially attenuated—but still significant—in MVMR.

Rationale: Endothelial-to-mesenchymal transition (EndMT) is a fundamental biological process in which endothelial cells lose their endothelial characteristics and acquire mesenchymal properties. EndMT contributes to physiological organ development such as valvulogenesis and is associated with a number of deleterious pathologies such as organ fibrosis. Several signaling pathways of TGF-β (transforming growth factor β), BMP (bone morphogenetic protein) and inflammation have been shown to regulate EndMT. However, the transcriptional and epigenetic programs governing EndMT remains largely unclarified. Objective: To identify the transcriptional or epigenetic mechanisms underlying EndMT and EndMT-associated formation of cardiac valves. Methods and Results: We identified the LARP7 (La ribonucleoprotein domain family member 7), a RNAPII (RNA-binding protein regulating RNA polymerase II) pausing, was downregulated in 2 cytokine-induced EndMT models. LARP7 depletion with lentivirus-mediated shRNA transformed endothelial cells to mesenchymal morphology and induced the expression of the EndMT key regulator, SLUG. Specific deletion of LARP7 in the endocardium in inducible CDH5 CreERT2 ;LARP7 f/f mouse enhanced EndMT in the atrioventricular and outflow tract cushion as revealed by lineage tracing approach. ChIP-seq analysis showed LARP7 and TRIM28 (tripartite motif containing 28) which is an epigenetic repressor were colocalized at SLUG promoter. LARP7 directly interacted with TRIM28 and facilitated it loading to SLUG promoter and repressed its transcription through deacetylating the histones. More importantly, inducible knockout of LARP7 or TRIM28 in the endocardium accelerated EndMT, leading to the valvular hyperplasia, which was further aggravated by the double knockout of these 2 genes. Conclusions: The present study uncovers an orchestrated transcriptional and epigenetic mechanism by which LARP7 cooperates with TRIM28 to govern the EndMT and valvulogenesis.