Genomic overview of INA-induced NPR1 targeting and transcriptional cascades in Arabidopsis.

The phytohormone salicylic acid (SA) triggers transcriptional reprogramming that leads to SA-induced immunity in plants. NPR1 is an SA receptor and master transcriptional regulator in SA-triggered transcriptional reprogramming. Despite the indispensable role of NPR1, genome-wide direct targets of NPR1 specific to SA signaling have not been identified. Here, we report INA (functional SA analog)-specific genome-wide targets of Arabidopsis NPR1 in plants expressing GFP-fused NPR1 under its native promoter. Analyses of NPR1-dependently expressed direct NPR1 targets revealed that NPR1 primarily activates genes encoding transcription factors upon INA treatment, triggering transcriptional cascades required for INA-induced transcriptional reprogramming and immunity. We identified genome-wide targets of a histone acetyltransferase, HAC1, including hundreds of co-targets shared with NPR1, and showed that NPR1 and HAC1 regulate INA-induced histone acetylation and expression of a subset of the co-targets. Genomic NPR1 targeting was principally mediated by TGACG-motif binding protein (TGA) transcription factors. Furthermore, a group of NPR1 targets mostly encoding transcriptional regulators was already bound to NPR1 in the basal state and showed more rapid and robust induction than other NPR1 targets upon SA signaling. Thus, our study unveils genome-wide NPR1 targeting, its role in transcriptional reprogramming, and the cooperativity between NPR1, HAC1, and TGAs in INA-induced immunity.

Exacerbating effects of single-dose acute ethanol exposure on neuroinflammation and amelioration by GPR110 (ADGRF1) activation.

BACKGROUND: Neuroinflammation is a widely studied phenomenon underlying various neurodegenerative diseases. Earlier study demonstrated that pharmacological activation of GPR110 in both central and peripheral immune cells cooperatively ameliorates neuroinflammation caused by systemic lipopolysaccharide (LPS) administration. Ethanol consumption has been associated with exacerbation of neurodegenerative and systemic inflammatory conditions. The goal of this study is to determine the effects of single-dose acute ethanol exposure and GPR110 activation on the neuro-inflammation mechanisms. METHODS: For in vivo studies, GPR110 wild type (WT) and knockout (KO) mice at 10-12 weeks of age were given an oral gavage of ethanol (3 g/kg) or maltose (5.4 g/kg) at 1-4 h prior to the injection of LPS (1 mg/kg, i.p.) followed by the GPR110 ligand, synaptamide (5 mg/kg). After 2-24 h, brains were collected for the analysis of gene expression by RT-PCR or protein expression by western blotting and enzyme-linked immunosorbent assay (ELISA). Microglial activation was assessed by western blotting and immunohistochemistry. For in vitro studies, microglia and peritoneal macrophages were isolated from adult WT mice and treated with 25 mM ethanol for 4 h and then with LPS (100 ng/ml) followed by 10 nM synaptamide for 2 h for gene expression and 12 h for protein analysis. RESULTS: Single-dose exposure to ethanol by gavage before LPS injection upregulated pro-inflammatory cytokine expression in the brain and plasma. The LPS-induced Iba-1 expression in the brain was significantly higher after ethanol pretreatment in both WT and GPR110KO mice. GPR110 ligand decreased the mRNA and/or protein expression of these cytokines and Iba-1 in the WT but not in GPR110KO mice. In the isolated microglia and peritoneal macrophages, ethanol also exacerbated the LPS-induced expression of pro-inflammatory cytokines which was mitigated at least partially by synaptamide. The expression of an inflammasome marker NLRP3 upregulated by LPS was further elevated with prior exposure to ethanol, especially in the brains of GPR110KO mice. Both ethanol and LPS reduced adenylate cyclase 8 mRNA expression which was reversed by the activation of GPR110. PDE4B expression at both mRNA and protein level in the brain increased after ethanol and LPS treatment while synaptamide suppressed its expression in a GPR110-dependent manner. CONCLUSION: Single-dose ethanol exposure exacerbated LPS-induced inflammatory responses. The GPR110 ligand synaptamide ameliorated this effect of ethanol by counteracting on the cAMP system, the common target for synaptamide and ethanol, and by regulating NLRP3 inflammasome.

FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation.

In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3ß-mediated STAT2 phosphorylation facilitated STAT2-FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.

The impact of depression on language function in individuals with Alzheimer's disease: a pre/post-treatment design.

BACKGROUND: It is uncertain whether depression might affect cognitive function in Alzheimer's disease (AD). Most of studies on the effect of depression treatment on cognitive function in AD were briefly evaluated by Mini-Mental State Examination (MMSE). MMSE is poor sensitive to detect cognitive change. This study examined the cognitive response to depression treatment in AD via multi-domain assessment. In addition, we explored whether effect of depression treatment in AD is different those of late-life depression (LLD). METHODS: This study include AD patients with depression (AD + D) and without depression (AD - D), LLD patients (LLD), and healthy controls (HC). The patients were treated according to their diagnosis for 16 weeks: acetylcholinesterase inhibitors (AChEIs) and selective serotonin reuptake inhibitors (SSRIs) for AD + D, AChEIs for AD - D, and SSRIs for LLD. The cognitive changes from pre- to post-treatment were compared between AD + D and AD - D or LLD and HC. An independent sample t test was performed to compare the degree of change between the groups. Paired t tests were used to determine cognitive function changes in each depression treatment responder group. RESULTS: At baseline, AD + D had more impairment in language function compared to AD - D, and LLD had greater deficit in executive function than HC. After depression treatment, more impaired cognitive domains at baseline were improved in AD + D and LLD, respectively. Moreover, AD + D showed an improvement in the global cognitive function (MMSE). CONCLUSIONS: Results indicated that language function was influenced by depression in AD, which is first evidence for specific cognitive domain related to depression in AD. Our finding indicates that depression could negatively impact cognitive function, and depression treatment may have beneficial cognitive effect in both AD and LLD. This study suggests the importance of early detection and treatment of depression in AD and LLD. Trial registration Clinical Research Information Service, CRIS, ID#: KCT0004041, Registered 5 June 2019, retrospectively registered after first patient enrollment date (4 March 2014) https://cris.nih.go.kr/cris/search/detailSearch.do?seq=14140&status=5&seq_group=14140&search_page=M .

Risk Factors Associated with Intraoperative Iatrogenic Fracture in Patients Undergoing Intramedullary Nailing for Atypical Femoral Fractures with Marked Anterior and Lateral Bowing.

Background and objectives: Iatrogenic fractures are potential complications during intramedullary (IM) nailing for atypical femoral fractures (AFFs). The risk factors associated with iatrogenic fractures remain unclear, although excessive femoral bowing and osteoporosis are hypothesized to be contributing factors. The present study aimed to determine the risk factors for the occurrence of iatrogenic fractures during IM nailing in patients with AFFs. Materials and Methods: This retrospective cross-sectional study evaluated 95 patients with AFF (all female; age range: 49-87 years) who underwent IM nailing between June 2008 and December 2017. The patients were divided into two groups: Group I (with iatrogenic fracture: n = 20) and Group II (without iatrogenic fracture: n = 75). Background characteristics were retrieved from medical records and radiographic measurements were obtained. Univariate and multivariate logistic regression analyses were performed to identify risk factors for the occurrence of intraoperative iatrogenic fractures. Receiver operating curve (ROC) analysis was conducted to determine a cut-off value for the prediction of iatrogenic fracture occurrence. Results: Iatrogenic fractures occurred in 20 (21.1%) patients. The two groups exhibited no significant differences regarding age and other background characteristics. Group I exhibited significantly lower mean femoral bone mineral density (BMD) and significantly greater mean lateral and anterior femoral bowing angles than Group II (all p < 0.05). There were no significant differences in AFF location, nonunion, and IM nail diameter, length, or nail entry point between the two groups. In the univariate analysis, femoral BMD and lateral bowing of the femur differed significantly between the two groups. On multivariate analysis, only lateral bowing of the femur remained significantly associated with iatrogenic fracture occurrence. The ROC analysis determined a cut-off value of 9.3° in lateral bowing of the femur for prediction of iatrogenic fracture occurrence during IM nailing for AFF treatment. Conclusions: The lateral bowing angle of the femur is an important predictive factor for intraoperative iatrogenic fracture occurrence in patients undergoing IM nailing for AFF treatment.

Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection.

BACKGROUND & AIMS: It is unknown whether HBsAg seroclearance affects the risk of hepatocellular carcinoma (HCC) recurrence after liver resection. We aimed to investigate the impact of HBsAg seroclearance on the recurrence of HCC after curative liver resection, with a focus on late recurrence. METHODS: This study comprised 2,520 consecutive patients who received curative liver resection for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2000 and 2017. To focus on late recurrence, patients with recurrence or a follow-up duration less than 2 years were excluded. The impact of HBsAg seroclearance on HCC recurrence was assessed by landmark analysis (2-, 5-and 8-year after liver resection), time-dependent Cox and multistate modeling. RESULTS: The mean patient age was 54.4 years and 75.7% were men. A total of 891 (35.4%) patients developed HCC recurrence at rates of 11.2%, 25.5%, and 46.8% at 3, 5, and 10 years after resection. HBsAg seroclearance was achieved in 172 (6.8%) patients during a median follow-up duration of 6.9 years after resection. HBsAg seroclearance, compared with persistent HBsAg positivity, was associated with a lower risk of late HCC recurrence in the 2-, 5-, and 8-year landmark analysis (p = 0.04, p = 0.02 and p = 0.03, respectively) and on time-dependent multivariable Cox modeling (adjusted hazard ratio 0.62; p = 0.005). Based on a 3-state unidirectional illness-death model, patients without HBsAg seroclearance transitioned to HCC recurrence more rapidly than patients who experienced HBsAg seroclearance. CONCLUSIONS: HBsAg seroclearance is associated with a lower risk of late recurrence of HBV-related HCC among Korean patients who undergo curative liver resection. LAY SUMMARY: Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC). Suppression of HBV replication is known to lower the risk of HCC recurrence after liver resection (a procedure used to treat and in some cases cure HCC). However, whether the loss of a specific HBV protein (hepatitis B surface antigen or HBsAg) has an impact on recurrence after liver resection remains unknown. Herein, we show that loss of HBsAg is associated with a reduce risk of late recurrence of HCC after liver resection in patients with HBV-related HCC.

A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance.

BACKGROUND & AIMS: After hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains, and the optimal surveillance strategy has yet to be determined. Herein, we aimed to evaluate incidence and risk factors for HCC and establish a novel prediction model for HCC development after HBsAg seroclearance. METHODS: A total of 1,443 patients with chronic hepatitis B who achieved HBsAg seroclearance between 1991 and 2020 were retrospectively screened for study eligibility. The data from 831 of these patients were included in the final analysis. A prediction model was developed based on multivariable Cox models. Harrell's C-index and a time-dependent AUROC were used for discrimination. Bootstrap analysis was performed for internal validation. RESULTS: Overall, 40 patients (4.8%) developed HCC after HBsAg seroclearance during a follow-up of 4,644 person-years (0.86%/year). Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently predictive of HCC, and these 4 independent variables were used to develop the prediction model. The C-index of the model was 0.804. The time-dependent AUROCs of the score for HCC prediction at 5, 10, and 15 years were 0.799, 0.835, and 0.817, respectively. The score also showed good discrimination in the internal validation and sensitivity analysis. CONCLUSIONS: The novel prediction model based on age, cirrhosis, family history of HCC, and alcohol consumption enables reliable risk estimation of HCC after HBsAg seroclearance and may serve as a useful reference for decision-making in HCC surveillance for HBsAg-cleared patients. LAY SUMMARY: After spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains. Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently associated with HCC development after HBsAg seroclearance. The novel prediction model using these 4 variables enables reliable risk estimation of HCC and serves as a useful reference for decision-making in HCC surveillance and management for HBsAg-cleared patients.

Epigenetic reprogramming by histone acetyltransferase HAG1/AtGCN5 is required for pluripotency acquisition in Arabidopsis.

Shoot regeneration can be achieved in vitro through a two-step process involving the acquisition of pluripotency on callus-induction media (CIM) and the formation of shoots on shoot-induction media. Although the induction of root-meristem genes in callus has been noted recently, the mechanisms underlying their induction and their roles in de novo shoot regeneration remain unanswered. Here, we show that the histone acetyltransferase HAG1/AtGCN5 is essential for de novo shoot regeneration. In developing callus, it catalyzes histone acetylation at several root-meristem gene loci including WOX5, WOX14, SCR, PLT1, and PLT2, providing an epigenetic platform for their transcriptional activation. In turn, we demonstrate that the transcription factors encoded by these loci act as key potency factors conferring regeneration potential to callus and establishing competence for de novo shoot regeneration. Thus, our study uncovers key epigenetic and potency factors regulating plant-cell pluripotency. These factors might be useful in reprogramming lineage-specified plant cells to pluripotency.

Risk of Hepatitis B Virus Reactivation in Patients Treated With Immunotherapy for Anti-cancer Treatment.

BACKGROUND & AIMS: Hepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology. METHODS: This historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment. RESULTS: The mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3-4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients. CONCLUSIONS: In general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.

Comparison of Long-Term Clinical Outcomes Between Spontaneous and Therapy-Induced HBsAg Seroclearance.

BACKGROUND AND AIMS: HBsAg seroclearance is considered a realistic goal in patients with chronic hepatitis B (CHB), known as "functional cure." However, it remains elusive whether nucleos(t)ide analogue (NUC)-induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, differs in its association with favorable long-term clinical outcomes. APPROACH AND RESULTS: A total of 1,972 CHB patients with confirmed HBsAg seroclearance at least two consecutive times, 6 months apart, were retrospectively analyzed. Risks of HCC development and composite clinical events, including HCC, liver-related death, and liver transplantation, were compared between spontaneous and NUC-induced HBsAg seroclearance. Of 1,972 patients, mean patient age was 53.7 years, and 64.4% were men. Cirrhosis was present in 297 (15.1%) patients. HBsAg seroclearance was achieved spontaneously in 1,624 (82.4%) patients and by NUC treatment in 348 (17.6%). HCC developed in 49 patients, with an annual incidence of 0.38 of 100 person-years (PY) during a median follow-up of 5.6 years. With 336 propensity-score-matched pairs, risks of HCC (P = 0.52) and clinical events (P = 0.14) were not significantly different between NUC-induced and spontaneous HBsAg seroclearance. By multivariable analysis, NUC-induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, was not associated with the significantly higher risk of HCC (adjusted HR [AHR], 1.49; P = 0.26) and clinical events (AHR, 1.78; P = 0.06). CONCLUSIONS: Risks of HCC and clinical events were not significantly different between spontaneous and NUC-induced HBsAg seroclearance. Nonetheless, annual risk of HCC exceeds the recommended cutoff for HCC surveillance even after HBsAg seroclearance, suggesting that continued HCC surveillance is required.

Factors Associated with Post-Acute Sequelae of SARS-CoV-2 (PASC) After Diagnosis of Symptomatic COVID-19 in the Inpatient and Outpatient Setting in a Diverse Cohort.

BACKGROUND: The incidence of persistent clinical symptoms and risk factors in Post-Acute Sequelae of SARS-CoV-2 (PASC) in diverse US cohorts is unclear. While there are a disproportionate share of COVID-19 deaths in older patients, ethnic minorities, and socially disadvantaged populations in the USA, little information is available on the association of these factors and PASC. OBJECTIVE: To evaluate the association of demographic and clinical characteristics with development of PASC. DESIGN: Prospective observational cohort of hospitalized and high-risk outpatients, April 2020 to February 2021. PARTICIPANTS: One thousand thirty-eight adults with laboratory-confirmed symptomatic COVID-19 infection. MAIN MEASURES: Development of PASC determined by patient report of persistent symptoms on questionnaires conducted 60 or 90 days after COVID-19 infection or hospital discharge. Demographic and clinical factors associated with PASC. KEY RESULTS: Of 1,038 patients with longitudinal follow-up, 309 patients (29.8%) developed PASC. The most common persistent symptom was fatigue (31.4%) followed by shortness of breath (15.4%) in hospitalized patients and anosmia (15.9%) in outpatients. Hospitalization for COVID-19 (odds ratio [OR] 1.49, 95% [CI] 1.04-2.14), having diabetes (OR, 1.39; 95% CI 1.02-1.88), and higher BMI (OR, 1.02; 95% CI 1-1.04) were independently associated with PASC. Medicaid compared to commercial insurance (OR, 0.49; 95% CI 0.31-0.77) and having had an organ transplant (OR 0.44, 95% CI, 0.26-0.76) were inversely associated with PASC. Age, race/ethnicity, Social Vulnerability Index, and baseline functional status were not associated with developing PASC. CONCLUSIONS: Three in ten survivors with COVID-19 developed a subset of symptoms associated with PASC in our cohort. While ethnic minorities, older age, and social disadvantage are associated with worse acute COVID-19 infection and greater risk of death, our study found no association between these factors and PASC.

Thermodiluted relative tidal volume estimation using a thermal camera in operating room under spinal anesthesia.

BACKGROUND: Estimating relative tidal volume is an important factor when monitoring breathing status. The relationship between temperature and respiration volume has rarely been studied. In this paper, a formula was derived for calculating thermodiluted respiration volume from temperature changes in the nasal cavity. To evaluate the proposed formula, the study compared the relative tidal volume estimated by the proposed formula with that recorded by a respiration volume monitor (Exspiron1Xi, RVM). Thermal data were obtained for 8 cases at a rate of 10 measurements per second. Simultaneous recordings by the RVM are regarded as the reference. RESULTS: The mean of ICC coefficient is 0.948 ± 0.030, RMSE is 0.1026 ± 0.0284, R-squared value is 0.8962 ± 0.065 and linear regression coefficient [Formula: see text] is 0.966 ± 0.104, [Formula: see text] is 0.042 ± 0.057. Bland-Altman plot showed 96.01% of samples that the difference between the measured and estimated values exists within 2 standard deviations. CONCLUSIONS: In this paper, a model that can thermodynamically calculate the relationship between thermal energy and respiration volume is proposed. The thermodiluted model is a feasible method for estimating relative respiration tidal volumes.

Repair integrity and functional outcomes of arthroscopic repair in chronic anterior shoulder instability: single-loaded versus double-loaded single-row repair.

INTRODUCTION: This study compared the clinical outcome and repair integrity of single-loaded and double-loaded single-row arthroscopic repair of chronic anterior shoulder instability. MATERIALS AND METHODS: Fifty consecutive chronic anterior shoulder instability cases treated by arthroscopic labral repair were included. A single-loaded single-row technique was used in the first 25 consecutive shoulders, and a double-loaded single-row technique was used in the next 25 consecutive shoulders. The number of suture anchors was 4 in the shoulders that underwent single-loaded repair and 3 in the shoulders that underwent double-loaded repair. 42 shoulders (84.0%) followed up clinical outcomes were evaluated a minimum 2 years (mean 28.5 months; range 24-46) postoperatively. The postoperative labral repair integrity was evaluated by MDCT-arthrogram at a minimum 6 months postoperatively. RESULTS: At the final follow-up, the average UCLA, ASES, Constant, Rowe score, VAS pain score, and VAS for instability scores improved significantly, to 33.05, 92.33, 89.05, 94.86, 0.90 and 0.52, respectively, in the single-loaded group and to 32.19, 90.10, 89.05, 94.52, 0.90, and 0.86, respectively, in the double-loaded group. The clinical scores improved in both groups postoperatively (all P < 0.05); however, there was no significant difference between the two groups at final follow-up (P = 0.414, 0.508, 1.000, 0.917, 1.000, and 0.470, respectively). The re-tear rate was 2 (9.5%) in the shoulders that underwent single-loaded repair and 3 (14.3%) in the shoulders that underwent double-loaded repair; this difference was statistically not significant (P = 0.634). CONCLUSION: The double-loaded single-row technique resulted in comparable clinical outcomes, and re-tear rate compared with the single-loaded single-row technique in chronic anterior shoulder instability at short-term follow-up. Number of used suture anchor in double-loaded single-row technique was fewer than that of single-loaded single-row technique. LEVEL OF EVIDENCE: Comparative retrospective study, level III.

Application of deep learning artificial intelligence technique to the classification of clinical orthodontic photos.

BACKGROUND: Taking facial and intraoral clinical photos is one of the essential parts of orthodontic diagnosis and treatment planning. Among the diagnostic procedures, classification of the shuffled clinical photos with their orientations will be the initial step while it was not easy for a machine to classify photos with a variety of facial and dental situations. This article presents a convolutional neural networks (CNNs) deep learning technique to classify orthodontic clinical photos according to their orientations. METHODS: To build an automated classification system, CNNs models of facial and intraoral categories were constructed, and the clinical photos that are routinely taken for orthodontic diagnosis were used to train the models with data augmentation. Prediction procedures were evaluated with separate photos whose purpose was only for prediction. RESULTS: Overall, a 98.0% valid prediction rate resulted for both facial and intraoral photo classification. The highest prediction rate was 100% for facial lateral profile, intraoral upper, and lower photos. CONCLUSION: An artificial intelligence system that utilizes deep learning with proper training models can successfully classify orthodontic facial and intraoral photos automatically. This technique can be used for the first step of a fully automated orthodontic diagnostic system in the future.

Improving the Prediction of Relapse After Nucleos(t)ide Analogue Discontinuation in Patients With Chronic Hepatitis B.

BACKGROUND: Current guidelines recommend rules for stopping nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB), but off-therapy relapse is still high. This study aimed to identify predictors of off-therapy relapse and improve existing stopping rules. METHODS: This retrospective study included 488 patients with CHB (262 hepatitis B e antigen [HBeAg]-positive and 226 HBeAg-negative) who discontinued NAs. Posttreatment relapse was investigated. RESULTS: During the median follow-up period of 73.3 months, the cumulative 5-year and 10-year virologic relapse (VR) rates were 73.5% and 76.1%, respectively. In HBeAg-positive patients, end-of-therapy hepatitis B surface antigen (HBsAg) levels (hazard ratio [HR], 1.93 [95% confidence interval {CI}, 1.42-2.61]) and consolidation duration ≥2 years (HR, 0.31 [95% CI: .17-.58]) were independent predictors of VR. Consolidation ≥2 years and low HBsAg levels (≤560 IU/mL) significantly lowered VR rates. In HBeAg-negative patients, only the HBsAg level (HR, 1.61 [95% CI: 1.24-2.11]) was independently predictive of VR. Cirrhosis was significantly associated with higher VR rates in HBeAg-negative patients with low HBsAg levels (≤800 IU/mL). Combining end-of-therapy HBsAg levels with current stopping rules or consolidation duration further reduced off-therapy relapse, with 2-year VR rates of approximately 15%-25% in HBeAg-positive patients and 35% in HBeAg-negative patients. CONCLUSIONS: End-of-therapy HBsAg levels, consolidation duration, and cirrhosis are key determinants of off-therapy relapse. Together with low HBsAg levels, extended consolidation therapy for ≥2 years should be ensured, and cirrhotic patients should continue NAs even if low HBsAg levels are achieved. A combination of these parameters will help identify individuals at low risk of relapse and significantly improve the predictive ability of the existing stopping rules.

Prediction of Hepatocellular Carcinoma by On-Therapy Response of Noninvasive Fibrosis Markers in Chronic Hepatitis B.

INTRODUCTION: Antiviral therapy improves hepatic fibrosis and reduces hepatocellular carcinoma (HCC) incidence. This study aimed to evaluate whether on-therapy changes in scores for fibrosis index based on 4 factors and aspartate aminotransferase-to-platelet ratio index are associated with HCC development and establish an HCC risk score model incorporating noninvasive fibrosis marker (NFM) response. METHODS: This multicenter study recruited 5,147 patients with chronic hepatitis B (4,028 for derivation cohort and 1,119 for validation cohort) who were given entecavir/tenofovir for >12 months between 2007 and 2018. A risk prediction model for HCC was developed using predictors based on multivariable Cox models, and bootstrapping was performed for validation. RESULTS: The 10-year cumulative HCC incidence rates were 12.6% and 13.7% in the derivation and validation cohorts, respectively. The risk of HCC significantly differed with early NFM response, with a marked reduction in HCC risk in patients achieving a significant decrease in NFM by 12 months (P < 0.001). NFM response, sex, age, and cirrhosis were independently predictive of HCC. We developed the Fibrosis marker response, Sex, Age, and Cirrhosis (FSAC) score based on regression coefficients of each variable. For the 10-year prediction of HCC, FSAC showed higher C-index values than PAGE-B, modified PAGE-B, CU-HCC, and REACH-B (0.84 vs 0.77, 0.80, 0.77, and 0.67, respectively; all P < 0.005). The predictive performance of FSAC was corroborated in the validation cohort, with higher C-index than other models (all P < 0.050). DISCUSSION: On-therapy changes in NFM are an independent indicator of HCC risk. FSAC incorporating NFM response is a reliable risk score for risk estimation for HCC with better performance than other models.

Segmentation of white matter hyperintensities on 18F-FDG PET/CT images with a generative adversarial network.

PURPOSE: White matter hyperintensities (WMH) are typically segmented using MRI because WMH are hardly visible on 18F-FDG PET/CT. This retrospective study was conducted to segment WMH and estimate their volumes from 18F-FDG PET with a generative adversarial network (WhyperGAN). METHODS: We selected patients whose interval between MRI and FDG PET/CT scans was within 3 months, from January 2017 to December 2018, and classified them into mild, moderate, and severe groups by following the semiquantitative rating method of Fazekas. For each group, 50 patients were selected, and of them, we randomly selected 35 patients for training and 15 for testing. WMH were automatically segmented from FLAIR MRI with manual adjustment. Patches of WMH were extracted from 18F-FDG PET and segmented MRI. WhyperGAN was compared with H-DenseUnet, a deep learning method widely used for segmentation tasks, for segmentation performance based on the dice similarity coefficient (DSC), recall, and average volume differences (AVD). For volume estimation, the predicted WMH volumes from PET were compared with ground truth volumes. RESULTS: The DSC values were associated with WMH volumes on MRI. For volumes >60 mL, the DSC values were 0.751 for WhyperGAN and 0.564 for H-DenseUnet. For volumes ≤60 mL, the DSC values rapidly decreased as the volume decreased (0.362 for WhyperGAN vs. 0.237 for H-DenseUnet). For recall, WhyperGAN achieved the highest value in the severe group (0.579 for WhyperGAN vs. 0.509 for H-DenseUnet). For AVD, WhyperGAN achieved the lowest score in the severe group (0.494 for WhyperGAN vs. 0.941 for H-DenseUnet). For the WMH volume estimation, WhyperGAN performed better than H-DenseUnet and yielded excellent correlation coefficients (r = 0.998, 0.983, and 0.908 in the severe, moderate, and mild group). CONCLUSIONS: Although limited by visual analysis, the WhyperGAN based can be used to automatically segment and estimate volumes of WMH from 18F-FDG PET/CT. This would increase the usefulness of 18F-FDG PET/CT for the evaluation of WMH in patients with cognitive impairment.

Sustained off therapy response after peglyated interferon favours functional cure and no disease progression in chronic hepatitis B.

BACKGROUND & AIMS: Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver-related mortality. However, long-term outcomes after pegylated interferon (PEG-IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long-term effectiveness and clinical outcomes of PEG-IFN therapy. METHODS: A total of 190 patients treated with PEG-IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6 months post-treatment and defined as achieving both <2000 IU/mL HBV DNA and HBeAg loss or seroconversion in the HBeAg-positive group, and <2000 IU/mL HBV DNA in the HBeAg-negative group. The rates of HBsAg loss, disease progression to cirrhosis or HCC, and sustained off-therapy response, defined as not requiring further NAs because of low viremia and liver enzymes, were analysed. RESULTS: The median follow-up period was 7.2 years. Forty-three (35.2%) patients achieved an initial response and 53 patients (43.4%) achieved a sustained response. Initial responders displayed higher rates of sustained response than noninitial responders (69.6% vs 32.5%, P < .001). A higher rate of HBsAg loss was observed in patients who achieved a sustained response than in non-sustained responders (16.2% vs 2.5%, P = .01). Disease progression to cirrhosis or HCC was observed in eight patients (6.6%) who were nonsustained responders. CONCLUSIONS: During long-term follow-up after PEG-IFN treatment, nearly half of patients achieved sustained response without the need of further NA and these patients displayed favourable outcomes, including HBsAg loss and no disease progression.

In vitro delivery efficiencies of nebulizers for different breathing patterns.

BACKGROUND: Nebulizers are medical devices that deliver aerosolized medication directly to lungs to treat a variety of respiratory diseases. However, breathing patterns, respiration rates, airway diameters, and amounts of drugs delivered by nebulizers may be respiratory disease dependent. METHOD: In this study, we developed a respiratory simulator consisting of an airway model, an artificial lung, a flow sensor, and an aerosol collecting filter. Various breathing patterns were generated using a linear actuator and an air cylinder. We tested six home nebulizers (jet (2), static (2), and vibrating mesh nebulizers (2)). Nebulizers were evaluated under two conditions, that is, for the duration of nebulization and at a constant output 1.3 mL using four breathing patterns, namely, the breathing pattern specified in ISO 27427:2013, normal adult, asthmatic, and COPD. RESULTS: One of the vibrating mesh nebulizers had the highest dose delivery efficiency. The drug delivery efficiencies of nebulizers were found to depend on breathing patterns. CONCLUSION: We suggest a quantitative drug delivery efficiency evaluation method and calculation parameters that include considerations of constant outputs and residual volumes. The study shows output rates and breathing patterns should be considered when the drug delivery efficiencies of nebulizers are evaluated.

An Increased Lateral Femoral Condyle Ratio Is an Important Risk Factor for a Medial Meniscus Ramp Lesion Including Red-Red Zone Tear.

PURPOSE: This study aimed to determine radiological findings associated with ramp lesions in knees with anterior cruciate ligament (ACL) injury. METHODS: This study included the primary ACL reconstructions from June 2011 to March 2019. The exclusion criteria were combined fractures and multiligament injuries. Patients were categorized based on arthroscopy-confirmed presence of ramp lesions, which was defined as a longitudinal tear around the meniscocapsular junction or red-red zone tear of medial meniscus posterior horn. Binary logistic regression analysis was performed to find the risk factors such as age, sex, body mass index, medial tibial slope, mechanical axis angle, presence of Segond fracture, and lateral femoral condyle (LFC) ratio. Additionally, receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were evaluated. RESULTS: Ramp lesions were identified in 89 (27.7%) patients among the total 321 included primary ACL reconstructions. The risk of ramp lesion was associated with increased LFC ratio (odds ratio [OR]: 62.929; 95% confidence interval [CI]: 8.473-467.351; P < .001), varus alignment >3° (OR: 5.858; 95% CI: 3.272-10.486; P < .001), and steeper medial tibial slope (OR: 1.183; 95% CI: 1.05-1.333; P = .006). The cutoff values of the LFC ratio and medial tibial slope for ramp lesions were >71% (AUC: 0.696; sensitivity: 43.82%; specificity: 91.38%; P < .001) and >12.1° (AUC: 0.643; sensitivity: 85.39%; specificity: 38.79%; P < .001), respectively. CONCLUSION: Deep posterior LFC, varus alignment, and steep medial tibial slope were associated factors for ramp lesions in knees with ACL injury. In patients with ACL injury who show the above-mentioned radiographic findings, careful assessment and suspicion for ramp lesions should be considered. STUDY DESIGN: Level III, retrospective cross-sectional study.