Detection of significant liver fibrosis in Chinese psoriasis patients receiving methotrexate: a comparison between transient elastography and liver histology.

INTRODUCTION: Methotrexate (MTX) is effective for treating psoriasis and psoriatic arthritis, but its potential hepatoxicity remains a concern. Liver biopsy, the gold standard for detecting MTX-induced liver injury, is invasive and carries considerable risk. Transient elastography (TE) offers a non-invasive alternative for detecting advanced liver fibrosis. This study investigated the performance of TE in detecting MTX-induced liver fibrosis among Chinese psoriasis patients, compared with liver biopsy. METHODS: This study included adult patients with clinical psoriasis. Liver stiffness measurement using TE was performed in patients receiving MTX. Exclusion criteria were known liver cirrhosis, positive viral hepatitis carrier status, or conditions influencing TE performance. Liver biopsy was performed when liver stiffness was ≥7.1 kilopascals (kPa) or when the total cumulative dose (TCD) of MTX was ≥3.5 g. RESULTS: A total of 228 patients were screened; among 34 patients who met the inclusion criteria, nine (26.5%) had significant liver fibrosis (Roenigk grade ≥3a). The area under the receiver operating characteristic curve was 0.76 (95% confidence interval=0.59-0.93; P=0.021), indicating that TE had satisfactory performance in detecting liver fibrosis. A cut-off value of 7.1 kPa of liver stiffness yielded 100% sensitivity and 68% specificity. Liver fibrosis was not correlated with the TCD of MTX or the duration of MTX use; it was significantly correlated with obesity and diabetes status (body mass index ≥30 kg/m2, waist circumference ≥138 cm, and glycated haemoglobin level ≥7.8%). CONCLUSION: Transient elastography is reliable and superior to the TCD for detecting liver fibrosis in Chinese psoriasis patients receiving MTX. Liver biopsy should be reserved for high-risk patients or patients with liver stiffness ≥11.7 kPa on TE.

Hong Kong consensus recommendations on the management of pancreatic ductal adenocarcinoma.

This project was undertaken to develop the first set of consensus statements regarding the management of pancreatic ductal adenocarcinoma (PDAC) in Hong Kong, with the goal of providing guidance to local clinicians. A multidisciplinary panel of experts discussed issues surrounding current PDAC management and reviewed evidence gathered in the local context to propose treatment recommendations. The experts used the Delphi approach to finalise management recommendations. Consensus was defined as ≥80% acceptance among all expert panel members. Thirty-nine consensus statements were established. These statements cover all aspects of PDAC management, including diagnosis, resectability criteria, treatment modalities according to resectability, personalised management based on molecular profiling, palliative care, and supportive care. This project fulfils the need for guidance regarding PDAC management in Hong Kong. To assist clinicians with treatment decisions based on varying levels of evidence and clinical experience, treatment options are listed in several consensus statements.

Thermographic visualization of facial vasoconstriction is associated with 30-day all-cause mortality in medical patients; prospective observational two-site cohort study.

INTRODUCTION: Quick and reliable assessment of acute patients is required for accurate triage. The temperature gradient between core and peripheral temperature could possibly instantly provide information on circulatory status. METHODS: Adult medical patients, who did not receive supplementary oxygen, attending two emergency departments, had a thermographic image taken on arrival. The association between 30-day mortality and gradients was tested using logistic regression. RESULTS: 726 patients were studied, median age was 64 years and 14 (1.9%) died within 30 days. There was a significant association between mortality and temperature gradient, comparable to vital signs, age, and clinical intuition. CONCLUSION: Temperature gradient between nose and eye had an acceptable discriminatory power for 30-day all-cause mortality.

Revitalizing the drug pipeline: AntibioticDB, an open access database to aid antibacterial research and development.

The current state of antibiotic discovery, research and development is insufficient to respond to the need for new treatments for drug-resistant bacterial infections. The process has changed over the last decade, with most new agents that are in Phases 1-3, or recently approved, having been discovered in small- and medium-sized enterprises or academia. These agents have then been licensed or sold to large companies for further development with the goal of taking them to market. However, early drug discovery and development, including the possibility of developing previously discontinued agents, would benefit from a database of antibacterial compounds for scrutiny by the developers. This article describes the first free, open-access searchable database of antibacterial compounds, including discontinued agents, drugs under pre-clinical development and those in clinical trials: AntibioticDB (AntibioticDB.com). Data were obtained from publicly available sources. This article summarizes the compounds and drugs in AntibioticDB, including their drug class, mode of action, development status and propensity to select drug-resistant bacteria. AntibioticDB includes compounds currently in pre-clinical development and 834 that have been discontinued and that reached varying stages of development. These may serve as starting points for future research and development.

Cross-sectional study on emergency department management of sepsis.

INTRODUCTION: Emergency departments (EDs) play an important role in the early identification and management of sepsis. Little is known about local EDs' processes of care for sepsis, adoption of international recommendations, and the impact of the new Sepsis-3 definitions. METHODS: Structured telephone interviews based on the United Kingdom Sepsis Trust 'Exemplar Standards for the Emergency Management of Sepsis' were conducted from January to August 2017 with nominated representatives of all responding public hospital EDs in Hong Kong, followed by a review of hospital/departmental sepsis guidelines by the investigators. RESULTS: Sixteen of the 18 public EDs in Hong Kong participated in the study. Among various time-critical medical emergencies such as major trauma, sepsis was perceived by the interviewees to be the leading cause of in-hospital mortality and the second most important preventable cause of death. However, only seven EDs reported having departmental guidelines on sepsis care, with four adopting the Quick Sequential Organ Failure Assessment score or its modified versions. All responding EDs reported that antibiotics were stocked within their departments, and all EDs with sepsis guidelines mandated early intravenous antibiotic administration within 1 to 2 hours of detection. Reported major barriers to optimal sepsis care included lack of knowledge and experience, nursing human resources shortages, and difficulty identifying patients with sepsis in the ED setting. CONCLUSION: There are considerable variations in sepsis care among EDs in Hong Kong. More training, resources, and research efforts should be directed to early ED sepsis care, to improve patient outcomes.

Radioembolisation of hepatocellular carcinoma: a primer.

Transarterial radioembolisation (TARE) has gained increasing acceptance as an additional/alternative locoregional treatment option for hepatocellular carcinoma, and colorectal hepatic metastases that present beyond potentially curative options. This is a catheter-based transarterial selective internal brachytherapy that involves injection of radioactive microspheres (usually Y-90) that are delivered selectively to the liver tumours. Owing to the combined radioactive and microembolic effect, the findings at follow-up imaging are significantly different from that seen with other transarterial treatment options. Considering increasing confidence among clinicians, refinement in techniques and increasing number of ongoing trials, TARE is expected to gain further acceptance and become an important tool in the armamentarium for the treatment of liver malignancies. So it is imperative that all radiologists involved in the management of liver malignancies are well versed with TARE to facilitate appropriate discussion at multidisciplinary meetings to direct further management. In this article, we provide a comprehensive review on various aspects of radioembolisation with Y-90 for hepatocellular carcinoma including the patient selection, treatment planning, radiation dosimetry and treatment, side effects, follow-up imaging and future direction.

Predictors of Stroke, Myocardial Infarction or Death within 30 Days of Carotid Artery Stenting: Results from the International Carotid Stenting Study.

OBJECTIVES: Stroke, myocardial infarction (MI), and death are complications of carotid artery stenting (CAS). The effect of baseline patient demographic factors, processes of care, and technical factors during CAS on the risk of stroke, MI, or death within 30 days of CAS in the International Carotid Stenting Study (ICSS) were investigated. METHODS: In ICSS, suitable patients with recently symptomatic carotid stenosis > 50% were randomly allocated to CAS or endarterectomy. Factors influencing the risk of stroke, MI, or death within 30 days of CAS were examined in a regression model for the 828 patients randomized to CAS in whom the procedure was initiated. RESULTS: Of the patients, 7.4% suffered stroke, MI, or death within 30 days of CAS. Independent predictors of risk were age (risk ratio [RR] 1.17 per 5 years of age, 95% CI 1.01-1.37), a right-sided procedure (RR 0.54, 95% CI 0.32-0.91), aspirin and clopidogrel in combination prior to CAS (compared with any other antiplatelet regimen, RR 0.59, 95% CI 0.36-0.98), smoking status, and the severity of index event. In patients in whom a stent was deployed, use of an open-cell stent conferred higher risk than use of a closed-cell stent (RR 1.92, 95% CI 1.11-3.33). Cerebral protection device (CPD) use did not modify the risk. CONCLUSIONS: Selection of patients for CAS should take into account symptoms, age, and side of the procedure. The results favour the use of closed-cell stents. CPDs in ICSS did not protect against stroke.

Rare cause of jaundice in a post liver transplant patient.

A hepatitis B virus carrier suffering from acute flare of chronic hepatitis B infection underwent deceased-donor liver transplantation. He was put on the immunosuppressive agent tacrolimus. On routine follow-up, he was found to have abnormal liver function. Computed tomography scan of the abdomen did not show any dilatation of the biliary system. Liver biopsy showed scattered microabscesses, and a microgranuloma was detected. Endoscopic retrograde cholangiography was performed and a biliary anastomotic stricture (BAS) was noted. In addition, the Chinese liver fluke, Clonorchis sinensis, was discovered. Balloon dilatation and stenting were performed. The patient was given a course of praziquantel. His liver function improved and normalized. We present the case of a liver transplant recipient with cholangitis caused by C. sinensis infestation and infection and biliary obstruction resulting from BAS.

Clinical relevance of cranial nerve injury following carotid endarterectomy.

OBJECTIVES: The benefit of carotid endarterectomy (CEA) may be diminished by cranial nerve injury (CNI). Using a quality improvement registry, we aimed to identify the nerves affected, duration of symptoms (transient vs. persistent), and clinical predictors of CNI. METHODS: We identified all patients undergoing CEA in the Vascular Study Group of New England (VSGNE) between 2003 and 2011. Surgeon-observed CNI rate was determined at discharge (postoperative CNI) and at follow-up to determine persistent CNI (CNIs that persisted at routine follow-up visit). Hierarchical multivariable model controlling for surgeon and hospital was used to assess independent predictors for postoperative CNI. RESULTS: A total of 6,878 patients (33.8% symptomatic) were included for analyses. CNI rate at discharge was 5.6% (n = 382). Sixty patients (0.7%) had more than one nerve affected. The hypoglossal nerve was most frequently involved (n = 185, 2.7%), followed by the facial (n = 128, 1.9%), the vagus (n = 49, 0.7%), and the glossopharyngeal (n = 33, 0.5%) nerve. The vast majority of these CNIs were transient; only 47 patients (0.7%) had a persistent CNI at their follow-up visit (median 10.0 months, range 0.3-15.6 months). Patients with perioperative stroke (0.9%, n = 64) had significantly higher risk of CNI (n = 15, CNI risk 23.4%, p < .01). Predictors for CNI were urgent procedures (OR 1.6, 95% CI 1.2-2.1, p < .01), immediate re-exploration after closure under the same anesthetic (OR 2.0, 95% CI 1.3-3.0, p < .01), and return to the operating room for a neurologic event or bleeding (OR 2.3, 95% CI 1.4-3.8, p < .01), but not redo CEA (OR 1.0, 95% CI 0.5-1.9, p = .90) or prior cervical radiation (OR 0.9, 95% CI 0.3-2.5, p = .80). CONCLUSIONS: As patients are currently selected in the VSGNE, persistent CNI after CEA is rare. While conditions of urgency and (sub)acute reintervention carried increased risk for postoperative CNI, a history of prior ipsilateral CEA or cervical radiation was not associated with increased CNI rate.

Pilot study evaluating catheter-directed contrast-enhanced ultrasound compared to catheter-directed computed tomography arteriography as adjuncts to digital subtraction angiography to guide transarterial chemoembolization.

AIM: To investigate the feasibility and procedural value of catheter-directed contrast-enhanced ultrasound (CCEUS) compared with catheter-directed computed tomography arteriography (CCTA) in patients undergoing transarterial chemoembolization (TACE) guided by digital subtraction angiography (DSA). MATERIALS AND METHODS: From December 2010 to December 2011, a pilot study was conducted including nine patients (mean age 66.6 years; SD 8.3 years; seven men) undergoing TACE with drug-eluting beads for unresectable hepatocellular carcinoma (HCC). Both CCEUS and CCTA were performed in addition to DSA. Alterations of treatment plan based on CCEUS were recorded and compared with CCTA. RESULTS: CCEUS provided additional information to DSA altering the treatment plan in four out of nine patients (44.4%). In these four patients, CCEUS helped to identify additional tumour feeders (n = 2) or led to a change in catheter position (n = 2). The information provided by CCEUS was similar to that provided by CCTA. CONCLUSION: CCEUS is a potentially valuable imaging tool in adjunction to DSA when performing TACE and may provide similar information to CCTA.

Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial.

BACKGROUND: The purpose of the present study was to determine whether intrahepatic injection of (131)I-lipiodol (Lipiodol) is effective against recurrence of surgically resected hepatocellular carcinoma (HCC). METHODS: From June 2001 through March 2007, this nationwide multi-center prospective randomized controlled trial enrolled 103 patients 4-6 weeks after curative resection of HCC with complete recovery (52: Lipiodol, 51: Control). Follow-up was every 3 months for 1 year, then every 6 months. Primary and secondary endpoints were recurrence-free survival (RFS) and overall survival (OS), respectively, both of which were evaluated by the Kaplan-Meier technique and summarized by the hazard ratio (HR). The design was based on information obtained from a similar trial that had been conducted in Hong Kong. RESULTS: The Lipiodol group showed a small, and nonsignificant, improvement over control in RFS (HR = 0.75; 95 % confidence interval [95 % CI] 0.46-1.23; p = 0.25) and OS (HR = 0.88; 95 % CI 0.51-1.51; p = 0.64). Only two serious adverse events were reported, both with hypothyroidism caused by (131)I-lipiodol and hepatic artery dissection during angiography. CONCLUSIONS: The randomized trial provides insufficient evidence to recommend the routine use of (131)I-lipiodol in these patients.

Ubiquitin-dependent degradation of TGF-beta-activated smad2.

SMAD proteins are phosphorylated by transforming growth factor-beta (TGF-beta) receptors and translocate to the nucleus, where they control transcription. Here we investigate the fate of activated Smad2. We show that receptor-mediated activation leads to multi-ubiquitination and subsequent degradation of Smad2 by the proteasome. Ubiquitination of Smad2 is a consequence of its accumulation in the nucleus. If degradation is averted, the phosphorylated Smad2 remains in the nucleus in an active state. By targeting Smad2 for destruction, TGF-beta ensures the irreversible termination of its own signalling function.

Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells.

Over half of cutaneous melanoma tumors have BRAFV600E/K mutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that ~50-60% of melanoma cell lines with vemurafenib resistance acquired in vitro show activation of RhoA family GTPases. In BRAFi-resistant melanoma cell lines and tumors, activation of RhoA is correlated with decreased expression of melanocyte lineage genes. Using a machine learning approach, we built gene expression-based models to predict drug sensitivity for 265 common anticancer compounds. We then projected these signatures onto the collection of TCGA cutaneous melanoma and found that poorly differentiated tumors were predicted to have increased sensitivity to multiple Rho kinase (ROCK) inhibitors. Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the RhoHigh BRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms. Taken together, these results support the concept of targeting Rho-regulated gene transcription pathways as a promising therapeutic approach to restore sensitivity to BRAFi-resistant tumors or as a combination therapy to prevent the onset of drug resistance.

Grading of carotid artery stenosis with multidetector-row CT angiography: visual estimation or caliper measurements?

To assess the optimal method for grading carotid artery stenosis with computed tomographic angiography (CTA), we compared visual estimation to caliper measurements, and determined inter-observer variability and agreement relative to digital subtraction angiography (DSA). We included 46 patients with symptomatic carotid stenosis for whom CTA and DSA of 55 carotids was available. Stenosis quantification by CTA using visual estimation (CTA(VE)) (method 1) was compared with caliper measurements using subjectively optimized wide window settings (method 2) or predefined contrast-dependent narrow window settings (method 3). Measurements were independently performed by two radiologists and two residents. To determine accuracy and inter-observer variability, we calculated linear weighted kappa, performed a Bland-Altman analysis and calculated mean difference (bias) and standard deviation of differences (SDD). For inter-observer variability, kappa analysis was "very good" (0.85) for expert observers using CTA(VE) compared with "good" (0.61) for experts using DSA. Compared with DSA, method 1 led to overestimation (bias 5.8-8.0%, SDD 10.6-14.4), method 3 led to underestimation (bias -6.3 to -3.0%, SDD 13.0-18.1). Measurement variability between DSA and visual estimation on CTA (SDD 11.5) is close to the inter-observer variability of repeated measurements on DSA that we found in this study (SDD 11.6). For CTA of carotids, stenosis grading based on visual estimation provides better agreement to grading by DSA compared with stenosis grading based on caliper measurements.

Identification of type C viruses by electron microscopy.

The cores of a small proportion of the particles in purified preparations of type C viruses are characterized by two concentric shells that have a "double-ring" appearance in specimens prepared for electron microscopy by negative staining or thin sectioning techniques. This distinctive feature allows such particles to be recognized as viral in impure preparations. Detectability of double-ring particles is considerably enhanced by treating the specimens with a non-ionic detergent before fixation and negative staining. The limit of detectablity of type C virus (identified by the double-ring feature) in the presence of a large excess of nonviral particulates of similar size and density was assessed.

Evolution of methotrexate resistance of human acute lymphoblastic leukemia cells in vitro.

A human acute lymphoblastic T-cell line, MOLT-3, was fed with Roswell Park Memorial Institute Medium 1640 supplemented with 10% fetal bovine serum and antibiotics which contained increasing concentrations of methotrexate (MTX). The development of drug resistance was associated initially with progressive decrease in MTX transport. When the cells became 200-fold resistant, a rise in the dihydrofolate reductase was noted which was short-lived in the absence of the drug. A 10,000-fold increase in MTX resistance was accompanied, in addition to further decrease in MTX transport, by a 10-fold increase in the dihydrofolate reductase activity. While the purely transport-related resistant cell lines had a collateral sensitivity to lipid-soluble antifols, the sublines which had both transport- and enzyme-related MTX resistance contained a subpopulation highly resistant to these antifols. Chromosome analysis of the subline with increased dihydrofolate reductase activity showed an expanded abnormally banded region in chromosome 5.

TbetaR-I(6A) is a candidate tumor susceptibility allele.

We have previously described a type I transforming growth factor (TGF)-beta receptor (TbetaR-I) polymorphic allele, TbetaR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TbetaR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TbetaR-I(6A) homozygosity is associated with cancer, we performed a case-control study in patients with a diagnosis of cancer and matched healthy individuals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-line frequencies of this allele. We found nine TbetaR-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TbetaR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TbetaR-I(6A) heterozygotes in cancer cases compared to controls (14.6% versus 10.6%; P = 0.02, Fisher's exact test). A subset analysis revealed that 4 of 112 patients with colorectal cancer were TbetaR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TbetaR-I, we established stably transfected TbetaR-I and TbetaR-I(6A) cell lines. We found that, compared to TbetaR-I, TbetaR-I(6A) was impaired as a mediator of TGF-beta antiproliferative signals. We conclude that TbetaR-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF-beta-mediated growth inhibition.

Disrupted development of the cerebral hemispheres in transgenic mice expressing the mammalian Groucho homologue transducin-like-enhancer of split 1 in postmitotic neurons.

Transducin-like Enhancer of split (TLE) 1 is a mammalian transcriptional corepressor homologous to Drosophila Groucho. In Drosophila, Groucho acts together with bHLH proteins of the Hairy/Enhancer of split (HES) family to negatively regulate neuronal differentiation. Loss of the functions of Groucho or HES proteins results in supernumerary central and peripheral neurons. This suggests that mammalian TLE/Groucho family members may also be involved in the regulation of neuronal differentiation. Consistent with this possibility, TLE1 is expressed in proliferating neural progenitor cells of the central nervous system, but its expression is transiently down-regulated in newly generated postmitotic neurons. Based on these observations, we investigated whether persistent TLE1 expression in postmitotic neurons would perturb the normal course of neuronal development. Transgenic mice were derived in which the human TLE1 gene is regulated by the promoter of the Talpha1 alpha-tubulin gene, which is exclusively expressed in postmitotic neurons. In these mice, constitutive expression of TLE1 inhibits neuronal development in the embryonic forebrain leading to increased apoptosis and neuronal loss in the ventral and dorsal telencephalon. These results provide the first direct evidence that TLE1 is an important negative regulator of postmitotic neuronal differentiation in the mammalian central nervous system.