Serum Beta-Defensin-2 is a biomarker for psoriasis but not subclinical atherosclerosis: Role of IL17a, PI-3 kinase and Rac1.

Background: Beta-defensins (BDs) are antimicrobial peptides secreted upon epithelial injury. Both chemotactic and antimicrobial properties of BDs function as initial steps in host defense and prime the adaptive immune system in the body. Psoriasis, a chronic immune-mediated inflammatory disease, has both visible cutaneous manifestations as well as known associations with higher incidence of cardiometabolic complications and vascular inflammation. Objectives: We aimed to investigate the circulating expression of beta-defensin-2 (BD2) in psoriasis at baseline compared to control subjects, along with changes in BD2 levels following biologic treatment at one-year. The contribution of BD2 to subclinical atherosclerosis is also assessed. In addition, we have sought to unravel signaling mechanisms linking inflammation with BD2 expression. Methods: Multimodality imaging as well inflammatory biomarker assays were performed in biologic naïve psoriasis (n=71) and non-psoriasis (n=53) subjects. A subset of psoriasis patients were followed for one-year after biological intervention (anti-Tumor Necrosis Factor-α (TNFα), n=30; anti-Interleukin17A (IL17A), n=21). Measurements of circulating BD2 were completed by Enzyme-Linked Immunosorbent Assay (ELISA). Using HaCaT transformed keratinocytes, expression of BD2 upon cytokine treatment was assessed by quantitative polymerase chain reaction (qPCR) and ELISA. Results: Herein, we confirm that human circulating BD2 levels associate with psoriasis, which attenuate upon biologic interventions (anti-TNFα, anti-IL-17A). A link between circulating BD2 and sub-clinical atherosclerosis markers was not observed. Furthermore, we demonstrate that IL-17A-driven BD2 expression occurs in a Phosphatidylinositol 3-kinase (PI3-kinase) and Rac1 GTPase-dependent manner. Conclusions: Our findings expand on the potential role of BD2 as a tractable biomarker in psoriasis patients and describes the role of an IL-17A-PI3-kinase/Rac signaling axis in regulating BD2 levels in keratinocytes.

Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Specialist and Patient Perspectives on Strategies to Improve Cardiovascular Disease Prevention Among Persons Living with Psoriatic Disease.

Background: Psoriasis is an immune-mediated disease associated with excess risk for cardiovascular disease (CVD). Guidelines recognize psoriasis as a CVD risk enhancer; however, psoriasis patients often do not have CVD risk factors identified nor managed. Objective: This study examines strategies to improve CVD prevention care from the perspective of dermatologists and patients with psoriasis. Methods: Qualitative interviews were conducted using the Consolidated Framework for Implementation Research to examine the perspectives of physicians (N = 16) and patients with psoriatic disease (N = 16) on barriers/facilitators to CVD prevention. Interviews were transcribed and coded using an integrated approach designed to enhance reliability and validity using NVivo software. Results: We found three major themes suggesting areas to target for the future: (1) Appropriateness: perceptions of whether CVD care should be deployed in this setting by both clinicians and patients, (2) Feasibility: whether CVD prevention care could be integrated into the current structure of specialist practice, and (3) Care Coordination: an interest by all parties to better integrate a team approach in CVD preventative care to reduce duplicative efforts, work practically in an already existing system rather than reinventing the wheel, and progress with the patients' best interests in mind. Conclusions: These findings will inform the design of a clinical trial comparing the effectiveness of specialist clinician implementation of CVD guideline-based prevention care in patients with psoriasis. Ultimately, this study aims to increase the lifespan and health of patients living with psoriatic disease by decreasing barriers to their receiving appropriate CVD prevention care.

Post hepatectomy liver failure - A comprehensive review of current concepts and controversies.

Post hepatectomy liver failure (PHLF) comprises of a conundrum of symptoms and signs following major hepatic resections. The pathophysiology essentially revolves around disruption of the normal hepatocyte regeneration and disturbed liver homeostasis. Prompt identification of the pre-operative predictors of PHLF in the form of biochemical parameters and imaging features are of paramount importance for any hepatic surgeon and forms the cornerstone of its management. Treatment revolves around a goal-directed resuscitation of the systemic organ failure. Auxiliary support systems such as liver dialysis devices and stem cell therapy are still under investigational trials for treatment of the same. Orthotopic liver transplantation (OLT) is the last resort in most cases not responding to other measures.

Minimizing Hepatic Artery Thrombosis and Establishing Safety of Grafts With Dual Arteries in Living Donor Liver Transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) is a dreaded complication following living donor liver transplantation (LDLT) and can lead to graft failure and biliary complications. We evaluated the results of our arterial anastomotic technique and outcomes in grafts with dual arterial supply. PATIENTS AND METHODS: Between July 2010 and June 2015, 225 patients underwent LDLT. The hepatic artery anastomosis was done using our "W technique". In grafts with a dual arterial supply, two anastomoses were performed unless there was significant pulsatile back-bleeding in the smaller artery after the larger anastomosis. RESULTS: The mean age of the recipients was 43±15.2 years (6 months to 66 years). There were 184 right liver, 30 left liver, 10 left lateral segment, and 1 dual lobe (right liver and left lateral segment) grafts. Twenty-three (10.2%) patients had 2 graft arteries, 10 of which required 2 separate anastomoses, and an interposition saphenous vein conduit was used in one. HAT occurred in 3 (1.3%) patients. The median intensive care unit and postoperative hospital stays were 5 and 14 days, respectively. Post-transplant operative mortality was 12.4%. There was no difference in mortality (8.7% vs 12.4%, P = >.99) and biliary complications (11.9% vs 21.7%, P = .19) between recipients of grafts with single or dual graft arteries, respectively. CONCLUSIONS: A careful surgical "W technique" and intraoperative confirmation of a good arterial flow helps in reducing the incidence of early HAT. The presence of two arteries in the graft was not associated with increased incidence of HAT, mortality, or biliary complications.

Effect of informed consent on patients undergoing gastrointestinal surgery and living donor liver transplantation and on their relatives in a developing country.

BACKGROUND: Informed consent is a systematic process for obtaining permission before conducting a healthcare intervention. In a developing country, gaining informed consent is generally perceived to be a ritual only to comply with legal requirements. The present study examined this by assessing the process of informed consent in patients undergoing gastrointestinal surgery or living donor liver transplantation (LDLT) and their relatives, based on their comprehension and overall satisfaction, in India. METHODS: All patients undergoing any gastrointestinal surgery or LDLT procedure between August 2015 and July 2016 and their relatives were included, and were administered a structured questionnaire 5 days after the procedure. RESULTS: The majority of patients (94·2 per cent) could recall the nature of their disease, the surgery performed (81·6 per cent) and anticipated complications (55·6 per cent). Among their relatives, these proportions were 97·8, 87·3 and 58·5 per cent respectively. Recall was associated with age, occupation and education among both patients and relatives. Patients undergoing LDLT, their donors and their relatives had better recall than those who had other gastrointestinal procedures (P < 0·001). Many patients found the process of informed consent useful and reassuring. CONCLUSION: The details and risks of an operation were understood by most of the patients, especially those undergoing liver transplantation. Patients from developing countries can generally understand 'informed consent', and value it.

Anti-inflammatory therapy with tumour necrosis factor inhibitors is associated with reduced risk of major adverse cardiovascular events in psoriasis.

BACKGROUND: Psoriasis is a systemic chronic inflammatory condition associated with increased risk of cardiovascular disease. Data demonstrating that decreased skin inflammation reduces cardiovascular events in patients with psoriasis may be generalizable to other chronic inflammatory states with heightened cardiovascular risk. OBJECTIVE: To determine whether tumour necrosis factor inhibitor (TNFi) therapy is associated with decreased major adverse cardiovascular events (MACE) in patients with psoriasis. METHODS: In this retrospective cohort study using the KPSC health plan, patients had at least three ICD-9 codes for psoriasis and no antecedent MACE codes. Propensity score-adjusted multivariable Cox regression assessed hazard ratios (HR) of MACE associated with TNFi use. RESULTS: After adjusting for cardiovascular risk factors, the TNFi cohort had significantly lower MACE HR compared with the topical cohort (HR, 0.80; 95% CI, 0.66-0.98). The oral/phototherapy cohort had similar MACE HR compared with the topical cohort (HR, 1.19 (95% CI, 0.99-1.42)). CONCLUSIONS: We observed significantly lower MACE risk in patients with psoriasis receiving TNFi compared to topical or oral/phototherapy agents. TNFi therapy may have benefits beyond skin disease in mitigating cardiovascular event risk.

Psoriasis is associated with decreased plasma adiponectin levels independently of cardiometabolic risk factors.

BACKGROUND: Psoriasis is an inflammatory skin disease that may be associated with an adverse cardiometabolic profile including modulated plasma adiponectin and leptin levels. Whether these levels are independent of cardiometabolic risk factors, which are also prevalent in psoriasis, is not known. METHODS: A consecutive sample of 122 participants with varying degrees of psoriasis severity, and a random sample of 134 participants without psoriasis, were recruited for this case-control study. Cardiometabolic risk factors including traditional cardiovascular risk factors, waist circumference, insulin resistance, and total plasma adiponectin and leptin were measured. Total plasma adiponectin and leptin levels were compared in unadjusted and adjusted analyses by psoriasis status. RESULTS: Participants with psoriasis had mostly mild disease and were mainly on topical therapies, but still had a more adverse cardiometabolic profile compared with those without psoriasis. Furthermore, plasma adiponectin levels were significantly lower in participants with psoriasis than those without {7.13 µg/mL [interquartile range (IQR) 4.9-11.3) vs. 14.5 µg/mL (IQR 8.4-24.1); P < 0.001]}. Plasma leptin (ng/mL) levels were higher in the psoriasis group but this did not reach statistical significance [11.3 (IQR 6.4-21.8) vs. 9.8 (IQR 4.9-20.5); P = 0.07]. In multivariable modelling, plasma adiponectin levels were still negatively associated with psoriasis status after adjusting for waist size (% difference = -41.2%, P < 0.001), insulin resistance (% difference = -39.5%, P < 0.001), and both waist size and insulin resistance (% difference = -38.5%, P < 0.001). CONCLUSIONS: Plasma levels of adiponectin were lower in psoriasis, and this relationship persisted after adjusting for cardiometabolic risk factors known to decrease adiponectin levels. These findings suggest that inflammation present in psoriasis may be associated with adipose tissue dysfunction; however, direct studies of adipose tissue are needed to confirm this.

Effect of preoperative chemotherapy on liver resection for colorectal liver metastases.

AIM: To compare the effects of preoperative chemotherapy on liver parenchyma morphology, as well as morbidity and mortality after liver resection for colorectal liver metastases. METHODS: Prospectively collected data on 173 patients undergoing liver resection for CLM between 1/2003 and 9/2005 was analysed in three groups: A: preoperative oxaliplatin (Ox, n=70); B: other chemotherapeutic agents (OC, n=60); and C: surgery alone without chemotherapy (SA, n=43). Blood transfusion, hospital stay, operative procedure, peak postoperative bilirubin levels, complications and histopathology of the resected liver were compared. RESULTS: Intra-operative blood transfusion requirement (34%) and biliary complications (16%) was higher in patients receiving oxaliplatin-based chemotherapy (p=0.01 and p=0.06, respectively). Oxaliplatin-based chemotherapy was also associated with sinusoidal dilatation of mild grade in 52.8% vs. 26.6% and 23.3% patients (p=0.007 and p=0.004) in other groups, respectively. Steatosis was similarly distributed across the study group. Postoperative mortality was 2, 1 and 4 patients, respectively (p=ns). CONCLUSION: Oxaliplatin-based preoperative chemotherapy is associated with vascular alterations in the liver parenchyma without significantly increasing the risk of steatosis, or postoperative morbidity and mortality.

Extraserosal pedunculated leiomyoma of stomach.

Leiomyoma of the stomach, a type of gastrointestinal stromal tumor, is uncommon. We report a 51-year-old woman with an extraserosal pedunculated leiomyoma of the stomach.

Ascitic fluid filtration and intravenous infusion versus total-volume paracentesis with infusion of plasma expander in cirrhosis with tense or intractable ascites.

BACKGROUND: Patients with cirrhotic ascites have low serum albumin levels, and paracentesis of ascitic fluid could compromise them further. AIM: We compared the therapeutic efficacy of ascitic fluid filtration and concentrate infusion (AFI) versus total-volume paracentesis (TVP) with colloid infusion in control of tense or intractable cirrhotic ascites. METHODS: Ten patients underwent AFI; their ascitic fluid was filtered repeatedly through hollow-fiber hemodialyzer, and the concentrate reinfused intravenously. In ten patients TVP was done with simultaneous intravenous colloid infusion. Follow-up was done weekly and the study terminated if the patient needed diuretics or developed complications. RESULTS: Pre-study parameters were similar in the two groups. In the AFI and TVP groups, the duration of procedure was median 12 hours and 5.5 hours; fluid removed by paracentesis was 10.2 L and 8.0 L, respectively; and fluid infused intravenously was 0.5 L [with mean (SD) protein content 5.7 (1.3) g/dl] and 1.1 L, respectively. Glomerular filtration rates were lower than normal in the two groups but did not change significantly with the procedure; body weight remained significantly lower up to week 3 and week 2, respectively. The study was terminated at median week 3 (range 1-8) and week 2 (1-4), respectively. Fever was an accompaniment of AFI and one patient developed peritonitis. CONCLUSION: Patients undergoing AFI remained diuretic-free longer; the procedure is cost-effective but needs to be further evaluated to minimize the side-effects.

Persistent transaminase elevation due to heterozygous (familial) apolipoprotein B deficiency.

Homozygous apolipoprotein B deficiency can present with fatty liver and raised levels of transaminases. Subjects with heterozygous deficiency are almost always asymptomatic. We report an asymptomatic 26-year-old man with persistently raised transaminases, in whom the diagnosis of heterozygous (familial) apolipoprotein B deficiency was made on the basis of characteristic lipid profile.