Background Immune check point inhibitors (ICPis) have transformed the treatment landscape for several cancers, but at the cost of triggering ICPi-induced colitis which resembles some aspects of IBD. Diagnosis is often made by symptoms, or by identifying endoscopic features of colitis. Little is known about histological findings in the absence of macroscopic disease. Furthermore, first-line management strategies beyond the use of systemic corticosteroids have not been explored. Our aim was to assess the incidence of microscopic inflammation in patients with ICPi-diarrhoea, and report our experience of treating two such patients with beclomethasone diproprionate (Clipper). Methods Electronic records of patients with advanced melanoma and ICPi- diarrhoea/colitis at the Royal Marsden Hospital (RMH) and Guy’s and St Thomas’ Hospital (GSTT) between 2011–2016, were retrospectively reviewed. Endoscopic, histological and clinical outcome data was recorded for patients who underwent flexible sigmoidoscopy and had colonic biopsies taken regardless of macroscopic findings. Two symptomatic patients (one treated with anti-PD-1, and another on combination -anti-PD-1/anti-CTLA-4 therapy) with isolated microscopic disease were managed with 5 mg Clipper, once a day, for 4 weeks. Endoscopic, histological and clinical outcomes were recorded 6 weeks after completion of therapy. Results A total of 63 flexible sigmoidoscopies were performed in 59 patients with ICPi diarrhoea/colitis. Microscopic inflammation with normal macroscopic appearances were recorded in 22% of cases. 6 patients were prescribed anti-CTLA-4, 4 anti-PD-1, and 4 combination therapy. Histological features that were distinct from conventional microscopic colitis were recorded in the majority of patients (10/14), which included acute and chronic inflammation, architectural distortion, crypt abscess formation and neutrophil infiltration. Four patients had changes consistent with conventional microscopic colitis (2 lymphocytic colitis, 2 collagenous colitis). Clipper induced clinical remission within 7 days, and histological remission by week 6 in both patients with ICPi-induced microscopic inflammation. There was no treatment associated adverse events. Conclusion Microscopic inflammation in the absence of macroscopic features of colitis is a common finding in ICPi-induced diarrhoea, justifying the routine practice of performing colonic biopsies even when endoscopy is normal. Our favourable clinical experience of using Clipper in 2 patients with microscopic inflammation merit further investigation in appropriately controlled clinical trials.

Background Immune checkpoint inhibitors (ICIs) including anti-CLTA-4 (e.g. ipilimumab (ipi)) and anti-PD-1 antibodies (e.g. nivolumab (nivo)) have improved outcomes in many cancers. However their use is complicated by ICI-related diarrhoea/colitis (irD/C), a common cause of morbidity and ICI discontinuation. The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) has been used to grade irD/C according to frequency of bowel movements over baseline. Grade 1–2 represents mild-moderate disease, grade 3–4 severe disease and grade 5 represents death. In clinical trials diarrhoea/colitis is more common in regimes using anti-CTLA-4 agents.1 There are few real world data reported in the UK. Methods Electronic medical records were reviewed for melanoma patients (pts) at The Royal Marsden Hospital (RMH) and melanoma, renal and lung cancer pts Guy’s and St Thomas’ Hospital (GSTT), receiving at least one ICI dose between 2011–2016. Clinical outcome data included class of ICI therapy and CTCAE grade of diarrhoea. Results 651 ICI treatment courses were administered mostly for melanoma (100% RMH, 53% GSTT). 285 (44%) received anti-CTLA-4 monotherapy, 288 (44%) anti-PD-1 monotherapy, and 77 (12%) combination ipi +nivo. The incidence of all-grade irD/C was 27% for anti-CTLA-4 therapy, 12% for anti-PD-1%–34% for ipi +nivo. The incidence of severe irD/C (grade 3–5) was 12% in anti-CTLA-4 monotherapy, 4% in anti-PD-1 therapy and 26% in combination therapy (figure 1). There was one only death reported in a pt who developed colitis following treatment with anti-CTLA-4 monotherapy.Abstract PTU-006 Figure 1 Conclusion This is the largest cohort of data reporting the incidence of irD/C involving real-world patients. Compared to trial data, the incidence of all-grade diarrhoea was slightly lower but the incidence of severe disease was higher in all treatment groups, particularly with ipi +nivo. Given the expansion of ICIs in other cancer types and use as an adjuvant therapy, there is an urgent need to engage gastroenterology services and to develop evidence-based management algorithms for treatment of irD/C. Reference . Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev2016;44:51–60.

Background Immune checkpoint inhibitors (CPI) against lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) are a novel therapeutic breakthrough in an increasing number of malignancies. CPI induced acute liver injury (ALI) is the second most frequently encountered organ toxicity occurring in up to 30% patients. There are no reported data on ALI disease pathogenesis, clinical evolution and outcome of patients treated with CPI therapy. Our multicentre cohort study evaluated clinico-pathological aspects of CPI-induced ALI. Method A retrospective analysis was performed of patients with CPI induced ALI presenting to 6 UK oncology centres between 2013 and 2017. Indices of acute liver injury, treatment related complications and outcome were recorded. Severity scoring of liver injury was based on Common Terminology Criteria for Adverse Events (ALI grade 1–4). Results 65% (36/57) patients received ipilimumab +pembrolizumab or nivolumab (combo group) and 35% (21/57) pembrolizumab or nivolumab alone (mono group). Median treatment duration to development of ALI was 96 days in the mono and 22 days in the combo group. All patients presented with acute elevations in transaminases (ALT 325 [155–543], ALP 111 [72–250]). Immungolulins and autoantibodies were normal. One patient developed acute synthetic dysfunction with no encephalopathy (Bilirubin 64, INR 1.5). 79% received steriods (mean dose:1.3 mg/kg); 34% MMF. Steroid refractory ALI was treated with anti-thymocyte globulin (ATG) in 4 patients. Pathological findings (n=6 liver biopsies) revealed lobular hepatitis and myelo-lymphoid cell infiltrate/aggregates (CD3+,CD8+,CD68+). Patients with severe, refractory (grade 4) ALI had signifcant reductions in circulating lymphocytes/monocytes. 63% (n=35) had a temporal association between recent infection and ALI. 15% (n=8) had colitis prior to onset of ALI. Anti-TNF-a administration for colitis was not associated with more severe ALI. 21% (n=11) developed bacterial infections. Fungal sepsis (aspergillus) occurred in all ATG (n=4) treated patients. Overall 14 patients died with 93% (n=13) due to disease progression and 7% (n=1) due to immunotherapy related neuropathy. All deaths due to progressive disease were in patients with grade 3–4 ALI. Acturial median survival was significantly lower in grade 3–4 (14.5 months) vs grade 1–2 (25 months) liver injury. Conclusion Our data report on the largest cohort of CPI induced ALI identifying disease evolution, markers of disease severity and strong correlation with increased morbidity and mortality. Further research is required to delineate triggers and pathogenesis of CPI induced ALI in order to develop calibrated therapies to ameliorate liver injury.

Introduction Immune checkpoint inhibitors (ICIs) such as ipilimumab (ipi), nivolumab (nivo) and pembrolizumab (pembro) and the combination of ipi +nivo have improved response rates and survival in patients (pts) with advanced melanoma. Nivo was recently approved by the FDA as an adjuvant therapy. Responses may be durable, however associated immune-related adverse events may result in significant morbidity. Current treatment algorithms suggest that pts treated with ICIs who develop corticosteroid (CS)-refractory (CSrefr) irD/C are prescribed anti-TNF alpha antibodies such as infliximab (IFX). Little is known about the clinical features and outcomes of pts who receive IFX. Methods Pts with advanced melanoma from the Royal Marsden NHS Foundation Trust who received CS and IFX were identified from an ethically approved irD/C database (pts treated with ICIs from 2011–2016) and their medical records were reviewed, including flexible sigmoidoscopy (FS) results. Descriptive statistics and percentages were used to summarise the features of the CSrefr versus CS-responsive (CSresp) groups. Results Rates of all-grade irD/C by course of treatment were as follows: ipi 77/285 (27%), nivo or pembro 17/166 (10%), ipi +nivo 23/68 (34%). CS were prescribed in 72 (62%). 17 (15%) received IFX; 9 received 2 doses and 3 received 3 doses. 76% responded to IFX within a week; median time to improvement was 4 days (range 1–28). Table 1 outlines clinical information for the CSrefr and CSresp groups. Infection occurred in 10 episodes of IFX prescription (59%), 9 requiring antibiotics, including 2 cases of Pneumocystic jirovecii pneumonia. Conclusions 35% of irD/C due to ipi +nivo is CS-refractory. In the CSrefr group, CS duration was longer, macroscopic colitis was more common and most pts developed an infection. Interestingly time to progression of disease was longer in the CSrefr group. Prospective clinical trials are warranted to evaluate whether early IFX may reduce the burden of CS in the management of irD/C without compromising disease control.Abstract PTU-005 Table 1 CS-refractory versus CS-responsive patients CSrefr (n= 17) CSresp (n= 54) N (range) % N (range) % Ipi 8 47 30 56 Nivo/pembro 1 6 9 16 Ipi+nivo 8 47 11 20 Days from start ICI to onset of irD/C 41 - 45 - Grade 1/2 1 6 14 26 Grade 3/4 16 94 40 74 Median days from start of D/C to CS (range) 5 - 5 - Days from start CS to IFX 14(1–100) - NA - Median duration CS - - Grade 1/2 160(160–160) - 49(6–295) - Grade 3/4 79(28–279) - 47(6–204) - Extra treatment 1(vedolizumab) 6 0 0 Macroscopic abnormality on FS 13/17 76 22/41 54 Microscopic abnormality only on FS 1/17 6 9/41 22 Normal FS 2/17 12 7/41 17 Unknown FS result 1/17 6 3/41 7 Disease progression 12 67 42 79 Median days to progressive disease 170 - 101 - NB: 1 patient who had CS but unknown status re IFX is not included

Introduction Immune Checkpoint inhibitors (ICPi) have revolutionised the management of melanoma, non-small cell lung cancer and renal cancer. They block receptors expressed by immune cells that reduce immune activation. ‘Turbo-charged’ immune cells deliver augmented anti-tumour immunity (hence the striking efficacy of these anti-cancer agents), but comes at the cost of immune mediated side effects. Immune-mediated damage to the gut is a common and serious side effect of ICPi therapy. Endoscopic and histological findings in the lower gastrointestinal (GI) tract have been described (colitis is a common feature), but little is known about manifestations in the upper GI tract. Methods We performed a retrospective analysis of all patients presenting with diarrhoea following treatment with ICPis (ipilimumab, nivolumab, pembrolizumab or combination therapy) who had been investigated with OGD. Endoscopic and histopathological data were recorded. Lower GI findings in this cohort were also analysed. Results We reviewed 40 OGDs performed in our unit for melanoma patients who developed diarrhoea after starting treatment with ICPi patients. In all cases flexible sigmoidoscopy or colonoscopy was also performed. Inflammatory changes were common, including gastritis (40%) and duodenitis (17.5%). Importantly, even in the absence of macroscopically visible mucosal injury, there was a significant burden of microscopic inflammation, especially in the duodenum. In patients with a normal duodenoscopy, significant microscopic changes were present in 28% of patients. Significant histological abnormalities included chronic inflammation and/or increased intraepithelial lymphocytes (86%) and villous atrophy (71%), consistent with pathologically relevant mucosal immune activation. Abnormalities in the oesophagus were also common (32%), but were dominated by candidiasis (15%), likely secondary to high-dose steroids used to treat this challenging condition. All patients in this cohort of ICPi-induced diarrhoea patients investigated with OGD additionally underwent lower GI endoscopy, which confirmed the presence of colitis in 65% of patients. Importantly, upper GI disease was just as common in patients with a normal lower GI investigation (57%) as those with overt colitis (54%). Conclusions There is a significant burden of upper GI pathology, including macroscopic and microscopic mucosal injury and excessive immune accumulation, most notably in the duodenum, in patients with diarrhoea secondary to ICPi therapy. Additional findings that altered management included oesophageal candidiasis (likely a side-effect steroid therapy, which is usually rapidly initiated as soon as patients present with diarrhoea). Importantly, upper GI pathology is just as common in patients without colonic disease. OGD should be part of diagnostic work up of patients developing diarrhoea in the context of ICPi therapy.

Power system stabilizers are controllers which damp power oscillations in electrical networks. They typically reside in the automation system of the power plant. Their design and structure are typically fixed in the design of the power plant. Optimal design and tuning of these decentralized controllers such that power oscillations are avoided is a challenging task. In the first part of the paper, we outline this problem and transform it into a so called structured controller synthesis problem where the control structure is fixed and optimal controller parameters need to be found. Based on this formulation, which preserves the real controller parameters, we propose a coordinate descent method to solve the controller design and tuning problem. To this end, we consider additional steady-state constraints in the system. We show the effectiveness of the proposed approach by detailed simulations of an established power system benchmark.

A variety of LQR-RRT kinodynamic motion planners are built on the idea of solving a two point boundary value problem in an LQR manner for affine systems. These planners can also be used for controllable nonlinear systems only if its linearized model at the equilibrium state is also controllable, and the cost function reflects only a time/control trade-off. We propose a class of RRT planners based on the SDRE (State Dependent Riccati Equation) control paradigm. The SDRE control is used both for finding the nearest state in the tree and for the tree expansion. By solving an LQR tracking problem for nonlinear systems within the SDRE framework, instead of a two point boundary value problem, the proposed planners deal with a wider range of controllable nonlinear systems and cost functions. We compare the proposed planners with LQR-RRT-like algorithms by observing the results obtained from the three specific benchmark examples.

Abstract The investigation of fish parasites in Bosnia and Herzegovina in recent years became significant, and therefore new records of parasitic trematodes and their hosts are important for better understanding of fish parasitology and pathology. In this study 41 parasitic specimens were collected and the basic taxonomical characters were measured (body length and width, diameter of oral and ventral sucker, length and width of pharynx, ovary length and width, testes length and width and eggs length and width). After the sampling of the parasites, they were collected and conserved in 70% ethanol. After that procedure the aforementioned characters were measured using Digimizer Image Analyzer Version 4.1. After all measurements, the trematode parasite Azygia robusta was confirmed for the first time on brown trout Salmo trutta. This first record was found in the Vrbas River near Banja Luka, Bosnia and Herzegovina (Sava River Basin). Former records of this parasite in Europe were observed on other salmonid fish species, as huchen Hucho hucho. This new record should be very important part of data of fish parasitology in Bosnia and Herzegovina.

This paper addresses the issue of modeling meanfield behavior in heterogeneous populations of linear timeinvariant SISO systems. Our analysis is conducted in the frequency domain, where the heterogeneity of input-output mappings (transfer functions) is modeled as a complex-valued Gaussian process. The mean-field model of diffusively coupled agents is obtained as a Gaussian approximation of averaged input-output behavior. It is shown that the strong coupling and the large number of agents reduce the population variance.

OBJECTIVE Outpatient anterior cervical discectomy and fusion (ACDF) is becoming more common and has been reported to offer advantages over inpatient procedures, including reducing nosocomial infections and costs, as well as improving patient satisfaction. The goal of this retrospective study was to evaluate and compare outcome parameters, complication rates, and costs between inpatient and outpatient ACDF cases performed by 1 surgeon at a single institution. METHODS In a retrospective study, the records of all patients who had undergone first-time ACDF performed by a single surgeon in the period from June 1, 2003, to January 31, 2016, were reviewed. Patients were categorized into 2 groups: those who had undergone ACDF as outpatients in a same-day surgical center and those who had undergone surgery in the hospital with a minimum 1-night stay. Outcomes for all patients were evaluated with respect to the following parameters: age, sex, length of stay, preoperative and postoperative pain (self-reported questionnaires), number of levels fused, fusion, and complications, as well as the presence of risk factors, such as an increased body mass index, smoking, and diabetes mellitus. RESULTS In total, 1123 patients were operated on, 485 (43%) men and 638 (57%) women, whose mean age was 50 years. The mean follow-up time was 25 months. Overall, 40.5% underwent 1-level surgery, 34.3% 2-level, 21.9% 3-level, and 3.2% 4-level. Only 5 patients had nonunion of vertebrae; thus, the fusion rate was 99.6%. Complications occurred in 40 patients (3.6%), with 9 having significant complications (0.8%). Five hundred sixty patients (49.9%) had same-day surgery, and 563 patients (50.1%) stayed overnight in the hospital. The inpatients were older, were more commonly male, and had a higher rate of diabetes. Smoking status did not influence the length of stay. Both groups had a statistically significant reduction in pain (expressed as a visual analog scale score) postoperatively with no significant difference between the groups. One- and 2-level surgeries were done significantly more often in the outpatient setting (p < 0.001). The complication rate was 4.1% in the outpatient group and 3.0% in the inpatient group; there was no statistically significant difference between the 2 groups (p = 0.339). Significantly more complications occurred with 3- and 4-level surgeries than with 1- and 2-level procedures (p < 0.001, chi-square test). The overall average inpatient cost for commercial insurance carriers was 26% higher than those for outpatient surgery. CONCLUSIONS Anterior cervical discectomy and fusion is safe for patients undergoing 1- or 2-level surgery, with a very significant rate of pain reduction and fusion and a low complication rate in both clinical settings. Outpatient and inpatient groups undergoing 3- or 4-level surgery had an increased risk of complications (compared with those undergoing 1- or 2-level surgery), with a negligible difference between the 2 groups. This finding suggests that these procedures can also be included as standard outpatient surgery. Comparable outcome parameters and the same complication rates between inpatient and outpatient groups support both operative environments.

The increasing energy demands of modern society require a deep understanding of the properties of energy storage materials, as well as the tuning of their performance. We show that the capacitance of graphene oxide (GO) can be precisely tuned using a simple electrochemical reduction route. In situ resistance measurements, in combination with cyclic voltammetry measurements and Raman spectroscopy, have shown that upon reduction GO is irreversibly deoxygenated, which is further accompanied by structural ordering and an increase in electrical conductivity. The capacitance is maximized when the concentration of oxygen functional groups is properly balanced with the conductivity. Any further reduction and deoxygenation leads to a gradual loss of capacitance. The observed trend is independent of the preparation route and the exact chemical and structural properties of GO. It is proposed that an improvement in the capacitive properties of any GO can be achieved by optimization of its reduction conditions.

To utilize cervical auscultation as a means of screening for risk of dysphagia, we must first determine how the signal differs between healthy subjects and subjects with swallowing disorders. In this experiment we gathered swallowing sound and vibration data from 53 (13 with stroke, 40 without) patients referred for imaging evaluation of swallowing function with videofluoroscopy. The analysis was limited to non-aspirating swallows of liquid with either thin (< 5 cps) or viscous (≈300cps\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\approx 300\,{\text{cps}}$$\end{document}) consistency. After calculating a selection of generalized time, frequency, and time frequency features for each swallow, we compared our data against our findings in a previous experiment that investigated identical features for a different group of 56 healthy subjects. We found that nearly all of our chosen features for both vibrations and sounds showed significant differences between the healthy and disordered swallows despite the absence of aspiration. We also found only negligible differences between dysphagia as a symptom of stroke and dysphagia as a symptom of another condition. Non-aspirating swallows from healthy controls and patients with dysphagia have distinct feature patterns. These findings should greatly help the development of the cervical auscultation field and serve as a reference for future investigations into more specialized characterization methods.