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Supplementary Figure 1 from Identification of Nuclear Export Inhibitors with Potent Anticancer Activity In vivo

Supplementary Figure 3 from Identification of Nuclear Export Inhibitors with Potent Anticancer Activity In vivo

Supplementary Methods and Materials from Identification of Nuclear Export Inhibitors with Potent Anticancer Activity In vivo

Supplementary Figure 2 from Identification of Nuclear Export Inhibitors with Potent Anticancer Activity In vivo

Introduction Acute liver failure (ALF) has a high short term mortality. Current prognostic models lack sensitivity. This study aimed to investigate the prognostic potential of iron metabolism in ALF. Methods 528 patients admitted to a liver transplant unit with ALF were selected. Aetiology, outcome (spontaneously survived vs. death/transplant) and hepatic encephalopathy (HE) were recorded. Patients without the relevant iron indices recorded were excluded. Results Paracetamol overdose (POD) patients (n=236) had a significantly higher transferrin if they survived (n=168) compared to those that died or were transplanted (n=68) (1.585 (1.363–1.918) vs. 1.285 (1.000–1.730) (p In non-POD patients (n=88) the median transferrin was also significantly higher in those patients that survived (n=48) compared to those that died or were transplanted (n=40) (1.965 (1.435–2.375) vs. 1.455 (1.078–1.803) (p=0.001)) In POD patients (n=246) the median ferritin was significantly higher in those who died or were transplanted (n=70) compared with survivors (n=176) (36,822(13,054–64,358) vs. 17,641 (5,120–42,895) (p=0.002)). There was no statistical difference in the non-POD group. Transferrin was significantly lower in POD patients with HE (n=143) compared to those that never developed HE (n=93) (1.420 (1.100–1.720) vs. 1.670 (1.400–1.990) (p Ferritin was significantly higher in POD patients with HE (n=146) compared to those who never developed HE (n=99). (24,828 (9,267–61,214) vs. 17,149 (3,153–37,994) (p=0.009)). There was no difference in the non-POD group. No significant results were found when comparing circulating iron levels and transferrin saturations. ROC curve analysis, however, showed that iron studies are poor at predicting survival in ALF. For example the area under the curve for transferrin to predict survival in POD patients was 0.662. To predict encephalopathy free course of disease in the same group of patients was 0.666. Conclusions Iron indices, specifically ferritin and transferrin, are significantly different in patients with ALF and relate to aetiology and outcome. However they are poor at predicting survival.

We describe the management of a Sierra Leonean health care worker with severe Ebola virus disease complicated by diarrhea, significant electrolyte disturbances, and falciparum malaria coinfection. With additional resources and staffing, high quality care can be provided to patients with Ebola infection and adverse prognostic factors in west Africa.

Introduction In the UK, 85% of pancreatic cancer (PC) patients are inoperable at presentation with a median survival of 6–9 months1. BSG guidelines recommend that patients with PC should receive pancreatic enzyme supplementation to maintain bodyweight and improve quality of life1. It is not known whether pancreatic enzyme supplementation prolongs survival. In this study, we examined the impact of pancreatic enzyme supplementation in inoperable pancreatic cancer. Methods This was a single-centre retrospective study between January 2016 and June 2017. Consecutive patients deemed inoperable in the MDT were identified. Patients were subdivided in two cohorts, pancreatic enzyme supplement (PES) and Non-PES. Date of diagnosis was determined by the date of cross-sectional imaging. Use of pancreatic enzymes was determined through patient summary care records. All cases were followed up from the date of diagnosis until the date of death or censor date (31st December 2017). Primary outcomes were all-cause mortality. Results 62 patients were included (51 had histological confirmation, 11 were radiological diagnosis). Adenocarcinoma was the commonest histological finding. Anatomical distribution of tumours was – head/uncinate (27), neck (5), body (18) and tail (12). MPD dilatation was noted in 33 patients. The mean age among the PES and Non-PES groups were comparable at 70.9 (±9.9) and 72.2 (±9.5) years respectively. 48% were female in PES group compared with 40% in non-PES group. Median follow up was 133 days (IQR 187). Unadjusted median survival days in PES group was 221 [95% CI 107.4, 334.6] compared with 61 [95% CI 35.5, 86.5] in non-PES group. Cox regression models were fitted to adjust for effects of baseline characteristics. Survival was significantly better in PES group (Log Rank p=0.004) than that seen in non-PES group (figure 1). The survival difference remained significant after adjusting for gender, age, histology of pancreatic cancer, neutrophil to lymphocyte ratio and presenting body-mass index (n=53). Lack of pancreatic enzyme supplementation was associated with significant mortality risk, adjusted hazard ratio of 2.7 [95% CI 1.38, 5.31; p=0.004]. 21 (78%) and 17 (49%) patients in PES group (n=27) and non-PES group respectively were treated with palliative chemotherapy and the rest were treated with best supportive care. Conclusions Our study concludes that pancreatic enzyme supplementation is associated with improved survival in inoperable pancreatic cancer. Further prospective studies are required to confirm our findings.

Introduction In the UK, management of cancer patients are streamlined following discussions in the multi-disciplinary (MDT) meetings. There is growing evidence that MDT meetings play a key role in the management of complex benign diseases.1 Management of patients with complex pancreatico-biliary diseases can be challenging due to the lack of robust evidence. Further, widespread use of cross-sectional imaging has led to increased detection of incidental pathologies that may or may not be clinically relevant. In view of this, we established a benign HPB MDT in our institution to streamline the management of complex PB patients and report our experience over a period of 12 months. Method The weekly benign HPB MDT at JCUH is attended by HPB physicians, interventional GI radiologist, specialist nurse, specialist registrars, upper GI surgeon and the visiting surgeon from the regional tertiary HPB unit. Referrals are sent via a dedicated pro-forma and recommendations are recorded electronically on the trust’s info-flex software system. Retrospective analysis of a prospective maintained database was carried out between January 2017 to December 2017. Data was collected on patient demographics, cross-sectional imaging, diagnosis and clinical outcomes. Results 263 patients were discussed (55% males) for benign indications. Median age was 67 years (range 21–91 years). The main reasons for MDT referral are summarised below: Incidental pancreatic cysts 76 (29%) Pancreatitis (acute/chronic/recurrent) 61 (23%) Complex CBD stones 33 (13%) Indeterminate biliary stricture 17 (6%) Complex GB pathology 16 (6%) Unexplained biliary and pancreatic duct dilation on imaging 11 (4%) Autoimmune pancreatitis 3 (1%) Others [e.g. bile leak, choledochal cyst, duodenal polyp, liver cyst, sphincter of Oddi dysfunction etc] 46 (18%) The MDT’s recommendations were the following; Medical pancreatic clinic follow up: 53 Radiological surveillance: 86 Surgical clinic follow up: 53 Endoscopic interventions: 49 Radiological intervention: 8 Referral to regional tertiary HPB surgical clinic: 43 Discharge back to GP: 22 Conclusion Our data shows that the Benign HPB MDT facilitated the management of this complex group of HPB patients locally by the appropriate teams and fast tracked further management of selected complex patients at the regional centre requiring surgery and specialised endoscopic intervention. Reference . Noor LH, Bekkali, et al. The role of multidisciplinary meetings for benign pancreatobiliary diseases: a tertiary centre experience. Frontline GastroenterologyJuly 2017;8(3).

Background and aim Safe clinical care within Ebola Virus Disease Treatment Units (EVDTUs) mandate the use of personal protective equipment (PPE), comprising a fluid impermeable hooded suit, visor, gloves and rubber boots. The aim of this study was to assess the impact of this PPE on clinical personnel9s performance in the EVDTU, Kerry Town, Sierra Leone. Methods An anonymous questionnaire was administered to healthcare professionals (HCPs) entering the EVDTU ward area (Red Zone (RZ)), during a 2-week period to assess perceived exertion using the Borg Rating of Perceived Exertion Scale. Results A total of 62 clinical episodes undertaken by 20 HCPs were analysed. There were no episodes of heat illness during the study. HCPs spent a median of 74 (IQR 55–95) minutes within the RZ. Median durations of RZ activity were similar throughout the 24 h period (p=0.22), but Borg scores were significantly higher between 11:00 and 14:59 compared with RZ entry between 15:00 and 10:59, respectively (12 (6–15), n=13; 8 (6–9), n=48; p=0.022). Rates of weight loss per minute spent within the RZ were significantly greater between 11:00 and 14:59 compared with 15:00–10:59, respectively (0.014 (0.009–0.023) kg/min, n=6; 0.007 (0.004–0.013) kg/min, n=37; p=0.037). Conclusions Despite acclimatisation and proactive clinical tasking, HCPs in the EVDTU experienced significantly greater rates of weight loss and perceived exertion scores during the hottest times of the day. These findings should be considered by those planning healthcare facilities for future humanitarian missions where HCPs will provide clinical care in full PPE.

Patients with febrile illnesses presenting to an Ebola treatment unit in Sierra Leone had a wide range of diagnoses other than Ebola virus disease. Rapid diagnostic tests were useful in confirming these diagnoses, reducing the length of patient stay with valuable consequences. These alternative diagnoses should assist in future planning.

In October 2014 the UK military deployed to Sierra Leone to provide care for healthcare workers affected by Ebola virus disease. A training package designed by the Army Medical Services Training Centre prepared the deploying personnel in the required infection prevention and control measures. The training used ultraviolet tracer to provide validation of the skills required when treating patients with Ebola and to confirm subsequent decontamination. This training construct provided useful feedback to clinicians on their infection control measures and would be useful in the context of any infection spread by droplets and fomites.

The innate immune system is profoundly dysregulated in paracetamol (acetaminophen)-induced liver injury. The neutrophil-lymphocyte ratio (NLR) is a simple bedside index with prognostic value in a number of inflammatory conditions.To evaluate the prognostic accuracy of the NLR in patients with significant liver injury following single time-point and staggered paracetamol overdoses.Time-course analysis of 100 single time-point and 50 staggered paracetamol overdoses admitted to a tertiary liver centre. Timed laboratory samples were correlated with time elapsed after overdose or admission, respectively, and the NLR was calculated.A total of 49/100 single time-point patients developed hepatic encephalopathy (HE). Median NLRs were higher at both 72 (P=0.0047) and 96 h after overdose (P=0.0041) in single time-point patients who died or were transplanted. Maximum NLR values by 96 h were associated with increasing HE grade (P=0.0005). An NLR of more than 16.7 during the first 96 h following overdose was independently associated with the development of HE [odds ratio 5.65 (95% confidence interval 1.67-19.13), P=0.005]. Maximum NLR values by 96 h were strongly associated with the requirement for intracranial pressure monitoring (P0.0001), renal replacement therapy (P=0.0002) and inotropic support (P=0.0005). In contrast, in the staggered overdose cohort, the NLR was not associated with adverse outcomes or death/transplantation either at admission or subsequently.The NLR is a simple test which is strongly associated with adverse outcomes following single time-point, but not staggered, paracetamol overdoses. Future studies should assess the value of incorporating the NLR into existing prognostic and triage indices of single time-point paracetamol overdose.

Venous thromboembolism (VTE) represents a significant preventable cause of hospital mortality. VTE assessment and prophylaxis rates are key patient safety and quality of care indicators. The aim of this study was to audit low molecular weight heparin (LMWH) and graduated elasticated compression stockings (GECS) prescriptions compared with the current Clinical Guidelines for Operations.Complete audit loop in the Role 3 Hospital, Camp Bastion, Afghanistan. A multifaceted intervention programme incorporating physician and nurse education and pre-printed medication charts was introduced to improve VTE assessment and prophylaxis rates.Only 111/301 (36.9%) of patients in the pre-intervention cohort had a VTE risk assessment performed; this improved to 142/155 (91.6%, p0.0001) post-intervention. A total of 57/88 (64.8%) patients prescribed LMWH pre-intervention had a documented assessment of bleeding risk performed; this rose to 65/66 (98.5%, p=0.0003) post-intervention. In pre-intervention, only 63/213 (29.6%) patients had a documented reassessment of VTE and bleeding risk at 24 h; reassessment rates rose to 68.8% (66/96 patients, p0.0001) post-intervention. Of those patients at risk of VTE without ongoing bleeding risk, 62/96 (64.6%) had LMWH prescribed pre-intervention; this rose to 57/62 (91.9%) post-intervention (p0.0001). Inappropriate LMWH prescription rates fell from 26/190 (13.7%) to 4/85 (4.7%, p=0.035) post-intervention. In those patients in whom GECS were not contraindicated, prescription rates rose from 23/95 (24.2%) to 42/62 (67.7%, p0.0001) post-intervention.Inclusion of pre-printed LMWH/GECS prescriptions and risk assessment stickers in the mediction chart significantly improved rates of VTE risk assessment and prophylaxis. These easily reproducible and low-cost interventions could improve patient safety on deployment.

Background. Small-for-size syndrome (SFSS) occurs in the presence of insufficient liver mass to maintain normal function after liver transplantation. Murine mortality following 85% hepatectomy can be reduced by the use of soluble receptor for advanced glycation end products (sRAGE) to scavenge damage-associated molecular patterns and prevent their engagement with membrane-bound RAGE.Aims. To explore serum levels of sRAGE, high-mobility group box-1 (HMGB1) protein, and other soluble inflammatory mediators in a fatal case of SFSS.Methods. Serum levels of HMGB1, sRAGE, IL-18, and other inflammatory mediators were measured by ELISA in a case of SFSS, and the results were compared with 8 patients with paracetamol-induced acute liver failure (ALF) and 6 healthy controls (HC).Results. HMGB1 levels were markedly higher in the SFSS patient (92.1 ng/mL) compared with the ALF patients (median (IQR) 11.4 (3.7–14.8) ng/mL) and HC (1.42 (1.38–1.56) ng/mL). In contrast, sRAGE levels were lower in the SFSS patient (1.88 ng/mL) compared with the ALF patients (3.53 (2.66–12.37) ng/mL) and were similar to HC levels (1.40 (1.23–1.89) ng/mL).Conclusion. These results suggest an imbalance between pro- and anti-inflammatory innate immune pathways in SFSS. Modulation of the HMGB1-RAGE axis may represent a future therapeutic avenue in this condition.

Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.

Summary Background Macrophage activation is implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS) following paracetamol (acetaminophen) overdose (POD). Neopterin is synthesised from macrophages and reflects the intensity of monocyte/macrophage activation. Soluble CD163 (sCD163) is a marker of alternatively activated M2 macrophages. Aim To examine neopterin and sCD163 levels in a cohort of acute liver injury patients. Methods Consecutive patients (n = 41, (18 (43.9%) male) with acute liver injury were enrolled. Neopterin and sCD163 levels were measured by ELISA. Results A total of 24/33 (72.7%) POD patients developed hepatic encephalopathy (HE), and therefore acute liver failure. Both neopterin and sCD163 levels were significantly higher in PODs compared with chronic liver disease (neopterin P

Objectives Pentraxin 3 (PTX3) is a long pentraxin with diverse humoral innate immune functions. The aims of this study were to measure levels of PTX3 and C-reactive protein (CRP), a hepatocyte-derived short pentraxin, in patients after acute liver injury. Methods PTX3 and CRP levels were measured in a total of 60 patients [48 paracetamol overdose (POD), 12 non-POD]. PTX3 expression was assessed by immunohistochemical analysis in explanted liver tissue. Results Admission PTX3 levels were significantly higher in POD acute liver failure (ALF) patients compared with POD non-ALF patients (P=0.0005) and non-POD patients (P=0.004). PTX3 levels in POD patients who died or required orthotopic liver transplantation (OLT, n=14) were significantly higher compared with those in spontaneous survivors (n=34, P=0.0011). The area under the receiver operator characteristic for PTX3 for death/OLT in POD patients was 0.80 (95% confidence interval 0.67-0.93). PTX3 levels were significantly higher in those POD patients who developed the systemic inflammatory response syndrome (P=0.001). Conversely, admission CRP levels were significantly lower in POD compared with non-POD patients (P=0.011), with no significant differences between survivors and nonsurvivors. After emergency OLT, PTX3 levels fell markedly; in contrast, CRP levels rapidly increased. Immunohistochemical analysis showed PTX3 expression in sinusoidal lining cells of a normal liver, infiltrating inflammatory cells in patients with ALF, and in a membranous distribution on injured hepatocytes in POD patients. Conclusion Increased PTX3 levels are associated with adverse outcomes following POD, suggesting that the humoral innate immune system plays an underrecognized role in this condition.

New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median ΔΔCt [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR-192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart-enriched miR-1 showed no difference between APAP-ALI patients and controls, whereas miR-218 (brain-enriched) was slightly higher in the APAP-ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR-122 and -192 were modestly higher, compared to controls (miR-122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR-122 and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied King's College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15). Conclusion: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury. (HEPATOLOGY 2011;)

Aliment Pharmacol Ther 2011; 34: 219–228 Summary Background The systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores are widely used as prognostic markers in critical care settings and could improve triage of high-risk paracetamol (acetaminophen) overdose patients. Aim To evaluate the prognostic accuracy of the SIRS and SOFA scores following single time point paracetamol overdose. Methods Analysis of 100 single time point paracetamol overdoses admitted to a tertiary liver centre, with subsequent prospective validation of identified thresholds. Individual laboratory samples were correlated with the corresponding clinical parameters in relation to time post-overdose, and the daily SOFA and SIRS scores calculated. Results A total of 74 (74%) patients developed the SIRS, which occurred significantly earlier in patients who died (n = 21) compared with spontaneous survivors (n = 53, P = 0.05). The SIRS occurred in 70 (70%) patients by 96 h post-overdose, with a 30% mortality rate; compared with 0% mortality in the 30 non-SIRS patients (P = 0.001). Median SOFA scores were significantly higher in nonsurvivors at 48 (P = 0.009), 72 (P 7 during the first 96 h post-overdose predicted death/transplantation with a sensitivity of 95.0 (95% CI 78.5–99.1) and specificity of 70.5 (95% CI 66.3–71.6). A validation cohort of 38 single time point paracetamol overdoses confirmed the extremely high negative predictive value of both the SIRS and SOFA thresholds. Conclusions The absence of either a SOFA score >7 or a SIRS response during the first 96 h following paracetamol overdose could improve triage and reduce transfers of lower risk patients to tertiary liver centres.

Background: The host response to cell death underpins the immune activation that follows acute liver injury, and measurement of circulating cell death markers could therefore aid prognostication following paracetamol overdose. Nucleosomes, formed during apoptosis, can complex with high-mobility group box 1 (HMGB1) protein and may play a pathogenic role in liver injury. Aims: To explore the levels and prognostic significance of nucleosomes, HMGB1, and other cell death markers following acute liver injury. Methods: Levels of plasma nucleosomes, HMGB1, caspase-cleaved cytokeratin-18 (M30) and total cytokeratin-18 (M65) were measured by immunoassay, in a cohort of 33 patients with paracetamol- and non-paracetamol-induced acute liver injury. Results: Admission nucleosome levels in paracetamol overdose patients were significantly higher than in chronic liver disease and healthy control subjects, but were similar in paracetamol and non-paracetamol patients (P=0.11). Nucleosome levels were not associated with death or requirement for liver transplantation, fulfillment of poor prognostic criteria or organ failure in paracetamol patients. Nucleosome levels correlated with levels of HMGB1 (r=0.500, P=0.009), alanine aminotransferase (r=0.410, P=0.038) and M65 (r=0.709, P

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Paracetamol hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. • Conflicting data exist regarding the impact of overdose pattern upon subsequent mortality or need for emergency liver transplantation. WHAT THIS STUDY ADDS • Unintentional paracetamol overdose is independently associated with reduced survival compared with intentional overdose. • Unintentional paracetamol overdoses should be treated as high-risk for the development of multiorgan failure, and should be considered for N-acetyl cysteine treatment irrespective of admission serum paracetamol concentrations. • The King's College poor prognostic criteria have reduced sensitivity in unintentional overdose patients and alternative prognostic criteria may be required. AIMS Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported. METHODS Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P Language: en

The export protein CRM1 is required for the nuclear export of a wide variety of cancer-related “cargo” proteins including p53, c-Abl, and FOXO-3A. Leptomycin B (LMB) is a highly specific inhibitor of CRM1 with significant in vitro potency but limited in vivo efficacy due to toxicity. We now report a series of semisynthetic LMB derivatives showing substantially improved therapeutic windows. Exposure of cancer cells to these compounds leads to a rapid and prolonged block of nuclear export and apoptosis. In contrast to what is observed in cancer cells, these agents induce cell cycle arrest, but not apoptosis, in normal lung fibroblasts. These new nuclear export inhibitors (NEI) maintain the high potency of LMB, are up to 16-fold better tolerated than LMB in vivo, and show significant efficacy in multiple mouse xenograft models. These NEIs show the potential of CRM1 inhibitors as novel and potent anticancer agents. [Cancer Res 2009;69(2):510–7]

Patients with febrile illnesses presenting to an Ebola treatment unit in Sierra Leone had a wide range of diagnoses other than Ebola virus disease. Rapid diagnostic tests were useful in confirming these diagnoses, reducing the length of patient stay with valuable consequences. These alternative diagnoses should assist in future planning.

An elevated troponin I (TnI) is associated with a poorer prognosis during critical illness.Our aims were to determine whether significant paracetamol-induced hepatotoxicity was associated with an elevated TnI; if this elevation was persistent and was associated with worse clinical outcomes.In this retrospective cohort study, the requirement for orthotopic liver transplantation (OLT) or death and/or the development of multiorgan failure (MOF) was evaluated for 48 consecutive patients admitted to the Royal Infirmary of Edinburgh (a university tertiary referral centre) with acute liver injury or acute liver failure secondary to paracetamol overdose.TnI was elevated (≥ 0.05 ng/L) in 13/48 patients (27%). This appeared to be sustained for at least 6 days which has not been shown previously in the context of Acute Liver Injury (ALI). Elevated TnI was strongly associated with MOF, with the requirement for inotropic support being the strongest predictor (p = 0.003, OR 9.00, 95% CI 2.13-37.98). TnI elevations also correlated strongly with Acute Physiology and Chronic Health Evaluation (APACHE) II scores (p = 0.0006, r = 0.482, 95% CI 0.22-0.68) and with interleukin 6 (IL-6) levels (p = 0.0001, r = 0.55, 95% CI 0.29-0.73). Although a raised TnI was associated with a markedly increased risk of death or orthotopic liver transplant (p = 0.005, OR 7.73, 95% CI 1.87-32.05) on univariate analysis, this was primarily seen in the context of MOF (SOFA score p = 0.003, OR 1.23, 95% CI 1.07-1.41) and was not an independent predictor of death. There was no correlation between TnI or outcome with other cardiac biomarkers and markers of cardiovascular risk.An elevated TnI in the context of acute liver injury or liver failure following paracetamol overdose is associated with a significantly worse patient outcome but it is not an independent prognostic factor. Further studies should be undertaken to investigate the mechanism behind this elevated troponin association.

Summary Background The sequential organ failure assessment (SOFA) score is an effective triage marker following single time point paracetamol (acetaminophen) overdose, but has not been evaluated following staggered (multiple supratherapeutic doses over >8 h, resulting in cumulative dose of >4 g/day) overdoses. Aim To evaluate the prognostic accuracy of the SOFA score following staggered paracetamol overdose. Methods Time-course analysis of 50 staggered paracetamol overdoses admitted to a tertiary liver centre. Individual timed laboratory samples were correlated with corresponding clinical parameters and the daily SOFA scores were calculated. Results A total of 39/50 (78%) patients developed hepatic encephalopathy. The area under the SOFA receiver operator characteristic for death/liver transplantation was 87.4 (95% CI 73.2–95.7), 94.3 (95% CI 82.5–99.1), and 98.4 (95% CI 84.3–100.0) at 0, 24 and 48 h, respectively, postadmission. A SOFA score of

Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation, respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis, and immune cell activation throughout the time course of clinical APAP hepatotoxicity.HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC-MS/MS assays in APAP overdose patients (n=78).HMGB1 (total; 15.4±1.9ng/ml, p0.01, acetylated; 5.4±2.6ng/ml, p0.001), cK18 (5649.8±721.0U/L, p0.01), and FL-K18 (54770.2±6717.0U/L, p0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R(2)=0.60 and 0.58, respectively, p0.0001) and prothrombin time (R(2)=0.62 and 0.71, respectively, p0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King's College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all p0.05-0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death.K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome.

Aliment Pharmacol Ther 31, 1064–1076 Summary Background Paracetamol (acetaminophen) toxicity remains the leading cause of acute liver failure (ALF) in the developed world. In the UK, the recently modified King’s College Criteria are used to list patients for emergency liver transplantation, but these criteria have been criticized for their low sensitivity and for spectrum bias in their application. Aim To evaluate existing prognostic criteria critically for predicting death without transplantation in paracetamol-induced ALF. Methods MEDLINE, EMBASE and CINAHL were searched to identify studies containing adult patients with paracetamol-induced ALF. Selected studies were evaluated and data were pooled if appropriate, to calculate sensitivity, specificity and diagnostic odds ratios (DORs) of applied prognostic tests. Results Of 6507 studies identified, 14 were eligible for inclusion, evaluating 1960 patients. The original King’s College Criteria had a pooled sensitivity of 58.2% and specificity of 94.6%, with a DOR of 27.7. Addition of arterial lactate to the King’s College Criteria reduced the DOR to 26.1. Several other clinical and laboratory variables had higher DORs than the King’s College Criteria, but were only evaluated in single studies of limited quality. Conclusions The original King’s College Criteria remain well-validated criteria with high prognostic accuracy. Other potential prognostic variables should be prospectively assessed in multicentre studies to refine the criteria further.

Acute abdominal pain is a common presenting complaint to both primary and secondary care, and is a frequent cause of hospital admission among deployed personnel. Identification of generalised peritonism on abdominal examination is a classical indicator of intra-abdominal pathology that may warrant exploratory laparotomy. Negative findings at laparotomy should serve as a diagnostic prompt to consider other non-surgical mimics of an acute abdomen.

We are very grateful to the editors for allowing us the opportunity to respond to the issues raised by Dr Reiter [1] following his analysis of our data from our two recent publications in the British Journal of Clinical Pharmacology (BJCP)[2, 3]. We fully acknowledge the seriousness of our omission in not citing our earlier paper [2]. This highly regrettable oversight stemmed from the close temporal nature of the drafting and review process of the two manuscripts. We sincerely apologize that we did not notify the BJCP Editorial Office about the acceptance of the first BJCP manuscript when submitting the second paper to the journal. We wish to assure all concerned that this did not arise from a deliberate attempt to hide this information and subvert the integrity of the scientific review process and publication policies of the BJCP and other peer review journals, which we fully support. We have reviewed the publication process within our group and communicated the importance of reference to all previous work to ensure that this highly regrettable omission does not occur in the future. Dr Reiter correctly identifies that both BJCP studies result from analysis of a prospectively collected cohort of 938 patients admitted to the Scottish Liver Transplantation Unit over a 16 year period, of whom 663 had taken a paracetamol overdose [1]. The two studies explore different hypotheses related to paracetamol overdose. The first BJCP study examines the impact of suicidal ideation upon outcome, and demonstrates, paradoxically, that deliberate overdoses are associated with reduced mortality [2]. The second study explores the time course of the overdose, and demonstrates that repeated, staggered dosing of paracetamol is associated with adverse outcomes [3]. The impact of time course of overdose is further explored in the second study by analysing the impact of delayed hospital presentation amongst single time point overdoses, and demonstrates the adverse impact of ‘delay to N-acetyl cysteine’. The second study also details the reasoning for the staggered overdoses, identifying the common use of paracetamol for the relief of pain. We would like to correct the errors made by Dr Reiter in his table. These may stem from an incorrect assumption that all intentional overdoses were taken at a single time point and, conversely, that all unintentional overdoses were staggered, and that the overdose categories analysed in the two papers are therefore interchangeable. This is a common misconception, and we welcome the opportunity to clarify this point. Dr Reiter suggests that the number of staggered cases (n= 161) in the most recent paper is very similar to the sum of cases defined in our previous paper as unintentional (n= 110) and patients in whom no clear history of suicidal ideation was available (n= 53) [1]. However, this ignores the 52 cases excluded from the total (n= 663) cohort in our most recent paper due to an incomplete overdose time course history. This is the same group described in our original paper, as ‘patients with unobtainable overdose history’. To further clarify this point, expand and correct Dr Reiter's analysis, as demonstrated in Figure 1 there are effectively five overdose categories: single time point suicidal (n= 443); staggered suicidal (n= 47); staggered accidental (n= 114); single time point accidental (n= 6); and cases where one or both elements of the time course or suicidal ideation were unknown (n= 53). The last four subgroups are all associated with a higher risk of adverse outcomes and should be classified as high risk (Figure 1). Other errors included in the table are as follows: an assumed mortality for the intention unknown group is stated to be ‘20/24’, when in the original paper this was clearly stated as 36/53 cases (67.9%) and Dr Reiter's unintentional mortality rate of 38.2% is incorrect and should read as 42.7% (47/110 cases). Figure 1 Survival curves of patients with paracetamol-induced acute severe liver injury according to the suicidal ideation and time course pattern of overdose. , single time point suicidal; , staggered suicidal; , staggered accidental; , single time point accidental; ... The clear message from the two BJCP papers is that atypical overdose patterns are associated with poor outcomes and should be treated as high risk. We hope that our most recent paper [3] helps to highlight the dangers of repeatedly exceeding the recommended dose of paracetamol and the importance of checking for inadvertent consumption of more than one paracetamol-containing product when self-medicating for pain control; a public health message that we consistently and repeatedly stated during the many interviews associated with the publication of this second article. We again thank the editors of the BJCP for giving us the opportunity of publicly stating our sincere regret in not citing our earlier BJCP paper. Although unintentional, we fully accept the seriousness of this omission and will ensure that this does not occur in future submissions.

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overdose had a NPV of 98.2%. 2 The SOFA score is similarly helpful at ruling out death following multiple timepoint (staggered) acetaminophen overdose, with a SOFA score < 6a t tertiary care admission carrying an NPV of 100.0% (Craig DG, unpubl. data). SOFA is a simple scoring system that can be rapidly recalculated at the bedside throughout admission, and, because it is an ordinal rather than a dichotomous variable, a rising SOFA score could function as a gatekeeper to identify deteriorating patients at an early stage and expedite transfer to liver centers. Although the MALD score appears promising as a triage marker, we would urge caution before adopting it as a primary transplant listing criterion. In keeping with several other prognostic studies, the authors compared the prognostic accuracy of their model with the King’s College Criteria (KCC) at a single timepoint (hospital admission) rather than dynamically throughout admission, as originally intended, which is likely to invalidate comparisons with the KCC. 3 Furthermore, MALD does not explicitly include hepatic encephalopathy, thereby raising the possibility of undertaking liver transplantation inappropriately in patients with high MALD scores from other (nonacetaminophen) etiologies. As ever, there remains a balance between ensuring patients at risk of death are not missed through the inappropriate use of highly specific listing criteria, such as the KCC, as triage markers, while minimizing unnecessary transplantation of patients who might spontaneously survive. Further evaluation of the MALD and SOFA scores as triage markers in prospective studies between several large centers would be welcome.