Circulating myeloid populations have prognostic utility in alcohol-related liver disease.

Introduction: Alcohol-related liver disease (ARLD) accounts for over one third of all deaths from liver conditions, and mortality from alcohol-related liver disease has increased nearly five-fold over the last 30 years. Severe alcohol-related hepatitis almost always occurs in patients with a background of chronic liver disease with extensive fibrosis or cirrhosis, can precipitate 'acute on chronic' liver failure and has a high short-term mortality. Patients with alcohol-related liver disease have impaired immune responses, and increased susceptibility to infections, thus prompt diagnosis of infection and careful patient management is required. The identification of early and non-invasive diagnostic and prognostic biomarkers in ARLD remains an unresolved challenge. Easily calculated predictors of infection and mortality are required for use in patients who often exhibit variable symptoms and disease severity and may not always present in a specialized gastroenterology unit. Methods: We have used a simple haematological analyser to rapidly measure circulating myeloid cell parameters across the ARLD spectrum. Results and Discussion: We demonstrate for the first time that immature granulocyte (IG) counts correlate with markers of disease severity, and our data suggests that elevated counts are associated with increased short-term mortality and risk of infection. Other myeloid populations such as eosinophils and basophils also show promise. Thus IG count has the potential to serve alongside established markers such as neutrophil: lymphocyte ratio as a simply calculated predictor of mortality and risk of infectious complications in patients with alcohol-related hepatitis. This would allow identification of patients who may require more intensive management.

Duke Activity Status Index and Liver Frailty Index predict mortality in ambulatory patients with advanced chronic liver disease: A prospective, observational study.

BACKGROUND: There remains a lack of consensus on how to assess functional exercise capacity and physical frailty in patients with advanced chronic liver disease (CLD) being assessed for liver transplantation (LT). Aim To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD. AIM: To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD. METHODS: We recruited patients from outpatient clinics at University Hospitals Birmingham, UK (2018-2019). We prospectively collated the DASI and LFI to identify the prevalence of, respectively, functional capacity and physical frailty, and to evaluate their accuracy in predicting overall and pre-LT mortality. RESULTS: We studied 307 patients (57% male; median age 54 years; UKELD 52). Median DASI score was 28.7 (IQR 16.2-50.2), mean LFI was 3.82 (SD = 0.72), and 81% were defined either 'pre-frail' or 'frail'. Female sex and hyponatraemia were significant independent predictors of both DASI and LFI. Age and encephalopathy were significant independent predictors of LFI, while BMI significantly predicted DASI. DASI and LFI were significantly related to overall (HR 0.97, p = 0.001 [DASI], HR 2.04, p = 0.001 [LFI]) and pre-LT mortality (HR 0.96, p = 0.02 [DASI], HR 1.94, p = 0.04 [LFI]). CONCLUSIONS: Poor functional exercise capacity and physical frailty are highly prevalent among ambulatory patients with CLD who are being assessed for LT. The DASI and LFI are simple, low-cost tools that predict overall and pre-LT mortality. Implementation of both should be considered in all outpatients with CLD to highlight those who may benefit from targeted nutritional and exercise interventions.

Long-term outcomes (beyond 5 years) of liver transplant recipients-A transatlantic multicenter study.

The long-term (>5 y) outcomes following liver transplantation (LT) have not been extensively reported. The aim was to evaluate outcomes of LT recipients who have survived the first 5 years. A multicenter retrospective analysis of prospectively collected data from 3 high volume LT centers (Dallas-USA, Birmingham-UK, and Barcelona-Spain) was undertaken. All adult patients, who underwent LT since the inception of the program to December 31, 2010, and survived at least 5 years since their LT were included. Patient survival was the primary outcome. A total of 3682 patients who survived at least 5 years following LT (long-term survivors) were included. Overall, median age at LT was 52 years (IQR 44-58); 53.1% were males; and 84.6% were Caucasians. A total of 49.4% (n=1820) died during a follow-up period of 36,828 person-years (mean follow-up 10 y). A total of 80.2% (n=1460) of all deaths were premature deaths. Age-standardized all-cause mortality as compared to general population was 3 times higher for males and 5 times higher for females. On adjusted analysis, besides older recipients and older donors, predictors of long-term mortality were malignancy, cardiovascular disease, and dialysis. Implementation of strategies such as noninvasive cancer screening, minimizing immunosuppression, and intensive primary/secondary cardiovascular prevention could further improve survival.

Quality standards for the management of alcohol-related liver disease: consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology ARLD special interest group.

OBJECTIVE: Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care. DESIGN: A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology ALD Special Interest Group developed the quality standards, with input from the British Liver Trust and patient representatives. RESULTS: The standards cover three broad themes: the recognition and diagnosis of people with ALD in primary care and the liver outpatient clinic; the management of acutely decompensated ALD including acute alcohol-related hepatitis and the posthospital care of people with advanced liver disease due to ALD. Draft quality standards were initially developed by smaller working groups and then an anonymous modified Delphi voting process was conducted by the entire group to assess the level of agreement with each statement. Statements were included when agreement was 85% or greater. Twenty-four quality standards were produced from this process which support best practice. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice and an audit tool provided. CONCLUSION: It is hoped that services will review their practice against these recommendations and key performance indicators and institute service development where needed to improve the care of patients with ALD.

Guidance document: risk assessment of patients with cirrhosis prior to elective non-hepatic surgery.

As a result of the increasing incidence of cirrhosis in the UK, more patients with chronic liver disease are being considered for elective non-hepatic surgery. A historical reluctance to offer surgery to such patients stems from general perceptions of poor postoperative outcomes. While this is true for those with decompensated cirrhosis, selected patients with compensated early-stage cirrhosis can have good outcomes after careful risk assessment. Well-recognised risks include those of general anaesthesia, bleeding, infections, impaired wound healing, acute kidney injury and cardiovascular compromise. Intra-abdominal or cardiothoracic surgery are particularly high-risk interventions. Clinical assessment supplemented by blood tests, imaging, liver stiffness measurement, endoscopy and assessment of portal pressure (derived from the hepatic venous pressure gradient) can facilitate risk stratification. Traditional prognostic scoring systems including the Child-Turcotte-Pugh and Model for End-stage Liver Disease are helpful but may overestimate surgical risk. Specific prognostic scores like Mayo Risk Score, VOCAL-Penn and ADOPT-LC can add precision to risk assessment. Measures to mitigate risk include careful management of varices, nutritional optimisation and where possible addressing any ongoing aetiological drivers such as alcohol consumption. The role of portal decompression such as transjugular intrahepatic portosystemic shunting can be considered in selected high-risk patients, but further prospective study of this approach is required. It is of paramount importance that patients are discussed in a multidisciplinary forum, and that patients are carefully counselled about potential risks and benefits.

Comparable Overall Survival in Patients with Hepatocellular Carcinoma Diagnosed within and outside a Surveillance Programme: The Potential Impact of Liver Cirrhosis.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, and its incidence is rising. Mortality from HCC is predicted to increase by 140% by 2035. Surveillance of high-risk patients with cirrhosis or chronic liver disease may be one means of reducing HCC mortality, but the level of supporting evidence for international guidelines is low/moderate. This study explores the real-world experience of HCC surveillance at a tertiary referral centre. Electronic patient records for all new HCCs diagnosed between August 2012 and December 2021 were retrospectively reviewed. Patient and tumour characteristics were evaluated, including the co-existence of chronic liver disease, cancer treatment and survival, and categorised according to HCC diagnosis within or outside a surveillance programme. Patients with HCC who presented through surveillance had smaller tumours diagnosed at an earlier stage, but this did not translate into improved overall survival. All patients in surveillance had chronic liver disease, including 91% (n = 101) with cirrhosis, compared to 45% (n = 29) in the non-surveillance cohort. We propose that the immune dysfunction associated with cirrhosis predisposes patients to a more aggressive tumour biology than the largely non-cirrhotic population in the non-surveillance group.

Cirrhosis and non-hepatic surgery in 2023 - a precision medicine approach.

INTRODUCTION: Patients with liver disease and portal hypertension frequently require surgery carrying high morbidity and mortality. Accurately estimating surgical risk remains challenging despite improved medical and surgical management. AREAS COVERED: This review aims to outline a comprehensive approach to preoperative assessment, appraise methods used to predict surgical risk, and provide an up-to-date overview of outcomes for patients with cirrhosis undergoing non-hepatic surgery. EXPERT OPINION: Robust preoperative, individually tailored, and precise risk assessment can reduce peri- and postoperative complications in patients with cirrhosis. Established prognostic scores aid stratification, providing an estimation of postoperative mortality, albeit with limitations. VOCAL-Penn Risk Score may provide greater precision than established liver severity scores. Amelioration of portal hypertension in advance of surgery may be considered, with prospective data demonstrating hepatic venous pressure gradient as a promising surrogate marker of postoperative outcomes. Morbidity and mortality vary between types of surgery with further studies required in patients with more advanced liver disease. Patient-specific considerations and practicing precision medicine may allow for improved postoperative outcomes.

Extra-hepatic morbidity and mortality in alcohol-related liver disease: Systematic review and meta-analysis.

BACKGROUND: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol-related liver disease (ALD) are therefore at risk from both extra-hepatic and hepatic disease. AIMS: This review synthesises information about non-liver-related mortality in persons with ALD. METHODS: A systematic literature review was performed to identify studies describing non-liver outcomes in ALD. Information about overall non-liver mortality was extracted from included studies and sub-categorised into major causes: cardiovascular disease (CVD), non-liver cancer and infection. Single-proportion meta-analysis was done to calculate incidence rates (events/1000 patient-years) and relative risks (RR) compared with control populations. RESULTS: Thirty-seven studies describing 50 302 individuals with 155 820 patient-years of follow-up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol-related fatty liver the rate of non-liver mortality was 43.4/1000 patient-years, whereas in alcoholic hepatitis the rate of non-liver mortality was 22.5/1000 patient-years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6-3.8), from non-hepatic cancer 2.2 (1.6-2.9) and from infection 8.2 (4.7-14.3). CONCLUSION: Persons with ALD are at high risk of death from non-liver causes such as cardiovascular disease and non-hepatic cancer.

Liver Transplantation for Porto-sinusoidal Vascular Liver Disorder: Long-term Outcome.

BACKGROUND: Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. METHODS: Retrospective multicentre study of 79 patients who received LT for PSVD. RESULTS: Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. CONCLUSIONS: LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.

Protocol for a case-control prospective study to investigate the impact of Hepatic Encephalopathy on Nutritional Intake and Sarcopenia status in patients with end-stage LIVer disease: HENS-LIV study.

INTRODUCTION: Hepatic encephalopathy (HE) is a debilitating symptom of end-stage liver disease (ESLD), but there remains a paucity of evidence regarding its impact on nutritional status, nutritional intake, compliance with nutritional support and resultant muscle health and function. Malnutrition and sarcopenia are associated with increased morbidity and mortality in patients with ESLD. The aim of the current case-control study is to prospectively investigate the impact of HE on nutritional intake and sarcopenia status in patients with ESLD. METHODS AND ANALYSIS: Patients with ESLD, with HE (n=10) and without HE (n=10) will be recruited at the outpatient liver unit, University Hospital Birmingham, UK. All patients will undergo clinical assessment at baseline and again at 6-8 weeks (in-line with their routine clinical follow-up), to assess the impact of HE on reported nutritional intake, nutritional status and sarcopenia/physical functional status. Standard medical, dietetic and home-based exercise physiotherapy care will continue for all participants as determined by their clinical team. Two methods of assessing nutritional intake will include the 24-hour food recall and 3-day food diaries. Assessment of sarcopenia status will be undertaken using anthropometry (mid-arm muscle circumference (MAMC)) and ultrasound imaging of the quadriceps muscle group. Markers of physical function (hand grip strength; chair rise time), frailty (Liver Frailty Index (LFI)), physical activity (accelerometery) and exercise capacity (Duke Activity Status Index (DASI)) will be assessed at both clinic visits. ETHICS AND DISSEMINATION: The study is approved by Wales Research Ethics Committee 2 and Health Research Authority (REC reference: 21/WA/0216). Recruitment into the study commenced November 2021. The findings will be disseminated through peer-reviewed publications and international presentations. TRIAL REGISTRATION NUMBER: RRK7156.

Outcomes of incoming and outgoing second opinions from a UK liver transplant centre.

OBJECTIVE: Second transplant centre opinions (STCOs) for patients declined for liver transplantation are infrequent. We aimed to identify STCOs outcomes from a tertiary transplant centre. DESIGN: Referrals between 2012 and 2020 to Birmingham Unit were reviewed. Incoming: all referrals from out-of-region centres were collated. Outgoing: patients not listed in Birmingham were reviewed to identify referrals for STCOs to the other UK centres (A-F). RESULTS: 2535 patients were assessed for liver transplantation during the study period. Incoming: among 1751 referrals, 23 STCOs (17 unit A, 3 unit B, 1 unit C, 1 unit D and 1 unit E) were provided by Birmingham. Of the STCOs, 13/23 (57%) patients remained unsuitable for transplantation. Therefore, 10/23 (43%) underwent a second liver transplant assessment, of whom five (50%) were still deemed unsuitable, three (30%) listed (one transplanted) and two (20%) died preassessment. Outgoing: among 426 patients not listed, eight (1.8%) patients were referred for STCO (4 unit E, 2 unit B, 1 unit D, 1 unit A). Three (38%) were listed, two (25%) were assessed and declined, two (25%) were unsuitable for assessment and one (12.5%) died while waiting. Combining incoming and outgoing Birmingham STCOs (n=31), six (19%) of STCOs were listed in a second centre. CONCLUSION: Second transplant centre opinions are rare with the majority still deemed unsuitable for liver transplantation. This highlights potential resource implications especially when undergoing a full second formal assessment. A streamlined STCO process with sharing of investigations and use of telemedicine in appropriate patients may allow for greater transparency, quicker decision making and less use of labour-intensive resources.

Acute-on-chronic liver failure (ACLF) in 2022: have novel treatment paradigms already arrived?

INTRODUCTION: Acute-on-chronic failure (ACLF) is a recognized syndrome in patients with chronic liver disease and is characterized by acute decompensation, organ failure(s), and a high short-term mortality. ACLF is often triggered by ongoing alcohol consumption, gastrointestinal bleeding and/or infections, and is pathophysiologically characterized by uncontrolled systemic inflammation coupled with paradoxical immunoparesis. Patients with ACLF require prompt and early recognition. Management requires extensive utilization of clinical resources often including escalation to intensive care. AREAS COVERED: Currently, there are no specific targeted treatments for established ACLF, and management revolves around treating underlying precipitants and providing organ support. In this article, we review the epidemiology and pathophysiology of ACLF and summarize recent advances in management strategies of this syndrome, focusing specifically on novel emerging therapies. EXPERT COMMENTARY: ACLF is a challenging condition with rapid clinical course, high short-term mortality and varying clinical phenotypes. Management of ACLF is broadly focused on supportive care often in an intensive care setting with liver transplantation proving to be an increasingly relevant and effective rescue therapy. This disease has clear pathogenesis and epidemiological burden, thus distinguishing it from decompensated cirrhosis; there is clear clinical need for the development of specific and nuanced therapies to treat this condition.

Palliative long-term abdominal drains for the management of refractory ascites due to cirrhosis: a consensus document.

Palliative care remains suboptimal in advanced cirrhosis, in part relating to a lack of evidence-based interventions. Ascites remains the most common cirrhosis complication resulting in hospitalisation. Many patients with refractory ascites are not candidates for liver transplantation or transjugular intrahepatic portosystemic shunt, and therefore, require recurrent palliative large volume paracentesis in hospital. We review the available evidence on use of palliative long-term abdominal drains in cirrhosis. Pending results of a national trial (REDUCe 2) and consistent with recently published national and American guidance, long-term abdominal drains cannot be regarded as standard of care in advanced cirrhosis. They should instead be considered only on a case-by-case basis, pending definitive evidence. This manuscript provides consensus to help standardise use of long-term abdominal drains in cirrhosis including patient selection and community management. Our ultimate aim remains to improve palliative care for this under researched and vulnerable cohort.

COVID-19: Effect on gastroenterology and hepatology service provision and training: Lessons learnt and planning for the future.

In late 2019, reports arose of a new respiratory disease in China, identified as a novel coronavirus, severe acute respiratory syndrome coronavirus 2. The World Health Organisation named the disease caused by the virus 'coronavirus disease 2019 (COVID-19)'. It was declared a pandemic in early 2020, after the disease rapidly spread across the world. COVID-19 has not only resulted in substantial morbidity and mortality but also significantly impacted healthcare service provision and training across all medical specialties with gastroenterology and Hepatology services being no exception. Internationally, most, if not all 'non-urgent' services have been placed on hold during surges of infections. As a result there have been delayed diagnoses, procedures, and surgeries which will undoubtedly result in increased morbidity and mortality. Outpatient services have been converted to remote consultations where possible in many countries. Trainees have been redeployed to help care for COVID-19 patients in other settings, resulting in disruption to their training - particularly endoscopy and outpatient clinics. This has led to significant anxiety amongst trainees, and risks prolongation of training. It is of the utmost importance to develop strategies that continue to support COVID-19-related service provision, whilst also supporting existing and future gastroenterology and Hepatology services and training. Changes to healthcare provision during the pandemic have generated new and improved frameworks of service and training delivery, which can be adopted in the post-COVID-19 world, leading to enhanced patient care.

Basiliximab With Delayed Tacrolimus Improves Short-Term Renal Outcomes Post-Liver Transplantation-a Real-World Experience.

BACKGROUND: Acute kidney injury (AKI) is common after liver transplantation (LT). Induction with interleukin-2 receptor antagonists is often used as a "renal-sparing" strategy. The aim of this study was to assess this approach in a real-world setting in an LT center. METHODS: A retrospective cohort analysis of LTs between 2011 and 2018 was performed to assess the impact of a renal-sparing strategy using basiliximab in conjunction with mycophenolate mofetil and corticosteroids from day 0 post-LT along with delayed introduction of tacrolimus. This was compared with a group receiving tacrolimus, mycophenolate mofetil, and corticosteroids from the outset. RESULTS: The renal-sparing regimen was associated with significantly lower incidence of all-stage AKI at day 7 post-LT (36% vs 55%, P = .006) and less decline in renal function at 3 months (39% vs 57%, P = .01). No further significant differences in renal outcomes were observed at other time points on follow-up to 1 year post-LT. There was no significant difference in the incidence of acute cellular rejection, inpatient length of stay or graft survival. The decision to adopt a renal-sparing regimen was predominantly made on a clinically reactive basis within the first 24 hours post-LT in 77%, and was preordained in 23%. Cost-effectiveness analysis did not find evidence of a significant cost saving when using a renal-sparing strategy. CONCLUSION: This study provides real-world analysis of the use of a renal-sparing immunosuppression regimen in LT. Although improvements in incidence of AKI in the short term were demonstrated, this did not translate to cost savings or improved renal outcomes after 3 months.

Tunnelled peritoneal drainage catheter placement for the palliative management of refractory ascites in patients with liver cirrhosis.

OBJECTIVE: Refractory ascites is an established indication for liver transplantation. While transplantation is regarded as the definitive therapy for this condition, many patients are unsuitable due to comorbidity or frailty. Alternatives such as transjugular intrahepatic portosystemic shunt (TIPSS) and large-volume paracentesis can lead to complications, including encephalopathy, circulatory and renal dysfunction, and protein-calorie deficiency that may accelerate sarcopenia. Cost and complication rates limit therapies such as alfapump. While there are data to support the use of indwelling catheters in the management of patients with malignant ascites, there is limited evidence to support their routine use in the context of end-stage liver cirrhosis. Here we describe our centres' experience using indwelling tunnelled ascitic drains over a 6-year period. METHODS: A retrospective review of data (January 2012-May 2018) was undertaken for all patients with refractory ascites who underwent a tunnelled ascitic drain. Demographics, disease aetiology, procedure data and follow-up data were obtained through interrogation of electronic records and reports. RESULTS: Twenty-five drains were placed. All procedures were technically successful with no immediate complications. Six patients were readmitted following their index admission with abdominal pain and suspected infected ascites (although only two had a positive ascitic fluid culture). There were three cases of abdominal wall cellulitis and three of leakage around the tunnel site; all managed conservatively. CONCLUSION: Indwelling drains appear an effective strategy for palliative management of select patients with liver cirrhosis complicated by refractory ascites who are not amenable to undergo TIPSS or transplantation. While complications can occur, these are most usually minor and can be managed on an outpatient basis.

Portal decompression with transjugular intrahepatic portosystemic shunt prior to nonhepatic surgery: a single-center case series.

BACKGROUND AND AIMS: Cirrhosis increases perioperative and postoperative mortality in nonhepatic surgery. Transjugular intrahepatic portosystemic shunt (TIPSS), by reducing portal pressure, may reduce intraoperative bleeding and postoperative decompensation. We report our experience of prophylactic TIPSS in nonhepatic surgery. METHODS: Patients who underwent prophylactic TIPSS before nonhepatic surgery were identified from database with retrospective data collection via an e-patient record system. Primary outcome was discharged without hepatic decompensation after a planned surgery. RESULTS: Twenty-one patients [age (median, range): 55, 33-76 years, Child's score: 6, 5-9] who underwent prophylactic TIPSS before nonhepatic surgery over a period of 9 years were included. All patients underwent successful TIPSS with a reduction in portal pressure gradient from 21.5 (11-35) to 16 (7-25) mmHg (P < 0.001). Immediate post-TIPSS complications were seen in 7 (33%) patients including hepatic encephalopathy in four. Eighteen patients (86%) underwent planned surgical intervention. Significant postoperative complications included hepatic encephalopathy (3), sepsis (2) and bleed (1). Two patients died postoperatively with multi-organ failure. The primary outcome was achieved in 12 (57%) patients. Post-TIPSS portal pressure gradient was significantly higher in patients with the adverse primary outcome. Over a follow-up period of 11 (1-78) months; 1-, 6- and 12-months' survival was 90, 80 and 76%, respectively. CONCLUSION: Prophylactic TIPSS is associated with complications in up to one-third of patients, with 57% achieving the primary outcome. Careful patient selection in a multidisciplinary team setting is essential. Multicentre studies are necessary before the universal recommendation of prophylactic TIPSS.