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In bats, the wing membrane is anchored not only to the body and forelimb, but also to the hindlimb. This attachment configuration gives bats the potential to modulate wing shape by moving the hindlimb, such as by joint movement at the hip or knee. Such movements could modulate lift, drag, or the pitching moment. In this study we address: 1) how the ankle translates through space during the wingbeat cycle; 2) whether amplitude of ankle motion is dependent upon flight speed; 3) how tension in the wing membrane pulls the ankle; and 4) whether wing membrane tension is responsible for driving ankle motion. We flew five individuals of the lesser dog-faced fruit bat, Cynopterus brachyotis (Family: Pteropodidae), in a wind tunnel and documented kinematics of the forelimb, hip, ankle, and trailing edge of the wing membrane. Based on kinematic analysis of hindlimb and forelimb movements, we found that: 1) during downstroke, the ankle moved ventrally and during upstroke the ankle moved dorsally; 2) there was considerable variation in amplitude of ankle motion, but amplitude did not correlate significantly with flight speed; 3) during downstroke, tension generated by the wing membrane acted to pull the ankle dorsally, and during upstroke, the wing membrane pulled laterally when taut and dorsally when relatively slack; and 4) wing membrane tension generally opposed dorsoventral ankle motion. We conclude that during forward flight in C. brachyotis, wing membrane tension does not power hindlimb motion; instead, we propose that hindlimb movements arise from muscle activity and/or inertial effects.

BackgroundDecompensated cirrhosis is associated with a marked susceptibility to infection with spontaneous bacterial peritonitis being one of the most common infections. Non-cirrhotic ascites rarely becomes infected so the degree and mechanism of immune-paresis in the ascitic immune environment is of particular interest.Immune checkpoints constitute a complex array of regulatory receptors and ligands expressed on the surface of immune cells. They serve as pivotal regulators of the host immunity and so we hypothesise they may be involved in immune dysfunction in the ascitic immune environment.CD96 and TIGIT are inhibitory receptors expressed on T cells and NK cells that are thought to exert immunosuppressive effects by outcompeting CD226, a co-stimulatory receptor also expressed on T cells and NK cells, for binding of its ligand CD155 on antigen presenting cells.MethodsPatients with decompensated cirrhosis were recruited from the inpatient ward and healthy volunteers recruited as controls. Blood samples were collected for isolation of peripheral blood mononuclear cells (PBMC), and ascites mononuclear cells were obtained by centrifugation of ascitic fluid. Cell surface expression of the immune checkpoints CD96, TIGIT, and CD226 on T cells and NK cells, and their ligand CD155 on monocytes/macrophages was determined with flow cytometry analysis.Healthy control PBMCs were cultured with TLR ligands and expression of CD155 on monocytes determined with flow cytometry analysis.ResultsA significantly higher percentage of ascitic CD8+ T cells and NK cells were CD96+ compared to paired peripheral cells from the same patient, whereas a significantly lower percentage were CD226+. There was a trend of higher CD155 expression on ascitic macrophages compared to peripheral monocytes. Healthy control monocyte expression of CD155 was significantly increased by TLR4 stimulation with the bacterial component lipopolysaccharide.Expression of these immune checkpoints on ascitic immune cells did not significantly change with severity of liver disease from stable decompensation, acute decompensation and acute-on-chronic liver failure.Abstract OP08 Figure 1(A) CD8+ T cells and (B) NK cells from healthy control PBMCs (n = 6) and decompensated cirrhosis PBMCs and ascites (n = 8). Percentage positive for CD96, TIGIT and CD226 as assessed by flow cytometry. (C) Peripheral monocytes and ascitic macrophages CD155 expression (MFI). (D) Healthy control monocytes (n = 5) cultured with TLR ligands and assessed for CD155 expression (MFI). Paired T test, **P < 0.01, *P <0.05DiscussionThe CD96, CD226 and CD155 expression on ascitic immune cells in decompensated cirrhosis is of a more immunosuppressive phenotype compared to corresponding peripheral immune cells. This may in part be explained by chronic background exposure to translocated bacterial products in the ascites and may pre-dispose to SBP.

IntroductionSevere acute alcohol-related hepatitis (sAAH) is associated with a high short-term mortality. Accurate prognostication is important to guide decision making for corticosteroid use, and to counsel patients and carers. Several models have been used to determine prognoses in this group, such as the Maddrey’s discriminant function (MDF) and Glasgow Alcoholic Hepatitis (GAHS) score. However, newer scores used in the acute decompensated cirrhosis and acute-on-chronic liver failure populations (e.g. CLIF-C AD and ALBI scores) have not been tested in an untargeted way on this population. We aimed to compare the MDF, MELD, GAHS, ALBI, NLR and CLIF-C-AD scores as predictors for admission to intensive care, 30- and 90-day mortality in patients admitted with any severity of acute alcohol-related hepatitis.MethodsWe retrospectively identified 66 patients with alcohol-related hepatitis admitted to a London teaching hospital from 2019 to 2021. Clinical and laboratory data was recorded from admission to discharge and/or death. Statistical analysis was undertaken using IBM SPSS v28.0. The prognostic utility of MDF, GAHS, MELD, ALBI, NLR and CLIF-C-AD scores in predicting 30-day mortality was determined by receiver operating curve analysis.ResultsThe cohort of 66 patients consisted of patients with a median age of 47, 58% were male, most had cirrhosis (pre-existing or subsequently proven), and most had sAAH with 74% recording an admission MDF >32 (table 1). All patients had an NIAAA classification of definite or probable. One third required intensive care admission. Overall short-term mortality was poor (34% died at 30-days). When admission prognostic scores were compared to predict 30-day mortality, CLIF-C AD score performed best with an AUROC of 0.779 (CI 0.640–0.919, p <0.001) with the GAHS as second best with AUROC of 0.752. The difference between CLIF-C AD scores in patients with and without cirrhosis and alcohol-related hepatitis did not reach significance (p=0.07). The CLIF-C AD score retained best prognostic performance for 90-day mortality with c-statistic of 0.734 (p<0.001), marginally better that GAHS (0.730). Using the cut-offs for low (CLIF-C AD ≤ 45) and high risk (CLIF-C AD ≥ 60) for 90-day survival did not reach significance (Log rank test, p = 0.079).Abstract P06 Figure 1Abstract P06 Table 1Summary of admission clinical and biochemical parameters Parameter Total (n=66) Survivors at 30-days (n=50) Non-Survivors at 30-days (n=16) p-value Age 47 46 48 0.419 Gender (male:female) 38:28 29:21 9:7 0.902a Cirrhosis* 48 38 10 0.291a Total bilirubin, umol/L 187 184 222 0.369 ALT, U/L 58 58 68 0.612 Serum sodium, mmol/L 133 134 132 0.034 Serum creatinine, umol/L 66 62 97 0.011 Albumin, g/L 23 24 22 0.165 CRP 30 27 41 0.096 White cell count, x109/L 10.7 10.4 13.8 0.265 Neutrophil Count 6.9 5.6 10.0 0.092 Monocyte Count 0.8 0.8 1.0 0.400 Lymphocyte Count 1.4 1.8 0.8 0.038 Neutrophil: lymphocyte ratio (NLR) 5.08 4.03 12.33 0.013 Platelets, x109/L 112 107 116 0.669 INR 1.80 1.70 1.90 0.031 MDF 54 51 72 0.031 sAAH (MDF > 32) 49 36 14 0.247a GAHS 8 8 9 0.002 Albumin-bilirubin (ALBI) score -0.47 -0.52 -0.33 0.08 CLIF-C AD score 57 55 67 <0.001 MELD score 24 23 28 0.004 Steroid treated 30 23 7 0.875a Intensive care admission 22 10 12 <0.001 a Chi squared test performed for categorical variablesFor continuous variables, Mann White test performed. Significance assumed p<0.05* cirrhosis proven by radiological or histological evidenceConclusionAdmission CLIF-C AD score had the highest predictive performance of all the scores tested. This score may better identify those patients who would benefit greatest from aggressive early intervention and possible future pharmacological therapies. Further work is required, however CLIF-C AD shows potential as a good prognostic marker in sAAH. ReferencesSehrawat TS, Liu M, Shah VH. The knowns and unknowns of treatment for alcoholic hepatitis. Lancet Gastroenterol Hepatol. 2020 May;5(5):494–506. doi: 10.1016/S2468-1253(19)30326-7Liu M, Shah VH. New Prospects for Medical Management of Acute Alcoholic Hepatitis. Clin Liver Dis. 2019;13(5):131–135. Baldin C, Piedade J, Guimarães L, Victor L, Duarte J, Veiga Z, Alcântara C, Fernandes F, Pereira JL, Pereira G. CLIF-C AD Score Predicts Development of Acute Decompensations and Survival in Hospitalized Cirrhotic Patients. Dig Dis Sci. 2021 Dec;66(12):4525–4535.Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33(6):550–558.Ali S, Hussain S, Hair M, Shah AA. Comparison of Maddrey Discriminant Function, Child-Pugh Score and Glasgow Alcoholic Hepatitis Score in predicting 28-day mortality on admission in patients with acute hepatitis. Ir J Med Sci. 2013 Mar;182(1):63–8.Singal AK, Louvet A, Shah VH, Kamath PS. Grand Rounds: Alcoholic Hepatitis. J Hepatol. 2018 Aug;69(2):534–543.

BackgroundAcute-on-chronic liver failure (ACLF) is a syndrome characterised by multiple organ failure and high short-term mortality. The condition represents an immunological paradox in that rampant systemic inflammation, which drives organ dysfunction, exists alongside immune cell dysfunction and increased susceptibility to bacterial infections. Understanding the mechanisms that control this balance is therefore critical.CD96 is an immune checkpoint expressed on T cells and NK cells that transmits an inhibitory signal when bound to its ligand CD155 (PVR). Both CD96 and CD155 have soluble forms, with elevated concentrations found in other immunosuppressive states such as cancer and chronic viral infections. In this study we explored the CD96-CD155 immune checkpoint axis in patients with ACLF.MethodThe expression of membrane bound CD96 on peripheral lymphoid cells was assessed by flow cytometry in patients with acute decompensated cirrhosis (AD) and ACLF, compared to healthy controls (HC) (n = 8 per group). In a separate cohort, concentrations of plasma soluble CD96 and CD155 in patients with AD (n = 8) or ACLF (n = 23), compared to HC (n = 8), was determined with a Luminex multiplex assay.ResultsCD4+ T cells from patients with ACLF had increased expression of CD96 than those from HC (46.69 versus 14.04%, p = 0.02, figure 1A) and sCD96 concentrations were higher in ACLF than HC (1541 versus 563.6pg/ml, p = 0.01, figure 1B). sCD96 concentration correlated positively with Child Pugh Score (r = 0.43, p = 0.02) and was higher in ACLF non-survivors at 1 month than survivors (2245 versus 1100 pg/ml, p = 0.01, figure 1C). sCD155 concentrations were also increased in ACLF compared to HC (8875 versus 2686pg/ml, p = 0.01).Abstract P44 Figure 1ConclusionExpression of the inhibitory immune checkpoint CD96 is increased on CD4+ T cells in ACLF patients and this is mirrored by higher plasma sCD96 concentrations. The latter correlates with cirrhosis disease severity and is higher in ACLF non-survivors. CD96 could therefore be an immunomodulatory target in ACLF, and sCD96 a useful prognostic marker.

The recent Improving Quality in Liver Services (IQILS) accreditation at St George’s University Hospitals NHS Foundation Trust (SGH) identified the pharmacist contribution as an exemplar part of the service provided by the hepatology team.A dedicated hepatology pharmacist was first appointed in 2015, the hepatitis C CQUIN providing an invaluable opportunity for specialist hepatology pharmacists as it mandated the inclusion of a pharmacist as part of the multidisciplinary team (MDT). The role has evolved since then, initially clinics focused on the provision of adherence and complex drug-drug interaction checks in hepatitis C. Now, the hepatology pharmacy service manages a cohort of patients with hepatitis C, hepatitis B; including antenatal patients with hepatitis B and patients at risk of hepatitis B reactivation, primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH), with 1,088 outpatient appointments booked between April 2021-March 2022, as compared to 89 patients in 2015/16.The value of pharmacists in outpatient clinics is well recognised; in promoting medication adherence, medication safety, assisting in improving patient outcomes and promoting the quality use of medicines. A recent patient experience survey showed 100% (n = 40) of patients were happy or very happy with the pharmacist-led hepatology clinic. At SGH, clinic protocols were developed to ensure safe, effective and independent management of these patient cohorts, recognising the limitations and referral points of the hepatology pharmacist led clinics. The skills of a pharmacist are utilised in the clinics, with more frequent monitoring (inc. therapeutic drug monitoring) of patients compared to a traditional consultant led clinic model, ensuring patient safety and improving patient experience. The patient experience survey showed 100% (n=40) felt their condition was managed well in the pharmacist-led clinic with 97.5% (n = 39) feeling supported and comfortable that they could discuss any concerns they had about their condition and that these were addressed. Pharmacists act as a point of contact for patients, providing medication supply and advice outside their scheduled appointments, between April 2021 – March 2022, 843 prescriptions were supplied outside clinic appointments preventing missed doses.There has been continued contribution to the inpatient hepatology cohort on ward rounds to ensure medicines optimisation, improve patient safety and the safe, effective and cost-effective use of medicines. Interventions are tracked and cost avoidance can be proven. Pharmacists are an integral part of the hepatology team at SGH and will continue to work in the MDT to provide the best possible care to patients.ReferencesHayward KL, Patel PJ, Valery PC, Horsfall LU, Li CY, Wright PL, et al. Medication-related problems in outpatients with decompensated cirrhosis: opportunities for harm prevention. Hepatol Commun 2019;3:620–31.Williams T, Purvis TL. Development of an outpatient pharmacist-managed clozapine clinic. Am J Health-Syst Pharm 2012;69:1192–5.Fuertes F, Soliman A, Bullas D. Evaluation of a pharmacist-led virtual thiopurine clinic. The Pharmaceutical Journal 2020. Accessed online June 2022:

The Hepatology Clinical Assessment Service (CAS) was established as a new service at St Georges Hospital in April 2020 during the COVID-19 pandemic. It is a novel way to assess new patients referred to the liver outpatient clinic with a view to streamlining the patient pathway, pre-investigation patients prior to a clinic appointment, avoiding inappropriate clinic appointments, rejecting inappropriate referrals, and improving the efficiency of the clinic.Hepatology CAS is a weekly consultant-led clinic supported by the Clinical Nurse Specialist (CNS) and the Patient Pathway Coordinator (PPC), the clinic happens virtually without the patient being present at the time of the triage and assessment. On average, every week 35 patients are referred to the Liver Clinic by their GPs or by other clinicians internally or externally to the hospital.Once, the patient’s referral has been assessed, the CNS requests the investigations, communicates with the patient, and dictates a clinical letter to the patient and referrer, while the PPC prioritizes the appointments based on their clinical needs. Following this assessment, most of the patients then attend a face-to-face appointment, although some patients can be managed entirely virtually if clinically appropriate. With the introduction of the community non-alcoholic fatty liver pathways GP, at a similar time to this service, referrals are rejected if this pathway has not been followed.Abstract P49 Table 1The impact of the clinical assessment service on the hepatology outpatient service2020 % Total ‘New appts 190 100% Total pts seen 134 71% Total DNAs 56 29% Total pts seen 134 100% Of pts seen & F/Up 113 84% Of pts seen & D/C’d 21 16% Total DNAs 56 100% DNA & Reschedule 33 59% DNA & D/C’d 23 41% 2022 % Total ‘New’ appts 181 100% Total pts seen 141 78% Total DNAs 40 22% Total pts seen 141 100% Of pts seen & F/Up 100 71% Of pts seen & D/C’d 41 29% Total DNAs 40 100% DNA & Reschedule 25 62.5% DNA & D/C’d 15 37.5% Since CAS has been introduced there have been several positive outcomes: in 2021, 18% of the referrals were appropriately repatriated to primary care with advice; 30% of the referrals were managed without needing a face-to-face appointment; the waiting time reduced from 8 weeks to 5 weeks for a clinical review, and from 16 weeks to 15 weeks for a follow-up appointment; from 2020 to 2022 the proportion of patients discharged after the first clinical review has increased from 16% to 29%; specialist treatment is instigated more quickly; patients can be discharged following their first face-to-face visit as all information is to hand, it has eliminated unnecessary follow-up and has resulted in a clear and concise pathway to refer the patients into the service, with the diagnostic tests being performed at an earlier stage In summary CAS was introduced as an urgent service response to COVID-19 but we have identified key benefits and intend to continue it.

BACKGROUNDThere is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell-mediated control of chronic viral infection and that these results are consistent with an increase in the CD8+ T cell lifespan due to iKIR-ligand interactions. Here, we tested this prediction and investigated whether iKIRs affect T cell lifespan in humans in vivo.METHODSWe used stable isotope labeling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections.RESULTSWe showed that an individual's iKIR-ligand genotype was a significant determinant of CD8+ T cell lifespan: in individuals with 2 iKIR-ligand gene pairs, memory CD8+ T cells survived, on average, for 125 days; in individuals with 4 iKIR-ligand gene pairs, the memory CD8+ T cell lifespan doubled to 250 days. Additionally, we showed that this survival advantage was independent of iKIR expression by the T cell of interest and, further, that the iKIR-ligand genotype altered the CD8+ and CD4+ T cell immune aging phenotype.CONCLUSIONSTogether, these data reveal an unexpectedly large effect of iKIR genotype on T cell survival.FUNDINGWellcome Trust; Medical Research Council; EU Horizon 2020; EU FP7; Leukemia and Lymphoma Research; National Institute of Health Research (NIHR) Imperial Biomedical Research Centre; Imperial College Research Fellowship; National Institutes of Health; Jefferiss Trust.

Owing to the unique opportunity to assess individuals before and after they develop depression within a short timeframe, interferon-α (IFN-α) treatment for chronic hepatitis C virus (HCV) infection is an ideal model to identify molecular mechanisms relevant to major depression, especially in the context of enhanced inflammation. Fifty-eight patients were assessed prospectively, at baseline and monthly over 24 weeks of IFN-α treatment. New-onset cases of depression were determined using the Mini International Neuropsychiatric Interview (MINI). Whole-blood transcriptomic analyses were conducted to investigate the following: (1) baseline gene expression differences associated with future development of IFN-α-induced depression, before IFN-α, and (2) longitudinal gene expression changes from baseline to weeks 4 or 24 of IFN-α treatment, separately in those who did and did not develop depression. Transcriptomics data were analyzed using Partek Genomics Suite (1.4-fold, FDR adjusted p⩽0.05) and Ingenuity Pathway Analysis Software. Twenty patients (34%) developed IFN-α-induced depression. At baseline, 73 genes were differentially expressed in patients who later developed depression compared with those who did not. After 4 weeks of IFN-α treatment, 592 genes were modulated in the whole sample, representing primarily IFN-α-responsive genes. Substantially more genes were modulated only in patients who developed depression (n=506, compared with n=70 in patients who did not), with enrichment in inflammation-, neuroplasticity- and oxidative stress-related pathways. A similar picture was observed at week 24. Our data indicate that patients who develop IFN-α-induced depression have an increased biological sensitivity to IFN-α, as shown by larger gene expression changes, and specific signatures both as predictors and as correlates.

We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29-May 22, 2020, we collected serum samples and associated clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%-8.5% of persons did not seroconvert 3-6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.

BackgroundOn World AIDS Day 2021, the UK Government committed £20 million to expand opt-out HIV testing in EDs in extremely high HIV prevalence (>5/1000) areas as part of their commitment to achieve zero new HIV infections, AIDS and HIV-related deaths by 2030. 34 EDs in London, Brighton, Greater Manchester and Blackpool were included. The initiative started in April 2022 and expanded to include hepatitis C (HCV) and hepatitis B (HBV) testing in collaboration with the HCV Elimination programme.MethodsAll adults undergoing blood tests in EDs had BBV testing (4th generation HIV test, HBV surface antigen and HCV antibody with reflex RNA if HCV antibody positive) unless they opted out. An opt-out approach was taken, based on successful pilots, to maximise uptake and minimise impact on ED workload. Testing information was displayed using accessible and translated posters in EDs. HIV/Sexual Health and Hepatology managed all reactive/positive results.ResultsBy March 2023, 33 EDs had implemented HIV testing, 25 HCV and 19 HBV. From April 2022 through March 2023 there were 1,384,378 adult ED attendances with blood tests and 853,015 HIV, 346,041 HBV and 452,284 HCV tests were performed. Median test uptake increased from 51.1% (HIV), 16.3% (HBV), 23.7% (HCV) in April 2022 to 62% (HIV), 57% (HBV) and 62% (HCV) in March 2023.ED opt-out BBV testing identified 2002 people who were newly diagnosed (343 HIV, 1190 HBV, 484 HCV) and 473 who were previously diagnosed but not in care (HIV 209, HBV 156, HCV 108). Initial linkage to care was 339/552 (61%) for HIV (268/343 (78%) for new HIV diagnoses), 329/1346 (24%) for HBV and 292/592 (49%) for HCV.ConclusionsOpt-out BBV testing in EDs has proven extremely effective for making new BBV diagnoses and re-engaging those previously diagnosed but not in care. We found very high rates of HBV. Initial linkage to care is encouraging and is expected to increase over time.