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The protein known as PI3K-interacting protein (PIK3IP1), or transmembrane inhibitor of PI3K (TrIP), is highly expressed by T cells and can modulate PI3K activity in these cells. Several studies have also revealed that TrIP is rapidly downregulated following T cell activation. However, it is unclear how this downregulation is controlled. Using a novel monoclonal antibody that robustly stains cell-surface TrIP, we demonstrate that TrIP is lost from the surface of activated T cells in a manner dependent on the strength of signaling through the T cell receptor and specific downstream signaling pathways, in particular classical PKC isoforms. TrIP expression returns by 24 h after stimulation, suggesting that it may play a role in resetting T cell receptor signaling at later time points. We also provide evidence that ADAM family proteases are required for both constitutive and stimulation-induced downregulation of TrIP in T cells. Finally, by expressing truncated forms of TrIP in cells, we identify the region in the extracellular stalk domain of TrIP that is targeted for proteolytic cleavage., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Head and neck paragangliomas (HNPGLs) are rare, usually benign, slow-growing tumours arising from neural crest-derived tissue. Definitive management pathways for HNPGLs have yet to be clearly defined., Objective: To review our experience of the clinical features and management of these tumours and to analyse outcomes of different treatment modalities., Methods: Demographic and clinical data were obtained from The Northern Ireland Electronic Care Record (NIECR) as well from a prospectively maintained HNPGL database between January 2011 through December 2023., Results: There were 87 patients; 50 females: 37 males with a mean age of 52.3 ± 14.2 years old (range 17-91 years old). 58.6% (n = 51) of patients had carotid body tumours, 25.2% (n = 22) glomus vagal tumours, 6.8% (n = 6) tumours in the middle ear, 2.2% (n = 2) in the parapharyngeal space and 1.1% (n = 1) in the sphenoid sinus. 5.7% (n = 5) of patients had multifocal disease. The mean tumour size at presentation was 3.2 ± 1.4 cm (range 0.5-6.9 cm). Pathogenic SDHD mutations were identified in 41.3% (n = 36), SDHB in 12.6% (n = 11), SDHC in 2.2% (n = 2) and SDHA in 1.1% (n = 1) of the patients. Overall treatment modalities included surgery alone in 51.7% (n = 45) of patients, radiotherapy in 14.9% (n = 13), observation in 28.7% (n = 25), and somatostatin analogue therapy with octreotide in 4.5% (n = 4) of patients. Factors associated with a significantly higher risk of recurrence included age over 60 years (p = .04), tumour size exceeding 2 cm (p = .03), positive SDHx variants (p = .01), and vagal and jugular tumours (p = .04)., Conclusion: The majority of our patients underwent initial surgical intervention and achieved disease stability. Our results suggest that carefully selected asymptomatic or medically unfit patients can be safely observed provided lifelong surveillance is maintained. We advocate for the establishment of a UK and Ireland national HNPGL registry, to delineate optimal management strategies for these rare tumours and improve long term outcomes., (© 2024 John Wiley & Sons Ltd.)

For many years, we have faced the complications of viral hepatitis and alcohol-related liver diseases such as cirrhosis, decompensation, portal hypertension, and hepatocellular carcinoma (HCC). Recently, we have seen a dynamic change in the field of hepatology. With the significant achievements in eradicating the hepatitis C virus by direct-acting antiviral agents and the rising epidemic of obesity, diabetes mellitus, and metabolic syndrome, there is a paradigm shift in the leading cause of liver cirrhosis and cancer to nonalcoholic fatty liver disease (NAFLD). Current data highlight the rapidly rising incidence of NAFLD-related HCC worldwide and expose the unseen part of the iceberg. In this review, we aim to update knowledge about the pathogenesis of NAFLD-induced HCC, surveillance difficulties, and promising disease markers. Molecular biomarkers, for example, may become a promising cornerstone for risk-stratified surveillance, early detection, and treatment selection for NAFLD-related HCC. Physicians can offer personalized and tailor-made clinical decisions for this unique patient subgroup.

Introduction: Over-the-scope clip (OTSC) has been used recently for primary haemostasis of peptic ulcers. This study aimed to compare the efficacy of OTSC to standard endoscopic therapy in primary treatment of patients with peptic ulcer bleeding that are of size ≥1.5 cm. The target population accounts for only 2.5% of all upper GI bleeders., Methods: This was a multicentre international randomised controlled trial from July 2017 to October 2020. All patients with Forest IIa or above peptic ulcers of ≥1.5 cm were included. Primary outcome was 30-day clinical rebleeding. Secondary endpoints include 3-day all-cause mortality, transfusion requirement, hospital stay, technical and clinical success, and further interventions. 100 patients are needed to yield a power of 80% to detect a difference of -0.15 at the 0.05 significance level (alpha) using a two-sided Z-test (pooled)., Results: 100 patients were recruited. Success in achieving primary haemostasis was achieved in 46/50 (92%) and 48/50 (96%) in the OTSC and conventional arm, respectively. Among patients who had success in primary haemostasis, 2/46 (4.35%) patients in the OTSC arm and 9/48 (18.75%) patients in the conventional arm developed 30-day rebleeding (p=0.03). However, in an intention-to-treat analysis, there was no difference in rebleeding within 30 days (5/50 (10%) OTSC vs 9/50 (18%) standard, p=0.23) or all-cause mortality (2/50 (4%) OTSC vs 4/50 (8%) standard, p=0.68; OR=2.09, 95% CI 0.37 to 11.95). There was also no difference in transfusion requirement, hospital stay, intensive care unit admission and further interventions., Conclusion: The routine use of OTSC as primary haemostasis in large bleeding peptic ulcers was not associated with a significant decrease in 30-day rebleeding., Trial Registration Number: NCT03160911., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The impact of faecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome is uncertain. We aimed to study whether combining FMT with lifestyle modification could enhance the engraftment of favourable microbiota in obese patients with type 2 diabetes mellitus (T2DM)., Design: In this double-blind, randomised, placebo-controlled trial, 61 obese subjects with T2DM were randomly assigned to three parallel groups: FMT plus lifestyle intervention (LSI), FMT alone, or sham transplantation plus LSI every 4 weeks for up to week 12. FMT solution was prepared from six healthy lean donors. Faecal metagenomic sequencing was performed at baseline, weeks 4, 16 and 24. The primary outcome was the proportion of subjects acquiring ≥20% of microbiota from lean donors at week 24., Results: Proportions of subjects acquiring ≥20% of lean-associated microbiota at week 24 were 100%, 88.2% and 22% in the FMT plus LSI, FMT alone, and sham plus LSI groups, respectively (p<0.0001). Repeated FMTs significantly increased the engraftment of lean-associated microbiota (p<0.05). FMT with or without LSI increased butyrate-producing bacteria. Combining LSI and FMT led to increase in Bifidobacterium and Lactobacillus compared with FMT alone (p<0.05). FMT plus LSI group had reduced total and low-density lipoprotein cholesterol and liver stiffness at week 24 compared with baseline (p<0.05)., Conclusion: Repeated FMTs enhance the level and duration of microbiota engraftment in obese patients with T2DM. Combining lifestyle intervention with FMT led to more favourable changes in recipients' microbiota and improvement in lipid profile and liver stiffness., Trial Registration Number: NCT03127696., Competing Interests: Competing interests: SCN has served as advisory board member for Pfizer, Ferring, Janssen, Abbvie and speaker for Ferring, Tillotts, Menarini, Janssen, Abbvie and Takeda. She has received research grants from Olympus, Ferring and Abbvie. FKLC has served as advisor and Lecture Speaker for Eisai Co. Ltd, AstraZeneca, Pfizer Inc, Takeda Pharmaceutical Co and Takeda (China) Holdings Co. Ltd. VW-SW has served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions and Terns; and a speaker for AbbVie, Bristol-Myers Squibb, Echosens and Gilead Sciences. He has received a grant from Gilead Sciences for fatty liver research. ZX: none to declare. JWYM: none to declare. KY: none to declare. QL: none to declare. TZ: none to declare. WT: none to declare. LL: none to declare. RNL: none to declare. SW: none to declare. YKT: none to declare. AYLL: none to declare. KC: none to declare. JYLC: none to declare. AP-SK: none to declare. RM: none to declare. EC: none to declare. SKHW: none to declare. CHH: none to declare. PC: none to declare., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Alloimmune responses driven by donor-specific antibodies (DSAs) can lead to antibody-mediated rejection (ABMR) in organ transplantation. Yet, the cellular states underlying alloreactive B cell responses and the molecular components controlling them remain unclear. Using high-dimensional profiling of B cells in a cohort of 96 kidney transplant recipients, we identified expanded numbers of CD27+CD21- activated memory (AM) B cells that expressed the transcription factor T-bet in patients who developed DSAs and progressed to ABMR. Notably, AM cells were less frequent in DSA+ABMR- patients and at baseline levels in DSA- patients. RNA-Seq analysis of AM cells in patients undergoing ABMR revealed these cells to be poised for plasma cell differentiation and to express restricted IGHV sequences reflective of clonal expansion. In addition to T-bet, AM cells manifested elevated expression of interferon regulatory factor 4 and Blimp1, and upon coculture with autologous T follicular helper cells, differentiated into DSA-producing plasma cells in an IL-21-dependent manner. The frequency of AM cells was correlated with the timing and severity of ABMR manifestations. Importantly, T-bet+ AM cells were detected within kidney allografts along with their restricted IGHV sequences. This study delineates a pivotal role for AM cells in promoting humoral responses and ABMR in organ transplantation and highlights them as important therapeutic targets.

Background: Although antibody-mediated rejection (ABMR) has been long recognized as a leading cause of allograft failure after kidney transplantation, the cellular and molecular processes underlying the induction of deleterious donor-specific antibody (DSA) responses remain poorly understood., Methods: Using high-dimensional flow cytometry, in vitro assays, and RNA sequencing, we concomitantly investigated the role of T follicular helper (T FH ) cells and B cells during ABMR in 105 kidney transplant recipients., Results: There were 54 patients without DSAs; of those with DSAs, ABMR emerged in 20 patients, but not in 31 patients. We identified proliferating populations of circulating T FH cells and activated B cells emerging in blood of patients undergoing ABMR. Although these circulating T FH cells comprised heterogeneous phenotypes, they were dominated by activated (ICOS + PD-1 + ) and early memory precursor (CCR7 + CD127 + ) subsets, and were enriched for the transcription factors IRF4 and c-Maf. These circulating T FH cells produced large amounts of IL-21 upon stimulation with donor antigen and induced B cells to differentiate into antibody-secreting cells that produced DSAs. Combined analysis of the matched circulating T FH cell and activated B cell RNA-sequencing profiles identified highly coordinated transcriptional programs in circulating T FH cells and B cells among patients with ABMR, which markedly differed from those of patients who did not develop DSAs or ABMR. The timing of expansion of the distinctive circulating T FH cells and activated B cells paralleled emergence of DSAs in blood, and their magnitude was predictive of IgG3 DSA generation, more severe allograft injury, and higher rate of allograft loss., Conclusions: Patients undergoing ABMR may benefit from monitoring and therapeutic targeting of T FH cell-B cell interactions., (Copyright © 2020 by the American Society of Nephrology.)

The four genetically divergent dengue virus (DENV) types are traditionally classified as serotypes. Antigenic and genetic differences among the DENV types influence disease outcome, vaccine-induced protection, epidemic magnitude, and viral evolution. We characterized antigenic diversity in the DENV types by antigenic maps constructed from neutralizing antibody titers obtained from African green monkeys and after human vaccination and natural infections. Genetically, geographically, and temporally, diverse DENV isolates clustered loosely by type, but we found that many are as similar antigenically to a virus of a different type as to some viruses of the same type. Primary infection antisera did not neutralize all viruses of the same DENV type any better than other types did up to 2 years after infection and did not show improved neutralization to homologous type isolates. That the canonical DENV types are not antigenically homogeneous has implications for vaccination and research on the dynamics of immunity, disease, and the evolution of DENV., (Copyright © 2015, American Association for the Advancement of Science.)

Background: The four dengue virus serotypes (DENV1-4) are responsible for the most prevalent mosquito-borne viral illness in humans. DENV causes a spectrum of disease from self-limiting dengue fever (DF) to severe, life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Antibodies from one infection can contribute to either protection or increased disease severity in a subsequent infection with a distinct DENV serotype. The effectiveness of the antibody response is modulated by both the affinity and avidity of the antibody/antigen interaction., Objectives: We investigated how antibody avidity developed over time following secondary DENV2 infection across different disease severities., Study Design: We analyzed sera from 42 secondary DENV2-infected subjects (DF, n=15; DHF, n=16; DSS, n=11) from a pediatric hospital-based dengue study in Nicaragua. IgG avidity against DENV2 virions was measured in samples collected during acute and convalescent phases as well as 3, 6, and 18 months post-illness using a urea enzyme-linked immunosorbent assay., Results: The data show a significant increase in avidity from acute to convalescent phase followed by a decrease from convalescent phase to 3 months post-symptom onset, then a plateau. Linear regression analysis comparing antibody avidity between disease severity groups over time indicate that individuals with more severe disease (DHF/DSS) experienced greater decay in antibody avidity over time compared to less severe disease (DF), and ROC curve analysis showed that at 18 months post-illness, lower avidity was associated with previously having experienced more severe disease., Conclusions: These data suggest that increased dengue disease severity is associated with lower antibody avidity at later time-points post-illness., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Although heterotypic secondary infection with dengue virus (DENV) is associated with severe disease, the majority of secondary infections are mild or asymptomatic. The mechanisms of antibody-mediated protection are poorly understood. In 2010, 108 DENV3-positive cases were enrolled in a pediatric hospital-based study in Managua, Nicaragua, with 61 primary and 47 secondary infections. We analyzed DENV-specific neutralization titers (NT50), IgM and IgG avidity, and antibody titer in serum samples collected during acute and convalescent phases and 3, 6, and 18 months post-infection. NT50 titers peaked at convalescence and decreased thereafter. IgG avidity to DENV3 significantly increased between convalescent and 3-month time-points in primary DENV infections and between the acute and convalescent phase in secondary DENV infections. While avidity to DENV2, a likely previous infecting serotype, was initially higher than avidity to DENV3 in secondary DENV infections, the opposite relation was observed 3-18 months post-infection. We found significant correlations between IgM avidity and NT50 in acute primary cases and between IgG avidity and NT50 in secondary DENV infections. In summary, our findings indicate that IgM antibodies likely play a role in early control of DENV infections. IgG serum avidity to DENV, analyzed for the first time in longitudinal samples, switches from targeting mainly cross-reactive serotype(s) to the current infecting serotype over time. Finally, serum avidity correlates with neutralization capacity.

Superior mesenteric artery (SMA) aneurysms are rare but associated with significant mortality (25-40%) when complicated by rupture or thrombosis. Symptomatic SMA aneurysms, asymptomatic aneurysms of ≥2 cm size and pseudoaneurysms need intervention. We report a case of a 6.5-cm symptomatic SMA aneurysm managed by open surgical repair. At intraoperative exploration, the aneurysm was recognized to be a pseudoaneurysm with a narrow neck (1 mm defect in the native vessel) and was dealt by primary repair. Clinical presentation, the role of radiological investigations and management are discussed. Detailed preoperative assessment of the anatomical characters is essential in planning the intervention for SMA aneurysms. The required information can be obtained by selective interventional angiogram or computed tomographic angiogram with three-dimensional reconstruction. Multi-institutional prospective databases might provide better evidence regarding the timing of intervention, treatment modality, postinterventional follow-up and surveillance of patients with mesenteric aneurysms.

Introduction: The complication of sexual dysfunction as a quality of life (QoL) component after abdominal aortic aneurysm (AAA) surgery in men is poorly studied., Aims: To investigate the prevalence of sexual dysfunction and to highlight the importance of discussing this issue with patients undergoing AAA repair., Main Outcome Measures: The self-reported sexual dysfunction prevalence pre- and postoperatively, the effects on sexual QoL, and the postoperative Sexual Health Inventory for Men (SHIM) scores., Methods: Between April 1999 and July 2002, a questionnaire-based study, including the SHIM, was conducted on male patients 1-2 years after their elective open (EO) and rupture open (RO) or endovascular repair (EVAR) AAA repair. Demographics, risk factors for sexual dysfunction, sexual history, and postoperative sexual QoL data were obtained., Results: Out of 142 alive male patients surveyed, 56 (40%) patients responded (26 EO, 21 EVAR, and 9 RO repair). The mean age was 69, 73, and 70 years, respectively, and 65%, 66%, and 66%, respectively, admitted to be sexually active postoperatively. The self-reported sexual dysfunction prevalence preoperatively was 27% (EO), 63% (EVAR), and 45% (RO); and postoperatively was 58%, 76%, and 67%, respectively. Detection using SHIM was higher at 70%, 95%, and 78%, respectively. There was a significantly greater increase in the postoperative prevalence of sexual dysfunction in the EO group than in the EVAR group (P < 0.05, chi(2)). The sexual QoL was worsened postoperatively in all groups: 53% (EO), 75% (EVAR), and 50% (RO); but only one-third of EO and EVAR patients, and none in RO patients, would seek treatment for their sexual dysfunction., Conclusion: There was a negative impact on the sexual QoL in all groups after surgery, and a significantly higher proportion of patients experienced deterioration in sexual QoL following EO surgical repair. Our results demonstrate the need for a prospective study.

Study Objectives: This study was conducted to examine the short-term effects of using a rollator on functional exercise capacity among individuals with COPD and to characterize which individuals benefit most from its use., Design: Repeated-measures randomized crossover design using the 6-min walk test (6MWT) as the primary outcome measure., Setting: Respiratory rehabilitation center., Patients: Forty stable subjects who had received a diagnosis of COPD., Interventions: Two 6MWTs were performed on each study day. One 6MWT was performed unaided, and the other was performed with a rollator. The order was randomized on the first day and reversed on the second day., Results: Use of the rollator was associated with a significant reduction in dyspnea (p < 0.001) and duration of rest (reduction for the total group, 19 s; and reduction for those who walked < 300 m unaided, 40 s; p = 0.001) during the 6MWT. For subjects who walked < 300 m unaided, there was also a significant improvement in distance walked (p = 0.02). No changes were found for the measures of cardiorespiratory function or gait (p > 0.05). The requirement to rest during an unaided 6MWT was a significant predictor of improved functional exercise capacity with the use of the rollator (p < 0.005). The majority of subjects whose unaided 6MWT distance was < 300 m preferred using the rollator to walking unaided., Conclusions: Use of a rollator was effective in improving functional exercise capacity by reducing dyspnea and rest duration among stable individuals with severe COPD. Individuals who walked < 300 m and individuals who required a rest during an unaided 6MWT benefited the most from using a rollator in terms of reduced dyspnea, reduced rest time, and improved distance walked.