PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial.

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96. METHODS: In this multicentre randomized controlled clinical trial, 180 non-cirrhotic HBeAg-negative chronic hepatitis B patients on continuous NUC therapy for ≥ 2.5 years with HBV DNA levels < 60 IU/mL were randomized to discontinue NUC (n=90) or receive 48 weeks of PegIFN-α-2a treatment (n=90) and followed up till 96 weeks. The primary endpoint was the virological relapse rate until week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, P < 0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, P = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, P = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, P = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and achieves higher HBsAg loss rates than NUC treatment cessation alone in HBeAg-negative chronic hepatitis B patients. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimised scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96 in HBeAg-negative chronic hepatitis B patients. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, P < 0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, P= 0.03) than the NUC cessation group until week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.

A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.

Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols.

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89 %, 99 : 1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5) and C(6), as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O⋅⋅⋅isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

Robotic-assisted total knee arthroplasty results in decreased incidence of anterior femoral notching compared to posterior referenced instrumented total knee arthroplasty.

OBJECTIVE: Periprosthetic fracture (PPF) is an uncommon but devastating complication after total knee arthroplasty (TKA). Anterior femoral notching (AFN) is one of a perioperative risk factor for PPF. The main purpose of this study was to compare between the rates of anterior femoral notching (AFN) and supracondylar periprosthetic femoral fracture (sPPF) of manual TKA and robotic arm-assisted TKA (RATKA). Meanwhile, blood loss, transfusion rates, inflammatory responses, complications, early clinical and radiological outcomes were also assessed. METHODS: This retrospective study included 330 patients (133 RATKA and 197 manual TKA). Differences in risks of inflammatory, blood loss, complications (periprosthetic fracture and periprosthetic joint infection), pre-operative and post-operative distal lateral femoral angle (LDFA), distal femoral width (DFW), prosthesis-distal femoral width (PDFW) ratio, AFN, femoral component flexion angle (FCFA), peri-operative and post-operative functional outcomes between the RATKA and manual TKA groups were compared. RESULTS: The operation time and postoperative CRP level in the RATKA group was significantly longer and higher than that in the manual TKA group (p < .001). However, there was no significant difference in postoperative WBC level (p = .217), hemoglobin loss (p = .362), postoperative drainage (p = .836), and periprosthetic fracture (p = 1.000). There was no significant difference in LDFA (p > .05), DFW(p = .834), PDFW ratio (p = .089) and FCFA (p = .315) between the two groups, but the rate of AFN in the RATKA group was significantly lower than that in the manual TKA group (p < .05). There was no significant difference in ROM between the two groups on POD3, POD 90 and 1 year (p < .05), but the FJS-12 score in the RATKA group was higher than that in the manual TKA group on 1 year (p = .001). CONCLUSION: Robotic-assisted total knee arthroplasty can decrease the incidence of anterior femoral notching compared to posterior referenced instrumented total knee arthroplasty.

The diagnosis and treatment of septic hip with osteonecrosis of the femoral head.

This article aims to provide clinical doctors with references for the diagnosis and treatment of osteonecrosis of the femoral head (ONFH) accompanied with septic hip by summarizing and analyzing clinical data and postoperative follow-up information of patients treated with two-stage arthroplasty. We retrospectively analyzed ten patients who underwent two-stage arthroplasty in our hospital due to ONFH accompanied with septic hip. The diagnosis of septic hip includes erythrocyte sedimentation rate (ESR) > 30 mm/h, C-reactive protein (CRP) > 10 mg/L, pus-like synovial fluid, positive microbiological culture, and the findings of septic arthritis on magnetic resonance imaging (MRI) scan. Patient's information was evaluated based on the review of medical records, including gender, age, symptoms, risk factor of ONFH and septic arthritis, blood test, radiograph, MRI scan, microbiological culture, treatment, follow-up period and outcome. A total of ten patients were diagnosed with ONFH accompanied with septic hip. The average follow-up period was 43.5 months. None of the patients experienced failure during the follow-up period. The risk factor of ONFH was alcohol-related (60%), steroid-related (20%) and idiopathic (20%). Nine patients (90%) have no risk factor of septic arthritis and one patient (10%) has nephrotic syndrome. All patients did not experience any fever symptoms before surgery, but all showed worsening symptoms of pain. There were three patients (30%) with abnormal WBC count > 10 × 109/L. All patients had elevated ESR and/or CPR. Nine patients (90%) had positive MRI findings, and seven patients (70%) had positive microbiological culture. When patients with ONFH experience worsening hip joint pain accompanied by unexplained elevated CRP and/or ESR, it should be suspected whether ONFH is accompanied with septic hip. In these cases, MRI scans should be performed to exclude septic hip. Patients with ONFH accompanied with septic hip showed satisfactory results after two-stage arthroplasty.

BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion.

B- and T-lymphocyte attenuator (BTLA) levels are increased in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This condition is characterized by susceptibility to infection and T-cell immune exhaustion. However, whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remains unclear. Here, we report that BTLA levels are significantly increased in the circulating and intrahepatic CD4+ T cells from patients with HBV-ACLF, and are positively correlated with disease severity, prognosis, and infection complications. BTLA levels were upregulated by the IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activated the PI3K-Akt pathway to inhibit the activation, proliferation, and cytokine production of CD4+ T cells while promoting their apoptosis. In contrast, BTLA knockdown promoted their activation and proliferation. BTLA-/- ACLF mice exhibited increased cytokine secretion, and reduced mortality and bacterial burden. The administration of a neutralizing anti-BTLA antibody reduced Klebsiella pneumoniae load and mortality in mice with ACLF. These data may help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets.