OBJECTIVE: This study aimed to investigate the predictive factors associated with the reactivation of herpes simplex virus (HSV) in patients with trigeminal neuralgia (TN) after surgery, and to determine whether there is a correlation between reactivation and surgical efficacy.
METHODS: This study included 190 patients who underwent surgery between January 2020 and December 2021. Postoperative HSV reactivation was defined as the presence of perioral or gingival herpes and herpes labialis within 1 week postoperatively. Logistic regression analysis was used to evaluate clinical characteristics as potential predictors of HSV reactivation. Additionally, Spearman\'s rank correlation coefficient was used to determine any correlation between the postoperative barrow neurological institute (BNI) pain intensity score and HSV reactivation.
RESULTS: Of the 190 patients, 56 (29.5%) experienced postoperative HSV reactivation. Both univariate and multivariate analyses identified several significant predictors of HSV reactivation, such as a history of HSV infection, previous trigeminal nerve-damaging surgery, the use of internal neurolysis (IN) as a surgical technique, and an operation time of ≥25 min. No significant correlation was found between HSV reactivation and pain relief, as measured by BNI scores.
CONCLUSIONS: HSV reactivation was observed in a considerable proportion of patients with TN. Long operative times (≥25 min), the use of IN as a surgical technique, a history of HSV infection, and previous trigeminal nerve-damaging surgery were identified as risk factors. Further research is needed to optimize surgical procedures and develop targeted management protocols to reduce the risk of HSV reactivation.

OBJECTIVE: Patients with overt or occult hepatitis B virus (HBV) infection receiving immunosuppressive treatments have a wide risk of HBV reactivation (HBVr). We performed meta-analysis with decision curve analyses (DCA) to estimate the risk of HBVr in HBsAg-negative anti-HBc-positive patients naïve to nucleos(t)ide analogues (NAs) receiving immunosuppressive treatments.
RESULTS: Studies were identified through literature search until October 2022. Pooled estimates were obtained using random-effects model. Subgroup analyses were performed according to underlying disease and immunosuppressive treatments. DCA was used to identify the threshold probability associated with the net benefit of antiviral prophylaxis in HBsAg-negative anti-HBc-positive patients. We selected 68 studies (40 retrospective and 28 prospective), including 8034 patients with HBsAg negative anti-HBc positive. HBVr was 4% (95% CI 3%-6%) in HBsAg-negative anti-HBc-positive patients, with a significantly high heterogeneity (I2 69%; p < .01). The number-needed-to-treat (NNT) by DCA ranged from 8 to 24 for chemotherapy plus rituximab, from 12 to 24 for targeted therapies in cancer patients and from 13 to 39 for immune-mediated diseases. Net benefit was small for monoclonal antibodies.
CONCLUSIONS: Our DCA in HBsAg-negative anti-HBc-positive patients provided evidence that NA prophylaxis is strongly recommended in patients treated with chemotherapy combined with rituximab and could be appropriate in patients with cancer treated with targeted therapies and in patients with immune-mediated diseases. Finally, in patients with cancer treated with monoclonal antibodies or with chemotherapy without rituximab, the net benefit is even lower.

Viruses normally reprogram the host cell metabolic pathways as well as metabolic sensors to facilitate their persistence. The serine-threonine liver kinase B1 (LKB1) is a master upstream kinase of 5\'-AMP-activated protein kinase (AMPK) that senses the energy status and therefore regulates the intracellular metabolic homeostasis. Previous studies showed that AMPK restricts Kaposi\'s sarcoma-associated herpesvirus (KSHV) lytic replication in endothelial cells during primary infection and promotes primary effusion lymphoma (PEL) cell survival. However, the role of LKB1 in KSHV lytic reactivation and KSHV-associated malignancies is unclear. In this study, we found that LKB1 is phosphorylated or activated in KSHV-positive PEL cells. Mechanistically, KSHV-encoded vCyclin mediated LKB1 activation in PEL cells, as vCyclin knockout ablated, while vCyclin overexpression enhanced LKB1 activation. Furthermore, knockdown of LKB1 inactivated AMPK and induced KSHV reactivation, as indicated by the increased expression of viral lytic genes and the increased virions in supernatants. Accordingly, AMPK inhibition by functional knockdown or a pharmacologic inhibitor, Compound C, promoted KSHV reactivation in PEL cells. Furthermore, inhibition of either LKB1 or AMPKα1 efficiently induced cell death by apoptosis of PEL cells both in vitro and in vivo. Together, these results identify LKB1 as a vulnerable target for PEL, which could be potentially exploited for treating other virus-associated diseases.IMPORTANCEKaposi\'s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with several human cancers, such as primary effusion lymphoma (PEL). Here, we showed that serine-threonine liver kinase B1 (LKB1), upstream of 5\' AMP-activated protein kinase (AMPK), is activated by KSHV-encoded vCyclin and maintains KSHV latency in PEL cells. Inhibition of either LKB1 or AMPK enhances KSHV lytic replication from latency, which at least partially accounts for PEL cell death by apoptosis. Compound C, a potent AMPK inhibitor, induced KSHV reactivation and efficiently inhibited PEL progression in vivo. Thus, our work revealed that LKB1 is a potential therapeutic target for KSHV-associated cancers.

The magnitude of the effector functions of memory T cells determines the consequences of the protection against invading pathogens and tumor development or the pathogenesis of autoimmune and allergic diseases. Tissue-resident memory T cells (TRM cells) are unique T-cell populations that persist in tissues for long periods awaiting re-encounter with their cognate antigen. Although TRM cell reactivation primarily requires the presentation of cognate antigens, recent evidence has shown that, in addition to the conventional concept, TRM cells can be reactivated without the presentation of cognate antigens. Non-cognate TRM cell activation is triggered by cross-reactive antigens or by several combinations of cytokines, including interleukin (IL)-2, IL-7, IL-12, IL-15 and IL-18. The activation mode of TRM cells reinforces their cytotoxic activity and promotes the secretion of effector cytokines (such as interferon-gamma and tumor necrosis factor-alpha). This review highlights the key features of TRM cell maintenance and reactivation and discusses the importance of effector functions that TRM cells exert upon being presented with cognate and/or non-cognate antigens, as well as cytokines secreted by TRM and non-TRM cells within the tissue microenvironment.

BACKGROUND: Hepatitis B virus (HBV) reactivation is a recognized complication of cytotoxic chemotherapy in patients with chronic hepatitis B. However, the risk of HBV reactivation with immune checkpoint inhibitors (ICIs) remains uncertain due to their exclusion from clinical trials. This study aimed to assess the incidence of HBV reactivation in patients with cancer undergoing ICI therapy, exploring associated risk factors.
METHODS: This retrospective study included patients with cancer who tested positive for hepatitis B surface antigen (HBsAg). The primary endpoint was incidence of HBV reactivation, whereas the secondary endpoint was occurrence of hepatic adverse events during ICI therapy.
RESULTS: Among the 162 eligible patients (median age 59 years; 85.8% men), HBV reactivation occurred in 4.3% at a median of 13 weeks post-treatment initiation. At baseline, HBV DNA was undetectable in 78 patients; 88 received antiviral prophylaxis, while 74 patients did not. Reactivation rates were 3.5% in HBsAg-positive and 10% in hepatitis B core antibody (HBcAb)-positive individuals, with an overall rate of 4.3%. These rates were 1.1% with prophylaxis and 8.1% without. Twenty-two patients had grade 3-4 hepatitis, and 25 tested HBsAg-negative but HBcAb-positive. No HBV-related fatalities occurred. The absence of antiviral treatment was a significant risk factor for HBV reactivation.
CONCLUSIONS: Our study underscores the risk of HBV reactivation in patients with cancer undergoing ICI therapy, especially among those lacking antiviral prophylaxis. Regular HBV DNA testing and antiviral prophylaxis are crucial preventive measures for HBV reactivation. These findings emphasize the importance of monitoring HBV status in patients receiving ICIs.

Although our understanding of herpes simplex virus type 1 (HSV-1) biology has been considerably enhanced, developing therapeutic strategies to eliminate HSV-1 in latently infected individuals remains a public health concern. Current antiviral drugs used for the treatment of HSV-1 complications are not specific and do not address latent infection. We recently developed a CRISPR-Cas9-based gene editing platform to specifically target the HSV-1 genome. In this study, we further used 2D Vero cell culture and 3D human induced pluripotent stem cell-derived cerebral organoid (CO) models to assess the effectiveness of our editing constructs targeting viral ICP0 or ICP27 genes. We found that targeting the ICP0 or ICP27 genes with AAV2-CRISPR-Cas9 vectors in Vero cells drastically suppressed HSV-1 replication. In addition, we productively infected COs with HSV-1, characterized the viral replication kinetics, and established a viral latency model. Finally, we discovered that ICP0- or ICP27-targeting AAV2-CRISPR-Cas9 vector significantly reduced viral rebound in the COs that were latently infected with HSV-1. In summary, our results suggest that CRISPR-Cas9 gene editing of HSV-1 is an efficient therapeutic approach to eliminate the latent viral reservoir and treat HSV-1-associated complications.

Background. Varicella-zoster virus (VZV) is a human neurotropic virus which commonly causes infection during childhood, presenting as chickenpox. Later in life it may reactivate as herpes zoster. We report a rare manifestation of reactivation of VZV infection presenting as cutaneous vasculitis and varicella pneumonia in a lung transplant recipient. Case presentation. A 65-year-old man was lung transplanted bilaterally for emphysema and had repeated posttransplant chest infections and colonization with Pseudomonas aeruginosa. Nine months post-transplant he presented with dyspnoea and a cutaneous vasculitis-like eruption with a predilection over face, thorax and distal extremities. Initially, VZV reactivation was not suspected due to absence of the typical vesicular eruptions. The diagnosis was confirmed by VZV PCR from the swabs of the ulcer after skin punch biopsy of a lesion and from bronchoalveolar lavage (BAL). The histology of skin biopsy demonstrated epithelial damage and vascular damage but no typical epithelial virus associated changes. The patient responded to antiviral therapy with total remission of rash and VZV DNA was finally not detectable from repeated BAL after 29 days of therapy. However, the pulmonary radiological features and dyspnoea persisted due to reasons possibly unrelated to the VZV infection. Conclusion. Had it not been for the patient to mention the resemblance of the vasculitic rash with his primary VZV infection, the diagnosis would easily have been overlooked. In this case, the biopsy did not show typical histopathologic findings of VZV-vasculitis. What led the diagnosis was a PCR from the wound swab taken after the punch biopsy. This case serves as a reminder for atypical presentation of common conditions in immunosuppressed patients and that extensive diagnostic sampling may be warranted in this group.

UNASSIGNED: To observe the vascular development results of tertiary anti-vascular endothelial growth factor (anti-VEGF) therapy following spontaneous second reactivation of retinopathy of prematurity (ROP).
UNASSIGNED: This retrospective study included 22 infants (42 eyes) with Type 1 or aggressive ROP (A-ROP) who received three anti-VEGF drug treatments for ROP from January 2018 to December 2022. The vascular growth, possible associated risk factors, and the retinal vascularization (DB/DF ratio) were assessed.
UNASSIGNED: The mean follow-up was 17.6 months. After the 3rd intravitreal injection, seven eyes showed complete vascularization (Group 1), while the remaining 35 eyes demonstrated persistent avascular retina (PAR) (Group 2). In Group 2, 17 eyes maintained a stable state and were classified in the regression subgroup. The other 18 eyes developed a 3rd reactivation (reactivation subgroup) and were treated with laser photocoagulation (LPC).Birth weight (BW) was significantly lower in Group 2 than in Group 1 (p < 0.001). The decision tree analysis shows that only infants weighing more than 1,250 g (17.50%) had a chance to achieve complete retinal vascularization. The possibility of PAR was higher in patients with BW <1,250 g than ≥1,250 g (70.00% vs. 12.50%). In addition, most infants with BW ≥ 1,290 g and initial ROP disease in Zone I or posterior Zone II developed PAR.
UNASSIGNED: Tertiary IVR can successfully treat a second ROP reactivation and improve peripheral retinal vascularization. BW is the most significant factor related to complete retinal vascularization. Our decision tree model may be helpful in predicting the prognosis of anti-VEGF drugs in the event of a second ROP reactivation.

OBJECTIVE: Acute retinal necrosis (ARN) is a vision-threatening uveitis caused by herpesviruses reactivation, which has recently been suggested to be associated with COVID-19 infection and after vaccination against it.
METHODS: We present the case of a 58-year-old Japanese woman with ARN in the left eye due to herpes simplex virus 2 (HSV2) two days after receiving the fifth dose of the BNT162b2 mRNA COVID-19 vaccine. The patient demonstrated an ARN history in the right eye and had been treated for it. The patient was administered oral steroids and immunosuppressive drugs for mixed connective tissue disease and organizing pneumonia. The patient was treated with intravenous acyclovir and foscarnet, and a vitrectomy was performed for retinal detachment. The lesion took approximately two months to scar.
CONCLUSIONS: This report suggests that patients with an ARN history might be at risk of ARN recurrence because of the reactivation of the herpes simplex virus induced by COVID-19 vaccination.

UNASSIGNED: Most neovascular age-related macular degeneration treatments involve long-term follow-up of disease activity. Home monitoring would reduce the burden on patients and those they depend on for transport, and release clinic appointments for other patients. The study aimed to evaluate three home-monitoring tests for patients to use to detect active neovascular age-related macular degeneration compared with diagnosing active neovascular age-related macular degeneration by hospital follow-up.
UNASSIGNED: There were five objectives: Estimate the accuracy of three home-monitoring tests to detect active neovascular age-related macular degeneration. Determine the acceptability of home monitoring to patients and carers and adherence to home monitoring. Explore whether inequalities exist in recruitment, participants\' ability to self-test and their adherence to weekly testing during follow-up. Provide pilot data about the accuracy of home monitoring to detect conversion to neovascular age-related macular degeneration in fellow eyes of patients with unilateral neovascular age-related macular degeneration. Describe challenges experienced when implementing home-monitoring tests.
UNASSIGNED: Diagnostic test accuracy cohort study, stratified by time since starting treatment.
UNASSIGNED: Six United Kingdom Hospital Eye Service macular clinics (Belfast, Liverpool, Moorfields, James Paget, Southampton, Gloucester).
UNASSIGNED: Patients with at least one study eye being monitored by hospital follow-up.
UNASSIGNED: Detection of active neovascular age-related macular degeneration by an ophthalmologist at hospital follow-up.
UNASSIGNED: KeepSight Journal: paper-based near-vision tests presented as word puzzles. MyVisionTrack®: electronic test, viewed on a tablet device. MultiBit: electronic test, viewed on a tablet device. Participants provided test scores weekly. Raw scores between hospital follow-ups were summarised as averages.
UNASSIGNED: Two hundred and ninety-seven patients (mean age 74.9 years) took part. At least one hospital follow-up was available for 317 study eyes, including 9 second eyes that became eligible during follow-up, in 261 participants (1549 complete visits). Median testing frequency was three times/month. Estimated areas under receiver operating curves were < 0.6 for all index tests, and only KeepSight Journal summary score was significantly associated with the lesion activity (odds ratio = 3.48, 95% confidence interval 1.09 to 11.13, p = 0.036). Older age and worse deprivation for home address were associated with lower participation (χ2 = 50.5 and 24.3, respectively, p < 0.001) but not ability or adherence to self-testing. Areas under receiver operating curves appeared higher for conversion of fellow eyes to neovascular age-related macular degeneration (0.85 for KeepSight Journal) but were estimated with less precision. Almost half of participants called a study helpline, most often due to inability to test electronically.
UNASSIGNED: Pre-specified sample size not met; participants\' difficulties using the devices; electronic tests not always available.
UNASSIGNED: No index test provided adequate test accuracy to identify lesion diagnosed as active in follow-up clinics. If used to detect conversion, patients would still need to be monitored at hospital. Associations of older age and worse deprivation with study participation highlight the potential for inequities with such interventions. Provision of reliable electronic testing was challenging.
UNASSIGNED: Future studies evaluating similar technologies should consider: Independent monitoring with clear stopping rules based on test performance. Deployment of apps on patients\' own devices since providing devices did not reduce inequalities in participation and complicated home testing. Alternative methods to summarise multiple scores over the period preceding a follow-up.
UNASSIGNED: This trial is registered as ISRCTN79058224.
UNASSIGNED: This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/97/02) and is published in full in Health Technology Assessment; Vol. 28, No. 32. See the NIHR Funding and Awards website for further award information.
Treatment for neovascular age-related macular degeneration, the most common cause of sight loss in those over 50 years, involves regular eye injections and frequent follow-up appointments. This is inconvenient for patients and causes capacity issues in the hospital eye service. Finding tests that could be undertaken at home that could detect if a further injection and hospital appointment was required or not would increase capacity to see those at highest risk of sight loss and also reduce the burden on patients and their carers. We investigated three different visual function tests, one paper-based and two applications on an iPod TouchTM tablet (Apple, Cupertino, CA, USA). We wanted to see if they could detect an increase in disease activity that would require treatment, compared to the decision by a retinal specialist at a traditional hospital eye outpatient visit based on clinical examination and retinal imaging. To encourage those without a smartphone or home internet to participate, we provided both an iPod Touch and Mobile Wireless-Fidelity device with a mobile contract. None of the tests performed well enough to safely monitor patients at home. Those who were willing to participate tended to be younger, had previous experience of using smartphones, sending e-mail and internet access and were more well-off than those who chose not to participate. Some participants also experienced difficulties with the devices provided and successfully uploading the data which were not related to the extent of previous information technology experience. There were also significant technical challenges for the research team. The study helpline was used heavily, considerably more than we anticipated. These tests are not ready to be used in this context. Future studies involving mobile health technology need to carefully consider how to reach those unlikely to participate and provide sufficient technical support to support long-term follow-up.