Reactivation of hepatitis B virus infection - an important aspect of multifaceted problem.

In this editorial we comment on the article published in the recent issue of the World Journal of Gastroenterology. We focus specifically on the problem of occult hepatitis B virus (HBV) infection, that is a result of previous hepatitis B (PHB) and a source for reactivation of HBV. The prevalence of PHB is underestimated due to the lack of population testing programs. However, this condition not only complicate anticancer treatment, but may be responsible for the development of other diseases, like cancer or autoimmune disorders. Here we unveil possible mechanisms responsible for realization of these processes and suggest practical approaches for diagnosis and treatment.

Successful Treatment of Hepatitis B Virus Reactivation With a Combination of Entecavir and Short-Term Administration of Interferon-ß Twice per Day.

Hepatitis B virus (HBV) reactivation-related hepatitis is likely to progress to acute liver failure, with high morbidity and mortality, even when nucleoside analogs are administered after the onset of hepatitis. We report a case of adult T-cell leukemia/lymphoma (ATLL) with the development of HBV reactivation-related hepatitis during chemotherapy and successful treatment by a combination of entecavir and short-term intravenous administration of interferon (IFN)-ß 3 MIU twice per day. This outcome suggests that this combination therapy has a potent effect in rapidly suppressing HBV replication in the early phase of hepatitis and may be effective and safe for the treatment of HBV reactivation-related hepatitis.

Patients beyond the optimal range of rATG-AUC still benefit from the targeted dosing strategy in unmanipulated haplo-PBSCT.

Rabbit anti-thymocyte globulin (rATG) is widely used in allogeneic hematopoietic stem cell transplantation to prevent graft failure and severe graft-versus-host disease (GVHD). We developed a rATG-targeted dosing strategy based on the optimal areas under the concentration-time curve (AUC) of active rATG. This study compared the outcomes of the optimal AUC arm with non-optimal AUC arm to assess the effect of the rATG-targeted dosing strategy. Eighty patients (median age: 32 years) with hematological malignancies who received their first haplo-PBSCT were enrolled successively. With rATG-targeted dosing, the AUC values of 60 patients (75%, optimal AUC arm) fell within the optimal range (100-148.5 UE/mL/day) and 20 fell beyond this range (non-optimal AUC arm). In the historical control group of 102 haplo-PBSCT patients who received a fixed dose of rATG (10 mg/kg), less patients fell within the optimal range (57.8%, P = .016). Looking at the non-optimal AUC arms in both groups, lower cumulative incidence of CMV was noted in the targeted dosing group compared with the historical control group(50.0%, 95% CI, 30.8%-72.9% versus 81.4%, 95% CI, 68.6%-91.3%; P = .004). The cumulative incidences of EBV, relapse, overall survival and disease-free survival tended to be superior in the non-optimal AUC arm in the targeted dosing group compared with the historical control. In the targeted dosing group, the cumulative incidence of cytomegalovirus (CMV) reactivation on day +180 tended to be lower in the optimal AUC arm (30.0%, 95% CI, 20.1%-43.3%) compared with the non-optimal AUC arm (50.0%, 95% CI, 30.8%-72.9%, P = .199) without statistical difference. There were no significant differences of acute or chronic GVHD, relapse, non-relapse mortality, overall survival, disease-free survival or lymphocyte reconstitution between the two arms. In conclusion, the rATG-targeted dosing strategy made the exposure of active rATG in more patients with the optimal AUC range. Even patients who fell beyond this range would still benefit from the strategy.

Atypical presentation of varicella-zoster virus reactivation in a lung transplant patient: a case report.

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.

Impact of protein and small molecule interactions on kinase conformations.

Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the kinase conformation (KinCon) reporter system. We first track BRAF kinase activity conformational changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1 kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP kinases in response to TNF pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps to identify cellular factors that impact drug efficacies. The understanding of the structural dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

Vascular development analysis: a study for tertiary anti-vascular endothelial growth factor therapy after second reactivation of retinopathy of prematurity.

Purpose: 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). Methods: 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. Results: 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. Conclusion: 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.

Disseminated, fatal reactivation of bovine tuberculosis in a patient treated with adalimumab: a case report and review of the literature.

PURPOSE: Tumor necrosis factor inhibitors (TNFi) are known to increase the risk of tuberculosis (TB) reactivation, though cases involving Mycobacterium bovis are rarely reported. CASE PRESENTATION/RESULTS: We describe a case of disseminated TB with M. bovis in a 78-year-old woman with a negative Interferon-Gamma-Release Assay (IGRA), taking adalimumab due to rheumatoid polyarthritis, which resulted in a fatal outcome. The atypical clinical and histopathological features were initially interpreted as sarcoidosis. The case occurred in Switzerland, an officially bovine tuberculosis-free country. The whole genome sequence of the patient's cultured M. bovis isolate was identified as belonging to the animal lineage La1.2, the main genotype in continental Europe, but showed significant genetic distance from previously sequenced Swiss cattle strains. In a literature review, four cases of bovine tuberculosis reactivation under TNFi treatment were identified, with pulmonal, oral and intestinal manifestations. Similar to our patient, two cases presented a negative IGRA before TNFi initiation, which later converted to positive upon symptomatic presentation of M. bovis infection. CONCLUSION: This case highlights the diagnostic challenges of TB in immunosuppressed patients, the limited sensitivity of IGRA, and the importance of considering TB reactivation even in regions declared free of bovine tuberculosis. Detailed patient histories, including potential exposure to unpasteurized dairy products, are essential for guiding preventive TB treatment before TNFi initiation.

Targeted memory reactivation to augment treatment in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder with traumatic memories at its core. Post-treatment sleep may offer a unique time window to increase therapeutic efficacy through consolidation of therapeutically modified traumatic memories. Targeted memory reactivation (TMR) enhances memory consolidation by presenting reminder cues (e.g., sounds associated with a memory) during sleep. Here, we applied TMR in PTSD patients to strengthen therapeutic memories during sleep after one treatment session with eye movement desensitization and reprocessing (EMDR). PTSD patients received either slow oscillation (SO) phase-targeted TMR, using modeling-based closed-loop neurostimulation (M-CLNS) with EMDR clicks as a reactivation cue (n = 17), or sham stimulation (n = 16). Effects of TMR on sleep were assessed through high-density polysomnography. Effects on treatment outcome were assessed through subjective, autonomic, and fMRI responses to script-driven imagery (SDI) of the targeted traumatic memory and overall PTSD symptom level. Compared to sham stimulation, TMR led to stimulus-locked increases in SO and spindle dynamics, which correlated positively with PTSD symptom reduction in the TMR group. Given the role of SOs and spindles in memory consolidation, these findings suggest that TMR may have strengthened the consolidation of the EMDR-treatment memory. Clinically, TMR vs. sham stimulation resulted in a larger reduction of avoidance level during SDI. TMR did not disturb sleep or trigger nightmares. Together, these data provide first proof of principle that TMR may be a safe and viable future treatment augmentation strategy for PTSD. The required follow-up studies may implement multi-night TMR or TMR during REM sleep to further establish the clinical effect of TMR for traumatic memories.

Hepatitis B Reactivation and Vaccination Effectiveness after Solid Organ Transplantation: A Matched Case-Control Study.

Solid organ transplant (SOT) recipients are at significant risk of hepatitis B (HB) virus (HBV) reactivation (HBVr). Despite the clinical significance of HBVr after solid organ transplantation, data on the risk factors for HBVr and vaccine effectiveness in SOT recipients with resolved HBV infection are limited. This study evaluated the risk factors for HBVr and the seroconversion rates after HBV vaccination in SOT recipients. Patients who had undergone solid organ transplantation and those with a resolved HBV infection were identified. We matched patients who experienced post-transplantation HBVr with those who did not. We also explored the characteristics and seroconversion rates of HBV-vaccinated patients following transplantation. In total, 1299 SOT recipients were identified as having a resolved HBV infection at the time of transplantation. Thirty-nine patients experienced HBVr. Pre-transplant HB surface antibodies (anti-HBs) positivity and allograft rejection within 3 months after transplantation were independently associated with HBVr. Among the 17 HBV-vaccinated patients, 14 (82.4%) received three or fewer vaccine doses, and 13 (76.5%) had seroconversion with positive anti-HBs results. Pre-transplant anti-HBs(-) status and allograft rejection were risk factors for HBVr in SOT recipients with a resolved HBV infection, and HBV vaccination after transplantation resulted in a high rate of anti-HBs seroconversion. HBV vaccination after transplantation should be considered to reduce the HBVr risk.

Recurring disease activity in relapsing remitting multiple sclerosis: The multicenter RDA-RMS study.

BACKGROUND: This study investigates the gap in understanding the dynamics of recurring disease activity (RDA) in RRMS patients after fingolimod (FGL) treatment discontinuation. The aim is to investigate RDA in RRMS patients after stopping FGL, aiming to improve management and comprehension of disease progression post-treatment. METHODS: In this multicenter, retrospective study, data from 172 of 944 RRMS patients aged 18-55, across nine centers in Turkey, who discontinued FGL treatment, were analyzed. The collected data included EDSS scores, annualized relapse rates (ARR), lymphocyte counts, and MRI findings, with follow-up assessments conducted at 6 months, 1 year, and up to 2 years. RESULTS: RDA was observed in 31.9 % of patients, with incidences of rebound and reactivation at 20.3 % and 11.6 %, respectively. Factors like younger age, longer treatment duration, lower lymphocyte counts, and higher lesion burden increased RDA risk. Notably, 52.9 % of pregnant patients experienced RDA (16.4 % of the overall RDA group), with rebound occurring in six and reactivation in three. Patients with RDA had longer medication-free intervals and increased ARR. Discontinuation reasons varied, with disease progression linked to a lower RDA risk. CONCLUSION: Findings highlight the necessity for personalized management and vigilant monitoring after FGL discontinuation in RRMS patients, offering critical insights into RDA risk factors, and the complex interplay between treatment cessation, pregnancy, and disease progression.

Characteristics of retinal vascularization in reactivated retinopathy of prematurity requiring treatment and clinical outcome after reinjection of ranibizumab.

This study aimed to determine whether the state of retinal vascularization after anti-vascular endothelial growth factor (anti-VEGF) injection can help predict the risk of reactivated retinopathy of prematurity (ROP) requiring treatment and whether repeated ranibizumab injection will be effective in such cases. We retrospectively reviewed 24 infants (43 eyes) who received ranibizumab monotherapy between January 2021 and December 2022. All eyes were classified as having non-retreated ROP or retreated ROP. The state of ROP at the time of treatment, the time required for resolution of plus disease, and the extent of vascularization at 4 and 8 weeks after treatment were analyzed. Extent of temporal retinal vascularization was measured with serial fundus images using disc-fovea distance (DF) unit and disc diameter (DD). Reactivated ROP requiring treatment occurred in six infants (25.0%) and ten eyes (23.3%) after ranibizumab treatment. The mean retreatment interval was 9.0 ± 3.3 weeks (range 4-16). In the retreated ROP group, the time required for the resolution of plus disease after primary injection was longer compared to the control group (13.3 days vs 5.2 days), with a mean ROP regression time of 3.4 weeks. All eyes in the retreated ROP showed retinal vascularization < 0.5 DF from the original site at 4 weeks after injection. In 90% of cases with retreated ROP, the extent of vascularization at 8 weeks after injection was within 1 DF from the original ROP site, and all cases showed reactivation in the posterior Zone II area. The extent of retinal neovascularization in the retreated group was an average of 0.7 DD (vs 1.7 DD) and 1.3 DD (vs 3.3 DD) at 4 and 8 weeks after injection, respectively. After ranibizumab retreatment, only one reactivated case with vitreous traction progressed to focal retinal detachment, while all other cases regressed with peripheral vascular development. The continuation of delayed retinal blood vessel development after ≥ 8 weeks may indicate a high likelihood of reactivated ROP requiring treatment. In the absence of vitreous traction, ranibizumab reinjection is likely to be effective in treating reactivated ROP requiring treatment.

Home-monitoring for neovascular age-related macular degeneration in older adults within the UK: the MONARCH diagnostic accuracy study.

Background: 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. Objectives: 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. Design: Diagnostic test accuracy cohort study, stratified by time since starting treatment. Setting: Six United Kingdom Hospital Eye Service macular clinics (Belfast, Liverpool, Moorfields, James Paget, Southampton, Gloucester). Participants: Patients with at least one study eye being monitored by hospital follow-up. Reference standard: Detection of active neovascular age-related macular degeneration by an ophthalmologist at hospital follow-up. Index tests: 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. Results: 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. Limitations: Pre-specified sample size not met; participants' difficulties using the devices; electronic tests not always available. Conclusions: 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. Future work: 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. Trial registration: This trial is registered as ISRCTN79058224. Funding: 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 Touch_TM 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.

Cytomegalovirus reactivation is frequent in multiple myeloma patients treated with daratumumab-based regimens.

BACKGROUND: Viral reactivations are frequent in hematologial patients due to their cancer-related and drug-induced immunosuppressive status. Daratumumab, an anti-CD38 monoclonal antibody, is used for multiple myeloma (MM) treatment, and causes immunosuppression by targeting CD38-expressing normal lymphocytes. In this single-center two-arm real-life experience, we evaluated incidence of cytomegalovirus (CMV) reactivation in MM patients treated with daratumumab-based regimens as first- or second-line therapy. METHODS: A total of 101 consecutive MM patients were included in this study and were divided into two cohorts: daratumumab and nondaratumumab-based (control) regimens. Patients treated with >2 lines of therapies were excluded to reduce the confounding factor of multi-treated cases. Primary endpoint was the CMV reactivation rate. RESULTS: CMV reactivation rate was significantly higher in the daratumumab cohort compared to control group (33% vs. 4%; p < 0.001), also with higher CMV-DNA levels (>1000 UI/mL in 12% of cases; p < 0.05). However, only one subject developed a CMV disease with severe pneumonia, while 12% of patients were successfully treated with preemptive therapy with valganciclovir. No subjects in the control cohort required anti-CMV agents (p = 0.02). CONCLUSION: Our single-center retrospective experience showed that daratumumab might significantly increase the risk of CMV reactivation in MM, while currently underestimated and related to morbility and mortality in MM patients under treatments. However, further validation on larger and prospective clinical trials are required.

Tumor Dormancy and Reactivation: The Role of Heat Shock Proteins.

Tumors are a heterogeneous group of cell masses originating in various organs or tissues. The cellular composition of the tumor cell mass interacts in an intricate manner, influenced by humoral, genetic, molecular, and tumor microenvironment cues that dictate tumor growth or suppression. As a result, tumors undergo a period of a dormant state before their clinically discernible stage, which surpasses the clinical dormancy threshold. Moreover, as a genetically imprinted strategy, early-seeder cells, a distinct population of tumor cells, break off to dock nearby or extravasate into blood vessels to secondary tissues, where they form disseminated solitary dormant tumor cells with reversible capacity. Among the various mechanisms underlying the dormant tumor mass and dormant tumor cell formation, heat shock proteins (HSPs) might play one of the most important roles in how the dormancy program plays out. It is known that numerous aberrant cellular processes, such as malignant transformation, cancer cell stemness, tumor invasion, metastasis, angiogenesis, and signaling pathway maintenance, are influenced by the HSPs. An accumulating body of knowledge suggests that HSPs may be involved in the angiogenic switch, immune editing, and extracellular matrix (ECM) remodeling cascades, crucial genetically imprinted strategies important to the tumor dormancy initiation and dormancy maintenance program. In this review, we highlight the biological events that orchestrate the dormancy state and the body of work that has been conducted on the dynamics of HSPs in a tumor mass, as well as tumor cell dormancy and reactivation. Additionally, we propose a conceptual framework that could possibly underlie dormant tumor reactivation in metastatic relapse.

The cellular Notch1 protein promotes KSHV reactivation in an Rta-dependent manner.

The cellular Notch signal transduction pathway is intimately associated with infections by Kaposi's sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposi's sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma-secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. Reduction of KSHV production is associated with gene-specific reduction of viral transcription in both Vero and PEL cells. Specific inhibition of Notch1 by siRNA partially reduces the production of infectious KSHV, and NICD1 forms promoter-specific complexes with viral DNA during reactivation. We conclude that constitutive Notch activity is required for the robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk/DNA complex during viral reactivation. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA-binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces the expression of specific viral genes yet does not affect the growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rta's ability to redistribute RBP-Jk DNA binding to the virus during reactivation.

Manipulated overlapping reactivation of multiple memories promotes explicit gist abstraction.

Sleep is considered to promote gist abstraction on the basis of spontaneous memory reactivation. As speculated in the theory of 'information overlap to abstract (iOtA)', 'overlap' between reactivated memories, beyond reactivation, is crucial to gist abstraction. Yet so far, empirical research has not tested this theory by manipulating the factor of 'overlap'. In the current study, 'overlap' itself was manipulated by targeted memory reactivation (TMR), through simultaneously reactivating multiple memories that either contain or do not contain spatially overlapped gist information, to investigate the effect of overlapping reactivation on gist abstraction. This study had a factorial design of 2 factors with 2 levels respectively (spatial overlap/no spatial overlap, TMR/no-TMR). Accordingly, 82 healthy college students (aged 19 âˆ¼ 25, 57 females) were randomized into four groups. After learning 16 pictures, paired with 4 auditory cues (4 pictures - 1 cue) according to the grouping, participants were given a 90-minute nap opportunity. Then TMR cueing was conducted during N2 and slow wave sleep of the nap. Performance in memory task was used to measure gist abstraction. The results showed a significant main effect of TMR on both implicit and explicit gist abstraction, and a marginally significant interaction effect on explicit gist abstraction. Further analyses showed that explicit gist abstraction in the spatial overlap & TMR group was significantly better than in the control group. Moreover, explicit gist abstraction was positively correlated with spindle density. The current study thus indicates that TMR facilitates gist abstraction, and explicit gist abstraction may benefit more from overlapping reactivation.

Hepatitis B Virus Reactivation after Switch to Cabotegravir/Rilpivirine in Patient with Low Hepatitis B Surface Antibody.

A patient in Japan with HIV began antiretroviral therapy because of acute hepatitis B virus (HBV) 15 years ago, with low hepatitis B surface antibody, and experienced breakthrough HBV reactivation 4 months after switching from bictegravir/emtricitabine/tenofovir alafenamide to cabotegravir/rilpivirine. An immune escape mutation, E164V, was identified in the isolated HBV DNA.

Pulmonary herpes simplex virus and cytomegalovirus in patients with acute respiratory distress syndrome related to COVID-19.

PURPOSE: Human herpesviruses, particularly cytomegalovirus (CMV) and herpes simplex virus (HSV), frequently reactivate in critically ill patients, including those with acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). The clinical interpretation of pulmonary herpesvirus reactivation is challenging and there is ongoing debate about its association with mortality and benefit of antiviral medication. We aimed to quantify the incidence and pathogenicity of pulmonary CMV and HSV reactivations in critically ill COVID-19 patients. METHODS: Mechanically ventilated COVID-19 patients seropositive for CMV or HSV were included in this observational cohort study. Diagnostic bronchoscopy with bronchoalveolar lavage was performed routinely and analyzed for alveolar viral loads and inflammatory biomarkers. Utilizing joint modeling, we explored the dynamic association between viral load trajectories over time and mortality. We explored alveolar inflammatory biomarker dynamics between reactivated and non-reactivated patients. RESULTS: Pulmonary reactivation (> 104 copies/ml) of CMV occurred in 6% of CMV-seropositive patients (9/156), and pulmonary reactivation of HSV in 37% of HSV-seropositive patients (63/172). HSV viral load dynamics prior to or without antiviral treatment were associated with increased 90-day mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.04-1.47). The alveolar concentration of several inflammatory biomarkers increased with HSV reactivation, including interleukin (IL)-6, IL-1ß, granulocyte colony stimulating factor (G-CSF), and tumor necrosis factor (TNF). CONCLUSION: In mechanically ventilated COVID-19 patients, HSV reactivations are common, while CMV reactivations were rare. HSV viral load dynamics prior to or without antiviral treatment are associated with mortality. Alveolar inflammation is elevated after HSV reactivation.

Impact of universal hepatitis B virus (HBV) screening using chemotherapy orders on the HBV reactivation in cancer patients.

INTRODUCTION: Hepatitis B virus (HBV) reactivation (HBVr) induced by chemotherapy in patients with resolved or chronic infection can lead to severe consequences. Despite recommendations, rates of HBV screening before chemotherapy are low due to poor recognition of risk factors by clinicians. The aim of the study is to assess whether routine HBV screening using universal HBV screening on chemotherapy orders (CO) could reduce HBVr incidence. METHODS: This is a 1-year retrospective single-center observational study of patients who received intravenous chemotherapy post implementation of CO. We compared the incidence of HBVr in three groups of patients: those screened through CO (group 1), those screened by the medical team (group 2), and those not screened (group 3). RESULTS: On a total of 1374 patients, 179 of 206 patients were screened as requested on CO (group 1) and 421 by the medical team (group 2), whereas 747 patients were not screened (group 3). Only one HBVr occurred, and no difference was seen on the incidence of HBVr between group 1 and group 3 (0% vs 0.1%; p = 1.00), probably because of a lack of follow-up after chemotherapy. Follow-up for HBVr was imperfect in group 1 and group 2 (16.7% vs 5.6%; p = 0.32). Screening was done for 92% of patients on anti-CD20 therapy. In group 3, 89 patients had ALT elevation during chemotherapy but only 17 (19%) were tested for HBVr. CONCLUSION: Systematic HBV detection requested on CO is an effective way to obtain a high percentage of patients with adequate screening, particularly when chemotherapy is at high risk of HBVr. Nevertheless, this screening method do not guarantee optimal follow-up and requires improvements.