To B or not to B: how the hepatitis B surveillance case definition can misdirect public health actions.

Abstract: Surveillance case definitions are utilised to understand the epidemiology of communicable diseases and to inform public health actions. We report a case of hepatitis B infection that meets the case definition for newly acquired infection. However, further investigation revealed that this was most likely past resolved hepatitis B infection with subsequent reactivation secondary to immunosuppression, rather than a newly acquired infection. This case highlights the importance of thorough case and clinician interviews, in combination with detailed assessment of pathology results in collaboration with treating clinicians, to determine the most appropriate public health actions.

Reactivation of herpes simplex virus 2 presenting as recurrent acute retinal necrosis following COVID-19 vaccination.

PURPOSE: 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. CASE DESCRIPTION: 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. CONCLUSION: 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.

Molecular basis and functional consequences of the interaction between the Base Excision Repair DNA glycosylase NEIL1 and RPA.

NEIL1 is a DNA glycosylase that recognizes and initiates base excision repair of oxidized bases. The ubiquitous ssDNA binding scaffolding protein, replication protein A (RPA), modulates NEIL1 activity in a manner that depends on DNA structure. Interaction between NEIL1 and RPA has been reported, but the molecular basis of this interaction has yet to be investigated. Using a combination of NMR spectroscopy and isothermal titration calorimetry (ITC), we show that NEIL1 interacts with RPA through two contact points. An interaction with the RPA32C protein recruitment domain was mapped to a motif in the common interaction domain (CID) of NEIL1 and a dissociation constant (Kd) of 200 nM was measured. A substantially weaker secondary interaction with the tandem RPA70AB ssDNA binding domains was also mapped to the CID. Together these two contact points reveal NEIL1 has a high overall affinity (Kd ∼ 20 nM) for RPA. A homology model of the complex of RPA32C with the NEIL1 RPA binding motif in the CID was generated and used to design a set of mutations in NEIL1 to disrupt the interaction, which was confirmed by ITC. The mutant NEIL1 remains catalytically active against a thymine glycol lesion in duplex DNA in vitro. Testing the functional effect of disrupting the NEIL1-RPA interaction in vivo using a Fluorescence Multiplex-Host Cell Reactivation (FM-HCR) reporter assay revealed an unexpected role for NEIL1 in nucleotide excision repair. These findings are discussed in the context of the role of NEIL1 in replication-associated repair.

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.

Risk of hepatitis B virus reactivation in cancer patients undergoing treatment with tyrosine kinase-inhibitors.

This editorial commented on an article in the World Journal of Gastroenterology titled "Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors: Case Report and Literature Analysis" by Colapietro et al. In this editorial, we focused on providing a more comprehensive exploration of hepatitis B virus reactivation (HBVr) associated with the usage of tyrosine kinase inhibitors (TKIs). It includes insights into the mechanisms underlying HBV reactivation, the temporal relationship between TKIs and HBV reactivation, and preventive measures. The aim is to understand the need for nucleos(t)ide analogs (NAT) and serial blood tests for early recognition of reactivation and acute liver injury, along with management strategies. TKIs are considered to be an intermediate (1%-10%) of HBVr. Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen, anti-hepatitis B core antigen (HBc), and anti-hepatitis B surface antibody. Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV. Nucleoside or nucleotide analogs (NAs) like entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) form the basis of HBV reactivation prophylaxis and treatment during immunosuppression. Conversely, lamivudine, telbivudine, and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains. However, these less effective NAs may still be utilized in cases where ETV, TDF, and TAF are not feasible treatment options.

Majocchi Granuloma Superinfected With Herpes Zoster.

Herpes zoster (HZ) infection is caused by the reactivation of the varicella-zoster virus (VZV) and has very rarely been reported at the site of a superficial fungal infection. Also, HZ occurring at the site of a deep fungal infection has not been reported in the literature. We discuss a unique case of a 45-year-old male patient presenting with a Majocchi granuloma (MG) superinfected with disseminated HZ.

Aversive memories can be weakened during human sleep via the reactivation of positive interfering memories.

Recollecting painful or traumatic experiences can be deeply troubling. Sleep may offer an opportunity to reduce such suffering. We developed a procedure to weaken older aversive memories by reactivating newer positive memories during sleep. Participants viewed 48 nonsense words each paired with a unique aversive image, followed by an overnight sleep. In the next evening, participants learned associations between half of the words and additional positive images, creating interference. During the following non-rapid-eye-movement sleep, auditory memory cues were unobtrusively delivered. Upon waking, presenting cues associated with both aversive and positive images during sleep, as opposed to not presenting cues, weakened aversive memory recall while increasing positive memory intrusions. Substantiating these memory benefits, computational modeling revealed that cueing facilitated evidence accumulation toward positive affect judgments. Moreover, cue-elicited theta brain rhythms during sleep predominantly predicted the recall of positive memories. A noninvasive sleep intervention can thus modify aversive recollection and affective responses.

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.

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.

Characterization of recurrent cytomegalovirus reactivations post allogenic stem cell transplantation in a population with high seropositivity.

OBJECTIVES: This study aimed to characterize incidences of CMV reactivations within one year post-allo-SCT and identify risk factors for CMV second reactivation episode in population with high seropositivity where first CMV reactivation episode deemed to be high. METHODS: This retrospective cohort study analyzed data from 359 allo-SCT patients aged 14 and older admitted to a tertiary academic hospital. Data on demographic and clinical factors, CMV serostatus, conditioning regimens, graft-versus-host disease prophylaxis, engraftment time, and CMV reactivations were collected. RESULTS: First and second CMV reactivations occurred in 88.9% and 18.4% of post-allo-SCT patients respectively. Patients were stratified into two groups based on primary disease necessitating allo-SCT, patients with malignant (Group 1) and non-malignant (Group 2) hematological disease. Factors associated with the second reactivation included cord blood as a stem cell source, human leukocyte antigen mismatch, acute graft-versus-host disease, and hematological malignancies. Patients with non-malignant hematological disease displayed better outcomes, including a higher rate of spontaneous clearance of first CMV reactivation (70% versus 49.4%) and lower rates of second CMV reactivation (9.6% versus 31%) than those with malignant hematological disease. The one-year overall survival rate was 87.7% (95.5% in non-malignant hematological disease and 78.13% in malignant hematological disease). CONCLUSION: Our findings are concordant with previous local study in regard to high rate of first CMV reactivation post-allo-SCT. It appears that patients with nonmalignant hematological disease had better outcomes, such as lower second CMV reactivation and higher survival rates compared to patients with malignant hematological disease. Further investigation is needed to identify other factors affecting recurrent CMV reactivations in allo-SCT in patients with malignant hematological disease.

Reactivation of cytomegalovirus and bloodstream infection and its impact on early survival after allogeneic haematopoietic stem cell transplantation: a multicentre retrospective study.

Cytomegalovirus reactivation (CMVr) and bloodstream infections (BSI) are the most common infectious complications in patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Both are associated with great high morbidity whilst the BSI is the leading cause of mortality. This retrospective study evaluated the incidence of CMVr and BSI, identified associated risk factors, assessed their impact on survival in allo-HSCT recipients during the first 100 days after transplantation. The study comprised 500 allo-HSCT recipients who were CMV DNA-negative and CMV IgG-positive before allo-HSCT. Amongst them, 400 developed CMVr and 75 experienced BSI within 100 days after allo-HSCT. Multivariate regression revealed that graft failure and acute graft-versus-host disease were significant risk factors for poor prognosis, whereas CMVr or BSI alone were not. Amongst all 500 patients, 56 (14%) developed both CMVr and BSI in the 100 days after HSCT, showing significantly reduced 6-month overall survival (p = 0.003) and long-term survival (p = 0.002). Specifically, in the initial post-transplant phase (within 60 days), BSI significantly elevate mortality risk, However, patients who survive BSI during this critical period subsequently experience a lower mortality risk. Nevertheless, the presence of CMVr in patients with BSI considerably diminishes their long-term survival prospects. This study provides real-world data on the impact of CMVr and BSI following transplantation on survival, particularly in regions such as China, where the prevalence of CMV IgG-positivity is high. The findings underscore the necessity for devising and executing focused prevention and early management strategies for CMVr and BSI to enhance outcomes for allo-HSCT recipients.

Does the ultrasensitive HBsAg Next assay enhance Hepatitis B diagnosis? An evaluation of analytical performances.

BACKGROUND: Accurate laboratory confirmation for Hepatitis B diagnosis and monitoring are crucial. Recently an ultrasensitive immunoassay test, the HBsAg Next (HBsAgNx), has been reported approximately eight times more sensitive than current HBsAg assays. The aim of our study was to assess the analytical performances of this new test. METHODOLOGY: 253 clinical samples from Saint Louis University Hospital were analyzed, splitted into four panels: (1) routine prospectively screening serums (n = 196), (2) retrospective serum samples before HBV reactivation (HBV-R) (n = 18), (3) occult HBV infection (OBI) (n = 10) and (4) a selection of wild type HBV genotypes (n = 29) RESULTS: Panel 1, showed robust agreement with the HBsAg Qualitative II (HBsAgQII) assay (Cohen's kappa = 0.83). Despite this agreement, 7 false positive with the HBsAgQII assay were found negative with HBsAgNx. One OBI was detected only with HBsAgNx. Panel 2 showed potential time savings in diagnosing HBV-R using HBsAgNx among 4/18 HBsAg positives samples. Panel 3 highlighted the ability of HBsAgNx to detect HBsAg in OBI patients defined by negative for HBsAg with HBsAgQII assay and positive for HBV DNA. Furthermore, the HBsAgNx assay detected all different genotypes. CONCLUSION: The study highlights the effectiveness of the HBsAgNx assay, showing its performance. It excels in detecting weakly positive samples and addressing challenging cases. HBsAgNx assay demonstrates promising analytical performances, with improved sensitivity and specificity compared to standard HBsAgQII assay, able to detect all genotypes. Its potential impact on early detecting and monitoring reactivations, and occult infections could be very useful in clinical practice.

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.

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.

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.

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.

A rare case of herpes simplex virus encephalitis from viral reactivation following surgically treated traumatic brain injury.

OBJECTIVE: Herpes simplex virus encephalitis (HSVE) is associated with significant morbidity and mortality. Here, we present the occurrence of HSVE in a 36-year-old immunocompetent patient following craniotomy for a traumatic acute subdural hematoma (ASDH). METHODS: Imaging after four days of progressive headache following a fall with head-strike demonstrated a 1 cm thick left holohemispheric ASDH with significant cerebral compression, edema, and 8 mm of left-to-right midline shift, and an emergent craniotomy and ASDH evacuation were performed, with additional treatment needed for reaccumulation. Postoperatively, the patient developed a worsening leukocytosis, became febrile, and was hypotensive requiring vasopressor support. RESULTS: Despite empiric antibiotics, the patient remained persistently febrile with significant leukocytosis. Repeat head CT showed a new left insular hypodensity and a subsequent viral encephalitis panel was positive for HSV-1. The patient was then started on intravenous acyclovir, with progressive neurological exam improvement. Of note, the patient was noted to have a positive serum HSV-1 IgG antibody titer, indicative of prior infection. CONCLUSIONS: Given the known systemic immunosuppression in brain injury and the high prevalence of HSV seropositivity, clinicians should consider the possibility of HSVE from HSV reactivation in TBI patients with persistent fever, leukocytosis, and/or neurological deficits without an obvious etiology.

Exploring long-term retention and reactivation of micropollutant biodegradation capacity.

The factors limiting micropollutant biodegradation in the environment and how to stimulate this process have often been investigated. However, little information is available on the capacity of microbial communities to retain micropollutant biodegradation capacity in the absence of micropollutants or to reactivate micropollutant biodegradation in systems with fluctuating micropollutant concentrations. This study investigated how a period of 2 months without the addition of micropollutants and other organic carbon affected micropollutant biodegradation by a micropollutant-degrading microbial community. Stimulation of micropollutant biodegradation was performed by adding different types of dissolved organic carbon (DOC)-extracted from natural sources and acetate-increasing 10 × the micropollutant concentration, and inoculating with activated sludge. The results show that the capacity to biodegrade 3 micropollutants was permanently lost. However, the biodegradation activity of 2,4-D, antipyrine, chloridazon, and its metabolites restarted when these micropollutants were re-added to the community. Threshold concentrations similar to those obtained before the period of no substrate addition were achieved, but biodegradation rates were lower for some compounds. Through the addition of high acetate concentrations (108 mg-C/L), gabapentin biodegradation activity was regained, but 2,4-D biodegradation capacity was lost. An increase of bentazon concentration from 50 to 500 µg/L was necessary for biodegradation to be reactivated. These results provide initial insights into the longevity of micropollutant biodegradation capacity in the absence of the substance and strategies for reactivating micropollutant biodegrading communities.

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.