Consensus Definitions of Cytomegalovirus (CMV) Infection and Disease in Transplant Patients Including Resistant and Refractory CMV for Use in Clinical Trials: 2024 Update From the Transplant Associated Virus Infections Forum.

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.

Food habits of 3 myrmecophilous bug species on myrmecophytic Macaranga (Malpighiales: Euphorbiaceae) vary from herbivory to predation.

Myrmecophytes have mutualistic relationships with symbiotic ants. Although myrmecophytic Macaranga (Malpighiales: Euphorbiaceae) species are well protected by aggressive Crematogaster (Hymenoptera: Formicidae) ants, some bug species occur on the myrmecophytes. To clarify the associations of these bugs with the plants and the ants, we studied the food habits of 3 bug species, Pilophorus lambirensis Nakatani et Komatsu, 2013 (Hemiptera: Miridae: Phylinae), Phylinae sp. 1, and Arbela sp. 1 (Hemiptera: Nabidae). We conducted field observations in a Bornean rainforest. First, we located these bugs and studied their behavioral responses to the ants on Macaranga species; we then conducted stable isotope analyses. All bugs avoided direct contact with ants, but they occurred only on trees with active ants. Pilophorus lambirensis and Phylinae sp. 1 were most commonly observed on the apical parts of host trees, whereas Arbela sp. 1 was mainly in areas distant from the apical parts where ants were sparse. The stable isotope ratios indicated that Phylinae sp. 1 fed on food bodies, which are nutrient-rich spherical bodies produced by Macaranga trees on the apical parts for ants. Although the main diet of the other 2 species remains unclear, nitrogen isotopic signatures demonstrated that P. lambirensis is herbivorous, whereas Arbela sp. 1 is carnivorous. However, the distant location from ants and its isotopic signatures indicated that Arbela sp. 1 rarely fed on the ants. At least 2 mirid bug species might obtain enemy-free space in addition to the food provided by the myrmecophytes.

Consensus Definitions of BK Polyomavirus Nephropathy in Renal Transplant Recipients for Clinical Trials.

BACKGROUND: BK polyomavirus (BKPyV) infection and BK polyomavirus nephropathy (BKPyVAN) are important causes of allograft dysfunction and premature allograft loss in renal transplant recipients. RESULTS AND DISCUSSION: Controlled clinical trials to evaluate new agents for prevention and treatment are needed but are hampered by the lack of outcome measures that accurately assess the effect of the intervention, are clinically relevant, and are acceptable from a regulatory perspective. METHODS: To facilitate consistent end points in clinical trials and to support clinical research and drug development, definitions of BKPyV infection and disease have been developed by the BK Disease Definitions Working Group of the Transplantation Associated Virus Infection Forum with the Forum for Collaborative Research, which consists of scientists, clinicians, regulators, and industry representatives. CONCLUSIONS: These definitions refine established principles of "proven" BKPyV disease and introduce a "probable" disease category that could be used in clinical trials to prevent or treat BKPyVAN in renal transplant recipients.

Immune Prophylaxis and Therapy for Human Cytomegalovirus Infection.

Human Cytomegalovirus (HCMV) infection is widespread and can result in severe sequelae in susceptible populations. Primary HCMV infection of naïve individuals results in life-long latency characterized by frequent and sporadic reactivations. HCMV infection elicits a robust antibody response, including neutralizing antibodies that can block the infection of susceptible cells in vitro and in vivo. Thus, antibody products and vaccines hold great promise for the prevention and treatment of HCMV, but to date, most attempts to demonstrate their safety and efficacy in clinical trials have been unsuccessful. In this review we summarize publicly available data on these products and highlight new developments and approaches that could assist in successful translation of HCMV immunotherapies.

Informing selection of drugs for COVID-19 treatment through adverse events analysis.

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic and there is an urgent need for safe and effective drugs for COVID-19 treatment. Since developing a new drug is time consuming, many approved or investigational drugs have been repurposed for COVID-19 treatment in clinical trials. Therefore, selection of safe drugs for COVID-19 patients is vital for combating this pandemic. Our goal was to evaluate the safety concerns of drugs by analyzing adverse events reported in post-market surveillance. We collected 296 drugs that have been evaluated in clinical trials for COVID-19 and identified 28,597,464 associated adverse events at the system organ classes (SOCs) level in the FDA adverse events report systems (FAERS). We calculated Z-scores of SOCs that statistically quantify the relative frequency of adverse events of drugs in FAERS to quantitatively measure safety concerns for the drugs. Analyzing the Z-scores revealed that these drugs are associated with different significantly frequent adverse events. Our results suggest that this safety concern metric may serve as a tool to inform selection of drugs with favorable safety profiles for COVID-19 patients in clinical practices. Caution is advised when administering drugs with high Z-scores to patients who are vulnerable to associated adverse events.

No Association Between DAA Treatment for HCV Infection and Herpes Zoster Infection in Analysis of Data From 37 Clinical Trials.

BACKGROUND AND AIMS: Recent case series and retrospective studies have raised concerns that patients who receive direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection are at increased risk of developing varicella-zoster virus infection (VZV reactivation). We investigated the relationship between DAA treatment and VZV reactivation by analyzing pooled participant-level data from 37 clinical trials of DAA agents. METHODS: We obtained demographic, adverse event, and laboratory data from 13,816 participants in 37 clinical trials submitted to the Food and Drug Administration for approval of DAA agents for treatment of HCV infection. Participants received DAAs (n = 12,249), placebo (n = 997), pegylated interferon (n = 243), or a combination of DAAs and pegylated interferon (n = 327). Occurrence of VZV reactivation was identified using systematically reported adverse event data. HCV virologic response was evaluated by measurement of HCV RNA. RESULTS: VZV reactivation occurred in 9.9 cases per 1000 person-years of DAA treatment (95% CI, 6.8-14.0 per 1000 person years) and 13.8 cases per 1000 person-years of placebo (95% CI, 3.5-37.5 per 1000 person years). No participants in the pegylated interferon or combination DAA and pegylated interferon groups experienced VZV reactivation. Within the placebo-controlled trials there was no significant difference in VZV reactivation between DAA treatment and placebo. VZV reactivation was associated with age older than 40 years, female sex, and HIV coinfection. We did not find an association between time of virologic response and time to VZV reactivation. CONCLUSION: In an analysis of data from 37 trials, we found no evidence for an association between DAA treatment for HCV infection and increased risk of VZV reactivation.

Eigenvalues of Two-State Quantum Walks Induced by the Hadamard Walk.

Existence of the eigenvalues of the discrete-time quantum walks is deeply related to localization of the walks. We revealed, for the first time, the distributions of the eigenvalues given by the splitted generating function method (the SGF method) of the space-inhomogeneous quantum walks in one dimension we had treated in our previous studies. Especially, we clarified the characteristic parameter dependence for the distributions of the eigenvalues with the aid of numerical simulation.

Cryptic Diversity in the Aphid-Parasitizing Wasp Protaphidius nawaii (Hymenoptera: Braconidae): Discovery of Two Attendant-Ant-Specific mtDNA Lineages.

The parasitoid wasp Protaphidius nawaii parasitizes the aphid Stomaphis japonica, which is obligatorily attended by several species of ants of genus Lasius. Subgenus Lasius or Dendrolasius ants use different defense strategies to protect the aphids that they attend (Lasius, shelter building; Dendrolasius, aggressive attack). We performed molecular phylogenetic analysis based on partial mitochondrial DNA sequences of P. nawaii and found that the parasitoid wasp consists of two highly differentiated genetic lineages. Although these two lineages distributed sympatrically, one tends to parasitize aphids attended by ants of subgenus Lasius, and the other parasitizes aphids attended by ants of subgenus Dendrolasius. The two lineages of P. nawaii appear to exhibit different oviposition behaviors adapted to the different aphid-protection strategies of the two ant subgenera.

Hepatitis C Virus RNA Levels Following Virologic Failure With Direct-acting Antivirals: Implications for Lower Sensitivity Diagnostic Assays.

We analyzed post-treatment hepatitis C virus (HCV) RNA levels from 330 subjects who experienced virologic failure in clinical trials of direct-acting antivirals. We demonstrated that 97% had post-treatment Week 12 HCV RNA >10 000 IU/mL, above reported sensitivity limits of novel diagnostic assays being considered for simplified HCV treatment monitoring.

Influenza A virus hemagglutinin mutations associated with use of neuraminidase inhibitors correlate with decreased inhibition by anti-influenza antibodies.

BACKGROUND: Vaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza. The activity of influenza vaccines and antivirals drugs such as the NAIs can be affected by mutations in the influenza hemagglutinin (HA) protein. Numerous HA substitutions have been identified in nonclinical NAI resistance-selection experiments as well as in clinical specimens from NAI treatment or surveillance studies. These mutations are listed in the prescribing information (package inserts) for FDA-approved NAIs, including oseltamivir, zanamivir, and peramivir. METHODS: NAI treatment-emergent H1 HA mutations were mapped onto the H1N1 HA1 trimeric crystal structure and most of them localized to the HA antigenic sites predicted to be important for anti-influenza immunity. Recombinant A/California/04/09 (H1N1)-like viruses carrying HA V152I, G155E, S162 N, S183P, and D222G mutations were generated. We then evaluated the impact of these mutations on the immune reactivity and replication potential of the recombinant viruses in a human respiratory epithelial cell line, Calu- 3. RESULTS: We found that the G155E and D222G mutations significantly increased viral titers ~ 13-fold compared to the wild-type virus. The hemagglutination and microneutralization activity of goat and ferret antisera, monoclonal antibodies, and human serum samples raised against pandemic A(H1N1)pdm09 viruses was ~ 100-fold lower against mutants carrying G155E or D222G compared to the wild-type virus. CONCLUSIONS: Although the mechanism by which HA mutations emerge during NAI treatment is uncertain, some NAI treatment-emergent HA mutations correlate with decreased immunity to influenza virus.

Radiofrequency catheter ablation for inappropriate sinus tachycardia in a patient with systemic lupus erythematosus: a case report.

BACKGROUND: Systemic lupus erythematosus (SLE) is known to cause inappropriate sinus tachycardia (IST). However, there is limited evidence available with regard to the treatment of IST in this setting. In this article, we report a case of drug refractory IST in a patient with SLE treated with radiofrequency catheter ablation (RFCA) using a non-contact mapping system. CASE SUMMARY: A 33-year-old woman had been diagnosed with SLE in 2001. She presented with complaints of persistent palpitations for 1 month and persistent sinus tachycardia. She underwent RFCA using a non-contact mapping system for drug refractory IST. The voltage and activation maps did not show obvious differences in the earliest activation site at heart rates (HRs) 90-150 b.p.m. In contrast, the areas of breakout sites were clearly distinguished between those from the normal P-wave zones at HR <140 b.p.m. and those from higher rate sites at HR >140 b.p.m. Radiofrequency catheter ablation was performed in those areas as the target for ablation. Thereafter, the symptoms steadily disappeared and the maximum HR-using 24-h Holter monitoring-decreased from 156 to 120 b.p.m. DISCUSSION: Radiofrequency catheter ablation using a non-contact mapping system was applied to the treatment of drug refractory IST in a patient with SLE. Of note, IST in such patients may be left untreated. This approach may be considered as a first-line therapy option for drug refractory IST in patients with SLE.

In-depth genomic analyses identified novel letermovir resistance-associated substitutions in the cytomegalovirus UL56 and UL89 gene products.

Letermovir is a human cytomegalovirus (HCMV) terminase inhibitor recently approved in the United States for prophylaxis of HCMV infection or disease in adult HCMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant. In the registrational trial, the rate of clinically significant HCMV infection, defined as the development of HCMV DNAemia leading to preemptive antiviral therapy or the diagnosis of HCMV end-organ disease, through 24 weeks post-transplant, was significantly lower among subjects who received letermovir prophylaxis through 14 weeks post-transplant compared to those who received placebo. We performed independent analyses of the HCMV nucleotide sequencing data generated by next-generation sequencing from this phase 3 registrational trial of letermovir to identify viral genetic characteristics associated with virologic failure during and following letermovir prophylaxis. The pUL56 substitutions V236M, E237G, and C325W, identified at previously known resistance-associated positions, were detected in the virus of subjects who were treated with letermovir and failed letermovir prophylaxis. Several additional substitutions were detected in pUL56 and pUL89, and further characterization is needed to determine if any of these substitutions are clinically relevant. The analyses reported herein were conducted to confirm sponsor-reported drug-resistance pathways, to assess the frequency of resistance, and to better understand the risk of prophylaxis failures and treatment-emergent drug resistance.

New-onset atrial fibrillation in patients with acute coronary syndrome may be associated with worse prognosis and future heart failure.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of atrial fibrillation (AF) in patients with acute coronary syndrome (ACS). METHODS: A total 648 of consecutive ACS patients were divided into non-AF and all-AF groups. The all-AF group was further subdivided into new-onset AF and pre-existing AF groups. We compared prognosis among these groups using the Cox regression analysis. RESULTS: The mean follow-up period was 1.4 ± 1.2 years. Overall patient numbers were 538 in non-AF and 110 in all-AF groups (67 in new-onset AF and 43 in pre-existing AF). Seventy-eight all-cause deaths and 42 cardiac deaths were observed. New-onset AF had a worse prognosis than the other groups in the Kaplan-Meier analysis (P = 0.025) after observation. Cox regression analysis indicated no significant difference for all-cause death among the three groups. The hazard ratio of congestive heart failure requiring hospitalization was significantly higher in the all-AF and new-onset AF group than in the non-AF group. Multivariate logistic regression analysis revealed that renal dysfunction, peripheral arterial disease, Killip classification ≥2, and left ventricular ejection fraction (LVEF) were independent predictors of all-cause death. The new-onset AF group had the highest prevalence of Killip classification ≥2 and the lowest LVEF. CONCLUSION: In our study, AF was not an independent predictor of all-cause death, but new-onset AF may be associated with worse prognosis and future heart failure.

Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials.

Despite advances in preventive strategies, cytomegalovirus (CMV) infection remains a major complication in solid organ and hematopoietic cell transplant recipients. CMV infection may fail to respond to commercially available antiviral therapies, with or without demonstrating genotypic mutation(s) known to be associated with resistance to these therapies. This lack of response has been termed "resistant/refractory CMV" and is a key focus of clinical trials of some investigational antiviral agents. To provide consistent criteria for future clinical trials and outcomes research, the CMV Resistance Working Group of the CMV Drug Development Forum (consisting of scientists, clinicians, regulatory officials, and industry representatives from the United States, Canada, and Europe) has undertaken establishing standardized consensus definitions of "resistant" and "refractory" CMV. These definitions have emerged from the Working Group's review of the available virologic and clinical literature and will be subject to reassessment and modification based on results of future studies.

Treatment and Prevention of CMV Disease in Transplant Recipients: Current Knowledge and Future Perspectives.

This review summarizes the significant impact of cytomegalovirus (CMV) infection on solid organ and hematopoietic stem cell transplant recipients. A discussion of the various CMV prevention and treatment strategies is provided, including a detailed description of each of the available CMV antiviral drugs.