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.

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.

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.

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.

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.

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.

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.

Impact of hepatitis C virus polymorphisms on direct-acting antiviral treatment efficacy: Regulatory analyses and perspectives.

Several highly effective, interferon-free, direct-acting antiviral (DAA)-based regimens are available for the treatment of chronic hepatitis C virus (HCV) infection. Despite impressive efficacy overall, a small proportion of patients in registrational trials experienced treatment failure, which in some cases was associated with the detection of HCV resistance-associated substitutions (RASs) at baseline. In this article, we describe methods and key findings from independent regulatory analyses investigating the impact of baseline nonstructural (NS) 3 Q80K and NS5A RASs on the efficacy of current United States Food and Drug Administration (FDA)-approved regimens for patients with HCV genotype (GT) 1 or GT3 infection. These analyses focused on clinical trials that included patients who were previously naïve to the DAA class(es) in their investigational regimen and characterized the impact of baseline RASs that were enriched in the viral population as natural or transmitted polymorphisms (i.e., not drug-selected RASs). We used a consistent approach to optimize comparability of results across different DAA regimens and patient populations, including the use of a 15% sensitivity cutoff for next-generation sequencing results and standardized lists of NS5A RASs. These analyses confirmed that detection of NS3 Q80K or NS5A baseline RASs was associated with reduced treatment efficacy for multiple DAA regimens, but their impact was often minimized with the use of an intensified treatment regimen, such as a longer treatment duration and/or addition of ribavirin. We discuss the drug resistance-related considerations that contributed to pretreatment resistance testing and treatment recommendations in drug labeling for FDA-approved DAA regimens. CONCLUSION: Independent regulatory analyses confirmed that baseline HCV RASs can reduce the efficacy of certain DAA-based regimens in selected patient groups. However, highly effective treatment options are available for patients with or without baseline RASs. (Hepatology 2018;67:2430-2448).

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.

Prolonged Autonomic Fluctuation Derived from Parasympathetic Hypertonia after Carotid Endarterectomy but not Stenting.

BACKGROUND: Carotid endarterectomy (CEA) is a standard treatment for carotid artery stenosis, but the incidence after periprocedural myocardial infarction (MI) is not negligible. The mechanism for the higher risk of MI following CEA compared with the carotid artery stenting (CAS) is unclear. We hypothesized that it may be explained by different autonomic nervous responses. METHODS: This prospective, nonrandomized, observational study enrolled 50 patients from 2 centers: 25 underwent CEA and 25 CAS. Cardiac autonomic nervous activity was evaluated using 24-hour high-resolution ambulatory electrocardiography with parameters such as deceleration capacity (DC) and heart rate variability before the procedure, and at 1 week and 1-3 months after the procedure. RESULTS: One week after CEA, decreased DC and increased acceleration capacity were recognized. Standard deviation of sequential 5-minute NN interval means and the low-frequency and high-frequency components were all decreased. By the later phase measurement, these changes returned to baseline or beyond. The results suggest that diminished autonomic activity reversed to excessive parasympathetic dominance. In contrast, the patients treated by CAS showed no remarkable autonomic modification in the early or later phases. CONCLUSIONS: Distinct changes of sympathovagal response observed after CEA coincides with the time at which MI onset occurs, suggesting prolonged autonomic fluctuation may be a factor in the MI incidence after CEA.

Use of Viral Load as a Surrogate Marker in Clinical Studies of Cytomegalovirus in Solid Organ Transplantation: A Systematic Review and Meta-analysis.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir.

BACKGROUND & AIMS: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin. METHODS: We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients. RESULTS: In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n = 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12. CONCLUSIONS: The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection.

Identification of Covert Atrial Fibrillation in Cryptogenic Ischemic Stroke: Current Clinical Practice in Japan.

BACKGROUND AND AIM: A new insertable cardiac monitor, Reveal LINQ (Medtronic, Dublin, Ireland), was approved for clinical use in Japan in March 2016 for detecting atrial fibrillation in patients who develop ischemic stroke with no clearly definable etiology even after extensive workup, so-called cryptogenic ischemic stroke. Cooperation between a specialist of the Japan Stroke Society and a trained cardiologist or cardiac surgeon is needed both for appropriate patient selection and appropriate management of the device. In this paper, the clinical significance of and diagnostic methods for cryptogenic stroke and covert atrial fibrillation are explained, along with our proposal for the clinical indications for this new device. METHODS, RESULTS, AND CONCLUSION: The majority of cryptogenic ischemic strokes are considered to be embolic. In particular, covert atrial fibrillation is drawing attention as the causal emboligenic disease, and it was identified in 30% of patients with long-term observation using an insertable cardiac monitor. Should atrial fibrillation be present, there is a high risk of recurrent stroke, and the cardioembolic stroke that appears is generally severe. The ability to identify atrial fibrillation would be beneficial for preventing stroke recurrence, as anticoagulants can then be used as an established method of secondary prevention. Because the use of insertable cardiac monitors is somewhat invasive, and long-term care systems are also needed, patients suitable for examination using the new device would need to be identified on the basis of detailed diagnostics in accordance withcurrent medical practice in Japan.

Brugada syndrome behind complete right bundle-branch block.

BACKGROUND: The characteristic ECG of Brugada syndrome (BS) can be masked by complete right bundle-branch block (CRBBB) and exposed by resolution of the block or pharmacological or pacing maneuvers. METHODS AND RESULTS: The study consisted of 11 patients who had BS and CRBBB. BS was diagnosed before the development of CRBBB, on the resolution of CRBBB, or from new characteristic ST-segment changes that could be attributable to BS. Structural heart diseases were excluded, and coronary spasm was excluded on the basis of a provocation test at catheterization. In 7 patients, BS was diagnosed before the development of CRBBB. BS was diagnosed when CRBBB resolved spontaneously (n=1) or by right ventricular pacing (n=3). The precipitating cause for the spontaneous resolution of CRBBB, however, was not apparent. On repeated ECGs, new additional upward-convex ST-segment elevation was found in V2 or V3 in 3 patients. In 2 patients, new ST-segment elevation was induced by class IC drugs. The QRS duration was more prolonged in patients with BS and CRBBB compared with age- and sex-matched controls: 170±13 versus 145±15 milliseconds in V1 and 144±19 versus 128±7 milliseconds in V5 (both P<0.0001). The amplitude of R in V1 was smaller [corrected] in the BS patients than in the control subjects (P=0.0323), but that of R' was similar (P=0.0560). CONCLUSIONS: BS can coexist behind CRBBB, and CRBBB can completely mask BS. BS might be demonstrated by relief of CRBBB or by spontaneous or drug-induced ST-segment elevation. The prevalence, mechanism, and clinical significance of a combination of CRBBB and BS are yet to be determined.

Comparison between CHADS2 and CHA2DS2-VASc score for risk stratification of ischemic stroke in Japanese patients with non-valvular paroxysmal atrial fibrillation not receiving anticoagulant therapy.

It remains unclear if the CHADS2 score or CHA2DS2-VASc score is more useful for the risk stratification of ischemic stroke/systemic thromboembolism in Japanese patients with non-valvular paroxysmal atrial fibrillation (NVPAF). We retrospectively investigated the incidence of ischemic stroke on the basis of CHADS2 and CHA2DS2-VASc scores in 332 NVPAF patients (224 men, mean age, 65 ± 13 years) who were not administered anticoagulation therapy before publication of the 2008 JCS guideline (mean follow-up period, 53 ± 35 months). Annual rates of ischemic stroke/ systemic thromboembolism underlying antiarrhythmic drug therapy were 0.2%/year for the 0-point group; 0.9%/year for the 1-point group; 2.8%/year for the 2-point group; 9.4 %/year for the 3-point group; and 10.9%/year for the ≥ 4-point group on the basis of the CHADS2 scores, and 0%/year for the 0-point group; 0.6%/year for the 1-point group; 1.0%/ year for the 2-point group; 2.0 %/year for the 3-point group; 5.5%/year for the 4-point group; 9.1%/year for the 5-point group; and 13.7%/year for the ≥ 6-point group on the basis of the CHA2DS2-VASc scores. Both higher CHADS2 and CHA2DS2-VASc scores were associated with greater annual rates of ischemic stroke/systemic thromboembolism (P < 0.001). In multivariate logistic regression analysis, the CHADS2 (odds ratio [OR]:4.74, 95% confidence interval [CI]:2.80-8.00, P < 0.001) and CHA2DS2-VASc scores (OR: 4.15, 95% CI:2.57-6.71, P < 0.001) were significant independent predictors for ischemic stroke/systemic thromboembolism. Area under the receiver-operator characteristic curves for predicting ischemic stroke/systemic thromboembolism were 0.89 in the CHA2DS2-VASc scores (P < 0.001) and 0.87 in the CHADS2 scores (P < 0.001). In Japanese patients with NVPAF, both the CHADS2 and CHA2DS2-VASc scores are useful parameters for the risk stratification of ischemic stroke/systemic thromboembolism.

Myrmecophilous rove beetles (Coleoptera: Staphylinidae) associated with Aenictus hodgsoni (Hymenoptera: Formicidae) from Thailand, with description of two new genera and three new species.

Three species of rove beetles (subfamily Aleocharinae) were collected from colonies of Aenictus hodgsoni Forel, 1901 in Khao Yai National Park, Thailand. They are classified into three genera, including two new genera, and described herein as: Aenictobia siamensis Maruyama, sp. n. (tribe Aenictoteratini), Aenictosymbia cornuta Maruyama, gen. & sp. n. (tribe Lomechusini) and Aenictoxenides mirabilis Maruyama, gen. & sp. n. (tribe Pygostenini). The systematic positions of the new genera are discussed.