We provide an update to the Association of Medical Microbiology and Infectious Disease Canada seasonal influenza foundation guideline on the use of antiviral drugs for influenza for the upcoming 2021-2022 influenza season in Canada. Peramivir and baloxavir marboxil were licensed in Canada in 2017 and 2020, respectively, but neither is currently marketed. Thus, this guidance continues to focus on further optimizing the use of oseltamivir and zanamivir. Important issues for this year include the implications of co-circulation of severe acute respiratory syndrome coronavirus 2 and influenza viruses; the role of diagnostic testing in relation to impact on patient management; and dosing and administration recommendations for neuraminidase inhibitors for various at-risk age groups.

Most healthy people fully recover from influenza illness without medical intervention or antiviral treatment However, given the potential for suboptimal VE this season, antiviral therapy may be of particular importance in the management of individuals with suspected influenza illness despite documentation of having received the 2019–2020 influenza vaccine

We provide an update to the Association of Medical Microbiology and Infectious Disease Canada foundation guidance for the upcoming 2020-2021 influenza season in Canada. Important issues for this year include the implications of co-circulation of SARS-CoV-2, the role of diagnostic testing, and a restatement of dosing and administration recommendations for neuraminidase inhibitors in various age groups and underlying health conditions. Although peramivir and baloxivir are now licensed in Canada, neither is currently marketed, so this guidance focuses on further optimizing the use of oseltamivir and zanamivir.

This document updates the previous AMMI Canada Foundation Guidance (2013) on the use of antiviral therapy for influenza.

Influenza vaccine is recommended annually to reduce the influenza-associated disease burden, particularly among those at high risk of serious influenza complications ( 1 ). However, a potential for low vaccine effectiveness (VE) has been identified for the 2017–2018 influenza season. To address that concern, the following antiviral drug recommendations have been revised (see Table 1 , changes in bold) from the AMMI Canada Foundation Document ( 2 ).

ABSTRACT We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (−1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.)

BACKGROUNDDespite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, the mortality rate is approximately 14%-19%. Among survivors, 45%-60% have neuropsychological sequelae at 1 year. Thus, improving therapeutic approaches to HSE remains a high priority.METHODSFollowing completion of a standard course of intravenous ACV, 87 adult patients with HSE (confirmed by positive polymerase chain reaction [PCR] for herpes simplex virus DNA in cerebrospinal fluid) were randomized to receive either valacyclovir (VACV) 2 g thrice daily (n = 40) or placebo tablets (n = 47) for 90 days (12 tablets of study medication daily). The primary endpoint was survival with no or mild neuropsychological impairment at 12 months, as measured by the Mattis Dementia Rating Scale (MDRS). Logistic regression was utilized to assess factors related to the primary endpoint.RESULTSThe demographic characteristics of the 2 randomization groups were statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in the MDRS scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group.CONCLUSIONSFollowing standard treatment with intravenous ACV for PCR-confirmed HSE, an additional 3-month course of oral VACV therapy did not provide added benefit as measured by neuropsychological testing 12 months later in a population of relatively high-functioning survivors.CLINICAL TRIALS REGISTRATIONNCT00031486.

The AMMI Canada Guidelines document 'The use of antiviral drugs for influenza: A foundation document for practitioners', published in the Autumn 2013 issue of the Journal, outlines the recommendations for the use of antiviral drugs to treat influenza. This article, which represents the first of two updates to these guidelines published in the current issue of the Journal, aims to inform health care professionals of the increased risk for influenza in long-term care facilities due to a documented mismatch between the components chosen for this season's vaccine and currently circulating influenza strains. Adjusted recommendations for the use of antiviral drugs for influenza in long-term care facilities for this season are provided.

This article represents the second update to the AMMI Canada Guidelines document on the use of antiviral drugs for influenza. The article aims to inform health care professionals of the increased risk for influenza in long-term care facilities due to a documented mismatch between the components chosen for this season's vaccine and currently circulating influenza strains. Adjusted recommendations for the use of antiviral drugs for influenza in the acute care setting for this season are provided.

Importance of the field: Famciclovir is the prodrug of penciclovir, a guanosine analogue that inhibits viruses of the a sub-family of the Herpesviridae, as well as hepatitis B virus. It is indicated for management of mucocutaneous herpes simplex virus disease and acute herpes zoster, and has been investigated for management of hepatitis B virus infection. Areas covered in this review: Data for this review were identified by searches of papers published in English on Medline and Scopus, spanning the years 1975 through 1 February 2010 with the key words: 'famciclovir', 'famvir', 'penciclovir', 'herpes', 'oral', 'genital', 'varicella', 'zoster' and 'virus' in association with 'safety', 'toxicity', 'tolerability', 'efficacy' and 'indications'. Relevant references were also obtained from articles acquired through the search strategy. What the reader will gain: Readers are also provided with up-to-date information on the use of famciclovir for infections due to herpes simplex, varicella zoster and hepatitis B viruses. Clinical data pertaining to the safety and tolerability of famciclovir are also reviewed. Take home message: Famciclovir is a safe, convenient, and well-tolerated drug when used for its approved indications. The most common side effects indicated in the majority of studies were headache and nausea. Data for its use in childhood and pregnancy are limited.

Eggerthella lenta is an anaerobic, Gram-positive bacillus commonly found in the human digestive tract. Occasionally, it can cause life-threatening infections. Bacteremia due to this organism is always clinically significant and is associated with gastrointestinal diseases and states of immune suppression. The authors report a case involving an elderly man with a newly diagnosed gastrointestinal malignancy who developed bacteremia caused by E lenta, treated successfully using empirical therapy with vancomycin and piperacillin-tazobactam, followed by directed therapy with metronidazole once the identity and antibiotic susceptibility of the organism was established. The present case reinforces the connection between E lenta bacteremia with gastrointestinal malignancy and highlights the importance of searching for a source of bacteremia due to this organism.

BACKGROUND:We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681).METHODS:Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15-25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463]).RESULTS:High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242-794), 204 (95% CI, 129-480), and 480 (95% CI, 250-5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively.CONCLUSIONS:Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type.

Elsewhere in the pages of the Journal, Muthuri et al answer a question of substantial contemporary importance to clinicians and public health decision makers, namely, whether antiviral therapy for influenza can reduce severe outcomes of the disease in hospitalized patients [1]. In a welcome affirmation of the effectiveness of neuraminidase inhibitor (NAI) treatment, they report that a meta-analysis of 90 observational studies involving 34 895 patients of whom 85% had laboratory-confirmed 2009 pandemic influenza A virus subtype H1N1 (A [H1N1]pdm09) infection revealed that antiviral therapy, principally oseltamivir, initiated within 48 hours of symptom onset reduced the likelihood of severe outcomes, namely admission to a critical care unit or death, by 49%–65%. The strength of the conclusions resides both in the methodologic rigor applied to the meta-analysis of the component studies and the large numbers of studies and patients analyzed. This finding confirms earlier reports of reduced mortality with oseltamivir therapy in those hospitalized with seasonal [2] or avian A(H5N1) [3, 4] influenza. The findings in the current report also complement observations from ecologic studies [5]. For example, Japan, the country with highest per capita use of NAIs during the 2009 pandemic, also had the lowest case-fatality rate and remarkably no reported deaths in A(H1N1)pdm09–infected pregnant women [6, 7]. More recently, a countrybased analysis found that each 10% increase in oseltamivir supply (calculated in kilograms per 100 000 people) was associated with a 1.6% reduction in A (H1N1)pdm09 mortality [8]. While previous analyses and the current one have generally found greater effects with earlier compared with later therapy, it is important to note that multiple observational reports in those hospitalized with seasonal, A(H1N1)pdm09, or avian A(H5N1) influenza indicate that a treatment benefit can be demonstrated up to 5 days after symptom onset, including studies in high-risk groups such as pregnant women [2–4, 9–11]. It makes sense that even delayed antiviral intervention would benefit patients, when one considers the protracted duration of viral replication in many patients with serious influenza, sometimes despite oseltamivir administration [12, 13], compared with its relatively short duration in outpatient adults with uncomplicated influenza. As pointed out by Muthuri et al, the timing of NAI initiation was examined carefully in only a few studies. Delayed initiation often reflected late diagnosis or presentation to care and belated efforts at salvage. Indeed, during the pandemic, misunderstanding the potential value of therapy initiated beyond 48 hours of illness unfortunately led many clinicians to not administer NAIs to those who might have benefited. Thus, using 48 hours as a threshold for delayed therapy in hospitalized patients covers a diversity of reasons for late onset of therapy and may be less relevant than in outpatient settings. While time to treatment initiation is a key variable in assessing effectiveness, future analyses should also examine illness severity, cause for hospitalization (eg, influenza-associated pneumonia, exacerbations of underlying conditions, and presence of secondary bacterial infections), comorbidities, and virologic markers at the time of initiating therapy, preferably with propensity scoring that takes such factors into consideration. This current meta-analysis has advanced our understanding of the effectiveness Received and accepted 31 October 2012; electronically published 29 November 2012. Correspondence: Fred Y. Aoki, MD, Room 510 Basic Medical Sciences Building, 745 Bannatyne Ave, Winnipeg, MB, Canada R3E 0J9 (aokify@cc.umanitoba.ca). The Journal of Infectious Diseases 2013;207:547–9 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jis727

Criteria for assessing suitability of applicants for professional degree programs such as veterinary medicine are usually treated as distinct components of a composite scoring procedure that determines applicant ranking. Some components are valued more than others, which is reflected in the relative weights assigned to each component. However, the patterns of dispersal of individual components have the potential to alter the assigned relative weights. Components with larger variances can have greater influences on composite scores than intended. Such unintended altered weighting can be avoided through standardization. Yet non-standardized approaches continue to be used for admissions ranking in several programs. In this study, we documented the potential for differential selection of applicants when non-standardized scoring approaches are applied to admissions assessment components. At our medical school, applicants' component scores with differing variances are standardized by determining Z-scores with a mean of 0 and standard deviation of 1 before mathematically combining to calculate composite scores and admissions ranking. We retrospectively and hypothetically ranked one applicant cohort using non-standardized methods and identified differences in ranking between the standardized and non-standardized approaches. Most differences were observed for applicants in the second, third, and fourth quintiles of the admissions rank list, that is, those for whom admissions cut-off decisions make a marked difference. Observations were supported by lower Spearman's rank correlation coefficients in these quintiles. Although standardization of component scores is not a novel topic, we document the implications of using non-standardized scoring approaches for applicant ranking and underscore the importance of standardization of component scores.

High air stability is the key issue for the organic thin film transistors (OTFTs). Recently developed high-mobility organic semiconductors, 2,7-diphenyl[1]benzothieno[3,2-b][1]benzothiophene (DPh-BTBT) and dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene (DNTT), are much more stable than pentacene. We measured the ultraviolet photoelectron spectra (UPS) of DPh-BTBT and DNTT and revealed that their HOMOs are situated at deeper energy levels than that of pentacene, which contributes to their high stability. The UPS of DNTT is well reproduced by the DFT calculation, while that of DPh-BTBT is not fully reproduced. This difference is discussed in terms of dihedral angle between the phenyl groups and the BTBT ring.

1C INDEX I. PURPOSE II. PROCESS STATEMENT III. GRADING OF RECOMMENDATIONS IV. THE DISEASE A. Influenza viruses B. Clinical aspects C. Clinical diagnosis of influenza illness V. TREATMENT OF INFLUENZA ILLNESS A. Antiviral drugs including off-label use B. Benefits of antiviral treatment C. Considerations in selecting treatments 1. Severity of illness 2. Presence of risk factors or co-morbid medical conditions 3. Interval between onset of illness and initiation of antiviral therapy 4. Likely influenza type(s) causing infection D. Treatment of children E. Treatment of immunocompromised patients F. Treatment of patients with renal impairment G. Treatment of pregnant patients VI. RECOMMENDATIONS FOR TREATMENT A. General principles B. Treatment of non-pregnant adults with mild or uncomplicated influenza C. Treatment of non-pregnant adults with moderate, progressive, severe or complicated illness with or without risk factors D. Treatment of infants, children and youth with mild or uncomplicated influenza illness E. Treatment of infants, children and youth with moderate, progressive, severe or complicated influenza illness with or without risk factors F. Treatment of immunocompromised patients G. Treatment of patients with renal impairment H. Treatment of pregnant women VII. RECOMMENDATIONS FOR CHEMOPROPHYLAXIS VERSUS EARLY THERAPY TABLES 1. Grading of recommendations 2. Clinical signs warranting urgent medical attention in infants, children and youth with suspected or proven influenza 3. At-risk groups and co-morbid medical conditions that predispose to severe influenza 4. Oseltamivir and zanamivir regimens 5. Recommended regimens for treatment of patients with renal impairment or failure 6. Selected surrogate indices of immunocompromised states REFERENCES APPENDICES A. Oseltamivir and zanamivir treatments for mild or uncomplicated influenza in non-pregnant adults B. Oseltamivir and zanamivir treatments for non-pregnant adults with moderate, progressive, severe or complicated illness C. Oseltamivir and zanamivir treatments for influenza in children (<18 years of age) D. Oseltamivir and zanamivir for chemoprophylaxis or early therapy in close contacts of infectious patients The use of antiviral drugs for influenza: A foundation document for practitioners

BackgroundThe control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants.Methods and findingsWomen aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear.ConclusionsCervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance.