Clinical effectiveness of neuraminidase inhibitors—oseltamivir,zanamivir, laninamivir,and peramivir—for treatment of influenza A(H3N2) and A(H1N1)pdm09 infection: an observational study in the 2010–2011 influenza season in Japan

The clinical effectiveness of the newly released neuraminidase inhibitors (NAIs) laninamivir and peramivir has not been sufficiently evaluated in influenza-infected patients in clinical and practical settings. In this study, we analyzed the clinical data of 211 patients infected with influenza A virus subtype H3N2 (A(H3N2)) and 45 patients infected with influenza A virus subtype H1N1pdm (A(H1N1)pdm09) who received the NAIs oseltamivir, zanamivir, laninamivir, or peramivir during the 2010-2011 influenza season. The duration of fever from the first dose of the NAI to fever alleviation to <37.5 °C was evaluated as an indicator of the clinical effectiveness of the NAIs in the influenza-infected patients. For the A(H3N2)-infected patients, Kaplan–Meier analysis showed the peramivir treatment group had the fastest time of fever alleviation to <37.5 °C (median 17.0 h, 95 % confidence interval [CI] 7.2–26.8 h) of the four treatment groups. No significant difference was found in the time to fever alleviation among the other antivirals, oseltamivir, zanamivir, and laninamivir. Results of multivariate analysis, using a Cox proportional-hazards model (hazard ratio 3.321) adjusted for the factors age, sex, body weight, vaccination status, time from onset to the clinic visit, and body temperature showed significantly faster fever alleviation in the peramivir treatment group compared with the oseltamivir treatment group. For the A(H1N1)pdm09-infected patients, only the oseltamivir and zanamivir treatment groups were compared, and no significant difference in time to alleviation of fever was observed between the two groups. Based on a cycling probe real-time polymerase chain reaction (PCR) assay, none of the A(H1N1)pdm09 strains in this study had the H275Y mutation conferring oseltamivir resistance. Further evaluation of the clinical effectiveness of the newly released NAIs for influenza-infected patients, including those infected with A(H1N1)pdm09, is needed.     

Continued effectiveness of laninamivir octanate hydrate for influenza treatment in Japan: Comparison between the 2011–2012 and 2012–2013 influenza seasons

The clinical effectiveness of Laninamivir octanoate hydrate (laninamivir) was investigated in the Japanese 2012–2013 influenza season for comparison with that of the Japanese 2011–2012 influenza season. A total of 235 patients were enrolled, of whom 210 were evaluated for the duration of fever and other symptoms. The median durations of fever for A(H3N2) were 32.0 and 38.0 h and the median durations of symptoms for the A(H3N2) were 102.0 and 84.0 h for patients aged under 10 and 10 years or older, respectively. All four influenza B patients were 10 years or older, and their median duration of fever was 43.0 h and the median duration of symptoms was 71.0 h. There was no significant difference in the duration of fever or symptoms between the two seasons. The rates of patients A(H3N2) virus positive at day 5 were 37.2% (16/43) and 12.8% (18/141) for those aged under 10 years and 10 years or older, respectively. The virus positive rate was significantly higher for the patients under 10 years than for the patients aged 10 years or older (p < 0.0001). No significant change in IC₅₀ value was found between days 1 and 5. Adverse drug reactions were reported by 2 of the 231 patients (0.87%), but neither was serious. These results suggest that laninamivir continued to be effective against influenza A(H3N2) with no safety issues and that it is unlikely that the clinical use of laninamivir will lead to virus resistance.     

Clinical and virologic effects of four neuraminidase inhibitors in influenza A virus-infected children (aged 4–12 years): an open-label,randomized study in Japan

Background: Neuraminidase inhibitors (NAIs) reduce influenza symptoms but clear evidence of relationships between viral titer reduction and symptom alleviation is lacking. This open-label, randomized study evaluated differences in viral dynamics between NAIs, and relationships between viral dynamics and influenza symptoms (trial registration number: UMIN000012670).

Methods: Patients (n = 123) aged 4–12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir. Patients received regular viral assessments of nasal discharge, at least until rapid antigen tests were negative. Time to virus clearance, based on influenza virus titer, was the primary endpoint.

Results: Peramivir recipients had a significantly shorter time to virus clearance than oseltamivir recipients (adjusted p = 0.035). Comparisons between the peramivir group and other NAI groups were not significant. There were no significant inter-group differences in other clinical efficacy endpoints (time to resolution of fever, time to alleviation of symptoms). However, the peramivir group showed a smaller numerical proportion of relapses with fever or positive virus than the other groups.

Conclusions: The time to virus clearance was significantly shorter with peramivir than with oseltamivir. Although no clear relationship between virus dynamics and symptoms was observed, ongoing studies should clarify the situation.     

Comparison of the clinical symptoms and the effectiveness of neuraminidase inhibitors for patients with pandemic influenza H1N1 2009 or seasonal H1N1 influenza in the 2007–2008 and 2008–2009 seasons

The clinical symptoms and effectiveness of neuraminidase inhibitors (NAI) have not been adequately compared among pandemic H1N1 2009 patients, seasonal H1N1 patients, and patients with H1N1 with the H275Y mutation. The data of 68 seasonal H1N1 patients in 2007–2008, 193 seasonal H1N1 patients in 2008–2009, and 361 pandemic H1N1 2009 patients diagnosed by PCR who received an NAI were analyzed. The duration of fever (body temperature ≥37.5oC) after the first dose of NAI and from onset was calculated. The H275Y neuraminidase mutation status was determined for 166 patients. Significantly lower mean age (18.4 ± 13.2 years) and a higher percentage of teenagers (53.7%) were found for pandemic 2009 influenza than for seasonal influenza (P < 0.001). The peak body temperature was equivalent (mean, 39.0oC) in the three seasons, and the frequency of symptoms was the same or lower for pandemic influenza compared with seasonal H1N1. None of the 34 analyzed pandemic H1N1 virus isolates contained the H275Y mutation, which was commonly detected in the 2008–2009 season. The duration of fever after the start of oseltamivir therapy was significantly shorter for patients with pandemic (23.0 ± 11.6 h) than with seasonal H1N1 in both the 2008–2009 (49.7 ± 32.3 h) and 2007–2008 seasons (32.0 ± 18.9 h). The mean duration of fever after the first dose of zanamivir was not different among the three seasons (26.9–31.5 h). Clinical symptoms were the same or somewhat milder, and oseltamivir was more effective, for pandemic 2009 than for seasonal H1N1 influenza with or without H275Y mutation.     

In vitro neuraminidase inhibitory activity of four neuraminidase inhibitors against influenza virus isolates in the 2011–2012 season in Japan

The neuraminidase inhibitors oseltamivir phosphate (Tamiflu^®), zanamivir (Relenza^®), laninamivir octanoate (Inavir^®), and peramivir (Rapiacta^®) have been available for the treatment of influenza in Japan since 2010. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC₅₀) of each drug for influenza virus isolates from the 2011–2012 influenza season.Specimens were obtained from patients prior to treatment. Viral isolation was done using Madine-Darby canine kidney cells, and the type and subtype of influenza A(H1N1)pdm09, A(H3N2), or influenza B were determined by RT-PCR using type- and subtype-specific primers. The IC₅₀ was determined by a neuraminidase inhibition assay using a fluorescent substrate. The lineage of influenza B virus was determined by direct sequencing of the hemagglutinin gene.Influenza A(H3N2) and influenza B viruses were isolated in 283 and 42 patients, respectively, while no influenza A(H1N1)pdm09 virus was isolated. No isolate showed an IC₅₀ value exceeding 50 nM for any of the neuraminidase inhibitors. IC₅₀ values for A(H3N2) were similar between the 2010–2011 and 2011–2012 seasons. In contrast, the IC₅₀ values for influenza B viruses in the 2011–2012 season to the four drugs were significantly lower than those found in the 2010–2011 season. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC₅₀ values to increase in Japan at present.     

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2017–18 season: Comparison with the 2010–11 to 2016–17 seasons

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) of the viruses epidemic in the 2017-18 Japanese influenza season, we measured the 50% inhibitory concentration (IC₅₀) for influenza virus isolates from patients and compared them with the results from the 2010–11 to 2016-17 seasons.Viral isolation was done with specimens obtained prior to treatment, and the type and subtype was determined by RT-PCR using type- and subtype-specific primers. The IC₅₀ was determined by a neuraminidase inhibition assay using a fluorescent substrate.A total of 237 virus isolates, 50 A(H1N1)pdm09, 92 A(H3N2), and 95 B were measured. No A(H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2017-18 season. No isolates with highly reduced sensitivity to the four NAIs have been found for A(H3N2) or B from the 2010–11 to 2017-18 seasons. The geometric mean IC₅₀s of the four NAIs were quite consistent during the eight studied seasons. These results indicate that the sensitivity to the four commonly used NAIs has been maintained.     

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2016–17 season: Comparison with the 2010–11 to 2015–16 seasons

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2016–17 Japanese influenza season, we measured the 50% inhibitory concentration (IC₅₀) of these NAIs for influenza virus isolates from patients and compared them with the results from the 2010–11 to 2015–16 seasons.Viral isolation was done with specimens obtained prior to treatment, and the type and subtype was determined by RT-PCR using type- and subtype-specific primers. The IC₅₀ was determined by a neuraminidase inhibition assay using a fluorescent substrate.A total of 276 virus isolates, 6 A (H1N1)pdm09 (2.2%), 249 A (H3N2) (90.2%), and 21 B (7.6%), had the IC₅₀ measured for the four NAIs. B isolates included 11 (52.4%), 9 (42.9%), and one (4.8%) of the Victoria, Yamagata, and undetermined strains, respectively.No A (H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2016–17 season. No isolate with highly reduced sensitivity to the four NAIs have been found for A (H3N2) or B from the 2010–11 to 2016–17 seasons. No significant trend of increase or decrease was found in the geometric mean IC₅₀s of the four NAIs during the seven studied seasons.These results indicate that the sensitivity to the four commonly used NAIs has been maintained and that any change in the effectiveness of these NAIs would be minute. Common usage of NAIs for patient treatment has not been a driving force in the selection of NAI resistant viruses.     

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2018–19 season: Comparison with the 2010–11 to 2017–18 seasons

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) of the epidemic viruses in the 2018-19 Japanese influenza season, we measured the 50% inhibitory concentration (IC₅₀) of four NAIs, oseltamivir, zanamivir, peramivir, and laninamivir, for influenza virus isolates from patients and compared them with the results from the 2010–11 to 2017-18 seasons.Viral isolation was done with specimens obtained prior to and after treatment, and the type/subtype was determined by RT-PCR using type- and subtype-specific primers. The IC₅₀ was determined by a neuraminidase inhibition assay using a fluorescent substrate.Virus isolates, 51 A(H1N1)pdm09, 125 A(H3N2), and one B, were measured in the 2018-19 season and the geometric mean IC₅₀s of the four NAIs were quite comparable to the previous eight studied seasons. No A(H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2018-19 season prior to drug administration, although such A(H1N1)pdm09 were found in two, two, and two samples in the 2010–11, 2013–14, and 2015-16 seasons, respectively. No isolates with highly reduced sensitivity to the four NAIs were found for A(H3N2) or B through the 2010–11 to 2018-19 seasons. Among 18 samples with A(H1N1)pdm09 virus isolated after NAI administration, highly reduced sensitivity to oseltamivir and peramivir was detected from one of the five patients treated with oseltamivir. These results suggest that the sensitivity to the four commonly used NAIs has been maintained, although viruses with highly reduced sensitivity to oseltamivir and peramivir have emerged in some adult patients treated with oseltamivir.     

Neuraminidase inhibitor susceptibility profile of human influenza viruses during the 2016–2017 influenza season in Mainland China

To understand the current situation of antiviral-resistance of influenza viruses to neuraminidase inhibitors (NAIs) in Mainland China, The antiviral-resistant surveillance data of the circulating influenza viruses in Mainland China during the 2016–2017 influenza season were analyzed.The total 3215 influenza viruses were studied to determine 50% inhibitory concentration (IC₅₀) for oseltamivir and zanamivir using a fluorescence-based assay.Approximately 0.3% (n = 10) of viruses showed either highly reduced inhibition (HRI) or reduced inhibition (RI) against at least one NAI. The most common neuraminidase (NA) amino acid substitution was H275Y in A (H1N1)pdm09 virus, which confers HRI by oseltamivir. Two A (H1N1)pdm09 viruses contained a new NA amino acid substitution respectively, S110F and D151E, which confers RI by oseltamivir or/and zanamivir. Two B/Victoria-lineage viruses harbored a new NA amino acid substitution respectively, H134Q and S246P, which confers RI by zanamivir. One B/Victoria-lineage virus contained dual amino acid substitution NA P124T and V422I, which confers HRI by zanamivir. One B/Yamagata-lineage virus was a reassortant virus that haemagglutinin (HA) from B/Yamagata-lineage virus and NA from B/Victoria-lineage virus, defined as B/Yamagata-lineage virus confers RI by oseltamivir, but as B/Victoria-lineage virus confers normal inhibition by oseltamivir. All new substitutions that have not been reported before, the correlation of these substitutions and observed changes in IC₅₀ should be further assessed.During the 2016–2017 influenza season in Mainland China the majority tested viruses were susceptible to oseltamivir and zanamivir. Hence, NAIs remain the recommended antiviral for treatment and prophylaxis of influenza virus infections.     

A study of the prevalence and severity of retinopathy of prematurity in East of Iran during 2015–2017: A descriptive cross-sectional study

IntroductionRetinopathy of prematurity (ROP) is a retinal vascular disease in preterm infants, which can cause partial defects in visual acuity or lead to serious defects including retinal detachment and blindness. In most cases, ROP can be prevented and treated if detected early. In this study, the prevalence of ROP and some factors affecting the severity of this disease have been examined.MethodThis cross-sectional study was implemented on 253 premature infants referred to Khatam-Al-Anbia hospital in Mashhad in 2015–2017 period for ROP screening. The sampling was performed using census method. The data-gathering tool was a demographic questionnaire and a checklist for recording the stage of the disease, follow-up and treatment of the patients.ResultsThe sample consisted of 104 female infants (41.1%) and 149 male infants (58.9%). The mean gestational age of infants was 32.1 ± 2.9 weeks and the mean birth weight was 1697.2 ± 566.5 g. Of the sample, 112 (44.3%) had some degrees of ROP and only 1.98% were in need of treatment. In the first examination, the severity of retinopathy in both eyes of infants was the highest in infants with gestational age of less than 32 weeks, and the lowest in infants older than 34 weeks (P < 0.001). There was a significant correlation between ROP severity and gestational age (p ≥ 0.001). The severity of retinopathy in natural pregnancy was also lower than assisted reproduction techniques (P < 0.001). In this study, there was no significant relationship between ROP severity and gender (p ≥ 0.10).ConclusionIn general, the prevalence of ROP in our sample was relatively high. Considering that the severity of ROP was found to be related to the gestational age of infants, and since early diagnosis is the key to ROP treatment, it is suggested to administer ROP screening for all infants with a gestational age of less than 34 weeks or premature infants born by assisted reproduction techniques.     

Comparison of the efficacies of amantadine treatment of swine-origin influenza virus A H1N1 and seasonal influenza H1N1 and H3N2 in Japan (2008–2009)

Amantadine is not thought to be effective for the treatment of swine-origin influenza virus (S-OIV) based on an analysis of genetic sequences of the M2 protein. However, the actual clinical efficacy of amantadine has not been well documented. Here, we were able to compare the efficacies of amantadine and neuraminidase inhibitors. Subjects consisted of 428 patients, including 144 with seasonal influenza (flu) identified between 2008 and 2009, and 284 with S-OIV identified between July 1 and November 30, 2009. Diagnosis of flu was established using a rapid diagnostic kit obtained commercially in Japan. Body temperature sheets were obtained from 95% of the S-OIV patients. Times required to recover normal body temperature were compared among subjects using different antiviral drugs. Genetic abnormalities in the M2 protein were also investigated in 66 randomly selected subjects from within the patient pool. Overall, the average hours required to recover normal body temperature in S-OIV patients treated with amantadine (160 cases), with oseltamivir (59 cases), or with zanamivir (65 cases) were 33.9 ± 20.7, 31.7 ± 16.0, or 36.3 ± 21.6, respectively. These differences were not statistically significant. The N31S abnormality was found in all 14 samples taken from the H3N2 patients and in all of the 23 samples taken from in S-OIV patients. However, this abnormality was not found in any of the 30 samples taken from seasonal H1N1 patients. Amantadine was found to be equally effective in treating S-OIV patients as neuraminidase inhibitors. The genetic abnormality resulting in S31N amino acid conversion identified in some of the H3N2 and S-OIV patients is thought to alter the function of M2 protein only mildly.     

The performance of the BD geneOhm MRSA™ assay for MRSA isolated from clinical patients in Japan,including the effects of specimen contamination and ways to improve it

The BD geneOhm MRSA™ assay has been increasingly used in recent years, and it is possible to use it to screen and detect methicillin-resistant Staphylococcus aureus (MRSA) from a specimen within 2 h. The purpose of the present study was to evaluate the performance, i.e., the specificity and sensitivity, of the BD geneOhm MRSA™ assay to detect MRSA. Its specificity was assessed to be 100% compared to bacterial culture methods, which are commonly used in medical laboratories. Its bacterial limit of detection was over 10 colony-forming units (cfu) per reaction, although MRSA was detected at a cfu below 10 per reaction in a few samples. Additionally, the effect of MRSA isolate contamination was examined. While contamination with protein or other bacteria did not affect the outcome, contamination with a high concentration of blood resulted in an unresolved outcome. To inactivate polymerase chain reaction (PCR) inhibitors, the DNA samples were freeze–thawed prior to the BD geneOhm MRSA™ assay, which led to the sensitivity of the assay increasing. In summary, the BD geneOhm MRSA™ assay is rapid and shows high specificity and sensitivity of cultured MRSA isolates. It will, therefore, be a valuable diagnostic tool for detecting MRSA in specimens from clinical patients.     

Demand for Emergency Services Trends in New South Wales Years 2010–2014 (DESTINY): Age and Clinical Factors Associated with Ambulance Transportation to Emergency Departments

Objectives: The study aimed to analyze ambulance transportations to Emergency Departments (EDs) in New South Wales (NSW) and to identify temporal changes in demographics, acuity, and clinical diagnoses. Methods: This was a retrospective analysis of a population based registry of ED presentations in New South Wales. The NSW Emergency Department data collection (EDCC) collects patient level data on presentations to designated EDs across NSW. Patients that presented to EDs by ambulance between January 2010 and December 2014 were included. Patients dead on arrival, transferred from another hospital, or planned ED presentations were excluded. Results: A total of 10.8 million ED attendances were identified of which 2.6 million (23%) were transported to ED by ambulance. The crude rate of ambulance transportations to EDs across all ages increased by 3.0% per annum over the five years with the highest rate observed in those 85 years and over (620.5 presentations per 1,000 population). There was an increase in the proportion of category 1 and 2 (life-threatening or potentially life-threatening) cases from 18.1% to 24.0%. Conclusion: Demand for ambulance services appears to be driven by older patients presenting with higher acuity problems. Alternative models of acute care for elderly patients need to be planned and implemented to address these changes.     

Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver–Update 2020 WFUMB in Cooperation with EFSUMB,AFSUMB, AIUM,and FLAUS

The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound, first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology. The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as, previously, the differences in the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration approval and the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCAs) and are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis to improve the management of patients.     

A Metric‐Based System for Evaluating the Productivity of Preclinical Faculty at an Academic Medical Center in the Era of Clinical and Translational Science

Academic medical centers are faced with increasing budgetary constraints due to a flat National Institutes of Health budget, lower reimbursements for clinical services, higher costs of technology including informatics and a changing competitive landscape. As such, institutional stakeholders are increasingly asking whether resources are allocated appropriately and whether there are objective methods for measuring faculty contributions and engagement. The complexities of translational research can be particularly challenging when trying to assess faculty contributions because of team science. For over a decade, we have used an objective scoring system called the Matrix to assess faculty productivity and engagement in four areas: research, education, scholarship, and administration or services. The Matrix was developed to be dynamic, quantitative, and able to insure that a fully engaged educator would have a Matrix score that was comparable to a fully engaged investigator. In this report, we present the Matrix in its current form in order to provide a well‐tested objective system of performance evaluation for nonclinical faculty to help academic leaders in decision making.