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4-Nitroquinoline-N-oxide (NQO) and 4-nitropyridine-N-oxide (NPO) are important precursors for the synthesis of substituted heterocycles while NQO is a popular model mutagen and carcinogen broadly used in cancer research; intermolecular interactions are critical for their reactions or functioning in vivo. Herein, the effects of the coordination of N-oxide's oxygen atom to Lewis acids on multicenter donor-acceptor bonding were explored via a combination of experimental and computational studies of the complexes of NQO and NPO with a typical π-electron donor, pyrene. Coordination with ZnCl2 increased the positive electrostatic potentials on the surfaces of these π-acceptors and lowered the energy of their LUMO. Analogous effects were observed upon the protonation of the N-oxides' oxygen or bonding with boron trifluoride. The interaction of ZnCl2, NPO, or NQO and pyrene resulted in the formation of dark co-crystals comprising π-stacked Zn-coordinated N-oxides and pyrene similar to that found with protonated or (reported earlier) BF3-bonded N-oxides. Computational studies indicated that the coordination of N-oxides to zinc(II), BF3, or protonation led to the strengthening of the multicenter bonding of the nitro-heterocycle with pyrene, and this effect was related both to the increased electrostatic attraction and molecular-orbital interactions in their complexes.

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BACKGROUND: Acute febrile illness is a common presentation for patients at hospitals globally. Assays that can diagnose a variety of common pathogens in blood could help to establish a diagnosis for targeted disease management. We aimed to evaluate the performance of the BioFire Global Fever Panel (GF Panel), a multiplex nucleic acid amplification test performed on whole blood specimens run on the BioFire FilmArray System, in the diagnosis of several pathogens that cause acute febrile illness. METHODS: We did a prospective, multicentre, cross-sectional diagnostic accuracy study to evaluate the GF Panel. Consenting adults and children older than 6 months presenting with fever in the previous 2 days were enrolled consecutively in sub-Saharan Africa (Ghana, Kenya, Tanzania, Uganda), southeast Asia (Cambodia, Thailand), central and South America (Honduras, Peru), and the USA (Washington, DC; St Louis, MO). We assessed the performance of six analytes (chikungunya virus, dengue virus [serotypes 1-4], Leptospira spp, Plasmodium spp, Plasmodium falciparum, and Plasmodium vivax or Plasmodium ovale) on the GF Panel. The performance of the GF Panel was assessed using comparator PCR assays with different primers followed by bidirectional sequencing on nucleic acid extracts from the same specimen. We calculated the positive percent agreement and negative percent agreement of the GF Panel with respect to the comparator assays. This study is registered with ClinicalTrials.gov, NCT02968355. FINDINGS: From March 26, 2018, to Sept 30, 2019, 1965 participants were enrolled at ten sites worldwide. Of the 1875 participants with analysable results, 980 (52·3%) were female and the median age was 22 years (range 0-100). At least one analyte was detected in 657 (35·0%) of 1875 specimens. The GF Panel had a positive percent agreement for the six analytes evaluated as follows: chikungunya virus 100% (95% CI 86·3-100), dengue virus 94·0% (90·6-96·5), Leptospira spp 93·8% (69·8-99·8), Plasmodium spp 98·3% (96·3-99·4), P falciparum 92·7% (88·8-95·6), and P vivax or P ovale 92·7% (86·7-96·6). The GF Panel had a negative percent agreement equal to or greater than 99·2% (98·6-99·6) for all analytes. INTERPRETATION: This 1 h sample-to-answer, molecular device can detect common causative agents of acute febrile illness with excellent positive percent agreement and negative percent agreement directly in whole blood. The targets of the assay are prevalent in tropical and subtropical regions globally, and the assay could help to provide both public health surveillance and individual diagnoses. FUNDING: BioFire Defense, Joint Project Manager for Medical Countermeasure Systems and US Army Medical Materiel Development Activity, and National Institute of Allergy and Infectious Diseases.

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BACKGROUND: Factors, such as age, comorbidities, vaccine type, herd immunity, previous influenza exposure, and antigenic shift may impact the immune response to the influenza vaccine, protection against circulating strains, and antibody waning. Evaluating vaccine effectiveness (VE) is important for informing timing of vaccine administration and evaluating overall vaccine benefit. METHODS: VE was assessed using febrile respiratory illness surveillance among Department of Defense non-active duty beneficiaries from influenza seasons 2010-2011 through 2013-2014. Respiratory specimens were taken from participants meeting the case definition and tested by polymerase chain reaction for influenza. VE was calculated using logistic regression and by taking 1 minus the odds ratio of being vaccinated in the laboratory confirmed positive influenza cases versus laboratory confirmed negative controls. RESULTS: This study included 1486 participants. We found an overall adjusted VE that provided significant and fairly consistent protection ranging from 54% to 67% during 0-180days postvaccination. This VE dropped to -11% (95% confidence interval: -102% to 39%) during 181-365days. CONCLUSIONS: Our study found moderate VE up to 6months postvaccination. Since the influenza season starts at different times each year, optimal timing is difficult to predict. Consequently, early influenza vaccination may still offer the best overall protection.

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BACKGROUND: Adenovirus is a recognized cause of influenza-like illness (ILI). The proportion of ILI attributable to adenovirus is not known. Moreover, knowledge gaps remain with respect to the epidemiologic, virologic, and clinical characteristics of adenovirus-associated ILI among otherwise healthy individuals. METHODS: An observational, longitudinal study of <65-year-old patients with febrile ILI at five medical centers was conducted from 2009 to 2014. Nasopharyngeal specimens obtained at enrollment were first tested by single-reaction PCR for adenovirus, then further evaluated by a multiplex PCR assay for other respiratory viral pathogens. Symptoms over a 28-day period were collected. RESULTS: We enrolled 1536 individuals, among whom 43 (2·8%) were positive for adenovirus. The median age of cases was 3·4 years (range: 4 months to 41 years). Three were hospitalized. Species and serotype information was available for 33 (76·7%) cases. Species C (n = 21) was the most common, followed by B3 (n = 9) and one each of E4a, D46, and A. Species C infections were more frequent in children (P < 0·01). Half of the cases were positive for at least one other respiratory viral pathogen. Symptoms were generally mild and most commonly included cough (90%), fatigue (79%), rhinorrhea (74%), loss of appetite (71%), and sore throat (64%). Children with non-C adenovirus infection were more likely to report sore throat (P = 0·05) and hoarseness (P = 0·06) than those with species C infection. CONCLUSIONS: Adenovirus is frequently detected with other respiratory viruses. Persons with non-C adenovirus infections reported more severe symptoms, suggesting there may be species-specific differences in virulence and/or host response to infection.

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OBJECTIVE: To obtain ear-specific bone conduction thresholds, masking of the nontest ear is often required. Bone conduction masking has not been formally investigated for infants assessed physiologically. The objective of this study was to determine effective masking levels (EMLs) for auditory steady state responses (ASSRs) elicited by bone-conducted stimuli in a group of normal-hearing infants and adults. DESIGN: Participants were 15 infants younger than 6 mo and 15 adults, all with normal hearing. EML was defined as the lowest level of a binaural air-conducted masker that resulted in absent bone conduction ASSRs. Stimuli were single bone-conducted tones that were 100% amplitude modulated and 25% frequency modulated at 85 and 101 for 1000 and 4000 Hz, respectively. The stimuli were calibrated in dB HL (ANSI S3.6-1996) and expressed in dB HL or dB SL (dB relative to mean bone conduction ASSR thresholds reported in a previous study). The maskers were 1 and 4 kHz narrowband noise generated by a clinical audiometer. Unmasked and masked ASSRs were obtained for each participant. Real ear-to-coupler differences (RECDs) were also obtained for each participant and were used to convert masker dB SPL measured in the coupler to dB SPL in the individual ear canal. RESULTS: Infant EMLs for ASSRs elicited to bone-conducted stimuli in dB HL were 6 to 7 dB higher and 8 to 10 dB lower for 1000 and 4000 Hz, respectively, compared with adults. When masker was adjusted for RECDs, infant EMLs were 12 dB higher at 1000 Hz and similar at 4000 Hz compared with adults. When the stimulus levels were corrected for the mean differences in ASSR bone conduction thresholds between infants and adults and the masker levels adjusted for RECDs, infants had lower EMLs at 1000 Hz and equal EMLs at 4000 Hz, in comparison to adults. Frequency- and level-dependent effects on ASSR amplitude due to masking were found and differed between infants and adults. CONCLUSIONS: Our findings indicate that there are frequency- and level-dependent infant-adult differences in EMLs for bone conduction ASSRs and confirm that a 1000 Hz stimulus is 12 dB more effective for infants compared with adults. The following infant preliminary masking levels for bone conduction stimuli are recommended: (i) 1000 Hz: 48 and 58 dB SPL at 15 and 25 dB HL, respectively, and (ii) 4000 Hz: 40 and 45 dB SPL at 25 and 35 dB HL, respectively.

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OBJECTIVES: (1) to estimate the amount of masking needed to eliminate perceptual responses to 1000- and 4000-Hz bone-conducted mixed amplitude- (AM) and frequency-modulated (FM) tonal stimuli in adults with normal hearing, and (2) to compare these findings to recently reported effective masking levels (EMLs) for bone-conducted 80-Hz ASSRs. DESIGN: Stimuli were bone-conducted single sinusoidal tones with carrier frequencies of 1000 and 4000 Hz (Mixed modulation (MM): 100% AM & 25% FM at 85-101 Hz) presented to the temporal bone at 15-45 dB HL for 1000 Hz and 25-35 dB HL for 4000 Hz. Air-conducted 1- and 4-Hz narrow-band noise maskers were presented to both ears simultaneously using ER-3A insert earphones. EMLs for each of the stimuli were determined behaviourally. STUDY SAMPLE: Seventeen adults (mean age: 27.6 years) with normal hearing participated. RESULTS: Overall, EMLs were 10-17 dB higher for perceptual responses compared to ASSRs for 1000 and 4000 Hz. Linear regression analyses revealed that behavioural and ASSR EMLs were not significantly correlated for most of the stimuli presented except for 1000-Hz presented at 45 dB HL (r =.64, p = .013). CONCLUSIONS: EMLs are frequency- and testing method-dependent for bone-conducted MM tonal stimuli for normal-hearing adults.

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