Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) A(H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we ...evaluated their susceptibility to influenza antivirals. Of 1,015 sequences of HPAI A(H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4b A(H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors, baloxavir and the investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A(H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling.
•Sporadic drug resistance was detected in clade 2.3.4.4b HPAI A(H5N1) viruses isolated from birds in the US, 2022.•Investigational oral neuraminidase inhibitor AV5080 was most effective at reducing virus enzyme activity.•Dual mutation N295S+T438N in the neuraminidase conferred reduced inhibition by all neuraminidase inhibitors tested.•Cap-dependent endonuclease inhibitors baloxavir and AV5116 showed similar antiviral activity in cell culture.•First report of A(H5N1) virus with PA-I38T and a cluster of PA-A37T viruses displaying reduced baloxavir susceptibility.
Clinic blood pressure (BP) is usually higher than daytime ambulatory BP in hypertensive patients, but some recent studies have challenged this view, suggesting that this relationship is strongly ...influenced by age. We used the Spanish ambulatory BP monitoring cohort to examine differences between clinic and daytime BP by age among 104 639 adult hypertensive patients (office systolic/diastolic BP ≥140/90 mm Hg or treated) in usual primary-care practice, across the wide age spectrum. To assess the impact of age, cardiovascular variables, and clinic BP on the clinic-daytime BP differences, we built multivariable regression models of the average BP differences, white-coat hypertension (high clinic BP and normal daytime BP), and masked hypertension (normal clinic BP and high daytime BP). In most patients, mean clinic BP values were higher than daytime BP at all ages. Some 36.7% of patients had white-coat hypertension (amounting to 50% at clinic systolic BP of 140-159 mm Hg) and 3.9% had masked hypertension (amounting to 18% at clinic systolic BP of 130-139 mm Hg). Age explained 0.1% to 1.7% of the variance of quantitative or categorical BP differences (P<0.001). Cardiovascular variables explained an additional 1.6% to 3.4% of the variance (P<0.001). Finally, clinic BP generally explained ≥20% more of the variance (P<0.01). In this large study in usual clinical practice, clinic BP misclassified hypertension status in >40% of patients. This misclassification was not importantly influenced by age but was more evident in patients with borderline/grade 1 hypertension. These findings reinforce the importance of ambulatory BP monitoring for defining BP status in routine clinical practice.
The appearance of wheezing sounds is widely considered by physicians as a key indicator to detect early pulmonary disorders or even the severity associated with respiratory diseases, as occurs in the ...case of asthma and chronic obstructive pulmonary disease. From a physician's point of view, monophonic and polyphonic wheezing classification is still a challenging topic in biomedical signal processing since both types of wheezes are sinusoidal in nature. Unlike most of the classification algorithms in which interference caused by normal respiratory sounds is not addressed in depth, our first contribution proposes a novel Constrained Low-Rank Non-negative Matrix Factorization (CL-RNMF) approach, never applied to classification of wheezing as far as the authors' knowledge, which incorporates several constraints (sparseness and smoothness) and a low-rank configuration to extract the wheezing spectral content, minimizing the acoustic interference from normal respiratory sounds. The second contribution automatically analyzes the harmonic structure of the energy distribution associated with the estimated wheezing spectrogram to classify the type of wheezing. Experimental results report that: (i) the proposed method outperforms the most recent and relevant state-of-the-art wheezing classification method by approximately 8% in accuracy; (ii) unlike state-of-the-art methods based on classifiers, the proposed method uses an unsupervised approach that does not require any training.
Ambulatory blood pressure (BP) monitoring has become useful in the diagnosis and management of hypertensive individuals. In addition to 24-hour values, the circadian variation of BP adds prognostic ...significance in predicting cardiovascular outcome. However, the magnitude of circadian BP patterns in large studies has hardly been noticed. Our aims were to determine the prevalence of circadian BP patterns and to assess clinical conditions associated with the nondipping status in groups of both treated and untreated hypertensive subjects, studied separately. Clinical data and 24-hour ambulatory BP monitoring were obtained from 42,947 hypertensive patients included in the Spanish Society of Hypertension Ambulatory Blood Pressure Monitoring Registry. They were 8384 previously untreated and 34,563 treated hypertensives. Twenty-four-hour ambulatory BP monitoring was performed with an oscillometric device (SpaceLabs 90207). A nondipping pattern was defined when nocturnal systolic BP dip was <10% of daytime systolic BP. The prevalence of nondipping was 41% in the untreated group and 53% in treated patients. In both groups, advanced age, obesity, diabetes mellitus, and overt cardiovascular or renal disease were associated with a blunted nocturnal BP decline (P<0.001). In treated patients, nondipping was associated with the use of a higher number of antihypertensive drugs but not with the time of the day at which antihypertensive drugs were administered. In conclusion, a blunted nocturnal BP dip (the nondipping pattern) is common in hypertensive patients. A clinical pattern of high cardiovascular risk is associated with nondipping, suggesting that the blunted nocturnal BP dip may be merely a marker of high cardiovascular risk.
Superoxide radicals and other reactive oxygen species (ROS) are implicated in influenza A virus-induced inflammation. In this in vitro study, we evaluated the effects of TG6-44, a novel ...quinazolin-derived myeloperoxidase-specific ROS inhibitor, on influenza A virus (A/X31) infection using THP-1 lung monocytic cells and freshly isolated peripheral blood mononuclear cells (PBMC). TG6-44 significantly decreased A/X31-induced ROS and virus-induced inflammatory mediators in THP-1 cells (IL-6, IFN-gamma, MCP-1, TNF-alpha, MIP-1beta) and in human PBMC (IL-6, IL-8, TNF-alpha, MCP-1). Interestingly, TG6-44-treated THP-1 cells showed a decrease in percent cells expressing viral nucleoprotein, as well as a delay in translocation of viral nucleoprotein into the nucleus. Furthermore, in influenza A virus-infected cells, TG6-44 treatment led to suppression of virus-induced cell death as evidenced by decreased caspase-3 activation, decreased proportion of Annexin V.sup.+ PI.sup.+ cells, and increased Bcl-2 phosphorylation. Taken together, our results demonstrate the anti-inflammatory and anti-infective effects of TG6-44.
Ambulatory blood pressure monitoring (ABPM) accurately classifies blood pressure (BP) status but its impact on the prevalence and control of hypertension is little known. The authors conducted a ...cross‐sectional study in 2012 among 1047 individuals 60 years and older from the follow‐up of a population cohort in Spain. Three casual BP measurements and 24‐hour ABPM were performed under standardized conditions. Approximately 68.8% patients were hypertensive based on casual BP (≥140/90 mm Hg or current BP medication use) and 62.1% based on 24‐hour ABPM (≥130/80 mm Hg or current BP medication use) (P=.009). The proportion of patients with treatment‐eligible hypertension who met BP goals increased from 37.4% based on the casual BP target to 54.1% based on the 24‐hour BP target (absolute difference, 16.7%; P<.01). These results were consistent across alternative BP thresholds. Therefore, compared with casual BP, 24‐hour ABPM led to a reduction in the proportion of older patients recommended for hypertension treatment and a substantial increase in the proportion of those with hypertension control.
Elderly patients can be particularly susceptible to the adverse effects of excessive blood pressure (BP) lowering by antihypertensive treatment. The identification of hypotension is thus especially ...important. Ambulatory BP monitoring (ABPM) is a more accurate technique than office for classifying BP status. This study examined the prevalence of hypotension and associated demographic and clinical factors among very old treated hypertensive patients undergoing ABPM.
Cross-sectional study in which 5066 patients aged 80 years and older with treated hypertension drawn from the Spanish ABPM Registry were included.
Office BP and 24-hour ambulatory BP were determined using validated devices under standardized conditions. Based on previous studies, hypotension was defined as systolic/diastolic BP <110 and/or 70 mmHg with office measurement, <105 and/or 65 mmHg with daytime ABPM, <90 and/or 50 mmHg with nighttime ABPM, and <100 and/or 60 mmHg with 24-hour ABPM.
Participants' mean age was 83.2 ± 3.1 years (64.4% women). Overall, 22.8% of patients had office hypotension, 33.7% daytime hypotension, 9.2% nighttime hypotension, and 20.5% 24-hour ABPM hypotension. Low diastolic BP values were responsible for 90% of cases of hypotension. In addition, 59.1% of the cases of hypotension detected by daytime ABPM did not correspond to hypotension according to office BP. The variables independently associated with office and ABPM hypotension were diabetes, coronary heart disease, and a higher number of antihypertensive medications.
One in 3 very elderly treated hypertensive patients attended in usual clinical practice were potentially at risk of having hypotension according to daytime ABPM. More than half of them had masked hypotension; that is, they were not identified if relying on office BP alone. Thus, ABPM could be especially helpful for identifying ambulatory hypotension and avoiding overtreatment, in particular, in patients with diabetes, heart disease, or on antihypertensive polytherapy.
Baloxavir, a new antiviral drug targeting cap-dependent endonuclease activity of polymerase acidic (PA) protein of influenza viruses, is now approved in multiple countries. Several substitutions at ...isoleucine 38 in PA protein (e.g., PA-I38T) have been associated with decreased baloxavir susceptibility in vitro and in vivo. In recent years, next generation sequencing (NGS) analysis and pyrosequencing have been used by CDC and U.S. Public Health Laboratories to monitor drug susceptibility of influenza viruses. Here we described an improved pyrosequencing assay for detecting influenza A viruses carrying substitutions at PA-38. Cyclic and customized orders of nucleotide dispensation were evaluated, and pyrosequencing results were compared to those generated using NGS. Our data showed that the customized nucleotide dispensation has improved the pyrosequencing assay performance in identification of double mixtures (e.g., PA-38I/T); however, identification of PA-38 variants in triple mixtures remains a challenge. While NGS analysis indicated the presence of PA-I38K in one clinical specimen and isolate, our attempts to detect this mutation by pyrosequencing or recover the virus carrying PA-I38K in cell culture were unsuccessful, raising a possibility of a rarely occurring sequencing error. Overall, pyrosequencing provides a convenient means to detect baloxavir resistant influenza viruses when NGS is unavailable or a faster turnaround time is required.
•Pyrosequencing assay was optimized to improve detection of baloxavir resistant influenza A viruses in mixtures.•Detection of PA-38 variants in virus mixtures of both subtypes was improved by using customized nucleotide dispensation.•Pyrosequencing and NGS data were comparable, except for lysine at PA-38 that was detected by NGS but not by pyrosequencing.•Attempts to recover virus carrying lysine at PA-38 were unsuccessful, raising the rare possibility of an NGS artifact.•Pyrosequencing provides an important addition to genotypic methods that can be used for baloxavir susceptibility testing.
Wheezing reveals important cues that can be useful in alerting about respiratory disorders, such as Chronic Obstructive Pulmonary Disease. Early detection of wheezing through auscultation will allow ...the physician to be aware of the existence of the respiratory disorder in its early stage, thus minimizing the damage the disorder can cause to the subject, especially in low-income and middle-income countries. The proposed method presents an extended version of Non-negative Matrix Partial Co-Factorization (NMPCF) that eliminates most of the acoustic interference caused by normal respiratory sounds while preserving the wheezing content needed by the physician to make a reliable diagnosis of the subject's airway status. This extension, called Informed Inter-Segment NMPCF (IIS-NMPCF), attempts to overcome the drawback of the conventional NMPCF that treats all segments of the spectrogram equally, adding greater importance for signal reconstruction of repetitive sound events to those segments where wheezing sounds have not been detected. Specifically, IIS-NMPCF is based on a bases sharing process in which inter-segment information, informed by a wheezing detection system, is incorporated into the factorization to reconstruct a more accurate modelling of normal respiratory sounds. Results demonstrate the significant improvement obtained in the wheezing sound quality by IIS-NMPCF compared to the conventional NMPCF for all the Signal-to-Noise Ratio (SNR) scenarios evaluated, specifically, an SDR, SIR and SAR improvement equals 5.8 dB, 4.9 dB and 7.5 dB evaluating a noisy scenario with SNR = -5 dB.
The aim of the present study was to examine the relationship between cardiorespiratory fitness and foreign language score, among primary and secondary education students in a group of 223 students ...(111 of primary school and 122 of secondary school) from Baleares region, Spain, aged between 9 and 16 years old that participated in the study. A statistical regression analysis was carried out for the comparison of the two variables (cardiorespiratory fitness and English subject score) in primary and secondary education. Physical fitness was assessed using the 6-minute walk test (6MWT) and the values obtained were shown in VO2max. English subject scores were collected at the end of the year prior to the test. The results obtained did not reveal any correlation between VO2max and final English score in primary school (r=.04, p=.65). However, dataset revealed a positive small correlation between VO2max and final English score in secondary school (r=.26, p=.01). These findings suggest that while physical activity may have some positive effect on final score, the relationship is complex and may be influenced by various other factors. Further research is needed to better understand the relationship between physical activity and learning, as well as the potential moderating factors involved.
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