Risk for Infection in Humans after Exposure to Birds Infected with Highly Pathogenic Avian Influenza A(H5N1) Virus, United States, 2022.

During February 7─September 3, 2022, a total of 39 US states experienced outbreaks of highly pathogenic avian influenza A(H5N1) virus in birds from commercial poultry farms and backyard flocks. Among persons exposed to infected birds, highly pathogenic avian influenza A(H5) viral RNA was detected in 1 respiratory specimen from 1 person.

Short and Mid-Term Economic Impact of Pulmonary Artery Catheter Use in Adult Cardiac Surgery: A Hospital and Integrated Health System Perspective.

OBJECTIVE: A monitoring pulmonary artery catheter (PAC) is utilized in approximately 34% of the US cardiac surgical procedures. Increased use of PAC has been reported to have an association with complication rates: significant decreases in new-onset heart failure (HF) and respiratory failure (RF), but increases in bacteremia and urinary tract infections. We assessed the impact of increasing PAC adoption on hospital costs among cardiac surgery patients for US-based healthcare systems. METHODS: An Excel-based economic model calculated annualized savings for a US hospital with various cardiac surgical volumes and PAC adoption rates. A second model, for an integrated payer-provider health system, analyzed outcomes/costs resulting from the cardiac surgical admission and for the treatment of persistent HF and RF complications in the year following surgery. Model inputs were extracted from published literature, and one-way and probabilistic sensitivity analyses were performed. RESULTS: For an acute care hospital with 500 procedures/year and 34% PAC adoption, annualized savings equalled $61,806 vs no PAC utilization. An increase in PAC adoption rate led to increased savings of $134,751 for 75% and $170,685 for 95% adoption. Savings ranged from $12,361 to $185,418 at volumes of 100 and 1500 procedures/year, respectively. For an integrated payer-provider health system with the base-case scenario of 3845 procedures/year and 34% PAC adoption, estimated savings were $596,637 for the combined surgical index admission and treatment for related complications over the following year. CONCLUSION: PAC utilization in adult cardiac surgery patients results in reduced costs for both acute care hospitals and payer-provider integrated health systems.

Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir.

Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A viruses collected from humans and other hosts. Screening PB2 sequences for substitutions previously associated with reduced pimodivir susceptibility revealed a very low frequency among seasonal viruses circulating in the U.S. during 2015-2020 (<0.03%; 3/11,934) and among non-seasonal viruses collected in various countries during the same period (0.2%; 18/8971). Pimodivir potently inhibited virus replication in two assays, a single-cycle HINT and a multi-cycle FRA, with IC50 values in a nanomolar range. Median IC50 values determined by HINT were similar for both subtypes of seasonal viruses, A(H1N1)pdm09 and A(H3N2), across three seasons. Human seasonal viruses with PB2 substitutions S324C, S324R, or N510K displayed a 27-317-fold reduced pimodivir susceptibility by HINT. In addition, pimodivir was effective at inhibiting replication of a diverse group of animal-origin viruses that have pandemic potential, including avian viruses of A(H5N6) and A(H7N9) subtypes. A rare PB2 substitution H357N was identified in an A(H4N2) subtype poultry virus that displayed >100-fold reduced pimodivir susceptibility. Our findings demonstrate a broad inhibitory activity of pimodivir and expand the existing knowledge of amino acid substitutions that can reduce susceptibility to this investigational antiviral.

Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aß production and related pathology in a mouse model of Alzheimer's disease.

Amyloid-ß (Aß) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aß generation, we postulated that 5HT2A -Rs may regulate Aß as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aß levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aß levels by almost 50% within hours, but had no effect on Aß levels in 5HT2A -R knock-out mice. The Aß-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aß levels and Aß pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.

Effect of escitalopram on Aß levels and plaque load in an Alzheimer mouse model.

BACKGROUND: Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into ß-amyloid (Aß). Serotonin signaling through a subset of serotonin receptors suppresses Aß generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aß levels in mice. OBJECTIVES: We hypothesized that acute treatment with escitalopram would reduce Aß generation, which would be reflected chronically with a significant reduction in Aß plaque load. METHODS: We performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in brain interstitial fluid (ISF) Aß and Aß plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically. RESULTS: Escitalopram acutely reduced ISF Aß by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time. CONCLUSIONS: Escitalopram significantly reduced Aß in mice, similar to previous findings in humans treated with acute dosing of an SSRI.

Primary Swine Respiratory Epithelial Cell Lines for the Efficient Isolation and Propagation of Influenza A Viruses.

Influenza virus isolation from clinical samples is critical for the identification and characterization of circulating and emerging viruses. Yet efficient isolation can be difficult. In these studies, we isolated primary swine nasal and tracheal respiratory epithelial cells and immortalized swine nasal epithelial cells (siNEC) and tracheal epithelial cells (siTEC) that retained the abilities to form tight junctions and cilia and to differentiate at the air-liquid interface like primary cells. Critically, both human and swine influenza viruses replicated in the immortalized cells, which generally yielded higher-titer viral isolates from human and swine nasal swabs, supported the replication of isolates that failed to grow in Madin-Darby canine kidney (MDCK) cells, and resulted in fewer dominating mutations during viral passaging than MDCK cells.IMPORTANCE Robust in vitro culture systems for influenza virus are critically needed. MDCK cells, the most widely used cell line for influenza isolation and propagation, do not adequately model the respiratory tract. Therefore, many clinical isolates, both animal and human, are unable to be isolated and characterized, limiting our understanding of currently circulating influenza viruses. We have developed immortalized swine respiratory epithelial cells that retain the ability to differentiate and can support influenza replication and isolation. These cell lines can be used as additional tools to enhance influenza research and vaccine development.

Unfit offenders in NSW: paying the price for gaps in service provision.

The Mental Health (Forensic Provisions) Act 1990 (NSW) was amended in 2013 to include section 54 A, enabling an application to be made for the extension of a forensic patient's status. Thirteen patients were subject to an extension order between 2014 and 30 June 2018. Shared characteristics of these forensic patients were considered with a view to identifying the types of patients involved in these applications and the gaps in service provision that this might reflect. Nine out of the 13 patients subject to an extension order had a background of sexual offences, and all patients had either an intellectual disability and/or complex comorbid disorders, such as severe personality disorder. The extension orders coincide with gaps in the service provision in relation to the management of certain complex mental disorders, intellectual disability and problematic behaviours that lead to justice system involvement. The authors discuss the potential implications that these findings have for future resource allocation, legislative reform and service provision.

Update: Influenza Activity in the United States During the 2017-18 Season and Composition of the 2018-19 Influenza Vaccine.

The United States 2017-18 influenza season (October 1, 2017-May 19, 2018) was a high severity season with high levels of outpatient clinic and emergency department visits for influenza-like illness (ILI), high influenza-related hospitalization rates, and elevated and geographically widespread influenza activity across the country for an extended period. Nationally, ILI activity began increasing in November, reaching an extended period of high activity during January-February, and remaining elevated through March. Influenza A(H3N2) viruses predominated through February and were predominant overall for the season; influenza B viruses predominated from March onward. This report summarizes U.S. influenza activity* during October 1, 2017-May 19, 2018.†.

Update: Influenza Activity - United States, October 1, 2017-February 3, 2018.

Influenza activity in the United States began to increase in early November 2017 and rose sharply from December through February 3, 2018; elevated influenza activity is expected to continue for several more weeks. Influenza A viruses have been most commonly identified, with influenza A(H3N2) viruses predominating, but influenza A(H1N1)pdm09 and influenza B viruses were also reported. This report summarizes U.S. influenza activity* during October 1, 2017-February 3, 2018,† and updates the previous summary (1).

Mammalian Pathogenesis and Transmission of Avian Influenza A(H7N9) Viruses, Tennessee, USA, 2017.

Infections with low pathogenicity and highly pathogenic avian influenza A(H7N9) viruses affected poultry in 4 states in the southeastern United States in 2017. We evaluated pathogenicity and transmission of representative viruses in mouse and ferret models and examined replication kinetics in human respiratory tract cells. These viruses can cause respiratory infections in mammalian models.

Update: Influenza Activity - United States, October 1-November 25, 2017.

Influenza activity in the United States was low during October 2017, but has been increasing since the beginning of November. Influenza A viruses have been most commonly identified, with influenza A(H3N2) viruses predominating. Several influenza activity indicators were higher than is typically seen for this time of year. The majority of influenza viruses characterized during this period were genetically or antigenically similar to the 2017-18 Northern Hemisphere cell-grown vaccine reference viruses. These data indicate that currently circulating viruses have not undergone significant antigenic drift; however, circulating A(H3N2) viruses are antigenically less similar to egg-grown A(H3N2) viruses used for producing the majority of influenza vaccines in the United States. It is difficult to predict which influenza viruses will predominate in the 2017-18 influenza season; however, in recent past seasons in which A(H3N2) viruses predominated, hospitalizations and deaths were more common, and the effectiveness of the vaccine was lower. Annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. Multiple influenza vaccines are approved and recommended for use during the 2017-18 season, and vaccination should continue to be offered as long as influenza viruses are circulating and unexpired vaccine is available. This report summarizes U.S. influenza activity* during October 1-November 25, 2017 (surveillance weeks 40-47).†.

Outbreak of Influenza A(H7N2) Among Cats in an Animal Shelter With Cat-to-Human Transmission-New York City, 2016.

We describe the first case of cat-to-human transmission of influenza A(H7N2), an avian-lineage influenza A virus, that occurred during an outbreak among cats in New York City animal shelters. We describe the public health response and investigation.

Reducing Door-in Door-out Intervals in Helicopter ST-segment Elevation Myocardial Infarction Interhospital Transfers.

BACKGROUND: Many health systems rely on helicopter EMS (HEMS) to transfer ST-elevation myocardial infarction (STEMI) patients for percutaneous coronary intervention (PCI) to a hospital with a catheterization laboratory. Mortality rates increase with the time to reperfusion, so reducing delays is imperative. For interhospital STEMI transfers, the time spent in the initial hospital from arrival until departure (door-in to door-out interval or DIDO) should be minimized. OBJECTIVE: To evaluate the impact of a series of process improvements to reduce DIDO intervals for STEMI patients transferred via a hospital based HEMS program. METHODS: Changes made to the STEMI transfer protocol in March 2011 were: (a) allowing transferring facilities to request HEMS before identifying an accepting cardiologist or hospital, with one hospital serving as a default PCI center in the case of delays, (b) limiting continuous infusions to those absolutely necessary for the transfer flights and (c) training flight crews to minimize time at bedside. Trained dual abstractors conducted structured medical record reviews for all STEMI patients 18 years and older, transferred to a PCI facility by HEMS from March 2011 to December 2012. Discrepancies were adjudicated. We compared DIDO intervals to a historical control cohort from 2007. We used the Mann-Whitney U test to compare times, and calculated differences with 95% confidence intervals. RESULTS: Of 244 patients identified, six were excluded due to incomplete data. The historical cohort included 179 cases. Mean age was 59 (SD 14) years, 81% were white and 66% male. There were no differences in patient characteristics or door to EKG times between the cohorts. Median door-in to door-out interval decreased from 83 minutes (IQR 43) to 68 minutes (IQR 31) (difference 15 minutes, 95% CI 8 to 21, P <.0001). EKG to HEMS request decreased 21 minutes (95% CI 17 to 25, P <.0001), and HEMS ground time decreased 3 minutes (95% CI 2 to 4, P <.0001). There was a 32% absolute increase in the proportion of patients with EKG to helicopter request interval <35 minutes (83% vs 51%, difference 32%, 95% CI 24% to 41%, P <.0001). CONCLUSION: HEMS-focused process improvements can significantly reduce the DIDO interval times for STEMI patients transferred for PCI.

Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins.

The pandemic threat posed by emerging zoonotic influenza A viruses necessitates development of antiviral agents effective against various antigenic subtypes. Human monoclonal antibody (hMAb) targeting the hemagglutinin (HA) stalk offers a promising approach to control influenza virus infections. Here, we investigated the ability of the hMAb 81.39a to inhibit in vitro replication of human and zoonotic viruses, representing 16 HA subtypes. The majority of viruses were effectively neutralized by 81.39a at a 50% effective concentration (EC50) of <0.01 to 4.9 µg/ml. Among group 2 HA viruses tested, a single A(H7N9) virus was not neutralized at 50 µg/ml; it contained HA2-Asp19Gly, an amino acid position previously associated with resistance to neutralization by the group 2 HA-neutralizing MAb CR8020. Notably, among group 1 HA viruses, H11-H13 and H16 subtypes were not neutralized at 50 µg/ml; they shared the substitution HA2-Asp19Asn/Ala. Conversely, H9 viruses harboring HA2-Asp19Ala were fully susceptible to neutralization. Therefore, amino acid variance at HA2-Asp19 has subtype-specific adverse effects on in vitro neutralization. Mice given a single injection (15 or 45 mg/kg of body weight) at 24 or 48 h after infection with recently emerged A(H5N2), A(H5N8), A(H6N1), or A(H7N9) viruses were protected from mortality and showed drastically reduced lung viral titers. Furthermore, 81.39a protected mice infected with A(H7N9) harboring HA2-Asp19Gly, although the antiviral effect was lessened. A(H1N1)pdm09-infected ferrets receiving a single dose (25 mg/kg) had reduced viral titers and showed less lung tissue injury, despite 24- to 72-h-delayed treatment. Taken together, this study provides experimental evidence for the therapeutic potential of 81.39a against diverse influenza A viruses. IMPORTANCE: Zoonotic influenza viruses, such as A(H5N1) and A(H7N9) subtypes, have caused severe disease and deaths in humans, raising public health concerns. Development of novel anti-influenza therapeutics with a broad spectrum of activity against various subtypes is necessary to mitigate disease severity. Here, we demonstrate that the hemagglutinin (HA) stalk-targeting human monoclonal antibody 81.39a effectively neutralized the majority of influenza A viruses tested, representing 16 HA subtypes. Furthermore, delayed treatment with 81.39a significantly suppressed virus replication in the lungs, prevented dramatic body weight loss, and increased survival rates of mice infected with A(H5Nx), A(H6N1), or A(H7N9) viruses. When tested in ferrets, delayed 81.39a treatment reduced viral titers, particularly in the lower respiratory tract, and substantially alleviated disease symptoms associated with severe A(H1N1)pdm09 influenza. Collectively, our data demonstrated the effectiveness of 81.39a against both seasonal and emerging influenza A viruses.

Rapid in vivo measurement of ß-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model.

Findings from genetic, animal model, and human studies support the observation that accumulation of the ß-amyloid (Aß) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer's disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aß clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aß clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aß levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aß levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aß40 in the ISF are relatively stable and begin to decline within minutes of blocking Aß production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood-brain barrier transport of Aß, resulted in significant prolongation of Aß40 half-life, but only in the latter phase of Aß clearance from the ISF.

Performance results for a workstation-integrated radiology peer review quality assurance program.

OBJECTIVE: To assess review completion rates, RADPEER score distribution, and sources of disagreement when using a workstation-integrated radiology peer review program, and to evaluate radiologist perceptions of the program. DESIGN: Retrospective review of prospectively collected data. SETTING: Large private outpatient radiology practice. PARTICIPANTS: Radiologists (n = 66) with a mean of 16.0 (standard deviation, 9.2) years of experience. INTERVENTIONS: Prior studies and reports of cases being actively reported were randomly selected for peer review using the RADPEER scoring system (a 4-point scale, with a score of 1 indicating agreement and scores of 2-4 indicating increasing levels of disagreement). MAIN OUTCOME MEASURES: Assigned peer review completion rates, review scores, sources of disagreement and radiologist survey responses. RESULTS: Of 31 293 assigned cases, 29 044 (92.8%; 95% CI 92.5-93.1%) were reviewed. Discrepant scores (score = 2, 3 or 4) were given in 0.69% (95% CI 0.60-0.79%) of cases and clinically significant discrepancy (score = 3 or 4) was assigned in 0.42% (95% CI 0.35-0.50%). The most common cause of disagreement was missed diagnosis (75.2%; 95% CI 66.8-82.1%). By anonymous survey, 94% of radiologists felt that peer review was worthwhile, 90% reported that the scores they received were appropriate and 78% felt that the received feedback was valuable. CONCLUSION: Workstation-based peer review can increase completion rates and levels of radiologist acceptance while producing RADPEER scores similar to those previously reported. This approach may be one way to increase radiologist engagement in peer review quality assurance.

Impact of magnetic field parameters and iron oxide nanoparticle properties on heat generation for use in magnetic hyperthermia.

Heating of nanoparticles (NPs) using an AC magnetic field depends on several factors, and optimization of these parameters can improve the efficiency of heat generation for effective cancer therapy while administering a low NP treatment dose. This study investigated magnetic field strength and frequency, NP size, NP concentration, and solution viscosity as important parameters that impact the heating efficiency of iron oxide NPs with magnetite (Fe3O4) and maghemite (γ-Fe2O3) crystal structures. Heating efficiencies were determined for each experimental setting, with specific absorption rates (SARs) ranging from 3.7 to 325.9 W/g Fe. Magnetic heating was conducted on iron oxide NPs synthesized in our laboratories (with average core sizes of 8, 11, 13, and 18 nm), as well as commercially-available iron oxides (with average core sizes of 8, 9, and 16 nm). The experimental magnetic coil system made it possible to isolate the effect of magnetic field parameters and independently study the effect on heat generation. The highest SAR values were found for the 18 nm synthesized particles and the maghemite nanopowder. Magnetic field strengths were applied in the range of 15.1 to 47.7 kA/m, with field frequencies ranging from 123 to 430 kHz. The best heating was observed for the highest field strengths and frequencies tested, with results following trends predicted by the Rosensweig equation. An increase in solution viscosity led to lower heating rates in nanoparticle solutions, which can have significant implications for the application of magnetic fluid hyperthermia in vivo.

Investigating a crow die-off in January-February 2011 during the introduction of a new clade of highly pathogenic avian influenza virus H5N1 into Bangladesh.

We investigated unusual crow mortality in Bangladesh during January-February 2011 at two sites. Crows of two species, Corvus splendens and C. macrorhynchos, were found sick and dead during the outbreaks. In selected crow roosts, morbidity was ~1 % and mortality was ~4 % during the investigation. Highly pathogenic avian influenza virus H5N1 clade 2.3.2.1 was isolated from dead crows. All isolates were closely related to A/duck/India/02CA10/2011 (H5N1) with 99.8 % and A/crow/Bangladesh/11rs1984-15/2011 (H5N1) virus with 99 % nucleotide sequence identity in their HA genes. The phylogenetic cluster of Bangladesh viruses suggested a common ancestor with viruses found in poultry from India, Myanmar and Nepal. Histopathological changes and immunohistochemistry staining in brain, pancreas, liver, heart, kidney, bursa of Fabricius, rectum, and cloaca were consistent with influenza virus infection. Through our limited investigation in domesticated birds near the crow roosts, we did not identify any samples that tested positive for influenza virus A/H5N1. However, environmental samples collected from live-bird markets near an outbreak site during the month of the outbreaks tested very weakly positive for influenza virus A/H5N1 in clade 2.3.2.1-specific rRT-PCR. Continuation of surveillance in wild and domestic birds may identify evolution of new avian influenza virus and associated public-health risks.

A workstation-integrated peer review quality assurance program: pilot study.

BACKGROUND: The surrogate indicator of radiological excellence that has become accepted is consistency of assessments between radiologists, and the technique that has become the standard for evaluating concordance is peer review. This study describes the results of a workstation-integrated peer review program in a busy outpatient radiology practice. METHODS: Workstation-based peer review was performed using the software program Intelerad Peer Review. Cases for review were randomly chosen from those being actively reported. If an appropriate prior study was available, and if the reviewing radiologist and the original interpreting radiologist had not exceeded review targets, the case was scored using the modified RADPEER system. RESULTS: There were 2,241 cases randomly assigned for peer review. Of selected cases, 1,705 (76%) were interpreted. Reviewing radiologists agreed with prior reports in 99.1% of assessments. Positive feedback (score 0) was given in three cases (0.2%) and concordance (scores of 0 to 2) was assigned in 99.4%, similar to reported rates of 97.0% to 99.8%. Clinically significant discrepancies (scores of 3 or 4) were identified in 10 cases (0.6%). Eighty-eight percent of reviewed radiologists found the reviews worthwhile, 79% found scores appropriate, and 65% felt feedback was appropriate. Two-thirds of radiologists found case rounds discussing significant discrepancies to be valuable. CONCLUSIONS: The workstation-based computerized peer review process used in this pilot project was seamlessly incorporated into the normal workday and met most criteria for an ideal peer review system. Clinically significant discrepancies were identified in 0.6% of cases, similar to published outcomes using the RADPEER system. Reviewed radiologists felt the process was worthwhile.

Microevolution of highly pathogenic avian influenza A(H5N1) viruses isolated from humans, Egypt, 2007-2011.

We analyzed highly pathogenic avian influenza A(H5N1) viruses isolated from humans infected in Egypt during 2007-2011. All analyzed viruses evolved from the lineage of subtype H5N1 viruses introduced into Egypt in 2006; we found minimal evidence of reassortment and no exotic introductions. The hemagglutinin genes of the viruses from 2011 formed a monophyletic group within clade 2.2.1 that also included human viruses from 2009 and 2010 and contemporary viruses from poultry; this finding is consistent with zoonotic transmission. Although molecular markers suggestive of decreased susceptibility to antiviral drugs were detected sporadically in the neuraminidase and matrix 2 proteins, functional neuraminidase inhibition assays did not identify resistant viruses. No other mutations suggesting a change in the threat to public health were detected in the viral proteomes. However, a comparison of representative subtype H5N1 viruses from 2011 with older subtype H5N1 viruses from Egypt revealed substantial antigenic drift.