Lecanemab Clarity AD: Quality-of-Life Results from a Randomized, Double-Blind Phase 3 Trial in Early Alzheimer's Disease.

BACKGROUND: Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to amyloid-beta protein protofibrils. In phase 3 development, lecanemab has been shown to reduce markers of amyloid in early Alzheimer's disease and reduce decline on clinical endpoints of cognition and function at 18 months. OBJECTIVES: To describe the health-related quality-of-life (HRQoL) results from Clarity AD which were exploratory outcomes in this trial. DESIGN: Clarity AD was an 18-month, multi-center, double-blind, phase 3 trial. SETTING: Early Alzheimer's disease. PARTICIPANTS: Individuals 50-90 years of age with a diagnosis of mild cognitive impairment or mild dementia due to Alzheimer's disease and positron emission tomography or cerebrospinal fluid evidence of cerebral amyloid accumulation. INTERVENTION: Placebo or lecanemab 10-mg/kg IV biweekly. MEASUREMENTS: HRQoL was measured at baseline and every 6 months using the European Quality of Life-5 Dimensions (EQ-5D-5L; by subject) and Quality of Life in AD (QOL-AD; by subject and proxy). Study partner burden was measured using the Zarit Burden Interview (ZBI). RESULTS: A total of 1795 participants were enrolled (lecanemab:898; placebo:897). At month 18, adjusted mean change from baseline in EQ-5D-5L and QOL-AD by subject showed 49% and 56% less decline, respectively. QOL-AD rated by study partner as proxy resulted in 23% less decline. ZBI adjusted mean change from baseline at 18 months resulted in 38% less increase of care partner burden. Individual HRQoL test items and dimensions also showed lecanemab benefit. CONCLUSIONS: Lecanemab was associated with a relative preservation of HRQoL and less increase in caregiver burden, with consistent benefits seen across different quality of life scales and within scale subdomains. These benefits provide valuable patient reported outcomes which, together with previously reported benefits of lecanemab across multiple measures of cognition, function, disease progression, and biomarkers, demonstrate that lecanemab treatment may offer meaningful benefits to patients, care partners, and society.

Reservoir hosts experiencing food stress alter transmission dynamics for a zoonotic pathogen.

Food limitation is a universal stressor for wildlife populations and is increasingly exacerbated by human activities. Anthropogenic environmental change can significantly alter the availability and quality of food resources for reservoir hosts and impact host-pathogen interactions in the wild. The state of the host's nutritional reserves at the time of infection is a key factor influencing infection outcomes by altering host resistance. Combining experimental and model-based approaches, we investigate how an environmental stressor affects host resistance to West Nile virus (WNV). Using American robins (Turdus migratorius), a species considered a superspreader of WNV, we tested the effect of acute food deprivation immediately prior to infection on host viraemia. Here, we show that robins food deprived for 48 h prior to infection, developed higher virus titres and were infectious longer than robins fed normally. To gain an understanding about the epidemiological significance of food-stressed hosts, we developed an agent-based model that simulates transmission dynamics of WNV between an avian host and the mosquito vector. When simulating a nutritionally stressed host population, the mosquito infection rate rose significantly, reaching levels that represent an epidemiological risk. An understanding of the infection disease dynamics in wild populations is critical to predict and mitigate zoonotic disease outbreaks.

The vector ecology of introduced Culex quinquefasciatus populations, and implications for future risk of West Nile virus emergence in the Galápagos archipelago.

Culex quinquefasciatus Say (Diptera: Culicidae), an important vector of West Nile virus (WNV) in the U.S.A., was first detected on the Galápagos Islands (Ecuador) in the 1980s. However, little is known of its ecology, distribution or capacity for arbovirus transmission in the Galápagos. We characterize details of lifecycle (including gonotrophic period), temporal abundance, spatial distribution, vector competence and host-feeding behaviour. Culex quinquefasciatus was detected on five islands of the Galápagos during 2006-2011. A period of 7-14 days was required for egg-adult emergence; water salinity above 5 ppt was demonstrated to hinder larval development. Blood-meal analysis indicated feeding on reptiles, birds and mammals. Assessment of WNV vector competency of Galápagos C. quinquefasciatus showed a median infectious dose of 7.41 log10 plaque-forming units per millilitre and evidence of vertical transmission (minimal filial infection rate of 3.7 per 1000 progeny). The distribution of C. quinquefasciatus across the archipelago could be limited by salt intolerance, and its abundance constrained by high temperatures. Feeding behaviour indicates potential to act as a bridge vector for transmission of pathogens across multiple taxa. Vertical transmission is a potential persistence mechanism for WNV on Galápagos. Together, our results can be used for epidemiological assessments of WNV and target vector control, should this pathogen reach the Galápagos Islands.

Development of perampanel in epilepsy.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors play a key role in mediating glutamatergic transmission in the cortex. Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile) is a potent, orally active, highly selective, non-competitive AMPA-type glutamate receptor antagonist, identified via a focused discovery program at Eisai Research Laboratories. Development of perampanel as adjunctive therapy for the treatment of partial-onset seizures was planned in keeping with regulatory guidance and guidelines on antiepileptic drug (AED) development. This is the first AED with a specific action on glutamate-mediated excitatory neurotransmission to show evidence of efficacy and tolerability in reducing treatment-refractory partial-onset seizures in Phase III clinical trials. Perampanel (Fycompa(®)) has been approved in the EU and the United States for adjunctive treatment of partial-onset seizures.

Fine-scale spatial and temporal population genetics of Aedes japonicus, a new US mosquito, reveal multiple introductions.

The newly introduced mosquito Aedes japonicus has expanded from its original range in Northeastern Asia to 29 US states (including Hawaii) plus Canada and northern Europe. Our objectives were to test an earlier hypothesis of multiple introductions of this species to the Northeastern US and evaluate putative temporal changes in genetic makeup. Using a panel of seven microsatellite loci, we confirmed the existence of two abundant genetic forms in specimens originally collected in 1999-2000 (F(ST) value based on microsatellite data = 0.26) that matches the disjunctive distribution of mitochondrial haplotypes. To examine the distribution of the two genetic 'types' across Pennsylvania we created a fine-scale genetic map of Ae. japonicus using 439 specimens collected from 54 Pennsylvania counties in 2002-2003. We also made direct comparisons between collections in 1999-2000 and new collections made in 2004-2005 obtained from the same areas in the northeastern US. We observed that the strong association between mtDNA haplotype and microsatellite signature seen in 1999-2000 had weakened significantly by 2002 across Pennsylvania, a trend continued to some extent in 2004-2005 in PA, NJ, and NY, indicating that once easily distinguishable separate introductions are merging. The two expanding genetic forms create a complex correlation between spatial and genetic distances. The existence of multiple introductions would be obscured without sampling early and across time with highly polymorphic molecular markers. Our results provide a high-resolution analysis of the spatial and temporal dynamics of a newly introduced disease vector and argue that successive introductions may be a common pattern for invasive mosquitoes.

Detection of encephalitis viruses in mosquitoes (Diptera: Culicidae) and avian tissues.

ABSTRACT Diagnostic assays for the detection of St. Louis encephalitis (SLE) and western equine encephalomyelitis (WEE) viruses in mosquito pools and avian tissues were compared for sensitivity, accuracy and specificity. The in situ enzyme immunoassay (EIA), plaque assay on Vero cells, passage in Aedes albopictus Skuse C6/36 and C7/10 cells, antigen capture enzyme immunoassay (AC-EIA), and single and multiplex reverse transcription-polymerase chain reactions (RT-PCR) were evaluated using pools of 50 mosquitoes containing 1-2 experimentally infected individuals. RT-PCR was the most sensitive assay, with a detection limit of <0.1 plaque forming unit. AC-EIA was the fastest and most economical procedure, but was the least sensitive, detecting only 38% of positive pools. The in situ EIA included initial virus amplification on Vero cells, thereby improving assay sensitivity to detect 68% of positive pools. Passage in C6/36 and/or C7/10 cell culture revealed the presence of infectious virus in samples positive by RT-PCR, but initially negative by plaque assay on Vero cell culture, indicating that detection was related to assay sensitivity and not to the absence of intact infectious virus. Combining WEE and SLE RT-PCR assays into a multiplex assay reduced sensitivity, but stilldetected viral RNA at titers below plaque assay sensitivity. Plaque assay on Vero cells, mosquito cell passage, and several RT-PCR procedures were evaluated for their ability to detect WEE and SLE in white-crowned sparrow tissues during acute and chronic stages of infection. All assays detected virus during acute infection at times of high viremia; however, only RT-PCR assays were positive by day 7 when virus was not detected in sera. RT-PCR detected SLE RNA in spleen tissue from one bird 51 d after infection. Assay sensitivity also was compared using extracts of homogenized bird organs spiked with known titers of WEE and SLE. Trizol RNA extraction followed by Qiagen one-step RT-PCR was the most sensitive method, but occasionally resulted in the presence of secondary bands confounding interpretation and requiring confirmatory assays. A balanced surveillance program should combine systems that allow the detection of new agents and the sensitive monitoring of endemic agents to provide an early warning of pending health risks.

Mosquito surveillance and polymerase chain reaction detection of West Nile virus, New York State.

West Nile (WN) virus was detected in the metropolitan New York City (NYC) area during the summer and fall of 1999. Sixty-two human cases, 7 fatal, were documented. The New York State Department of Health initiated a departmental effort to implement a statewide mosquito and virus surveillance system. During the 2000 arbovirus surveillance season, we collected 317,676 mosquitoes, submitted 9,952 pools for virus testing, and detected 363 WN virus-positive pools by polymerase chain reaction (PCR). Eight species of mosquitoes were found infected. Our mosquito surveillance system complemented other surveillance systems in the state to identify relative risk for human exposure to WN virus. PCR WN virus-positive mosquitoes were detected in NYC and six counties in the lower Hudson River Valley and metropolitan NYC area. Collective surveillance activities suggest that WN virus can disperse throughout the state and may impact local health jurisdictions in the state in future years.

West Nile virus infection in birds and mosquitoes, New York State, 2000.

West Nile (WN) virus was found throughout New York State in 2000, with the epicenter in New York City and surrounding counties. We tested 3,403 dead birds and 9,954 mosquito pools for WN virus during the transmission season. Sixty-three avian species, representing 30 families and 14 orders, tested positive for WN virus. The highest proportion of dead birds that tested positive for WN virus was in American Crows in the epicenter (67% positive, n=907). Eight mosquito species, representing four genera, were positive for WN virus. The minimum infection rate per 1,000 mosquitoes (MIR) was highest for Culex pipiens in the epicenter: 3.53 for the entire season and 7.49 for the peak week of August 13. Staten Island had the highest MIR (11.42 for Cx. pipiens), which was associated with the highest proportion of dead American Crows that tested positive for WN virus (92%, n=48) and the highest number of human cases (n=10).

Partial genetic characterization of West Nile virus strains, New York State, 2000.

We analyzed nucleotide sequences from the envelope gene of 11 West Nile (WN) virus strains collected in New York State during the 2000 transmission season to determine whether they differed genetically from each other and from the initial strain isolated in 1999. The complete envelope genes of these strains were amplified by reverse transcription-polymerase chain reaction. The resulting sequences were aligned, the genetic distances were computed, and a phylogenetic tree was constructed. Ten (0.7%) of 1,503 positions in the envelope gene were polymorphic in one or more sequences. The genetic distances were 0.003 or less. WN virus strains circulating in 2000 were homogeneous with respect to one another and to a strain isolated in 1999.

West Nile virus outbreak among horses in New York State, 1999 and 2000.

West Nile (WN) virus was identified in the Western Hemisphere in 1999. Along with human encephalitis cases, 20 equine cases of WN virus were detected in 1999 and 23 equine cases in 2000 in New York. During both years, the equine cases occurred after human cases in New York had been identified.

Encephalitis virus persistence in California birds: preliminary studies with house finches.

Field-collected house finches of mixed sex and age were infected experimentally with either western equine encephalomyelitis (WEE) or St. Louis encephalitis (SLE) viruses during the summer or fall of 1998 and maintained over the winter under ambient conditions. To detect natural relapse during the spring, 32 birds were bled weekly from February through June 1999, and then necropsied 1 yr after infection to detect chronic infections using a reverse transcription polymerase chain reaction (RT-PCR). After 10 mo, 13/14 surviving birds previously infected with WEE were antibody positive by enzyme immunoassay (EIA), and 11/14 had plaque reduction neutralization test (PRNT) antibody titers >1:20, whereas only of 8/13 birds previously infected with SLE were positive by EIA and all had PRNT titers <1:20. When necropsied, 1/14 and 1/13 birds had WEE and SLE RT-PCR positive lung or spleen tissue, respectively; blood, brain, and liver tissues were negative as were all previous blood samples. All tissues from these birds including weekly blood samples tested negative for infectious virus by plaque assay on Vero cell culture. To determine if persistent antibody was protective, birds infected initially with WEE or SLE in November 1998 were challenged 6 mo later with homologous virus. WEE antibody persisted well (5/6 birds remained PRNT positive before challenge) and remained protective, because 0/6 birds were viremic after challenge. In contrast, SLE antibody decayed rapidly (0/6 birds remained PRNT positive before challenge) and was not protective, because 3/6 birds developed an ephemeral viremia on day 1 after infection (mean titer, 10(2.73) plaque forming units/0.1 ml). When necropsied 7 wk after challenge, 1/110 birds infected with WEE and 1/10 birds infected with SLE exhibited an RT-PCR positive spleen, despite the fact that both birds had PRNT antibody titers >1:40 at this time. To determine if immunosuppression would cause a chronic infection to relapse, eight birds initially infected with either WEE or SLE were treated with cyclophosphamide and then tested repeatedly for viremia; all samples were negative for virus by plaque assay. Collectively, our results indicated that a low percentage of birds experimentally infected with WEE or SLE developed chronic infections in the spleen or lung that could be detected by RT-PCR, but not by plaque assay. Birds did not appear to relapse naturally or after immunosuppression. The rapid decay of SLE, but not WEE, antibody may allow the relapse of chronic infections of SLE, but not WEE, to produce viremias sufficiently elevated to infect mosquitoes.

High-throughput detection of West Nile virus RNA.

The recent outbreaks of West Nile virus (WNV) in the northeastern United States and other regions of the world have made it essential to develop an efficient protocol for surveillance of WNV. In the present report, we describe a high-throughput procedure that combines automated RNA extraction, amplification, and detection of WNV RNA. The procedure analyzed 96 samples in approximately 4.5 h. A robotic system, the ABI Prism 6700 Automated Nucleic Acid workstation, extracted RNA and set up reactions for real-time reverse transcription (RT)-PCR in a 96-well format. The robot extracted RNA with a recovery as efficient as that of a commercial RNA extraction kit. A real-time RT-PCR assay was used to detect and quantitate WNV RNA. Using in vitro transcribed RNA, we estimated the detection limit of the real-time RT-PCR to be approximately 40 copies of RNA. A standard RT-PCR assay was optimized to a sensitivity similar to that of the real-time RT-PCR. The standard assay can be reliably used to test a small number of samples or to confirm previous test results. Using internal primers in a nested RT-PCR, we increased the sensitivity by approximately 10-fold compared to that of the standard RT-PCR. The results of the study demonstrated for the first time that the use of an automated system for the purpose of large-scale viral RNA surveillance dramatically increased the speed and efficiency of sample throughput for diagnosis.

Detection of St. Louis encephalitis and western equine encephalomyelitis RNA in mosquitoes tested without maintenance of a cold chain.

Western equine encephalomyelitis and St. Louis encephalitis viral RNA can be detected 20 days after death of infected Culex tarsalis in the absence of a cold chain. Viral RNA was detected with the reverse transcription-polymerase chain reaction in mosquitoes infected either parenterally or perorally in the laboratory and then killed and held for up to 20 days at 27 degrees C. Cell culture assay and in situ enzyme immunoassay did not detect infectious virus in the same mosquitoes.

Phylogenetic analysis of the envelope gene of St. Louis encephalitis virus.

The complete nucleotide sequences of the envelope gene of 62 geographic isolates of St. Louis encephalitis (SLE) virus were determined. Phylogenetic analyses of the sequences, conducted using both maximum parsimony and neighbor-joining methods, included four other members of the Japanese encephalitis serogroup. The results indicated that the SLE isolates formed a monophyletic group in which isolates generally clustered according to geographic origin. Isolates from Panama and South America predominantly formed two large groupings, while isolates from the U.S. formed two other major groups. Several South and Central American strains were more closely related to strains isolated in the U.S., e.g., one isolate from Mexico and Panama, each, were closely related to two Tampa Bay, Florida, isolates, and an isolate, from Brazil was closely related to three isolates from Texas. The U.S. isolates also were not strictly grouped according to geographic source, e.g., some California isolates were closely related to Texas or midwestern isolates, and a Florida isolate was closely related to three isolates from Maryland. The results of the phylogenetic analyses indicated that SLE virus is predominantly maintained locally, but has been transported occasionally between areas, both within and outside the U.S.

West Nile virus infection in birds and mammals.

West Nile virus (WNV) was found throughout New York State in year 2000. The epicenter was located in New York City with a high level of activity in the immediately surrounding counties, including Rockland, Westchester, Nassau, and Suffolk. During 2000, WNV testing was performed by the Wadsworth Center on 3,687 dead birds, representing 153 species, 46 families, and 18 orders. There were 1,203 WNV-positive birds, representing 63 species, 30 families and 14 orders. The percentage of WNV-positive birds was 33% for all birds tested throughout the state, with no significant difference in infection rates in migratory versus resident birds, although significantly more resident birds were submitted for testing. The highest apparent mortality for the entire season was observed in American crows in Staten Island, a location that also showed the highest minimal infection rate in Culex pipiens complex mosquitoes. Studies examining tissue tropism of WNV in corvids and noncorvids from the epicenter and from remote locations indicated that the kidney was the most consistently infected tissue in birds, regardless of level of infection. The brain was the next most consistently positive tissue. The differences in infection among the tissues were most apparent when low levels of virus were present. Experimental mouse inoculation demonstrated a classical flavivirus infection pattern.