Preclinical Evaluation of Azabenzimidazole-Based PET Radioligands for γ-8 Dependent Transmembrane AMPA Receptor Regulatory Protein Imaging.

AMPA glutamate receptors (AMPARs) play a pivotal role in excitatory neurotransmission, particularly in the hippocampus where the TARP γ-8 subunit is enriched and serves as a target for emerging anti-epileptic drugs. To enable in vivo visualization of TARP γ-8 distribution and expression by positron emission tomography (PET), this study focuses on the development of novel 18 F-labeled TARP γ-8 inhibitors and their corresponding precursors, stemming from the azabenzimidazole scaffold. The resulting radioligands [18 F]TARP-2204 and [18 F]TARP-2205 were successfully synthesized with acceptable radiochemical yield, high molar activity, and excellent radiochemical purity. In vitro autoradiography demonstrates high level of specific binding of [18 F]TARP-2205 to TARP γ-8 in both rat and nonhuman primate brain tissues. However, unexpected radiodefluorination in PET imaging studies of rodents emphasizes the need for further structural refinement. This work serves as an excellent starting point for the development of future 18 F-labeled TARP γ-8 PET tracers, offering valuable insights into medicinal chemistry design, radiosynthesis and subsequent PET evaluation.

Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility.

Baloxavir marboxil (BXM) was approved in 2018 for treating influenza A and B virus infections. It is a first-in-class inhibitor targeting the endonuclease activity of the virus polymerase acidic (PA) protein. Clinical trial data revealed that PA amino acid substitutions at residue 38 (I38T/F/M) reduced BXM potency and caused virus rebound in treated patients, although the fitness characteristics of the mutant viruses were not fully defined. To determine the fitness impact of the I38T/F/M substitutions, we generated recombinant A/California/04/2009 (H1N1)pdm09, A/Texas/71/2017 (H3N2), and B/Brisbane/60/2008 viruses with I38T/F/M and examined drug susceptibility in vitro, enzymatic properties, replication efficiency, and transmissibility in ferrets. Influenza viruses with I38T/F/M substitutions exhibited reduced baloxavir susceptibility, with 38T causing the greatest reduction. The I38T/F/M substitutions impaired PA endonuclease activity as compared to that of wild-type (I38-WT) PA. However, only 38T/F A(H3N2) substitutions had a negative effect on polymerase complex activity. The 38T/F substitutions decreased replication in cells among all viruses, whereas 38M had minimal impact. Despite variable fitness consequences in vitro, all 38T/M viruses disseminated to naive ferrets by contact and airborne transmission, while 38F-containing A(H3N2) and B viruses failed to transmit via the airborne route. Reversion of 38T/F/M to I38-WT was rare among influenza A viruses in this study, suggesting stable retention of 38T/F/M genotypes during these transmission events. BXM reduced susceptibility-associated mutations had variable effects on in vitro fitness of influenza A and B viruses, but the ability of these viruses to transmit in vivo indicates a risk of their spreading from BXM-treated individuals.

The Effect of Emergency Financial Assistance on Healthcare Use.

Does providing financial assistance to people who have just experienced an income shock affect their healthcare use? To address this question, we examine healthcare outcomes in a setting where people at risk of homelessness due to an income shock were offered or denied referral to financial assistance quasi-randomly. Among callers who have been screened as eligible for assistance at Chicago's Homelessness Prevention Call Center (HPCC), some are denied assistance because the availability of funding varies. Conditional on some observable characteristics, funding availability is as-good-as-randomly assigned to callers. We link callers to healthcare utilization records and observe their inpatient hospital stays and emergency department visits. We find that referral to financial assistance has little effect on overall healthcare use-we can reject increases in total utilization greater than 7% of the base rate and decreases of more than 4%. This null effect can be explained, in part, by the fact that the income shock does not significantly change overall healthcare use among those not receiving assistance, suggesting that these individuals can insure health and healthcare demand against these shocks in other ways.

Detection of Variants With Reduced Baloxavir Marboxil and Oseltamivir Susceptibility in Children With Influenza A During the 2019-2020 Influenza Season.

BACKGROUND: We aimed to detect influenza variants with reduced susceptibility to baloxavir marboxil (baloxavir) and oseltamivir and identify differences in the clinical course between children with and without these variants after antiviral treatment. METHODS: During the 2019-2020 influenza season, we enrolled children with confirmed influenza A (20 treated with baloxavir and 16 with oseltamivir). We analyzed patients' sequential viral RNA loads and infectious virus titers, the drug susceptibilities of clinical isolates, and amino acid substitutions in the viral polymerase acidic protein subunits or neuraminidase. We assessed patients' clinical information using questionnaires. RESULTS: All viral RNA loads and virus titers were significantly decreased after treatment, but we detected baloxavir-resistant and oseltamivir-resistant variants in 5 of 20 and 3 of 16 patients, respectively. The duration of fever was similar between patients with and without the variants, but infectious viral shedding lasted 3 days longer in patients with baloxavir-resistant variants. In addition, the duration to improvement of clinical symptoms was longer in these patients (75.0 vs 29.5 hours; P = .106). CONCLUSIONS: After antiviral treatment, the emergence of baloxavir-resistant variants may affect the patients' clinical course, but oseltamivir-resistant variants had no clinical impact.

Replication and transmission of an influenza A(H3N2) virus harboring the polymerase acidic I38T substitution, in guinea pigs.

The polymerase acidic (PA) I38T substitution is a dominant marker of resistance to baloxavir. We evaluated the impact of I38T on the fitness of a contemporary influenza A(H3N2) virus. Influenza A/Switzerland/9715293/2013 (H3N2) wild-type (WT) virus and its I38T mutant were rescued by reverse genetics. Replication kinetics were compared using ST6GalI-MDCK and A549 cells and infectivity/contact transmissibility were evaluated in guinea pigs. Nasal wash (NW) viral titres were determined by TCID50 ml-1 in ST6GalI-MDCK cells. Competition experiments were performed and the evolution of viral population was assessed by droplet digital RT-PCR. I38T did not alter in vitro replication. I38T induced comparable titres vs the WT in guinea pigs NWs and the two viruses transmitted equally by direct contact. However, a 50 %:50 % mixture inoculum evolved to mean WT/I38T ratios of 71 %:29 % and 66.4 %:33.6 % on days 4 and 6 p.i., respectively. Contemporary influenza A(H3N2)-I38T PA variants may conserve a significant level of viral fitness.

Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ-8 with JNJ-55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self-administration.

BACKGROUND: A prominent therapeutic indication for alcohol use disorder (AUD) is reduction in chronic repetitive alcohol use. Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) regulate chronic alcohol self-administration in preclinical models. Recent evidence indicates that the expression and function of AMPARs require the transmembrane AMPAR regulatory protein γ-8 (TARP γ-8). This study evaluated the preclinical efficacy of JNJ-55511118, a novel, selective, high-affinity inhibitor of TARP γ-8-bound AMPARs, in reducing chronic operant alcohol self-administration. METHODS: Separate groups of male and female C57BL/6J mice (n = 8/sex/group) were trained to lever press for sweetened alcohol (9% v/v + sucrose 2% w/v) or sucrose only (2% w/v) in operant conditioning chambers using an FR-4 schedule of reinforcement. After a 40-day baseline, JNJ-55511118 (0, 1, and 10 mg/kg, p.o.) was administered in randomized order 1 h before self-administration sessions. Parameters of operant behavior including response rate, total reinforcers, and head entries in the drinking troughs were computer recorded. RESULTS: During baseline, responding to alcohol, but not sucrose, was greater in female than male mice. In male mice, both doses of JNJ-55511118 decreased multiple parameters of alcohol self-administration but did not reduce behavior-matched sucrose-only self-administration. JNJ-55511118 had no effect on sweetened alcohol or sucrose self-administration in female mice. Subsequent tests of motor function showed that the lowest effective dose of JNJ-55511118 (1 mg/kg) had no effect on open-field activity in male mice. CONCLUSIONS: This study shows for the first time that TARP γ-8-bound AMPARs regulate a behavioral pathology associated with addiction. The preclinical efficacy of JNJ-55511118 in reducing alcohol self-administration in male mice suggests that inhibition of TARP γ-8-bound AMPARs is a novel and highly significant neural target for developing medications to treat AUD and other forms of addiction.

Prep School for Poor Kids: The Long-Run Impacts of Head Start on Human Capital and Economic Self-Sufficiency.

This paper evaluates the long-run effects of Head Start using large-scale, restricted administrative data. Using the county rollout of Head Start between 1965 and 1980 and age-eligibility cutoffs for school entry, we find that Head Start generated large increases in adult human capital and economic self-sufficiency, including a 0.65-year increase in schooling, a 2.7 percent increase in high school completion, an 8.5 percent increase in college enrollment, and a 39 percent increase in college completion. These estimates imply sizable, long-term returns to investments in means-tested, public preschool programs.

The Effect of the US Safety Net on Material Hardship over Two Decades.

We address a question at the center of many policy debates: how effective is the US safety net? Many existing studies evaluate the effect of one program on economic hardship in isolation, though families typically participate in multiple programs. Using 1992-2011 data from the Survey of Income and Program Participation, our analyses examine the simultaneous effect of participation in three programs, TANF, SNAP, or Medicaid/SCHIP, on a set of outcomes of intrinsic importance-measures of material hardship. We find that a 10 percentage point increase in participation in any of these three safety net programs by low-to-moderate income families with children reduces their average number of hardships by 0.11 (-0.41 elasticity), and the incidence of food insufficiency by 1.7 percentage points (-1.27 elasticity). This analysis suggests that hardship would be even more prevalent in the United States without the existence of the current safety net programs.

Impact of the Baloxavir-Resistant Polymerase Acid I38T Substitution on the Fitness of Contemporary Influenza A(H1N1)pdm09 and A(H3N2) Strains.

BACKGROUND: Baloxavir is a cap-dependent inhibitor of the polymerase acid (PA) protein of influenza viruses. While appearing virologically superior to oseltamivir, baloxavir exhibits a low barrier of resistance. We sought to assess the impact of the common baloxavir-resistant I38T PA substitution on in vitro properties and virulence. METHODS: Influenza A/Quebec/144147/2009 (H1N1)pdm09 and A/Switzerland/9715293/2013 (H3N2) recombinant viruses and their I38T PA mutants were compared in single and competitive infection experiments in ST6GalI-MDCK cells and C57/BL6 mice. Virus titers in cell culture supernatants and lung homogenates were determined by virus yield assays. Ratios of wild-type (WT) and I38T mutant were assessed by digital RT-PCR. RESULTS: I38T substitution did not alter the replication kinetics of A(H1N1)pdm09 and A(H3N2) viruses. In competition experiments, a 50%:50% mixture evolved to 70%:30% (WT/mutant) for A(H1N1) and 88%:12% for A(H3N2) viruses after a single cell passage. The I38T substitution remained stable after 4 passages in vitro. In mice, the WT and its I38T mutant induced similar weight loss with comparable lung titers in both viral subtypes. The mutant virus tended to predominate over the WT in mouse competition experiments. CONCLUSION: The fitness of baloxavir-resistant I38T PA mutants appears relatively unaltered in seasonal subtypes warranting surveillance for its dissemination.

Impact of the NREGS on Children's Intellectual Human Capital.

This paper uses panel data from the Young Lives Survey to examine the effect of the world's largest public works program and India's flagship social protection program, the National Rural Employment Guarantee Scheme (NREGS), on children's learning outcomes such as grade progression, reading comprehension test scores, writing test scores, math test scores, and Peabody Picture Vocabulary Test (PPVT) scores. We find that the program has strong positive effects on these outcomes in both the short-and-medium run. Finally, the impact estimates reported here are robust to a number of econometric concerns such as -program placement, selective attrition, and type I error.

Human-to-Human Transmission of Influenza A(H3N2) Virus with Reduced Susceptibility to Baloxavir, Japan, February 2019.

In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses' whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility.

Mutated influenza A virus exhibiting reduced susceptibility to baloxavir marboxil from an experimentally infected horse.

Baloxavir marboxil (BXM), an inhibitor of the cap-dependent endonuclease of the influenza virus polymerase acidic protein (PA), exerts an antiviral effect against influenza A virus. It has been available in Japan since March 2018. This study evaluated the antiviral efficacy of BXM against equine influenza A virus (EIV) by an experimental challenge study using horses. Six horses were experimentally inoculated with EIV, and BXM was administered to the three horses at 2 days post inoculation. Horses treated with BXM showed milder clinical signs than horses without treatment and shed less virus. These results suggest that BXM is effective against EIV. The PA gene of viruses present in the nasopharyngeal swabs collected from horses treated with BXM was sequenced. Two mutations have been detected in viruses recovered from horses treated with BXM. These mutations were the substitution of isoleucine with threonine at position 38 (PA-I38T) and that of asparagine with aspartic acid at position 675 in PA (PA-N675D). A mutated virus with PA-I38T was less susceptible to BXM than viruses with PA-N675D or without mutation. A PA-I38T mutation has also been detected in viruses recovered from humans treated with BXM and is responsible for the reduction in susceptibility to BXM. This suggests that we should not unthinkingly use BXM for the treatment of EI. BXM is likely to easily induce resistance in influenza A viruses, not only in humans but also in horses.

The household and individual-level productive impacts of cash transfer programs in Sub-Saharan Africa.

Silvio Daidone is a economist and Benjamin Davis is a Strategic Program Leader, both with the Food and Agriculture Organization of the United Nations, Rome, Italy. Sudhanshu Handa is a professor at the University of North Carolina at Chapel Hill. Paul Winters is the Associate Vice-President of the Strategy and Knowledge Department, International Fund for Agricultural Development, Rome, Italy. The research presented in this article has been carried out under the auspices of the "From Protection to Production" (PtoP) project, a collaborative effort of the United Nations Children's Fund, the United Kingdom Department for International Development (DFID) and the Food and Agriculture Organization of the United Nations (FAO). The project has received funding from the DFID Research and Evidence Division, the European Union through the "Improved Global Governance for Hunger Reduction Programme", and the FAO Regular Fund. The authors would like to thank the following: two anonymous reviewers and the journal editor, who have provided excellent comments and significantly contributed to the improvement of the article; Alejandro Grinspun, Fabio Veras Soares, and Marco Knowles for technical review of previous drafts; Ervin Prifti and Noemi Pace for their useful suggestions and comments. The authors are also grateful to participants at the following conferences and workshops: 2017 APPAM International Conference, Brussels; 2016 Transfer Project workshop, Addis Ababa; 2016 IFAD-3IE Designing and implementing high-quality, policy-relevant impact evaluations, Rome; 2015 SASPEN Conference on Social Protection, Johannesburg; 2015 Global Food Security Conference, Ithaca; 2014 IPEA International Seminar "Social protection, entrepreneurship and labor market activation - Evidence for better policies", Brasilia; 2014 University of Florence, Department of Economics & Management Seminars, Florence; 2014 Africa Community of Practice (CoP) on Conditional Cash Transfers and Cash Transfers; 2014 African Union Expert Consultation on Children and Social Protection Systems, Cape Town; 2014 IDS Graduation and Social Protection Conference, Kigali. The authors would also like to remember Josh Dewbre, a founding member of the PtoP team, who passed away in April 2015, who had participated in the fieldwork and in the analysis of several programs included in this study. All mistakes and omissions are those of the authors.

The educational and labor market returns to preschool attendance in Austria.

Preschool attendance is widely recognized as a key ingredient for later socioeconomic success, mothers' labor market participation, and leveling the playing field for children from disadvantaged backgrounds. However, the empirical evidence for these claims is still relatively scarce, particularly in Europe. Using data from the 2011 Austrian European Union Statistics of Income and Living Conditions (EU-SILC), we contribute to this literature by studying the effects of having attended preschool for the adult Austrian population. We find strong and positive effects of preschool attendance on later educational attainment, the probability of working full time, hourly wages, and the probability that the mother is in the labor market. Full time workers at the bottom and the top of the distribution benefit less than those in the middle. Women in particular benefit more in terms of years of schooling and the probability of working full time. Other disadvantaged groups (second generation migrants; people with less educated parents) also often benefit more in terms of education and work.

How Does Household Income Affect Child Personality Traits and Behaviors?

We examine the effects of a quasi-experimental unconditional household income transfer on child emotional and behavioral health and personality traits. Using longitudinal data, we find that there are large beneficial effects on children's emotional and behavioral health and personality traits during adolescence. We find evidence that these effects are most pronounced for children who start out with the lowest initial endowments. The income intervention also results in improvements in parental relationships which we interpret as a potential mechanism behind our findings.

Does the Timing of Food Stamp Distribution Matter? A Panel-Data Analysis of Monthly Purchasing Patterns of US Households.

In this paper, we examine the relationship between the timing of food stamp receipt and purchasing patterns. We combine data on state distribution dates of food stamps with scanner data on a panel of households purchases tracked between 2004 and 2011. We find that purchases of a variety of goods are meaningfully higher on receipt days, consistent with previous work that suggests that recipients are very impatient. Additionally, and importantly, estimates indicate that when food stamp receipt days fall on weekends, total monthly purchases within the same households are affected. In particular, monthly purchases of beer are higher when food stamps are distributed on a weekend rather than in months where benefits are distributed on weekdays. For these households, total beer purchases are between 4 and 5% higher in those months. Among households ineligible for food stamps, no effect is identified. These results demonstrate that the 'day-of-the-week' of SNAP treatment may have important impacts on household purchase habits. Copyright © 2016 John Wiley & Sons, Ltd.

National well-being policy and a weighted approach to human feelings.

Governments are becoming interested in the concept of human well-being and how truly to assess it. As an alternative to traditional economic measures, some nations have begun to collect information on citizens' happiness, life satisfaction, and other psychological scores. Yet how could such data actually be used? This paper is a cautious attempt to contribute to thinking on that question. It suggests a possible weighting method to calculate first-order changes in society's well-being, discusses some of the potential principles of democratic 'well-being policy', and (as an illustrative example) reports data on how sub-samples of citizens believe feelings might be weighted.

Is Graduation from Social Safety Nets Possible? Evidence from Sub-Saharan Africa.

In the last decade social cash transfer programmes have become extremely popular in sub-Saharan Africa, and often portrayed as an instrument that can facilitate graduation out of poverty. The evidence on whether social cash transfers have had actual effects on graduation, however, is limited. This paper provides a cross-country reflection of the potential effects of social cash transfers on graduation, drawing from impact evaluation results of cash transfer programmes in Ghana, Kenya, Lesotho and Zambia. We analyse whether social cash transfers have improved the likelihood of graduation, through increased productivity, income generation and resilience to shocks. We identify which factors in terms of programme implementation and household characteristics can increase the likelihood of cash transfer programmes facilitating graduation from poverty.

Empowering Expecting Women to Obtain High-Quality Healthcare in Pakistan: An Evaluation of Khyber Pakhtunkhwa's Conditional Cash Transfer Program.

Maternal mortality, largely stemming from complications during pregnancy and childbirth, impacts poor expecting women with limited healthcare access in rural Pakistan. Conditional Cash Transfers (CCTs), commonly implemented in developing nations, are designed to improve the well-being of vulnerable populations by focusing on health and education. A CCT initiative named Chief Minister's Special Initiative for Mother and Child Health (CM-SIMCH) was launched in Khyber Pakhtunkhwa (KP), one of the less-developed provinces of Pakistan, to empower expecting women to access quality healthcare. This study investigates the factors influencing CM-SIMCH program participation and assesses its impact on the health of expecting women by analyzing health-seeking hospital visits in KP, Pakistan. The study utilizes the Propensity Score Matching (PSM) technique to analyze cross-sectional data obtained from 303 expecting women residing in the Nowshera district of KP. The PSM allows for a balanced comparison of participants who received the CM-SIMCH transfers with those who did not, assessing its impact on maternal healthcare access and outcomes. Empirical results show that factors such as education and family system positively influence the participation of expecting women in the CM-SIMCH program, whereas travel costs exert a negative effect. The intervention leads to a notable increase in hospital visits among these women, contributing to improved health outcomes in KP. This underscores the program's potential effectiveness in addressing maternal healthcare challenges and enhancing healthcare access for vulnerable women in less-developed areas. Therefore, empirical evidence supports the CM-SIMCH program's potential to promote maternal health and improve healthcare access in KP. The study recommends government intervention in health sector as a strategic imperative to empower women and enhance infant health.

Detection of influenza A(H3N2) viruses with polymerase acidic subunit substitutions after and prior to baloxavir marboxil treatment during the 2022-2023 influenza season in Japan.

Baloxavir marboxil (baloxavir), approved as an anti-influenza drug in Japan in March 2018, can induce reduced therapeutic effectiveness due to PA protein substitutions. We assessed PA substitutions in clinical samples from influenza-infected children and adults pre- and post-baloxavir treatment, examining their impact on fever and symptom duration. During the 2022-2023 influenza season, the predominant circulating influenza subtype detected by cycling-probe RT-PCR was A(H3N2) (n = 234), with a minor circulation of A(H1N1)pdm09 (n = 10). Of the 234 influenza A(H3N2) viruses collected prior to baloxavir treatment, 2 (0.8%) viruses carry PA/I38T substitution. One virus was collected from a toddler and one from an adult, indicating the presence of viruses with reduced susceptibility to baloxavir, without prior exposure to the drug. Of the 54 paired influenza A(H3N2) viruses collected following baloxavir treatment, 8 (14.8%) viruses carried E23 K/G, or I38 M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6-100 %), a polymorphism and a mixture of PA/E23 K/G, and I38 M/T substitutions in the clinical samples. These eight viruses were obtained from children aged 7-14 years, with a median fever duration of 16.7 h and a median symptom duration of 93.7 h, which were similar to those of the wild type. However, the delayed viral clearance associated with the emergence of PA substitutions was observed. No substitutions conferring resistance to neuraminidase inhibitors were detected in 37 paired samples collected before and following oseltamivir treatment. These findings underscore the need for ongoing antiviral surveillance, informing public health strategies and clinical antiviral recommendations for seasonal influenza.