Investigating if high-quality kindergarten teachers sustain the pre-K boost to children's emergent literacy skill development in North Carolina.

This study tested the hypothesis that high-quality kindergarten teachers sustain and amplify the skill development of children who participated in North Carolina's NC Pre-K program during the previous year, compared to matched non-participants (N = 17,330; 42% African American, 40% Non-Hispanic White, 15% Hispanic; 51% male; Mage = 4.5 years at fall of pre-K). Kindergarten teacher quality was measured using a "value-added" approach. NC Pre-K participants outperformed non-participants in the fall of kindergarten (ß = .22) and 11% of this boost remained evident by the spring of kindergarten. Higher value-added teachers promoted the skill development of all children (ß = .30 in the spring) but did not differentially benefit the skill development of former NC Pre-K participants compared to non-participants.

Can Peers Help Sustain the Positive Effects of an Early Childhood Mathematics Intervention?

Our study assessed whether the peer environment in kindergarten and first grade affected student learning following an early mathematics intervention. We leveraged longitudinal data from a cluster-RCT to examine whether math achievement in kindergarten (n = 1,218) and first grade (n = 1,126) was affected by either the share of high-achieving classmates or the proportion of classroom peers who received a preschool math curriculum intervention. Analyses indicated that exposure to treated peers in first grade, but not kindergarten, was significantly associated with small gains in end-of-year achievement. Some analyses also suggested that average peer math achievement was generally positively related to children's kindergarten and first-grade achievement across conditions, though these results were less robust. We did not find consistent evidence to suggest that the proportion of treated peers coincided with better teaching practices. Taken together, these findings suggest that classroom peer effects may play only a limited role in sustaining early intervention effects.

Understanding Heterogeneity in the Impact of Public Preschool Programs.

We examine the North Carolina Pre-K (NC Pre-K) program to test the hypothesis that observed variation in effects resulting from exposure to the program can be attributed to interactions with other environmental factors that occur before, during, or after the pre-k year. We examine student outcomes in 5th grade and test interaction effects between NC's level of investment in public pre-k and moderating factors. Our main sample includes the population of children born in North Carolina between 1987 and 2005 who later attended a public school in that state, had valid achievement data in 5th grade, and could be matched by administrative record review (n = 1,207,576; 58% White non-Hispanic, 29% Black non-Hispanic, 7% Hispanic, 6% multiracial and Other race/ethnicity). Analyses were based on a natural experiment leveraging variation in county-level funding for NC Pre-K across NC counties during each of the years the state scaled up the program. Exposure to NC Pre-K funding was defined as the per-4-year-old-child state allocation of funds to a county in a year. Regression models included child-level and county-level covariates and county and year fixed effects. Estimates indicate that a child's exposure to higher NC Pre-K funding was positively associated with that child's academic achievement 6 years later. We found no effect on special education placement or grade retention. NC Pre-K funding effects on achievement were positive for all subgroups tested, and statistically significant for most. However, they were larger for children exposed to more disadvantaged environments either before or after the pre-k experience, consistent with a compensatory model where pre-k provides a buffer against the adverse effects of prior negative environmental experiences and protection against the effects of future adverse experiences. In addition, the effect of NC Pre-K funding on achievement remained positive across most environments, supporting an additive effects model. In contrast, few findings supported a dynamic complementarity model. Instrumental variables analyses incorporating a child's NC Pre-K enrollment status indicate that program attendance increased average 5th grade achievement by approximately 20% of a standard deviation, and impacts were largest for children who were Hispanic or whose mothers had less than a high school education. Implications for the future of pre-k scale-up and developmental theory are discussed.

Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease.

OBJECTIVE: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication. METHODS: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study. RESULTS: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated. INTERPRETATION: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.

Examining the Effects of Changes in Classroom Quality on Within-Child Changes in Achievement and Behavioral Outcomes.

This study examines whether changes in classroom quality predict within-child changes in achievement and behavioral problems in elementary school (ages spanning approximately 6-11 years old). Drawing on data from a longitudinal study of children in predominantly low-income, nonurban communities (n = 1,078), we relied on child fixed effects modeling, which controlled for stable factors that could bias the effects of classroom quality. In general, we found that changes in classroom quality had small and statistically nonsignificant effects on achievement and behavior. However, we found that moving into a high-quality classroom, particularly those rated as high in Classroom Organization, had positive effects on achievement and behavior for children with significant exposure to poverty in early life.

Origins and genetic legacies of the Caribbean Taino.

The Caribbean was one of the last parts of the Americas to be settled by humans, but how and when the islands were first occupied remains a matter of debate. Ancient DNA can help answering these questions, but the work has been hampered by poor DNA preservation. We report the genome sequence of a 1,000-year-old Lucayan Taino individual recovered from the site of Preacher's Cave in the Bahamas. We sequenced her genome to 12.4-fold coverage and show that she is genetically most closely related to present-day Arawakan speakers from northern South America, suggesting that the ancestors of the Lucayans originated there. Further, we find no evidence for recent inbreeding or isolation in the ancient genome, suggesting that the Lucayans had a relatively large effective population size. Finally, we show that the native American components in some present-day Caribbean genomes are closely related to the ancient Taino, demonstrating an element of continuity between precontact populations and present-day Latino populations in the Caribbean.

Effects of North Carolina's Pre-Kindergarten Program at the End of Kindergarten: Contributions of School-Wide Quality.

The positive effects of pre-kindergarten (pre-K) programming may be enhanced in later grades for children who subsequently experience high-quality educational environments in elementary school. The current study tested this hypothesis in relation to the effects of North Carolina's NC Pre-K program on child outcomes at the end of kindergarten, including language, literacy, mathematics, and working memory. Measures of elementary school quality were examined as moderators of the NC Pre-K effects, including school-wide academic proficiency and school-wide growth in academic achievement. We found no reliable effects of NC Pre-K participation for children attending elementary schools with average levels of quality. However, the positive effects of NC Pre-K participation on language and working memory skills were evident for children attending elementary schools with higher levels of academic proficiency and academic growth, respectively. No evidence of moderation was found in relation to literacy and mathematics skills.

Discovery of 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs for delivering nucleoside HCV NS5B polymerase inhibitors.

Our HCV research program investigated novel 2'-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5'-phosphoramidate prodrug of 2'-deoxy-2'-α-bromo-ß-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5'-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose).

Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.

Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.

Infant and Toddler Child-Care Quality and Stability in Relation to Proximal and Distal Academic and Social Outcomes.

This study considered the quality and stability of infant and toddler nonparental child care from 6 to 36 months in relation to language, social, and academic skills measured proximally at 36 months and distally at kindergarten. Quality was measured separately as caregiver-child verbal interactions and caregiver sensitivity, and stability was measured as having fewer sequential child-care caregivers. This longitudinal examination involved a subsample (N = 1,055) from the Family Life Project, a representative sample of families living in rural counties in the United States. Structural equation modeling revealed that children who experienced more positive caregiver-child verbal interactions had higher 36-month language skills, which indirectly led to higher kindergarten academic and social skills. Children who experienced more caregiver stability had higher kindergarten social skills.

Latent Class Growth Trajectories of Letter Name Knowledge During Pre-Kindergarten and Kindergarten.

A major developmental task for young children in the United States involves the acquisition of knowledge about the letters in the English alphabet. In the current study, we examined the growth trajectories of children's letter name knowledge (LNK) during pre-kindergarten and kindergarten. A diverse sample of 1,015 children was drawn from the National Center for Early Development and Learning Multi-State Study of Pre-Kindergarten. Latent class growth analyses were used to identify three heterogeneous classes of children based on their LNK growth trajectories. Children's fall-of-pre-kindergarten language skills were associated with trajectory class membership, which in turn was associated with children's spring-of-kindergarten literacy skills. We also found that the association between children's fall-of-pre-kindergarten language skills and spring-of-kindergarten literacy skills was partially mediated by trajectory class membership. These findings point to the importance of LNK skill development as a marker variable to monitor and support children's emergent literacy development.

Preventive Medicine: A hidden asset for building a dominant culture of prevention.

We explore three issues related to the practice of preventive medicine. First, how does the dearth of preventive medicine physicians on state licensure boards affect quality of medical care? Second, should a process be established to assess the training and skills of candidates for population health positions, like the "credentialing" or "privilege-granting" process used by hospitals and health systems for clinical positions? And third, how should the pervasive lack of recognition of preventive medicine as a bona fide medical specialty be addressed? In exploring these issues, we conclude that preventive medicine physicians are critical to the US health care ecosystem at every level, and to building a dominant culture of prevention. Preventive medicine physicians are actively engaged in the practice of medicine and should be party to the same licensure, credentialing, and privilege-granting procedures as all other specialties. Further, we raise a call to action to our profession to define and raise awareness of preventive medicine, participate in state licensure boards, and establish clear standards of practice for which we are uniquely trained and capable.

Reversible Transformation of Pt Nanoparticles into Single Atoms inside High-Silica Chabazite Zeolite.

We report the encapsulation of platinum species in highly siliceous chabazite (CHA) crystallized in the presence of N,N,N-trimethyl-1-adamantammonium and a thiol-stabilized Pt complex. When compared to Pt/SiO2 or Pt-containing Al-rich zeolites, the materials in this work show enhanced stability toward metal sintering in a variety of industrial conditions, including H2, O2, and H2O. Remarkably, temperatures in the range 650-750 °C can be reached without significant sintering of the noble metal. Detailed structural determinations by X-ray absorption spectroscopy and aberration-corrected high-angle annular dark-field scanning transmission electron microscopy demonstrate subtle control of the supported metal structures from ∼1 nm nanoparticles to site-isolated single Pt atoms via reversible interconversion of one species into another in reducing and oxidizing atmospheres. The combined used of microscopy and spectroscopy is critical to understand these surface-mediated transformations. When tested in hydrogenation reactions, Pt/CHA converts ethylene (∼80%) but not propylene under identical conditions, in contrast to Pt/SiO2, which converts both at similar rates. These differences are attributed to the negligible diffusivity of propylene through the small-pore zeolite and provide final evidence of the metal encapsulation.

School outbreak of Escherichia coli O157 with high levels of transmission, Staffordshire, England, February 2012.

BACKGROUND: Verocytotoxin-producing Escherichia coli (VTEC) are bacteria that cause infectious gastroenteritis and in certain settings can cause widespread infection due to secondary transmission. We describe the findings of an investigation of a school-based outbreak of VTEC in Staffordshire, England. METHODS: Outbreak investigation at a school in February 2012 after two children were diagnosed with VTEC infection. Cases were defined as pupils and staff (or their household contacts) with gastrointestinal symptoms or asymptomatic screened persons, with laboratory confirmed VTEC O157 infection (phage type 32, verocytotoxin 2) occurring on or after 1 February 2012. Microbiological tests of food and faecal samples plus screening of asymptomatic contacts were undertaken. Epidemiological and clinical data were descriptively analysed. RESULTS: Thirty-eight cases were detected. Nineteen were asymptomatic and identified via screening of 191 pupils. Infection was introduced into the school from an earlier household cluster, followed by extensive person-to-person transmission within the nursery/infant group with limited spread to the wider school population. CONCLUSIONS: Control measures included several interventions, in particular, universal screening of pupils and staff. Screening during school outbreaks is not underpinned by guidance but proved to be a key control measure. Screening of asymptomatic contacts should be considered in similar outbreaks.

PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement.

We investigated whether positron emission tomography combined with computed tomography (PET-CT) identifies clinically important bone marrow involvement by diffuse large B-cell lymphoma (DLBCL) with sufficient accuracy to replace routine staging bone marrow biopsy. All patients from a single centre diagnosed as DLBCL since 2005 had data extracted from staging PET-CT, marrow biopsy, and treatment records. Of 130 patients, 35 (27%) were judged to have marrow involvement; 33 were identified by PET-CT compared with 14 by marrow histology. PET identified all clinically important marrow lymphoma, while biopsy did not upstage any patient. Sensitivity and specificity were 94% and 100% for PET-CT and 40% and 100% for marrow biopsy. As a secondary aim, we compared the prognosis of marrow involvement, as detected by PET-CT or biopsy. Cases with marrow deposits identified by PET-CT but not biopsy had progression-free survival (PFS) and overall survival similar to stage IV disease without involved marrow. Positive biopsy conferred significantly inferior PFS (P = .003); these cases frequently had other markers of poor-risk disease. These data confirm that in experienced hands PET-CT has a high level of accuracy for identifying marrow disease in DLBCL, and provide new insight into the nature and clinical significance of marrow involvement.

Ionic and covalent stabilization of intermediates and transition states in catalysis by solid acids.

Reactivity descriptors describe catalyst properties that determine the stability of kinetically relevant transition states and adsorbed intermediates. Theoretical descriptors, such as deprotonation energies (DPE), rigorously account for Brønsted acid strength for catalytic solids with known structure. Here, mechanistic interpretations of methanol dehydration turnover rates are used to assess how charge reorganization (covalency) and electrostatic interactions determine DPE and how such interactions are recovered when intermediates and transition states interact with the conjugate anion in W and Mo polyoxometalate (POM) clusters and gaseous mineral acids. Turnover rates are lower and kinetically relevant species are less stable on Mo than W POM clusters with similar acid strength, and such species are more stable on mineral acids than that predicted from W-POM DPE-reactivity trends, indicating that DPE and acid strength are essential but incomplete reactivity descriptors. Born-Haber thermochemical cycles indicate that these differences reflect more effective charge reorganization upon deprotonation of Mo than W POM clusters and the much weaker reorganization in mineral acids. Such covalency is disrupted upon deprotonation but cannot be recovered fully upon formation of ion pairs at transition states. Predictive descriptors of reactivity for general classes of acids thus require separate assessments of the covalent and ionic DPE components. Here, we describe methods to estimate electrostatic interactions, which, taken together with energies derived from density functional theory, give the covalent and ionic energy components of protons, intermediates, and transition states. In doing so, we provide a framework to predict the reactive properties of protons for chemical reactions mediated by ion-pair transition states.

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.

OBJECTIVE: ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. METHODS: UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. RESULTS: UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009). CONCLUSION: These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.

From personal survival to public health: community leadership by men who have sex with men in the response to HIV.

Community leadership and participation by gay men and men who have sex with men (MSM) have been central to the response to HIV since the beginning of the epidemic. Through a wide array of actions, engagement of MSM has been important in the protection of communities. The connection between personal and community health as drivers of health advocacy continue to be a powerful element. The passion and urgency brought by MSM communities have led to the targeting and expansion of HIV and AIDS research and programming, and have improved the synergy of health and human rights, sustainability, accountability, and health outcomes for all people affected by HIV. MSM are, however, frequently excluded from the evidence-based services that they helped to develop, despite them generally being the most effective actors in challenging environments. Without MSM community involvement, government-run health programmes might have little chance of effectively reaching communities or scaling up interventions to lessen, and ultimately end, the HIV pandemic.