School Closure and Child Maltreatment During the COVID-19 Pandemic.

It is not known how school closure affected child maltreatment. We conducted a retrospective cohort, linear mixed-models study of 133 counties (comprising 8,582,479 children) in Virginia between 2018 and 2021. Exposure was the opening of schools at least 2 days a week. Outcomes were referrals and incidence of child maltreatment reported to the Department of Social Services. In 2020-2021, there were descriptively more referrals (in-person: 50.9 per 10,000 [95% CI: 47.9, 54.0]; virtual: 45.8 per 10,000 [95% CI: 40.7, 50.9]) and incidence (in-person: 3.7 per 10,000 [95% CI: 3.3, 4.2]; virtual: 2.9 per 10,000 [95% CI: 2.3, 3.5]) of child maltreatment in counties with in-person schooling, though these differences did not reach statistical significance. The referral rate variations (between pandemic and pre-pandemic eras) of counties with in-person schooling was significantly greater than rate changes in counties with virtual schooling during the summer period. There were no differences in incidence in any quarter. Higher poverty within a county was associated with both higher referrals and incidence. Our findings suggest that child maltreatment is driven primarily by underlying differences in counties (namely, poverty) rather than the type of schooling children receive.

Evolution of the structure of lipid nanoparticles for nucleic acid delivery: From in situ studies of formulation to colloidal stability.

The development of lipid nanoparticle (LNP) based therapeutics for delivery of RNA has triggered the advance of new strategies for formulation, such as high throughput microfluidics for precise mixing of components into well-defined particles. In this study, we have characterised the structure of LNPs throughout the formulation process using in situ small angle x-ray scattering in the microfluidic chip, then by sampling in the subsequent dialysis process. The final formulation was investigated with small angle x-ray (SAXS) and neutron (SANS) scattering, dynamic light scattering (DLS) and cryo-TEM. The effect on structure was investigated for LNPs with a benchmark lipid composition and containing different cargos: calf thymus DNA (DNA) and two model mRNAs, polyadenylic acid (polyA) and polyuridylic acid (polyU). The LNP structure evolved during mixing in the microfluidic channel, however was only fully developed during the dialysis. The colloidal stability of the final formulation was affected by the type of incorporated nucleic acids (NAs) and decreased with the degree of base-pairing, as polyU induced extensive particle aggregation. The main NA LNP peak in the SAXS data for the final formulation were similar, with the repeat distance increasing from polyU

On the interactions between RNA and titrateable lipid layers: implications for RNA delivery with lipid nanoparticles.

Characterising the interaction between cationic ionisable lipids (CIL) and nucleic acids (NAs) is key to understanding the process of RNA lipid nanoparticle (LNP) formation and release of NAs from LNPs. Here, we have used different surface techniques to reveal the effect of pH and NA type on the interaction with a model system of DOPC and the CIL DLin-MC3-DMA (MC3). At only 5% MC3, differences in the structure and dynamics of the lipid layer were observed. Both pH and %MC3 were shown to affect the absorption behaviour of erythropoietin mRNA, polyadenylic acid (polyA) and polyuridylic acid (polyU). The adsorbed amount of all studied NAs was found to increase with decreasing pH and increasing %MC3 but with different effects on the lipid layer, which could be linked to the NA secondary structure. For polyA at pH 6, adsorption to the surface of the layer was observed, whereas for other conditions and NAs, penetration of the NA into the layer resulted in the formation of a multilayer structure. By comparison to simulations excluding the secondary structure, differences in adsorption behaviours between polyA and polyU could be observed, indicating that the NA's secondary structure also affected the MC3-NA interactions.

Structural insights on ionizable Dlin-MC3-DMA lipids in DOPC layers by combining accurate atomistic force fields, molecular dynamics simulations and neutron reflectivity.

Ionizable lipids such as the promising Dlin-MC3-DMA (MC3) are essential for the successful design of lipid nanoparticles (LNPs) as drug delivery agents. Combining molecular dynamics simulations with experimental data, such as neutron reflectivity experiments and other scattering techniques, is essential to provide insights into the internal structure of LNPs, which is not fully understood to date. However, the accuracy of the simulations relies on the choice of force field parameters and high-quality experimental data is indispensable to verify the parametrization. For MC3, different parameterizations in combination with the CHARMM and the Slipids force fields have recently emerged. Here, we complement the existing efforts by providing parameters for cationic and neutral MC3 compatible with the AMBER Lipid17 force field. Subsequently, we carefully assess the accuracy of the different force fields by providing a direct comparison to neutron reflectivity experiments of mixed lipid bilayers consisting of MC3 and DOPC at different pHs. At low pH (cationic MC3) and at high pH (neutral MC3) the newly developed MC3 parameters in combination with AMBER Lipid17 for DOPC give good agreement with the experiments. Overall, the agreement is similar compared to the Park-Im parameters for MC3 in combination with the CHARMM36 force field for DOPC. The Ermilova-Swenson MC3 parameters in combination with the Slipids force field underestimate the bilayer thickness. While the distribution of cationic MC3 is very similar, the different force fields for neutral MC3 reveal distinct differences ranging from strong accumulation in the membrane center (current MC3/AMBER Lipid17 DOPC), over mild accumulation (Park-Im MC3/CHARMM36 DOPC) to surface accumulation (Ermilova-Swenson MC3/Slipids DOPC). These pronounced differences highlight the importance of accurate force field parameters and their experimental validation.

Cation and buffer specific effects on the DNA-lipid interaction.

Knowledge of DNA - lipid layer interactions is key for the development of biosensors, synthetic nanopores, scaffolds, and gene-delivery systems. These interactions are strongly affected by the ionic composition of the solvent. We have combined quartz crystal microbalance (QCM) and ellipsometry measurements to reveal how pH, buffers and alkali metal chloride salts affect the interaction of DNA with lipid bilayers (DOTAP/DOPC 30:70 in moles). We found that the thickness of the DNA layer adsorbed onto the lipid bilayer decreased in the order citrate > phosphate > Tris > HEPES. The effect of cations on the thickness of the DNA layer decreased in the order (K+ > Na+ > Cs+ ∼ Li+). Rationalization of the experimental results requires that adsorption, due to cation specific charge screening, is driven by the simultaneous action of two mechanisms namely, the law of matching water affinities for kosmotropes (Li+) and ion dispersion forces for chaotropes (Cs+). The outcome of these two opposing mechanisms is a "bell-shaped" specific cations sequence. Moreover, a superimposed buffer specificity, which goes beyond the simple effect of pH regulation, further modulated cation specificity. In summary, DNA-lipid bilayer interactions are maximized if citrate buffer (50 mM, pH 7.4) and KCl (100 mM) are used.

Patient Preferences for Discussing and Acting on Health-Related Needs in Primary Care.

BACKGROUND: Addressing social needs, health behaviors, and mental health may help patients more than traditional medical care. However, these root causes of poor health are difficult to address and the role of primary care is unclear. This qualitative study assesses patient's willingness and motivations to discuss and accept assistance for these needs from their primary care team. METHODS: In July and August of 2020, semi-structured virtual interviews were conducted with family medicine patients (n = 6) and residents of low resource neighborhoods (n = 11) in Richmond, Virginia. Interviews were conducted over Zoom. We conducted a qualitative analysis of patient and resident interview transcripts. A rapid qualitative analysis approach and immersion-crystallization processes were used to identify themes and categories. RESULTS: Interviewees reported varying degrees of comfort discussing topics with their health care team. They were less comfortable discussing needs they considered outside the realm of "traditional primary care" including finances, transportation, and housing, but interviewees expressed willingness to discuss these needs under certain conditions. Important factors were a strong patient-clinician relationship to create a trusted and safe space for discussion, adequate time for discussion during visits, communication of practices' ability to provide resources to help patients, and ensuring appropriate high quality referrals. CONCLUSIONS: Primary care provides opportunity for identifying and addressing needs that adversely impact health. Some needs are more sensitive for patients to work with their care team on, though, there was willingness to work on any need when a strong provider relationship and clinic structure for providing support were in place. This study highlights critical care delivery factors which may be used to enhance patient comfort accepting support for their needs and ultimately improve clinical care and chronic disease management.

Effect of encapsulated protein on the dynamics of lipid sponge phase: a neutron spin echo and molecular dynamics simulation study.

Lipid membranes are highly mobile systems with hierarchical, time and length scale dependent, collective motions including thickness fluctuations, undulations, and topological membrane changes, which play an important role in membrane interactions. In this work we have characterised the effect of encapsulating two industrially important enzymes, ß-galactosidase and aspartic protease, in lipid sponge phase nanoparticles on the dynamics of the lipid membrane using neutron spin echo (NSE) spectroscopy and molecular dynamics (MD) simulations. From NSE, reduced membrane dynamics were observed upon enzyme encapsulation, which were dependent on the enzyme concentration and type. By fitting the intermediate scattering functions (ISFs) with a modified Zilman and Granek model including nanoparticle diffusion, an increase in membrane bending rigidity was observed, with a larger effect for ß-galactosidase than aspartic protease at the same concentration. MD simulations for the system with and without aspartic protease showed that the lipids relax more slowly in the system with protein due to the replacement of the lipid carbonyl-water hydrogen bonds with lipid-protein hydrogen bonds. This indicates that the most likely cause of the increase in membrane rigidity observed in the NSE measurements was dehydration of the lipid head groups. The dynamics of the protein itself were also studied, which showed a stable secondary structure of protein over the simulation, indicating no unfolding events occurred.

Cement-Augmented and Dual-Headed Posterior Screw Reconstruction After Corpectomy for Metastatic Tumor Resection.

BACKGROUND: Metastatic spinal tumors have a well-documented deleterious effect on the overall strength of the bony spine. Surgical interventions must address not only removal of the tumor itself, but the integrity of reconstructive hardware constructs as well. METHODS: We present a series of 8 patients with metastatic spine tumors who were successfully treated with tumor resection and reconstruction of residual 3-column defect with cement-augmented fenestrated pedicle screws and dual-rod posterior stabilization. RESULTS: All patients demonstrated resolution of their presenting neurologic symptoms. CONCLUSIONS: This series supports the use of the aforementioned constructs in conjunction to provide added stability and reduce hardware failure when treating a diversity of spinal tumors.

Morphogenesis of the Islets of Langerhans Is Guided by Extraendocrine Slit2 and Slit3 Signals.

The spatial architecture of the islets of Langerhans is vitally important for their correct function, and alterations in islet morphogenesis often result in diabetes mellitus. We have previously reported that Roundabout (Robo) receptors are required for proper islet morphogenesis. As part of the Slit-Robo signaling pathway, Robo receptors function in conjunction with Slit ligands to mediate axon guidance, cell migration, and cell positioning in development. However, the role of Slit ligands in islet morphogenesis has not yet been determined. Here, we report that Slit ligands are expressed in overlapping and distinct patterns in both endocrine and nonendocrine tissues in late pancreas development. We show that the function of either Slit2 or Slit3, which are predominantly expressed in the pancreatic mesenchyme, is required and sufficient for islet morphogenesis, while Slit1, which is predominantly expressed in the ß cells, is dispensable for islet morphogenesis. We further show that Slit functions as a repellent signal to ß cells. These data suggest that clustering of endocrine cells during islet morphogenesis is guided, at least in part, by repelling Slit2/3 signals from the pancreatic mesenchyme.

Retention Strategies for Medications for Opioid Use Disorder in Adults: A Rapid Evidence Review.

OBJECTIVES: Although medications for opioid use disorder (MOUD) save lives, treatment retention remains challenging. Identification of interventions to improve MOUD retention is of interest to policymakers and researchers. On behalf of the Agency for Healthcare Research and Quality, we conducted a rapid evidence review on interventions to improve MOUD retention. METHODS: We searched MEDLINE and the Cochrane Library from February 2009 through August 2019 for systematic reviews and randomized trials of care settings, services, logistical support, contingency management, health information technology (IT), extended-release (XR) formulations, and psychosocial interventions that assessed retention at least 3 months. RESULTS: Two systematic reviews and 39 primary studies were included; most did not focus on retention as the primary outcome. Initiating MOUD in soon-to-be-released incarcerated people improved retention following release. Contingency management may improve retention using antagonist but not agonist MOUD. Retention with interventions integrating medical, psychiatric, social services, or IT did not differ from in-person treatment-as-usual approaches. Retention was comparable with XR- compared to daily buprenorphine formulations and conflicting with XR-naltrexone monthly injection compared to daily buprenorphine. Most psychosocial interventions did not improve retention. DISCUSSION: Consistent but sparse evidence supports criminal justice prerelease MOUD initiation, and contingency management interventions for antagonist MOUD. Integrating MOUD with medical, psychiatric, social services, delivering through IT, or administering via XR-MOUD formulations did not worsen retention. Fewer than half of the studies we identified focused on retention as a primary outcome. Studies used different measures of retention, making it difficult to compare effectiveness. Additional inquiry into the causes of low retention would inform future interventions.Registration: PROSPERO: CRD42019134739.

GalliForm, a database of Galliformes occurrence records from the Indo-Malay and Palaearctic, 1800-2008.

Historical as well as current species distribution data are needed to track changes in biodiversity. Species distribution data are found in a variety of sources, each of which has its own distinct bias toward certain taxa, time periods or places. We present GalliForm, a database that comprises 186687 galliform occurrence records linked to 118907 localities in Europe and Asia. Records were derived from museums, peer-reviewed and grey literature, unpublished field notes, diaries and correspondence, banding records, atlas records and online birding trip reports. We describe data collection processes, georeferencing methods and quality-control procedures. This database has underpinned several peer-reviewed studies, investigating spatial and temporal bias in biodiversity data, species' geographic range changes and local extirpation patterns. In our rapidly changing world, an understanding of long-term change in species' distributions is key to predicting future impacts of threatening processes such as land use change, over-exploitation of species and climate change. This database, its historical aspect in particular, provides a valuable source of information for further studies in macroecology and biodiversity conservation.

Using an item-specific predictor to test the dimensionality of the orthographic choice task.

The orthographic choice (OC) task-requiring individuals to choose the correct spelling between a word and a pseudohomophone foil (e.g., goat vs. gote)-has been used as an outcome measure of orthographic learning and as a predictor of individual differences in word reading development. Some consider the OC task a measure of orthographic knowledge (e.g., Conrad, Harris, & Williams (Reading and Writing, 26(8), 1223-1239, 2013)), whereas others have suggested that the task measures a reader's familiarity with the word's orthographic representation and thus measures word reading skill (e.g., Castles & Nation, 2006). We examined this assertion by testing OC task performance of individuals ages 8 to 18 (J = 296) and their ability to read the OC target words (I = 80) in isolation using crossed random effects item-response models. Results reveal that response on the OC task is not fully determined by the ability of an individual to read the target word in isolation. Specifically, the probability of choosing the correct orthographic form when the word was pronounced incorrectly was .79; whereas it was .90 when the word was pronounced correctly. Measures of receptive spelling and phonemic awareness (person-characteristics) and word frequency and orthographic neighborhood size (item-characteristics) accounted for significant variance in orthographic choice after controlling for target item reading and other reading-related abilities. We interpret the results to suggest that the OC task taps both item-specific orthographic knowledge and more general orthographic knowledge.

Sight word acquisition in first grade students at risk for reading disabilities: an item-level exploration of the number of exposures required for mastery.

The purpose of this study was to examine word learning efficiency in at-risk first grade students (N = 93) participating in a yearlong study evaluating a multicomponent intervention targeting word reading and decoding skills. As part of each intervention lesson, students participated in a 1 to 3-min sight word reading activity in which high-frequency words were read from a list until mastered, at which point the word dropped off the list. This study explored factors predicting the number of exposures required for item reading mastery (N = 145 words). Specifically, we explored how the number of word exposures required to reach mastery varied as a function of linguistic features of the words and cognitive characteristics of the students. Using item-level crossed-random effects models, we found students required an average of 5.65 exposures for mastery, with word features representing word length, vocabulary grade, and imageability being significant predictors of learning efficiency. We also found a significant interaction between pretest word reading skill and imageability of a word, with this semantic feature being especially important for the poorest readers. Results indicate that in the absence of typical word recognition skills, poor readers tend to rely on other sources of information to learn words, which tend to be related to the semantic features of words.

Do the Processes Engaged During Mathematical Word-Problem Solving Differ Along the Distribution of Word-Problem Competence?

Conventional research methods for understanding sources of individual differences in word-problem solving (WPS) only permit estimation of average relations between component processes and outcomes. The purpose of the present study was instead to examine whether and if so how the component processes engaged in WPS differ along the spectrum of WPS performance. Second graders (N = 1,130) from 126 classrooms in 17 schools were assessed on component processes (reasoning, in-class attentive behavior, working memory, language comprehension, calculation fluency, word reading) and WPS. Multilevel, unconditional quantile multiple regression indicated that 3 component processes, calculation fluency, language comprehension, and working memory, are engaged in WPS differentially depending on students' overall word-problem skill. The role of calculation fluency and language comprehension was stronger with more competent word-problem solving ability. By contrast, the role of working memory was stronger with intermediate-level than for strong problem solving. Results deepen insight into the role of these processes in WPS and provide the basis for hypothesizing how instructional strategies may be differentiated depending on students' overall level of WPS competence.

Prevention: Necessary But Insufficient? A 2-Year Follow-Up of an Effective First-Grade Mathematics Intervention.

We present first-grade, second-grade, and third-grade impacts for a first-grade intervention targeting the conceptual and procedural bases that support arithmetic. At-risk students (average age at pretest = 6.5) were randomly assigned to three conditions: a control group (n = 224) and two variants of the intervention (same conceptual instruction but different forms of practice: speeded [n = 211] vs. nonspeeded [n = 204]). Impacts on all first-grade content outcomes were significant and positive, but no follow-up impacts were significant. Many intervention children achieved average mathematics achievement at the end of third grade, and prior math and reading assessment performance predicted which students will require sustained intervention. Finally, projecting impacts 2 years later based on nonexperimental estimates of effects of first-grade math skills overestimates long-term intervention effects.

Immobilisation of ß-galactosidase within a lipid sponge phase: structure, stability and kinetics characterisation.

In the formulation of an active enzyme enclosed in a matrix for controlled delivery, it is a challenge to achieve a high protein load and to ensure high activity of the protein. For the first time to our knowledge, we report the use of a highly swollen lipid sponge (L3) phase for encapsulation of the large active enzyme, ß-galactosidase (ß-gal, 238 kDa). This enzyme has large relevance for applications in, e.g. the production of lactose free milk products. The formulation consisted of diglycerol monooleate (DGMO), and a mixture of mono-, di- and triglycerides (Capmul GMO-50) stabilised by polysorbate 80 (P80). The advantage of this type of matrix is that it can be produced on a large scale with a fairly simple and mild process as the system is in practice self-dispersing, yet it has a well-defined internal nano-structure. Minor effects on the sponge phase structure due to the inclusion of the enzyme were observed using small angle X-ray scattering (SAXS). The effect of encapsulation on the enzymatic activity and kinetic characteristics of ß-galactosidase activity was also investigated and can be related to the enzyme stability and confinement within the lipid matrix. The encapsulated ß-galactosidase maintained its activity for a significantly longer time when compared to the free solution at the same temperature. Differences in the particle size and charge of sponge-like nanoparticles (L3-NPs) with and without the enzyme were analysed by dynamic light scattering (DLS) and zeta-potential measurements. Moreover, all the initial ß-galactosidase was encapsulated within L3-NPs as revealed by size exclusion chromatography.

Embedding Self-Regulation Instruction Within Fractions Intervention for Third Graders With Mathematics Difficulties.

The purpose of this study was to explore the efficacy of fractions intervention with and without an embedded self-regulation (SR) component for third-grade students at risk for mathematics disabilities. Fractions intervention focused on magnitude understanding and word problems. Embedded SR was designed to support a growth mindset (fostering belief that intellectual and academic abilities can be developed) along with SR processes in which students set goals, self-monitor, and use strategies to engage motivationally, metacognitively, and behaviorally through challenging tasks. Students (n = 69) were randomly assigned to business-as-usual control and the two versions of fractions intervention. Multilevel models, accounting for the nested structure of the data, identified a moderation effect on fraction word problems: For students receiving fractions intervention with embedded SR, response to intervention was robust across the continuum of students' pretest word problem skill; by contrast, without SR, response to fractions intervention depended on students' pretest word problem skill. On the remaining outcomes, results reflected stronger outcomes when fractions intervention embedded SR instruction without moderation.

Does the Severity of Students' Pre-Intervention Math Deficits Affect Responsiveness to Generally Effective First-Grade Intervention?

The purpose of this analysis was to assess whether effects of 1st-grade mathematics intervention apply across the range of at-risk learners' initial skill levels. Students were randomly assigned to control (n=213) and 2 variants of intervention (n=385) designed to improve arithmetic. Of each 30-minute intervention session (48 over 16 weeks), 25 minutes were identical in the 2 variants, focused on number knowledge that provides the conceptual bases for arithmetic. The other 5 minutes provided non-speeded conceptual practice (n=196) or speeded strategic practice (n=199). Contrasts tested effects of intervention (combined across variants) versus control and effects between the variants. Moderation analysis indicated no significant interactions between at-risk children's pre-intervention mathematics skill and either contrast on any outcome. Across pre-intervention math skill, effects favored intervention over control on arithmetic and transfer to double-digit calculations and number knowledge and favored speeded over non-speeded practice on arithmetic.

Using Moderator Analysis to Identify the First-Grade Children Who Benefit More and Less from a Reading Comprehension Program: A Step Toward Aptitude-by-Treatment Interaction.

Because of the importance of teaching reading comprehension to struggling young readers and the infrequency with which it has been implemented and evaluated, we designed a comprehensive first-grade reading comprehension program. We conducted a component analysis of the program's decoding/fluency (DF) and reading comprehension (COMP) dimensions, creating DF and DF+COMP treatments to parse the value of COMP. Students (N = 125) were randomly assigned to the 2 active treatments and controls. Treatment children were tutored 3 times per week for 21 weeks in 45-min sessions. Children in DF and DF+COMP together performed more strongly than controls on word reading and comprehension. However, pretreatment word reading appeared to moderate these results such that children with weaker beginning word reading across the treatments outperformed similarly low-performing controls to a significantly greater extent than treatment children with stronger beginning word reading outperformed comparable controls. DF+COMP children did not perform better than DF children. Study limitations and implications for research and practice are discussed.

A Longitudinal Analysis of the Trajectories and Predictors of Word Reading and Reading Comprehension Development Among At-Risk Readers.

This study explored the developmental trajectories and predictors of word reading and reading comprehension among young at-risk readers. In fall of first grade, 185 students identified as at-risk for reading difficulties were assessed on measures of domain-specific skills (phonological awareness, letter knowledge, and vocabulary), domain-general skills (working memory, nonverbal reasoning, and processing speed), and word reading and reading comprehension. Word reading and reading comprehension were assessed again in spring of grades 1-4. Individual growth curve modeling showed that the children demonstrated decelerated growth on word reading and linear growth on reading comprehension, although their performance on both word reading and reading comprehension were consistently below average on national norms. After controlling for word reading and reading comprehension in first grade, letter knowledge predicted growth in word reading; vocabulary and nonverbal reasoning predicted growth in reading comprehension. That is, we found different developmental trajectories and different predictors for word reading and reading comprehension among our at-risk sample. Implications are discussed for theory and early reading instruction for at-risk children.