Biocatalytic Strategy for the Highly Stereoselective Synthesis of Fluorinated Cyclopropanes.

Fluorinated cyclopropanes are highly desired pharmacophores in drug discovery owing to the rigid nature of the cyclopropane ring and the beneficial effects of C-F bonds on the pharmacokinetic properties, cell permeability, and metabolic stability of drug molecules. Herein a biocatalytic strategy for the stereoselective synthesis of mono-fluorinated and gem-difluoro cyclopropanes is reported though the use of engineered myoglobin-based catalysts. In particular, this system allows for a broad range of gem-difluoro alkenes to be cyclopropanated in the presence of diazoacetonitrile with excellent diastereo and enantiocontrol (up to 99 : 1 d.r. and 99 % e.e.), thereby enabling a transformation not currently accessible with chemocatalytic methods. The synthetic utility of the present approach is further exemplified through the gram-scale synthesis of a key gem-difluorinated cyclopropane intermediate useful for the preparation of fluorinated bioactive molecules.

Linkage of public health and all payer claims data for population-level opioid research.

OBJECTIVE: Our objective is to describe how we combine, at an individual level, multiple administrative datasets to create a Comprehensive Opioid Risk Registry (CORR). The CORR will characterize the role that individual characteristics, household characteristics, and community characteristics have on an individual's risk of opioid use disorder or opioid overdose. DATA SOURCES: Study data sources include the voluntary Oregon All Payer Claims Database (APCD), American Community Survey Census Data, Oregon Death Certificate data, Oregon Hospital Discharge Data (HDD), and Oregon Prescription Drug Monitoring (PDMP) Data in 2013-2018. STUDY DESIGN: To create the CORR we first prepared the APCD data set by cleaning and geocoding addresses, creating a community grouper and adding census indices, creating household grouper, and imputing patient race. Then we deployed a probabilistic linkage methodology to incorporate other data sources maintaining compliance with strict data governance regulations. DATA COLLECTION/EXTRACTION METHODS: Administrative datasets were obtained through an executed data use agreement with each data owner. The APCD served as the population universe to which all other data sources were linked. PRINCIPAL FINDINGS: There were 3 628 992 unique people in the APCD over the entire study period. We identified 968 767 unique households in 2013 and 1 209 236 in 2018, and geocoded patient addresses representing all census tracts in Oregon. Census, death certificate, HDD, and PDMP datasets were successfully linked to this population universe. CONCLUSIONS: This methodology can be replicated in other states and may also apply to a broad array of health services research topics.

Ambulance Calls for Substance-Related Issues Before and After COVID-19.

Background: The United States is currently facing 2 epidemics: sustained morbidity and mortality from substance use and the more recent COVID-19 pandemic. We tested the hypothesis that the pandemic has disproportionately affected individuals with substance use disorder by evaluating average daily 9-1-1 ambulance calls for substance use-related issues compared with all other calls. Methods: This was a retrospective cross-sectional analysis of 9-1-1 ambulance calls before and after the start of COVID-19 in Massachusetts. We used consecutive samples of 9-1-1 ambulance calls, categorized into those which were substance-related or not. An interrupted time series analysis was performed to determine if there were changes in numbers of daily calls before a statewide declaration of emergency for COVID-19 (February 15-March 9, 2020), from the emergency declaration until a stay-at-home advisory (March 10-March 22, 2020) and following the stay-at-home advisory (March 23-May 15, 2020). Results: Compared with prior to the statewide emergency, the post-statewide emergency average of daily ambulance calls decreased from 2,453.2 to 1,969.6, a 19.7% decrease. Similarly, calls for substance-related reasons decreased by 16.4% compared with prior to the statewide emergency. However, despite an initial decrease in calls, after the stay-at-home advisory calls for substance use began increasing by 0.7 (95% confidence interval (CI) 0.4-1.1) calls/day, while calls for other reasons did not significantly change (+1.2 (95% CI -0.8 to 3.1) calls/day). Refusal of transport for substance-related calls increased from 5.0% before the statewide emergency to 7.5% after the declaration (p < 0.001). Conclusions: After an initial decline in substance-related ambulance calls following a statewide declaration of emergency, calls for substance use increased to pre-COVID-19 levels, while those for other reasons remained at a lower rate. The results suggest that COVID-19 is disproportionately affecting individuals with substance use disorder.

Prescription and Prescriber Specialty Characteristics of Initial Opioid Prescriptions Associated with Chronic Use.

OBJECTIVE: This study evaluated the characteristics of opioid prescriptions, including prescriber specialty, given to opioid-naïve patients and their association with chronic use. DESIGN: Cross-sectional analysis of the Ohio prescription drug monitoring program from January 2010 to November 2017. SETTING: Ohio, USA. SUBJECTS: Patients who had no opioid prescriptions from 2010 to 2012 and a first-time prescription from January 2013 to November 2016. METHODS: Chronic use was defined as at least six opioid prescriptions in one year and either one or more years between the first and last prescription or an average of ≤30 days not covered by an opioid during that year. RESULTS: A total of 4,252,809 opioid-naïve patients received their first opioid prescription between 2013 and 2016; 364,947 (8.6%) met the definition for chronic use. Those who developed chronic use were older (51.7 vs 45.6 years) and more likely to be female (53.6% vs 52.8%), and their first prescription had higher pill quantities (44.9 vs 30.2), higher morphine milligram equivalents (MME; 355.3 vs 200.0), and was more likely to be an extended-release formulation (2.9% vs 0.7%, all P < 0.001). When compared with internal medicine, the adjusted odds of chronic use were highest with anesthesiology (odds ratio [OR] = 1.46) and neurology (OR = 1.43) and lowest with ophthalmology (OR = 0.33) and gynecology (OR = 0.37). CONCLUSIONS: Eight point six percent of opioid-naïve individuals who received an opioid prescription developed chronic use. This rate varied depending on the specialty of the provider who wrote the prescription. The risk of chronic use increased with higher MME content of the initial prescription and use of extended-release opioids.

Counseling on Access to Lethal Means (CALM): An Evaluation of a Suicide Prevention Means Restriction Training Program for Mental Health Providers.

This paper evaluates the effectiveness of the Counseling on Access to Lethal Means (CALM) suicide prevention program. CALM trains mental health providers how to counsel suicidal individuals and those who support them on mean restriction during times of crisis. Pre/post/3-month follow-up assessments measured knowledge of lethal means, confidence and comfort in discussing means restriction (self-efficacy), and future intentions to counsel clients on means restriction. Change in the number of clients receiving lethal means counseling was also assessed. All constructs increased significantly at posttest. Confidence and counseling intentions were sustained at follow-up and significantly more clients received means counseling in the 3 months following the CALM training. Knowledge and comfort levels decreased at follow-up but not to pre-training levels. CALM is effective at increasing mental health professionals' comfort, knowledge, and frequency of talking about means restriction with clients. an effective means restriction training program. A template to assess clients for suicidality and lethal means access and booster sessions are recommended to further sustain effects.

Individual differences in cognitive control processes and their relationship to emotion regulation.

Cognitive control and emotional control share many similarities, but the specific relationship between these processes is not well understood. This study explored the relationship between three types of cognitive control (working memory updating, response inhibition and set-shifting) and two emotional regulation strategies (expressive suppression and cognitive reappraisal). Corrugator electromyography, behaviour and self-reports of affect were measured as indices of emotion regulation. Results indicate that working memory updating predicted negative affect reduction during reappraisal and during expressive suppression. This study specifically shows that the working memory component of cognitive control is associated with negative affect reduction. Response inhibition and set-shifting were not specifically related to negative affect reduction, but these variables did predict aspects of emotional behaviour and regulation. These results suggest a general role for cognitive control in some aspects of emotion regulation as well as a specific modulatory role for working memory updating in the regulation of negative affect.

Effect of integration of prescription drug monitoring program data in the electronic health record on queries by primary care providers.

Objective: To evaluate the impact of PDMP integration in the EHR on provider query rates within twelve primary care clinics in one academic medical center. Methods: Using linked data from the EHR and state PDMP program, we evaluated changes in PDMP query rates using a stepped-wedge observational design where integration was implemented in three waves (four clinics per wave) over a five-month period (May, July, September 2019). Multivariable negative binomial general estimating equations (GEE) models assessed changes in PDMP query rates, overall and across several provider and clinic-level subgroups. Results: Among 206 providers in PDMP integrated clinics, the average number of queries per provider per month increased significantly from 1.43 (95% CI 1.07 - 1.91) pre-integration to 3.94 (95% CI 2.96 - 5.24) post-integration, a 2.74-fold increase (95% CI 2.11 to 3.59; p < .0001). Those in the lowest quartile of PDMP use pre-integration increased 36.8-fold (95% CI 16.91 - 79.95) after integration, significantly more than other pre-integration PDMP use quartiles. Conclusions: Integration of the PDMP in the EHR significantly increased the use of the PDMP overall and across all studied subgroups. PDMP use increased to a greater degree among providers with lower PDMP use pre-integration.

Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment.

Shortcomings of previously reported preclinical models of nonalcoholic steatohepatitis (NASH) include inadequate methods used to induce disease and assess liver pathology. We have developed a dietary model of NASH displaying features observed clinically and methods for objectively assessing disease progression. Mice fed a diet containing 40% fat (of which ∼18% was trans fat), 22% fructose, and 2% cholesterol developed three stages of nonalcoholic fatty liver disease (steatosis, steatohepatitis with fibrosis, and cirrhosis) as assessed by histological and biochemical methods. Using digital pathology to reconstruct the left lateral and right medial lobes of the liver, we made comparisons between and within lobes to determine the uniformity of collagen deposition, which in turn informed experimental sampling methods for histological, biochemical, and gene expression analyses. Gene expression analyses conducted with animals stratified by disease severity led to the identification of several genes for which expression highly correlated with the histological assessment of fibrosis. Importantly, we have established a biopsy method allowing assessment of disease progression. Mice subjected to liver biopsy recovered well from the procedure compared with sham-operated controls with no apparent effect on liver function. Tissue obtained by biopsy was sufficient for gene and protein expression analyses, providing the opportunity to establish an objective method of assessing liver pathology before subjecting animals to treatment. The improved assessment techniques and the observation that mice fed the high-fat diet exhibit many clinically relevant characteristics of NASH establish a preclinical model for identifying pharmacological interventions with greater likelihood of translating to the clinic.

Association of Household Opioid Availability With Opioid Overdose.

Importance: Previous studies that examined the role of household opioid prescriptions in opioid overdose risk were limited to commercial claims, did not include fatal overdoses, and had limited inclusion of household prescription characteristics. Broader research is needed to expand understanding of the risk of overdose. Objective: To assess the role of household opioid availability and other household prescription factors associated with individuals' odds of fatal or nonfatal opioid overdose. Design, Setting, and Participants: A retrospective cohort study assessing patient outcomes from January 1, 2015, through December 31, 2018, was conducted on adults in the Oregon Comprehensive Opioid Risk Registry database in households of at least 2 members. Data analysis was performed between October 16, 2020, and January 26, 2023. Exposures: Household opioid prescription availability and household prescription characteristics. Main Outcomes and Measures: Opioid overdoses were captured from insurance claims, death records, and hospital discharge data. Household opioid prescription availability and prescription characteristics for individuals and households were modeled as 6-month cumulative time-dependent measures, updated monthly. To assess the association between household prescription availability, household prescription characteristics, and overdose, multilevel logistic regression models were developed, adjusting for demographic, clinical, household, and prescription characteristics. Results: The sample included 1 691 856 individuals in 1 187 140 households, of which most were women (53.2%), White race (70.7%), living in metropolitan areas (75.8%), and having commercial insurance (51.8%), no Elixhauser comorbidities (69.5%), and no opioid prescription fills in the study period (57.0%). A total of 28 747 opioid overdose events were observed during the study period (0.0526 per 100 person-months). Relative to individuals without personal or household opioid fills, the odds of opioid-related overdose increased by 60% when another household member had an opioid fill in the past 6 months (adjusted odds ratio [aOR], 1.60; 95% CI, 1.54-1.66) and were highest when both the individual and another household member had opioid fills in the preceding 6 months (aOR, 6.25; 95% CI, 6.09-6.40). Conclusions and Relevance: In this cohort study of adult Oregon residents in households of at least 2 members, the findings suggest that household prescription availability is associated with increased odds of opioid overdose for others in the household, even if they do not have their own opioid prescription. These findings underscore the importance of educating patients about proper opioid disposal and the risks of household opioids.

The association between community social vulnerability and prescription opioid availability with individual opioid overdose.

BACKGROUND: This study aims to assess the association of community social vulnerability and community prescription opioid availability with individual non-fatal or fatal opioid overdose. METHODS: We identified patients 12 years of age or older from the Oregon All Payer Claims database (APCD) linked to other public health datasets. Community-level characteristics were captured in an exposure period (EP) (1/1/2018-12/31/2018) and included: census tract-level social vulnerability domains (socio-economic status, household composition, racial and ethnic minority status, and housing type and transportation), census tract-level prescriptions and community-level opioid use disorder (OUD) diagnoses per 100 capita binned into quartiles or quintiles. We employed Cox models to estimate the risk of fatal and non-fatal opioid overdoses events in the 12 months following the EP. MAIN FINDINGS: We identified 1,548,252 individuals. Patients were mostly female (54%), White (61%), commercially insured (54%), and lived in metropolitan areas (81%). Of the total sample, 2485 (0.2%) experienced a non-fatal opioid overdose and 297 died of opioid overdose. There was higher hazard for non-fatal overdose in communities with greater OUD per 100 capita. We also found higher non-fatal and fatal hazards for opioid overdose among patients in communities with higher housing type and transportation-related vulnerability compared to the lowest quintile. Conversely, patients were at less risk of opioid overdose when living in communities with greater prevalence of the young or the elderly, the disabled, single parent families or low English proficiency. CONCLUSION: These findings underscore the importance of the environmental context when considering public health policies to reduce opioid harms.

A primary colonic crypt model enriched in enteroendocrine cells facilitates a peptidomic survey of regulated hormone secretion.

To enable the first physiologically relevant peptidomic survey of gastrointestinal tissue, we have developed a primary mouse colonic crypt model enriched for enteroendocrine L-cells. The cells in this model were phenotypically profiled using PCR-based techniques and showed peptide hormone and secretory and processing marker expression at mRNA levels that were increased relative to the parent tissue. Co-localization of glucagon-like peptide-1 and peptide YY, a characteristic feature of L-cells, was demonstrated by double label immunocytochemistry. The L-cells displayed regulated hormone secretion in response to physiological and pharmacological stimuli as measured by immunoassay. Using a high resolution mass spectrometry-based platform, more than 50 endogenous peptides (<16 kDa), including all known major hormones, were identified a priori. The influence of culture conditions on peptide relative abundance and post-translational modification was characterized. The relative abundance of secreted peptides in the presence/absence of the stimulant forskolin was measured by label-free quantification. All peptides exhibiting a statistically significant increase in relative concentration in the culture media were derived from prohormones, consistent with a cAMP-coupled response. The only peptides that exhibited a statistically significant decrease in secretion on forskolin stimulation were derived from annexin A1 and calcyclin. Biophysical interactions between annexin A1 and calcyclin have been reported very recently and may have functional consequences. This work represents the first step in characterizing physiologically relevant peptidomic secretion of gastrointestinally derived primary cells and will aid in elucidating new endocrine function.

Opioid-related overdose and chronic use following an initial prescription of hydrocodone versus oxycodone.

BACKGROUND: Hydrocodone and oxycodone are prescribed commonly to treat pain. However, differences in risk of opioid-related adverse outcomes after an initial prescription are unknown. This study aims to determine the risk of opioid-related adverse events, defined as either chronic use or opioid overdose, following a first prescription of hydrocodone or oxycodone to opioid naïve patients. METHODS: A retrospective analysis of multiple linked public health datasets in the state of Oregon. Adult patients ages 18 and older who a) received an initial prescription for oxycodone or hydrocodone between 2015-2017 and b) had no opioid prescriptions or opioid-related hospitalizations or emergency department visits in the year preceding the prescription were followed through the end of 2018. First-year chronic opioid use was defined as ≥6 opioid prescriptions (including index) and average ≤30 days uncovered between prescriptions. Fatal or non-fatal opioid overdose was indicated from insurance claims, hospital discharge data or vital records. RESULTS: After index prescription, 2.8% (n = 14,458) of individuals developed chronic use and 0.3% (n = 1,480) experienced overdose. After adjustment for patient and index prescription characteristics, patients receiving oxycodone had lower odds of developing chronic use relative to patients receiving hydrocodone (adjusted odds ratio = 0.95, 95% confidence interval (CI) 0.91-1.00) but a higher risk of overdose (adjusted hazard ratio (aHR) = 1.65, 95% CI 1.45-1.87). Oxycodone monotherapy appears to greatly increase the hazard of opioid overdose (aHR 2.18, 95% CI 1.86-2.57) compared with hydrocodone with acetaminophen. Oxycodone combined with acetaminophen also shows a significant increase (aHR 1.26, 95% CI 1.06-1.50), but not to the same extent. CONCLUSIONS: Among previously opioid-naïve patients, the risk of developing chronic use was slightly higher with hydrocodone, whereas the risk of overdose was higher after oxycodone, in combination with acetaminophen or monotherapy. With a goal of reducing overdose-related deaths, hydrocodone may be the favorable agent.

Factors Associated With Opioid Overdose After an Initial Opioid Prescription.

Importance: The opioid epidemic continues to be a public health crisis in the US. Objective: To assess the patient factors and early time-varying prescription-related factors associated with opioid-related fatal or nonfatal overdose. Design, Setting, and Participants: This cohort study evaluated opioid-naive adult patients in Oregon using data from the Oregon Comprehensive Opioid Risk Registry, which links all payer claims data to other health data sets in the state of Oregon. The observational, population-based sample filled a first (index) opioid prescription in 2015 and was followed up until December 31, 2018. Data analyses were performed from March 1, 2020, to June 15, 2021. Exposures: Overdose after the index opioid prescription. Main Outcomes and Measures: The outcome was an overdose event. The sample was followed up to identify fatal or nonfatal opioid overdoses. Patient and prescription characteristics were identified. Prescription characteristics in the first 6 months after the index prescription were modeled as cumulative, time-dependent measures that were updated monthly through the sixth month of follow-up. A time-dependent Cox proportional hazards regression model was used to assess patient and prescription characteristics that were associated with an increased risk for overdose events. Results: The cohort comprised 236 921 patients (133 839 women [56.5%]), of whom 667 (0.3%) experienced opioid overdose. Risk of overdose was highest among individuals 75 years or older (adjusted hazard ratio [aHR], 3.22; 95% CI, 1.94-5.36) compared with those aged 35 to 44 years; men (aHR, 1.29; 95% CI, 1.10-1.51); those who were dually eligible for Medicaid and Medicare Advantage (aHR, 4.37; 95% CI, 3.09-6.18), had Medicaid (aHR, 3.77; 95% CI, 2.97-4.80), or had Medicare Advantage (aHR, 2.18; 95% CI, 1.44-3.31) compared with those with commercial insurance; those with comorbid substance use disorder (aHR, 2.74; 95% CI, 2.15-3.50), with depression (aHR, 1.26; 95% CI, 1.03-1.55), or with 1 to 2 comorbidities (aHR, 1.32; 95% CI, 1.08-1.62) or 3 or more comorbidities (aHR, 1.90; 95% CI, 1.42-2.53) compared with none. Patients were at an increased overdose risk if they filled oxycodone (aHR, 1.70; 95% CI, 1.04-2.77) or tramadol (aHR, 2.80; 95% CI, 1.34-5.84) compared with codeine; used benzodiazepines (aHR, 1.06; 95% CI, 1.01-1.11); used concurrent opioids and benzodiazepines (aHR, 2.11; 95% CI, 1.70-2.62); or filled opioids from 3 or more pharmacies over 6 months (aHR, 1.38; 95% CI, 1.09-1.75). Conclusions and Relevance: This cohort study used a comprehensive data set to identify patient and prescription-related risk factors that were associated with opioid overdose. These findings may guide opioid counseling and monitoring, the development of clinical decision-making tools, and opioid prevention and treatment resources for individuals who are at greatest risk for opioid overdose.

COVID-19-related adaptations to the implementation and evaluation of a clinic-based intervention designed to improve opioid safety.

The United States faces an opioid crisis with an unprecedented and increasing death rate from opioid overdose. Successfully reducing the rates of opioid use disorder (OUD) and overdose will require the engagement of frontline clinicians to prescribe opioids more safely and to build their capacity to treat patients with OUD using evidence-based approaches. The COVID-19 pandemic has created significant challenges for patients, clinicians and health systems and has been associated with increasing risks of overdoses and deaths. Herein, we review a multidisciplinary project designed to implement and evaluate clinic-based interventions in Oregon, USA, to improve pain management, opioid prescribing and treatment of OUD. The intervention, called Improving PaIn aNd OPiOId MaNagemenT in Primary Care (PINPOINT), combines practice facilitation, academic detailing and education through the Oregon ECHO Network. Implementation of PINPOINT has occurred across the Oregon Rural Practice-based Research Network and has involved 49 clinic sites to date. To evaluate the impact of the intervention, the research team created the Provider Results of Opioid Management and Prescribing Training (PROMPT), a dataset that links information from the state prescription drug monitoring program, all-payer claims database, emergency medical services, vital records and substance use disorder treatment system. The PROMPT dataset will allow evaluation of the impact of the intervention at both the clinician and clinic levels. Due to the constraints of the COVID-19 pandemic, elements of both implementation and evaluation required significant adaptations to continue to meet the original project goals.

Comparison of Community-Level and Patient-Level Social Risk Data in a Network of Community Health Centers.

Importance: Responding to the substantial research on the relationship between social risk factors and health, enthusiasm has grown around social risk screening in health care settings, and numerous US health systems are experimenting with social risk screening initiatives. In the absence of standard social risk screening recommendations, some health systems are exploring using publicly available community-level data to identify patients who live in the most vulnerable communities as a way to characterize patient social and economic contexts, identify patients with potential social risks, and/or to target social risk screening efforts. Objective: To explore the utility of community-level data for accurately identifying patients with social risks by comparing the social deprivation index score for the census tract where a patient lives with patient-level social risk screening data. Design, Setting, and Participants: Cross-sectional study using patient-level social risk screening data from the electronic health records of a national network of community health centers between June 24, 2016, and November 15, 2018, linked to geocoded community-level data from publicly available sources. Eligible patients were those with a recorded response to social risk screening questions about food, housing, and/or financial resource strain, and a valid address of sufficient quality for geocoding. Exposures: Social risk screening documented in the electronic health record. Main Outcomes and Measures: Community-level social risk was assessed using census tract-level social deprivation index score stratified by quartile. Patient-level social risks were identified using food insecurity, housing insecurity, and financial resource strain screening responses. Results: The final study sample included 36 578 patients from 13 US states; 22 113 (60.5%) received public insurance, 21 181 (57.9%) were female, 17 578 (48.1%) were White, and 10 918 (29.8%) were Black. Although 6516 (60.0%) of those with at least 1 social risk factor were in the most deprived quartile of census tracts, patients with social risk factors lived in all census tracts. Overall, the accuracy of the community-level data for identifying patients with and without social risks was 48.0%. Conclusions and Relevance: Although there is overlap, patient-level and community-level approaches for assessing patient social risks are not equivalent. Using community-level data to guide patient-level activities may mean that some patients who could benefit from targeted interventions or care adjustments would not be identified.

The Impact of Social and Clinical Complexity on Diabetes Control Measures.

PURPOSE: In an age of value-based payment, primary care providers are increasingly scrutinized on performance metrics that assess quality of care, including the outcomes of their patient population in key areas such as diabetes control. Although such measures often adjust for patient clinical risk factors or clinical complexity, most do not account for the social complexity of patient populations, despite research demonstrating the strong association between social factors and health. METHODS: Using patient electronic health record data from 2 large community health center networks serving safety net patients, we assessed the effect of both clinical and social risk factors on poor glucose control among diabetics. Logistic regression results were used to estimate the impact of adjusting for both clinical and social complexity on provider performance metrics. Clinical complexity was measured at the patient-level using the Charlson Comorbidity Index. Social complexity was measured at the community-level using the Social Deprivation Index. RESULTS: Clinical complexity alone was not consistently associated with poor diabetes control (ie, HbA1c > 9%) in diabetic patients with HbA1c testing during the study period. However, increasing social complexity was significantly associated with higher rates of poor diabetic control in both cohorts. After adding adjustment for social complexity down to the national median score, our models suggest that approximately 25% of providers would have 1 to 2% improvement in the assessment of their diabetes control measures, with 45% showing a 2 to 5% improvement, and 5% showing more than a 5% improvement. CONCLUSIONS: Providers caring for patients with greater social risk factors may benefit from having their performance metrics adjusted for the social complexity of their patient populations.

Closing Gaps in Public Services for US Residents With Intellectual and Developmental Disabilities.

This Viewpoint describes existing public health and social service systems for persons with intellectual and developmental disabilities as they transition to adult care, barriers and opportunities faced in service access, and potential actions to narrow these gaps and enhance equity.

Exploring the neurodevelopment of visual statistical learning using event-related brain potentials.

Implicit statistical learning (ISL) allows for the learning of environmental patterns and is thought to be important for many aspects of perception, cognition, and language development. However, very little is known about the development of the underlying neural mechanisms that support ISL. To explore the neurodevelopment of ISL, we investigated the event-related potential (ERP) correlates of learning in adults, older children (aged 9-12), and younger children (aged 6-9) using a novel predictor-target paradigm. In this task, which was a modification of the standard oddball paradigm, participants were instructed to view a serial input stream of visual stimuli and to respond with a button press when a particular target appeared. Unbeknownst to the participants, covert statistical probabilities were embedded in the task such that the target was predicted to varying degrees by different predictor stimuli. The results were similar across all three age groups: a P300 component that was elicited by the high predictor stimulus after sufficient exposure to the statistical probabilities. These neurophysiological findings provide evidence for developmental invariance in ISL, with adult-like competence reached by at least age 6.

Poly I:CLC induction of the interferon system in mice: an initial study of four detection methods.

Induction of a large number of the components of the interferon (IFN) system (IFN genes, their mRNAs, IFN proteins, IFN receptors, IFN signaling molecules, the IFN response genes, and their effector proteins) has been studied. Less well studied is the comparative induction of these components in vivo. Induction of IFN by double-stranded RNA (dsRNA) treatment mimics certain aspects of viral infection and induces the components of the IFN system. To determine the comparative sensitivity of detection of induction in mice, we initially studied the limiting concentrations of polyribinosinic-polyribocytidylic acid, polylysine complex (poly I:CLC, a synthetic dsRNA preparation), for induction of four representative components of the IFN system: (1) IFN in serum, (2) the IFN response gene mRNA ISG54 in spleen and liver, (3) the IFN-beta mRNA in spleen, and (4) resistance of mice to Banzi viral infection. The results of this initial study showed that resistance to infection was 7-fold more sensitive for detection of the IFN response than was ISG54 mRNA and 70-fold more sensitive than either IFN-beta mRNA or IFN production in serum. In comparison, mouse cells in vitro treated with poly I:CLC were 3-10-fold less sensitive to its antiviral action than is the mouse. The results demonstrate that in the four tests in mice, the most sensitive indicator of poly I:CLC induction of the IFN system was protection against Banzi viral infection, followed by ISG54 mRNA levels, IFN-beta mRNA, and IFN protein levels. It is hypothesized that the highest sensitivity of mouse protection may be due to priming by the initial poly I:CLC-induced IFN of the subsequent Banzi virus-induced IFN, resulting in rapid and high concentrations of IFN at the local site of viral replication. Future studies are needed to study other molecular components of the IFN system to identify those that cause the unanticipated high sensitivity of mice to protection against Banzi virus.