Envelope-dimer epitope-like broadly protective antibodies against dengue in children following natural infection and vaccination.

Cross-reactive antibodies (Abs) to epitopes that span envelope proteins on the virion surface are hypothesized to protect against dengue. Here, we measured Abs targeting the quaternary envelope dimer epitope (EDE) as well as neutralizing and binding Abs and evaluate their association with dengue virus (DENV) infection, vaccine response, and disease outcome in dengue vaccinated and unvaccinated children (n=252) within a longitudinal cohort in Cebu, Philippines (n=2,996). Abs targeting EDE were prevalent and strongly associated with broad neutralization of DENV1-4 in those with baseline multitypic immunity. Subsequent natural infection and vaccination boosted EDE-like, neutralizing, and binding Abs. EDE-like Abs were associated with reduced dengue risk and mediated the protective effect of binding and neutralizing Abs on symptomatic and severe dengue. Thus, Abs targeting quaternary epitopes help explain broad cross protection in those with multiple prior DENV exposures, making them useful for evaluation and development of future vaccines and therapeutics.

Using decision tree models and comprehensive statewide data to predict opioid overdoses following prison release.

PURPOSE: Identifying predictors of opioid overdose following release from prison is critical for opioid overdose prevention. METHODS: We leveraged an individually linked, state-wide database from 2015-2020 to predict the risk of opioid overdose within 90 days of release from Massachusetts state prisons. We developed two decision tree modeling schemes: a model fit on all individuals with a single weight for those that experienced an opioid overdose and models stratified by race/ethnicity. We compared the performance of each model using several performance measures and identified factors that were most predictive of opioid overdose within racial/ethnic groups and across models. RESULTS: We found that out of 44,246 prison releases in Massachusetts between 2015-2020, 2237 (5.1%) resulted in opioid overdose in the 90 days following release. The performance of the two predictive models varied. The single weight model had high sensitivity (79%) and low specificity (56%) for predicting opioid overdose and was more sensitive for White non-Hispanic individuals (sensitivity = 84%) than for racial/ethnic minority individuals. CONCLUSIONS: Stratified models had better balanced performance metrics for both White non-Hispanic and racial/ethnic minority groups and identified different predictors of overdose between racial/ethnic groups. Across racial/ethnic groups and models, involuntary commitment (involuntary treatment for alcohol/substance use disorder) was an important predictor of opioid overdose.

ZOom Delivered Intervention Against Cognitive decline (ZODIAC) COVID-19 pandemic adaptations to the Post-Ischaemic Stroke Cardiovascular Exercise Study (PISCES): protocol for a randomised controlled trial of remotely delivered fitness training for brain health.

BACKGROUND: Stroke increases subsequent dementia risk yet there are no specific post-stroke therapies to protect cognition. Cardiorespiratory exercise is recommended for secondary prevention of stroke and may be neuroprotective. The Post Ischaemic Stroke Cardiovascular Exercise Study (PISCES) aims to reduce post-stroke secondary neurodegeneration and cognitive decline. During the pandemic, we pivoted to a ZOom Delivered Intervention Against Cognitive decline (ZODIAC) protocol, reducing pandemic-amplified barriers to exercise. METHODS: We present pandemic adaptions for a multicentre phase IIb assessor-blinded randomised controlled trial of ischaemic stroke survivors testing the efficacy and feasibility of an 8-week home-based exercise intervention delivered at 2 months post-stroke. We compare cardiorespiratory exercise (intervention arm) versus balance and stretching (active control arm). Participants are assessed with magnetic resonance imaging (MRI), fitness, blood, microbiome, and neuropsychological tests at three study visits: before and after the exercise intervention and at 12 months. Modifications to the original protocol include pre-exercise safety home visits, commercial delivery of exercise equipment to facilitate assessor blinding, and reconsideration of statistical plan to allow pooling of the studies. We have reduced in-person study visits from 27 to 3. Primary outcome remains between-group (intervention versus control) difference in brain volume change; secondary outcome is between-group difference in global cognitive ability to allow remote administration of a validated cognitive scale. DISCUSSION: Remotely delivered exercise interventions reduce participant burden and may reduce barriers to recruitment. A decrease in the number of in-person study visits can be supported by greater information capture via self-reported questionnaires and phone surveys. TRIAL REGISTRATION: Prospectively ACTRN12616000942459. Registered on July 2016.

Listening to School Nurses' Voices: A Mixed Methods Study on the Continued Impact of COVID-19 on School Nursing Practice.

School closures in March 2020 due to the COVID-19 pandemic precipitated losses of critical student resources as physical, mental, emotional, and social needs escalated. Identifying the challenges, strategies, and changes in school nurse (SN) practice in Massachusetts during this pandemic is fundamental to understanding how to manage future anticipated pandemics while protecting children, communities, and SNs. The purpose of this mixed-methods descriptive study in the second year of the global pandemic was to (a) listen to SN voices through a novel online survey including the prompts of challenges, strategies, and practice changes and (b) describe the SN experience of COVID-19 response in Massachusetts schools, including identification of intent to leave school nursing. Responses were analyzed using descriptive qualitative analysis (n = 73). The prompts each elicited subthemes that coalesced to a cohesive theme: Finding one's way required the support of others to pave untraversed roads.

Dengue virus IgG and serotype-specific neutralizing antibody titers measured with standard and mature viruses are associated with protection.

Recent work demonstrates the limitations of the standard dengue virus (DENV) neutralization assay to predict protection against dengue. We perform studies to compare how a commercial IgG ELISA, envelope domain III (EDIII) or non-structural protein 1 (NS1) binding antibodies, and titers from plaque reduction neutralization tests (PRNTs) using reference standard and clinical mature viruses are associated with dengue disease. Healthy children (n = 1,206) in Cebu, Philippines were followed for 5 years. High ELISA values (≥3) were associated with reduced dengue probability relative to naïve children (3% vs. 10%, p = 0.008), but antibody binding EDIII or NS1 from each serotype had no association. High standard and mature geometric mean PRNT titers were associated with reduced dengue disease overall (p < 0.01), and high DENV2 and DENV3 titers in both assays provided protection against the matched serotype (p < 0.02). However, while 52% of dengue cases had standard virus PRNT titers > 100, only 2% of cases had mature virus PRNT titers > 100 (p < 0.001), indicating a lower, more consistent threshold for protection. Each assay may be useful for different purposes as correlates of protection in population and vaccine trials.

Effect of single-dose, live, attenuated dengue vaccine in children with or without previous dengue on risk of subsequent, virologically confirmed dengue in Cebu, the Philippines: a longitudinal, prospective, population-based cohort study.

BACKGROUND: A three-dose dengue vaccine (CYD-TDV) was licensed for use in children aged 9 years and older starting in 2015 in several dengue-endemic countries. In 2016, the Philippine Department of Health implemented a dengue vaccination programme, which was discontinued because of safety concerns. We assessed the relative risk of developing virologically confirmed dengue among children who did or did not receive a single dose of CYD-TDV by previous dengue virus (DENV) infections at baseline classified as none, one, and two or more infections. METHODS: In this longitudinal, prospective, population-based cohort study, we enrolled healthy children (aged 9-14 years) residing in Bogo or Balamban, Cebu, Philippines, between May 2, and June 2, 2017, before a mass dengue vaccination campaign, via the Rural Health Unit in Bogo and three Rural Health Units in Balamban. We collected demographic information and sera for baseline DENV serostatus and conducted active surveillance for acute febrile illness. Children who developed acute febrile illness were identified, clinical data were collected, and blood was drawn for confirmation of dengue by RT-PCR. The primary outcome was the relative risk of developing virologically confirmed dengue among children who received or did not receive a single dose of CYD-TDV by DENV serostatus at baseline. FINDINGS: A single dose of CYD-TDV did not confer protection against virologically confirmed dengue in children who had none or one previous DENV infection at baseline. One dose conferred significant protection against hospital admission for virologically confirmed dengue among participants who had two or more previous DENV infections at baseline during the first 3 years (70%, 95% CI 20-88; p=0·017) and the entire follow-up period (67%, 19-87; p=0·016). INTERPRETATION: The risk of developing virologically confirmed dengue after a single dose of CYD-TDV varied by baseline DENV serostatus. Since the study assessed the effect of only a single dose, the findings cannot inform decisions on vaccination by public health officers. However, the findings have implications for children who receive an incomplete vaccination regimen and these results should prompt more detailed analyses in future trials on dengue vaccines. FUNDING: The Philippine Department of Health, Hanako Foundation, WHO, Swedish International Development Cooperation Agency, International Vaccine Institute, University of North Carolina, and US National Institute of Allergy and Infectious Diseases.

Intersectional inequities and longitudinal prevalence estimates of opioid use disorder in Massachusetts 2014-2020: a multi-sample capture-recapture analysis.

Background: As overdoses continue to increase worldwide, accurate estimates are needed to understand the size of the population at risk and address health disparities. Capture-recapture methods may be used in place of direct estimation at nearly any geographic level (e.g., city, state, country) to estimate the size of the population with opioid use disorder (OUD). We performed a multi-sample capture-recapture analysis with persons aged 18-64 years to estimate the prevalence of OUD in Massachusetts from 2014 to 2020, stratified by sex and race/ethnicity. Methods: We used seven statewide administrative data sources linked at the individual level. We developed log-linear models to estimate the unknown OUD-affected population. Uncertainty was characterized using 95% confidence intervals (95% CI) on the total counts and prevalence estimates. Findings: The estimated OUD prevalence increased from 5.47% (95% CI = 4.89%, 5.98%) in 2014 to 5.79% (95% CI = 5.34%, 6.19%) in 2020. Prevalence among Hispanic females doubled (2.46% in 2014 to 4.23% in 2020) and prevalence rose to nearly 10% among Black non-Hispanic males and Hispanic males from 2014 through 2019. Estimates for Black non-Hispanic females more than doubled from 2014 through 2019 (3.39% to 7.09%), and then decreased to 5.69% in 2020. Interpretation: This study is the first to provide OUD prevalence trend estimates by binary sex and race/ethnicity at a state level using capture-recapture methods. Using these methods as the international overdose crisis worsens can allow jurisdictions to appropriately allocate resources and targeted interventions to marginalised populations. Funding: NIDA.

Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter (SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathologic and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1 and SLCO1B3. Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1 expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multifactorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55-fold from the diet alone and the 1.88-fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multifactorial pharmacokinetic interactions. SIGNIFICANCE STATEMENT: Advanced stages of NAFLD cause decreased hepatic OATP1B abundance and increase systemic exposure to OATP substrates in human patients. The humanized OATP1B mouse strain may provide a clinically relevant model to recapitulate these observations and predict pharmacokinetic interactions in NAFLD. This research characterized three diet-induced and one drug-induced NAFLD model in a humanized OATP1B mouse model. Additionally, a multifactorial pharmacokinetic interaction was observed between silymarin and NAFLD.

Test characteristics for combining non-invasive liver fibrosis staging modalities in individuals with Hepatitis C virus.

Non-invasive methods have largely replaced biopsy to identify advanced fibrosis in hepatitis C virus (HCV). Guidelines vary regarding testing strategy to balance accuracy, costs and loss to follow-up. Although individual test characteristics are well-described, data comparing the accuracy of using two tests together are limited. We calculated combined test characteristics to determine the utility of combined strategies. This study synthesizes empirical data from fibrosis staging trials and the literature to estimate test characteristics for Fibrosis-4 (FIB4), APRI or a commercial serum panel (FibroSure®), followed by transient elastography (TE) or FibroSure®. We simulated two testing strategies: (1) second test only for those with intermediate first test results (staged approach), and (2) second test for all. We summarized empiric data with multinomial distributions and used this to estimate test characteristics of each strategy on a simulated population of 10,000 individuals with 4.2% cirrhosis prevalence. Negative predictive value (NPV) for cirrhosis from a single test ranged from 98.2% (95% CB 97.6-98.8%) for FIB-4 to 99.4% (95% CB 99.0-99.8%) for TE. Using a staged approach with TE second, sensitivity for cirrhosis rose to 93.3-96.9%, NPV to 99.7-99.8%, while PPV dropped to <32%. Using TE as a second test for all minimally changed estimated test characteristics compared with the staged approach. Combining two non-invasive fibrosis tests barely improves NPV and decreases or does not change PPV compared with a single test, challenging the utility of serial testing modalities. These calculated combined test characteristics can inform best methods to identify advanced fibrosis in various populations.

Looking under the lamp-post: quantifying the performance of contact tracing in the United States during the SARS-CoV-2 pandemic.

Contact tracing forms a crucial part of the public-health toolbox in mitigating and understanding emergent pathogens and nascent disease outbreaks. Contact tracing in the United States was conducted during the pre-Omicron phase of the ongoing COVID-19 pandemic. This tracing relied on voluntary reporting and responses, often using rapid antigen tests due to lack of accessibility to PCR tests. These limitations, combined with SARS-CoV-2's propensity for asymptomatic transmission, raise the question "how reliable was contact tracing for COVID-19 in the United States"? We answered this question using a Markov model to examine the efficiency with which transmission could be detected based on the design and response rates of contact tracing studies in the United States. Our results suggest that contact tracing protocols in the U.S. are unlikely to have identified more than 1.65% (95% uncertainty interval: 1.62-1.68%) of transmission events with PCR testing and 1.00% (95% uncertainty interval 0.98-1.02%) with rapid antigen testing. When considering a more robust contact tracing scenario, based on compliance rates in East Asia with PCR testing, this increases to 62.7% (95% uncertainty interval: 62.6-62.8%). We did not assume presence of asymptomatic transmission or superspreading, making our estimates upper bounds on the actual percentages traced. These findings highlight the limitations in interpretability for studies of SARS-CoV-2 disease spread based on U.S. contact tracing and underscore the vulnerability of the population to future disease outbreaks, for SARS-CoV-2 and other pathogens.

Assessing the ecological risk of heavy metal sediment contamination from Port Everglades Florida USA.

Port sediments are often contaminated with metals and organic compounds from anthropogenic sources. Remobilization of sediment during a planned expansion of Port Everglades near Fort Lauderdale, Florida (USA) has the potential to harm adjacent benthic communities, including coral reefs. Twelve sediment cores were collected from four Port Everglades sites and a control site; surface sediment was collected at two nearby coral reef sites. Sediment cores, sampled every 5 cm, were analyzed for 14 heavy metals using inductively coupled plasma-mass spectrometry. Results for all three locations yielded concentration ranges (µg/g): As (0.607-223), Cd (n/d-0.916), Cr (0.155-56.8), Co (0.0238-7.40), Cu (0.004-215), Pb (0.0169-73.8), Mn (1.61-204), Hg (n/d-0.736), Mn (1.61-204), Ni (0.232-29.3), Se (n/d-4.79), Sn (n/d-140), V (0.160-176), and Zn (0.112-603), where n/d = non-detected. The geo-accumulation index shows moderate-to-strong contamination of As and Mo in port sediments, and potential ecological risk indicates moderate-to-significantly high overall metal contamination. All four port sites have sediment core subsamples with As concentrations above both threshold effect level (TEL, 7.24 µg/g) and probable effect level (PEL, 41.6 µg/g), while Mo geometric mean concentrations exceed the background continental crust level (1.5 µg/g) threshold. Control site sediments exceed TEL for As, while the reef sites has low to no overall heavy metal contamination. Results of this study indicate there is a moderate to high overall ecological risk from remobilized sediment due to metal contamination. Due to an imminent dredging at Port Everglades, this could have the potential to harm the threatened adjacent coral communities and surrounding protected habitats.

Protocol for the EACH trial: a multicentre phase II study evaluating the safety and antitumour activity of the combination of avelumab, an anti-PD-L1 agent, and cetuximab, as any line treatment for patients with recurrent/metastatic head and neck squamous cell cancer (HNSCC) in the UK.

INTRODUCTION: Head and neck cancer is the eighth most common cancer in the UK. Current standard of care treatment for patients with recurrent/metastatic squamous cell head and neck carcinoma (HNSCC) is platinum-based chemotherapy combined with the anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, cetuximab. However, most patients will have poor median overall survival (OS) of 6-9 months despite treatment. HNSCC tumours exhibit an immune landscape poised to respond to immunotherapeutic approaches, with most tumours expressing the immunosuppressive receptor programmed death-ligand 1 (PD-L1). We undertook the current study to determine the safety and efficacy of avelumab, a monoclonal antibody targeting the interaction between PD-L1 and its receptor on cytotoxic T-cells, in combination with cetuximab. METHODS AND ANALYSIS: This is a multi-centre, single-arm dose de-escalation phase II safety and efficacy study of avelumab combined with cetuximab; the study was to progress to a randomised phase II trial, however, the study will now complete after the safety run-in component. Up to 16 participants with histologically/cytologically recurrent/metastatic squamous cell carcinoma (including HNSCC) who have not received cetuximab previously will be recruited. All patients will receive 10 mg/kg avelumab and cetuximab (500, 400 or 300 mg/m2 depending on the cohort open at time of registration) on days 1 and 15 of 4-week cycles for up to 1 year, (avelumab not given cycle 1 day 1). A modified continual reassessment method will be used to determine dose de-escalation. The primary objective is to establish the safety of the combination and to determine the optimum dose of cetuximab. Secondary objectives include assessing evidence of antitumour activity by evaluating response rates and disease control rates at 6 and 12 months as well as progression-free and OS. ETHICS AND DISSEMINATION: Approval granted by City and East REC (18/LO/0021). Findings will be published in peer-reviewed journals and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT03494322.

Antibody escape, the risk of serotype formation, and rapid immune waning: Modeling the implications of SARS-CoV-2 immune evasion.

As the COVID-19 pandemic progresses, widespread community transmission of SARS-CoV-2 has ushered in a volatile era of viral immune evasion rather than the much-heralded stability of "endemicity" or "herd immunity." At this point, an array of viral strains has rendered essentially all monoclonal antibody therapeutics obsolete and strongly undermined the impact of vaccinal immunity on SARS-CoV-2 transmission. In this work, we demonstrate that antibody escape resulting in evasion of pre-existing immunity is highly evolutionarily favored and likely to cause waves of short-term transmission. In the long-term, invading strains that induce weak cross-immunity against pre-existing strains may co-circulate with those pre-existing strains. This would result in the formation of serotypes that increase disease burden, complicate SARS-CoV-2 control, and raise the potential for increases in viral virulence. Less durable immunity does not drive positive selection as a trait, but such strains may transmit at high levels if they establish. Overall, our results draw attention to the importance of inter-strain cross-immunity as a driver of transmission trends and the importance of early immune evasion data to predict the trajectory of the pandemic.

Trends in buprenorphine dosage and days supplied for new treatment episodes for opioid use disorder, 2010-2019.

BACKGROUND: Buprenorphine reduces risk of opioid overdose mortality. However, its benefits are limited by low retention, particularly in early treatment. Optimizing initial dosage may impact retention. However, little is known about the prescription characteristics of new buprenorphine treatment episodes. METHODS: In a US sample of commercial and employer-sponsored pharmacy claims, we identified new buprenorphine treatment episodes (days 1-30) from individuals ≥16 years following 90 days without buprenorphine from 2010 to 2019. Outcomes included first prescription average days supplied, first prescription average daily dosage, and average dosage on days 2, 8, 15 and 30. RESULTS: We identified 117,793 new episodes among 96,451 unique individuals. Episodes per 10,000 person-years decreased slightly over time. Stratifying by age, sex and region demonstrated decreasing episodes among individuals ≤34 years and increasing episodes among individuals ≥35 years. From 2010-2019, first prescription average days supplied and daily dosage decreased from 17.1 to 15.3 days and 13.6mg to 11.6mg, respectively. Simultaneously, the proportion of episodes without possession and with dosages <16mg increased across all days and years. By day 30, episodes without buprenorphine possession grew from 27.9% to 30.8% and episodes involving dosages of <16mg grew from 26.4% to 33.4%. CONCLUSIONS: We found that buprenorphine dosage and days supplied for new treatment episodes decreased from 2010 to 2019 while buprenorphine possession worsened. Further investigation examining the relationship between buprenorphine dosage and retention in the early treatment period is needed.

The Cajal body protein p80-coilin forms a complex with the adenovirus L4-22K protein and facilitates the nuclear export of adenovirus mRNA.

IMPORTANCE: The architecture of sub-nuclear structures of eucaryotic cells is often changed during the infectious cycle of many animal and plant viruses. Cajal bodies (CBs) form a major sub-nuclear structure whose functions may include the regulation of cellular RNA metabolism. During the lifecycle of human adenovirus 5 (Ad5), CBs are reorganized from their spherical-like structure into smaller clusters termed microfoci. The mechanism of this reorganization and its significance for virus replication has yet to be established. Here we show that the major CB protein, p80-coilin, facilitates the nuclear export of Ad5 transcripts. Depletion of p80-coilin by RNA interference led to lowered levels of viral proteins and infectious virus. p80-coilin was found to form a complex with the viral L4-22K protein in Ad5-infected cells and in some reorganized microfoci. These findings assign a new role for p80-coilin as a potential regulator of infection by a human DNA virus.

Dengue virus 4/2 envelope domain chimeric virus panel maps type-specific responses against dengue serotype 2.

IMPORTANCE: The four dengue virus (DENV) serotypes infect several hundred million people each year. Although primary infection is generally mild, subsequent infection by differing serotypes increases the risk for symptomatic disease ranging from fever to life-threatening shock. Despite the availability of licensed vaccines, a comprehensive understanding of antibodies that target the viral envelope protein and protect from infection remains incomplete. In this manuscript, we develop a panel of recombinant viruses that graft each envelope domain of DENV2 onto the DENV4 envelope glycoprotein, revealing protein interactions important for virus viability. Furthermore, we map neutralizing antibody responses after primary DENV2 natural infection and a human challenge model to distinct domains on the viral envelope protein. The panel of recombinant viruses provides a new tool for dissecting the E domain-specific targeting of protective antibody responses, informing future DENV vaccine design.

Massachusetts Prevalence of Opioid Use Disorder Estimation Revisited: Comparing a Bayesian Approach to Standard Capture-Recapture Methods.

BACKGROUND: The National Survey on Drug Use and Health (NSDUH) estimated the prevalence of opioid use disorder (OUD) among the civilian, noninstitutionalized people aged 12 years or older in Massachusetts as 1.2% between 2015 and 2017. Accurate estimation of the prevalence of OUD is critical to the success of treatment and resource planning. Various indirect estimation approaches have been used but are subject to data availability and infrastructure-related issues. METHODS: We used 2015 data from the Massachusetts Public Health Data Warehouse (PHD) to compare the results of two approaches to estimating OUD prevalence in the Massachusetts population. First, we used a seven-dataset capture-recapture analysis under log-linear model parameterization, controlling for the source dependence and effects of age, sex, and county through stratification. Second, we applied a benchmark-multiplier method in a Bayesian framework by linking health care claims data to death certificate data assuming an extrapolation of death rates from observed untreated OUD to unobserved OUD. RESULTS: Our estimates for OUD prevalence among Massachusetts residents (aged 18-64 years) were 4.62% (95% CI = 4.59%, 4.64%) in the capture-recapture approach and 4.29% (95% CrI = 3.49%, 5.32%) in the Bayesian model. Both estimates were approximately four times higher than NSDUH estimates. CONCLUSION: The synthesis of our findings suggests that the disease surveillance system misses a large portion of the population with OUD. Our study also suggests that concurrent use of multiple methods improves the justification and facilitates the triangulation and interpretation of the resulting estimates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04111939.

Evolution of a functionally intact but antigenically distinct DENV fusion loop.

A hallmark of dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. Antibody-dependent enhancement is linked to antibodies targeting the fusion loop (FL) motif of the envelope protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. In the current study, we utilized saturation mutagenesis and directed evolution to engineer a functional variant with a mutated FL (D2-FL), which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4)-infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2)-infected NHP. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live-attenuated DENV vaccines suitable for naïve individuals and children.

Aspirin and nonaspirin nonsteroidal antiinflammatory drug use and occurrence of colorectal adenoma in Black American women.

Evidence suggests that aspirin use reduces the occurrence of colorectal neoplasia. Few studies have investigated the association among Black Americans, who are disproportionately burdened by the disease. We assessed aspirin use in relation to colorectal adenoma among Black women. The Black Women's Health Study is a prospective cohort of self-identified Black American women established in 1995. Participants reported regular aspirin use on baseline and follow-up questionnaires. Beginning in 1999, participants reported undergoing a colonoscopy or sigmoidoscopy, the only procedures through which colorectal adenomas can be diagnosed. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between aspirin use and colorectal adenoma among 34 397 women who reported at least 1 colonoscopy or sigmoidoscopy. From 1997 through 2018, 1913 women were diagnosed with an adenoma. Compared to nonaspirin users, regular users had 14% (OR = 0.86, 95% CI: 0.78-0.95) lower odds of adenoma. The odds of adenoma decreased with increasing duration of aspirin use (≥10 years: OR = 0.80, 95% CI: 0.66-0.96). Initiating aspirin at a younger age was associated with a reduced adenoma occurrence (age < 40 years at initiation: OR = 0.69, 95% CI: 0.55-0.86). Regular aspirin use was associated with a decreased odds of colorectal adenoma in our study of Black women. These findings support evidence demonstrating a chemopreventive impact of aspirin on colorectal neoplasia and suggest that aspirin may be a useful prevention strategy among US Black women.

Perspectives of Speech-Language Pathologists and Students on Providing Care to People Living With Dementia: A Scoping Review.

PURPOSE: This scoping review aimed to explore the extant literature on the experiences and views of speech-language pathologists (SLPs) and SLP students regarding the provision of care to people living with dementia (PLWD). METHOD: A systematic search was conducted using 10 databases for sources published in English from January 2000 through January 2022. Sources were included if participants were practicing SLPs and/or students enrolled in undergraduate communicative disorders or graduate SLP programs and if the concepts of experiences or views on the provision of SLP services to PLWD were explored in the context of any clinical or educational setting. Included sources were systematically extracted for pertinent study characteristics, including SLP roles and settings, concept domains, measures utilized, and facilitators/barriers to effective dementia care. RESULTS: The majority of the 29 included sources were published in either academic journals (n = 20) or professional organization publications (n = 5) and used a cross-sectional study design (n = 19). Participants included SLPs (n = 22 studies) and graduate (n = 6 studies), undergraduate (n = 3 studies), and doctoral students (n = 1 study). The included studies addressed five primary conceptual domains: experiences, attitudes, roles, knowledge, and confidence. The most commonly addressed barriers and facilitators of effective dementia care were education and training. CONCLUSIONS: Mapping and analysis of the current body of knowledge within this scoping review illuminated several knowledge gaps that we propose need to be addressed to meet the education and training needs of SLPs to provide optimal care to PLWD. These include systematically measuring access to and outcomes of evidence-based education and training programs both within and outside of an interprofessional collaborative context.