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Prior work suggests perceived COVID-19-related threat and existential isolation (EI) would be associated with greater anxiety and depression, worse subjective health and well-being, and lower hope. However, it was unclear whether such concerns might have additive effects (no interaction, two independent main effects) or interact (one effect modifies the other). Two studies collected data via MTurk during the COVID-19 pandemic. Study 1 (N = 110) measured perceived COVID19-related threat, EI, anxiety and depression, subjective well-being, and hope. Study 2 (N = 2,673) measured perceived COVID19-related threat, EI, anxiety, subjective health, and hope. In general, perceived COVID19-related threat and EI were associated with anxiety and depression, worse subjective health and well-being, and reduced hope. On one outcome (hope, Study 2), an interaction was observed: perceived threat was associated with lower hope among those with high EI, but higher hope among those with low EI. However, on most outcomes (6 of 7), across both studies, additive effects were observed: greater cumulative existential stress (perceived COVID-19-related threat, EI) was associated with worse anxiety and depression, subjective health and well-being, and hope. Discussion highlights theoretical considerations, practical implications, and the therapeutic value of addressing existential concerns in mental health. What is already known about this topic:Prior work found perceived COVID-19-related threat and other death-related existential concerns were related to anxiety, depression, and undermined well-being and hopeful engagement.Prior work found existential isolation was related to anxiety, depression, and undermined well-being.COVID-19-related threat was associated with worse anxiety, depression, and well-being, but not subjective health or hope. Prior work found perceived COVID-19-related threat and other death-related existential concerns were related to anxiety, depression, and undermined well-being and hopeful engagement. Prior work found existential isolation was related to anxiety, depression, and undermined well-being. COVID-19-related threat was associated with worse anxiety, depression, and well-being, but not subjective health or hope. What this topic adds:EI was consistently associated with worse anxiety and depression, subjective health and well-being, and reduced hope.In one outcome (hope, Study 2), an interaction found that perceived COVID-19-related threat decreased hope when people felt existentially isolated, but increased hope when people felt a sense of existential connection (e.g., “we’re all in this together”).However, on six of seven outcomes, across two studies, additive effects were observed such that the more existential stress (COVID-19-related threat, existential isolation) experienced the worse the outcome. EI was consistently associated with worse anxiety and depression, subjective health and well-being, and reduced hope. In one outcome (hope, Study 2), an interaction found that perceived COVID-19-related threat decreased hope when people felt existentially isolated, but increased hope when people felt a sense of existential connection (e.g., “we’re all in this together”). However, on six of seven outcomes, across two studies, additive effects were observed such that the more existential stress (COVID-19-related threat, existential isolation) experienced the worse the outcome.

Background: Patients presenting for emergency department (ED) evaluation may be appropriate for treatment with monoclonal antibodies for mild to moderate COVID-19. While many sites have implemented infusion centers for these agents, EDs will continue to evaluate these patients where appropriate identification and efficient infusion of eligible patients is critical. Objectives: Patients receiving bamlanivimab in the EDs of an academic medical center are described. The primary objective was to describe operational metrics and secondary objectives reported clinical outcomes. Methods: Patients receiving bamlanivimab and discharged from the ED were included from November 16, 2020 to January 16, 2021 in the retrospective, observational cohort. Primary outcome was adherence to institutional criteria. Secondary outcomes included ED visit metrics, clinical characteristics, and return visits within 30 days. Risk factors for return visits were assessed with regression. Results: One hundred nineteen patients were included. Most (71%) were diagnosed with COVID-19 during the ED visit and median symptom duration was 3(IQR 2-5) days. Median number of risk factors for progression to severe disease was 2 (IQR 1-2). Thirty percent had a documented abnormal chest x-ray. Institutional criteria adherence was 99.2%. Median time from ED room to bamlanivimab was 4 (IQR 3.1-5.2) hours. Thirty patients had return visit within 30 days; 19 were COVID-19 related. Two multivariable regression models were analyzed for COVID-19 related return visit. Characteristics on ED presentation were considered in Model I: male gender (OR 3.01[0.97-9.31]), age (per 10 years) (OR 1.49[1.05-2.12]), African-American race (OR 3.46[1.09-11.06]), and symptom duration (per day) (OR 1.34[1.05-1.73]). Model II included labs and imaging acquired in ED. In Model II, age (per 10 years) (OR 1.52[1.07-2.16]) and abnormal CXR (OR 5.74[1.95-16.9]) were associated with COVID-19 related return visits. Conclusions: Administration of bamlanivimab to ED patients can be done efficiently, with the potential to reduce COVID-19 related return visits. Age and abnormal imaging were independent predictors of COVID-19 return visits.

Emergency department (ED) providers play a critical role in the stabilization and diagnostic evaluation of patients presenting with acute heart failure (AHF), and EDs are key areas for establishing current best practices and future considerations for the disposition of and decision making for patients with AHF. These elements include accurate risk assessment; response to initial treatment and shared decision making concerning optimal venue of care; reframing of physicians' risk perceptions for patients presenting with AHF; exploration of alternative venues of care beyond hospitalization; population-level changes in demographics, management and outcomes of HF patients; development and testing of data-driven pathways to assist with disposition decisions in the ED; and suggested outcomes for measuring success.

While effective in treating abdominal pain, opioids have significant side effects. Recent legalization of cannabis will likely promote use of cannabinoids as an adjunct or alternative to opioids, despite a lack of evidence. We aimed to investigate whether cannabinoids inhibit mouse colonic nociception, alone or in combination with opioids at low doses. Experiments were performed on C57BL/6 male and female mice. Visceral nociception was evaluated by measuring visceromotor responses (VMR), afferent nerve mechanosensitivity in flat-sheet colon preparations, and excitability of isolated DRG neurons. Blood oxygen saturation, locomotion, and defecation were measured to evaluate side effects. An agonist of cannabinoid 1 receptor (CB1R), arachidonyl-2′-chloroethylamide (ACEA), dose-dependently decreased VMR. ACEA and HU-210 (another CB1R agonist) also attenuated colonic afferent nerve mechanosensitivity. Additionally, HU-210 concentration-dependently decreased DRG neuron excitability, which was reversed by the CB1R antagonist AM-251. Conversely, cannabinoid 2 receptor (CB2R) agonists did not attenuate VMR, afferent nerve mechanosensitivity, or DRG neuron excitability. Combination of subanalgesic doses of CB1R and µ-opioid receptor agonists decreased VMR; importantly, this analgesic effect was preserved after 6 d of twice daily treatment. This combination also attenuated afferent nerve mechanosensitivity and DRG neuron excitability, which was inhibited by neuronal nitric oxide synthase and guanylate cyclase inhibitors. This combination avoided side effects (decreased oxygen saturation and colonic transit) caused by analgesic dose of morphine. Activation of CB1R, but not CB2R, decreased colonic nociception both alone and in synergy with µ-opioid receptor. Thus, CB1R agonists may enable opioid dose reduction and avoid opioid-related side effects. SIGNIFICANCE STATEMENT One of the most cited needs for patients with abdominal pain are safe and effective treatment options. The effectiveness of opioids in the management of abdominal pain is undermined by severe adverse side effects. Therefore, strategies to replace opioids or reduce the doses of opioids to suppress abdominal pain is needed. This study in mice demonstrates that cannabinoid 1 receptor (CB1R) agonists inhibit visceral sensation. Furthermore, a combination of subanalgesic doses of µ-opioid receptor agonist and CB1R agonist markedly reduce abdominal pain without causing the side effects of high-dose opioids. Thus, CB1R agonists, alone or in combination with low-dose opioids, may be a novel and safe treatment strategy for abdominal pain.

Background: The present study explores trauma-related factors (human trafficking or physical or sexual violence during transactional sex) associated with interest in future community mobilization around health and human rights. Community mobilization among persons selling sex aims to help participants overcome trauma and increase self-reliance through peer advocacy and collective action for improved human conditions. However, how violence and human trafficking impact community mobilization participation among men and women selling sex is less known. Methods: The current study uses data (n = 96) from the baseline survey of participants in the pilot Kapihan community mobilization intervention, which recruited 37 men and 59 women from Metro Manila, Philippines. Multiple logistic regression was used to analyze factors (violence, human trafficking) independently associated with the desire to participate in community mobilization, adjusting for socio-demographic variables. Results: An increased interest in participating in community mobilization around health and human rights was significantly associated with having experienced physical or sexual abuse in the sex trade (AOR = 10.86; CI 1.48–79.69) and less history of trafficking (AOR = 0.14; 95% CI 0.02–0.97), adjusting for age, gender, income, number of children, and whether they considered group goals or had previously participated in community mobilization. Conclusion: Understanding the impact of experiences with physical and sexual violence and human trafficking on health and human rights mobilization participation can inform the design and recruitment for future community-based interventions. Further investigation needs to explore why experiences with human trafficking, having more children, or being a woman lessened the desire to mobilize in this Philippines context. Findings imply that trauma may be more complex. More work is needed to better identify interventions for those with a history of being trafficked or victimized by physical or sexual violence during transactional sex exchanges.

The physical processes of heat exchange between lakes and the surrounding atmosphere are important in simulating and predicting terrestrial surface energy balance. Latent and sensible heat fluxes are the dominant physical process controlling ice growth and decay on the lake surface, as well as having influence on regional climate. While one-dimensional lake models have been used in simulating environmental changes in ice dynamics and water temperature, understanding the seasonal to daily cycles of lake surface energy balance and its relationship to lake thermal properties, atmospheric conditions, and how those are represented in models is still an open area of research. We evaluated a pair of one-dimensional lake models, Freshwater Lake (FLake) and the General Lake Model (GLM), to compare modeled latent and sensible heat fluxes against observed data collected by an eddy covariance tower during a 1-yr period in 2017, using Lake Mendota in Madison, Wisconsin, as our study site. We hypothesized transitional periods of ice cover as a leading source of model uncertainty, and we instead found that the models failed to simulate accurate values for large positive heat fluxes that occurred from late August into late December. Our results ultimately showed that one-dimensional models are effective in simulating sensible heat fluxes but are considerably less sensitive to latent heat fluxes than the observed relationships of latent heat flux to environmental drivers. These results can be used to focus future improvement of these lake models especially if they are to be used for surface boundary conditions in regional numerical weather models. Significance Statement While lakes consist of a small amount of Earth’s surface, they have a large impact on local climate and weather. A large amount of energy is stored in lakes during the spring and summer, and then removed from lakes before winter. The effect is particularly noticeable in high latitudes, when the seasonal temperature difference is larger. Modeling this lake energy exchange is important for weather models and measuring this energy exchange is challenging. Here we compare modeled and observed energy exchange, and we show there are large amounts of energy exchange happening in the fall, which models struggle to capture well. During periods of partial ice coverage in early winter, lake behavior can change rapidly.

When appropriately used, helicopter emergency medical services (HEMSs) allow for timely delivery of severely injured patients to definitive care. Inappropriate utilization of HEMSs results in increased cost to the patient and trauma system. The purpose of this study was to review current HEMS criteria in the central Gulf Coast region and evaluate for potential areas of triage refinement and cost savings. We hypothesized that a significant number of patients received potentially unwarranted HEMS transport.A retrospective cohort study of all patients with trauma arriving to a level I trauma center by helicopter over 28 mo was performed; 381 patients with trauma and with HEMS transport from the scene were included. Data were collected from prehospital sources, as well as hospital chart review for each patient. The primary outcome was the rate of unwarranted HEMS transport.A total of 381 adult patients with trauma transported by the HEMS were analyzed, of which 34% were deemed potentially nonwarranted transports. The significant factors correlating with warranted HEMS transport included age, multiple long bone fractures, penetrating mechanism, and vehicle ejection. Insurance demographics did not correlate to transport modality. Many of these patients were transported from a location within the same county or the county adjacent to the trauma center. When comparing patients transported by ground and HEMSs from the same scene, no time savings were identified. Unwarranted transports at the trauma center represented an estimated health care expenditure of over $3 million.HEMSs may be overused in the central Gulf Coast region, creating the risk for a substantial resource and financial burden to the trauma system. Further collaboration is needed to establish HEMS triage criteria, that is, more appropriate use of resources.

INTRODUCTION: Video telehealth can offer people convenient, real-time access to clinicians without arranging transportation or time off work. Among people with diabetes, this study examines the association between video telehealth access and changes in HbA1c. METHODS: This longitudinal cohort study (2016–2019) used linear regression with person-level fixed effects, stratified by baseline HbA1c (last value in 2015), to examine the association between video visit access and changes in HbA1c. HbA1c values were categorized into 3 periods of video visit exposure: (1) before any video visit, (2) video visit transition year (calendar year of the first video visit), and (3) after video visits. The model compared changes in HbA1c values collected before the patient had any video visits with those collected after the transition year. Analyses was conducted in September 2020. RESULTS: Among 204,301 people with diabetes, video visit access was associated with a statistically significant reduction of 0.15 (95% CI= −0.19, −0.11) percentage points in HbA1c, with greater reductions among patients with an elevated baseline HbA1c value (−0.22 percentage points, 95% CI= −0.32, −0.11) and with no baseline HbA1c measurement (−0.39 percentage points, 95% CI= −0.71, −0.07). CONCLUSIONS: Gaining access to video telehealth was associated with reductions in HbA1c among people with diabetes. Video telehealth offers people with chronic conditions a new, convenient way to access health care, is not associated with worsening HbA1c, and may support better disease management, particularly among patients with higher baseline HbA1c.

The mismatch between when individuals breed and when we think they should breed has been a long-standing problem in evolutionary ecology. Price et al. is a classic theory paper in this field and is mainly cited for its most obvious result: if individuals with high nutritional condition breed early, then the advantage of breeding early may be overestimated when information on nutritional condition is absent. Price at al.'s less obvious result is that individuals, on average, are expected to breed later than the optimum. Here, we provide an explanation of their non-intuitive result in terms of hard selection, and go on to show that neither of their results are expected to hold if the relationship between breeding date and nutrition is allowed to evolve. By introducing the assumption that the advantage of breeding early is greater for individuals in high nutritional condition, we show that their most cited result can be salvaged. However, individuals, on average, are expected to breed earlier than the optimum, not later. More generally, we also show that the hard selection mechanisms that underpin these results have major implications for the evolution of plasticity: when environmental heterogeneity becomes too great, plasticity is selected against, prohibiting the evolution of generalists.

It is unclear whether referral for cardiac noninvasive testing (NIT) following emergency department (ED) chest pain encounters improves short-term outcomes.This was a retrospective cohort study of patients presenting with chest pain, without ST-elevation myocardial infarction or myocardial injury by serum troponin testing, between 2013 and 2019 to 21 EDs within an integrated health care system. We examined the association between NIT referral (within 72 h of the ED encounter) and a primary outcome of 60-day major adverse cardiac events (MACE). Secondary outcomes were 60-day MACE without coronary revascularization (MACE-CR) and 60-day all-cause mortality. To account for confounding by indication for NIT, we grouped patient encounters into ranked tertiles of NIT referral intensity based on the likelihood of 72-h NIT referral associated with the initially assigned emergency physician, relative to local peers and within discrete time periods. Associations between NIT referral-intensity tertile and outcomes were assessed using risk-adjusted multivariable logistic regression.Among 210,948 eligible patient encounters, 72-h NIT referral frequency was 11.9%, 18.3%, and 25.9% in low, intermediate, and high NIT referral-intensity encounters, respectively. Compared with the low referral-intensity tertile, there was a higher risk of 60-day MACE within the high referral-intensity tertile (odds ratio [OR] = 1.11, 95% confidence interval [CI] = 1.04 to 1.17) due to more coronary revascularizations without corresponding differences in MACE-CR or all-cause mortality. In analyses stratified by patients' estimated risk (HEART score; 50.5% lower risk, 38.7% moderate risk, 10.8% higher risk), the difference in 60-day MACE was primarily attributable to moderate-risk encounters (OR = 1.15, 95% CI = 1.08 to 1.24), with no differences among either lower- (OR = 1.10, 95% CI = 0.92 to 1.31) or higher- (OR = 1.01, 95% CI = 0.90 to 1.14) risk encounters.Higher referral intensity for 72-h NIT was associated with higher risk of coronary revascularization but no difference in adverse events within 60 days. These findings further call into question the urgency of NIT among ED patients without objective evidence of myocardial injury.

Background The dural puncture epidural technique may improve analgesia quality by confirming midline placement and increasing intrathecal translocation of epidural medications. This would be advantageous in obese parturients with increased risk of block failure. This study hypothesizes that quality of labor analgesia will be improved with dural puncture epidural compared to standard epidural technique in obese parturients. Methods Term parturients with body mass index greater than or equal to 35 kg · m–2, cervical dilation of 2 to 7 cm, and pain score of greater than 4 (where 0 indicates no pain and 10 indicates the worst pain imaginable) were randomized to dural puncture epidural (using 25-gauge Whitacre needle) or standard epidural techniques. Analgesia was initiated with 15 ml of 0.1% ropivacaine with 2 µg · ml–1 fentanyl, followed by programed intermittent boluses (6 ml every 45 min), with patient-controlled epidural analgesia. Parturients were blinded to group allocation. The data were collected by blinded investigators every 3 min for 30 min and then every 2 h until delivery. The primary outcome was a composite of (1) asymmetrical block, (2) epidural top-ups, (3) catheter adjustments, (4) catheter replacement, and (5) failed conversion to regional anesthesia for cesarean delivery. Secondary outcomes included time to a pain score of 1 or less, sensory levels at 30 min, motor block, maximum pain score, patient-controlled epidural analgesia use, epidural medication consumption, duration of second stage of labor, delivery mode, fetal heart tones changes, Apgar scores, maternal adverse events, and satisfaction with analgesia. Results Of 141 parturients randomized, 66 per group were included in the analysis. There were no statistically or clinically significant differences between the dural puncture epidural and standard epidural groups in the primary composite outcome (34 of 66, 52% vs. 32 of 66, 49%; odds ratio, 1.1 [0.5 to 2.4]; P = 0.766), its individual components, or any of the secondary outcomes. Conclusions A lack of differences in quality of labor analgesia between the two techniques in this study does not support routine use of the dural puncture epidural technique in obese parturients. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

This review considers sociological perspectives and research on the outcomes and implications of forced and refugee migration for migrants and communities of settlement. Analytic constraints and opportunities posed by concepts of forced and refugee migration and migrants for empirical research are underscored. The tendencies for research on forced and refugee migration to serve policy and programs are addressed in relationship to the conceptualization of processes of displacement as well as research design. A social demographic lens is used to illustrate a record of research on the consequences of forced and refugee migration and settlement. Accordingly, we review empirical literature on patterns of spatial mobility, health and well-being, social and economic integration, and family and community dynamics at different scales. Implications of global issues such as climate change and the COVID-19 pandemic are considered. Analytic issues emerge from the intersections, and lack thereof, between forced migration, refugee studies, and migration policy analysis and provide critical opportunities for contributions by sociologists and social scientists more generally. Expected final online publication date for the Annual Review of Sociology, Volume 49 is July 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients, and still lacks an effective targeted therapy. Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer. Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4′-phosphate of phosphatidylinositol-(3, 4)-bisphosphate (PI-3,4-P2), creating phosphatidylinositol-3-phosphate. There is debate concerning whether PI-3,4-P2 contributes to Akt and downstream effector activation with the known canonical signaling second messenger, phosphatidylinositol-(3, 4, 5)-trisphosphate (PIP3). If PI-3,4-P2 is a positive effector, INPP4B would be a negative regulator of PI3K signaling, and there is some evidence to support this. Utilizing phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null triple-negative breast tumor cell lines, it was unexpectedly found that silencing INPP4B decreased basal phospho-Akt (pAkt) and cellular proliferation, and in most cases sensitized cells to PI3K-α and PI3K-β isoform-specific inhibitors. Conversely, overexpression of INPP4B desensitized cells to PI3K inhibitors in a phosphatase activity-dependent manner. In summary, the current investigation of INPP4B in PTEN-null TNBC suggests new mechanistic insight and the potential for targeted therapy for this aggressive subset of breast cancer.Implications: These data support a model where PI-3,4-P2 is inhibitory toward PI3K, revealing a novel feedback mechanism under conditions of excessive signaling, and potentially an indication for PI3K-β isoform-specific inhibitors in PTEN-null TNBC that have lost INPP4B expression. Mol Cancer Res; 15(6); 765–75. ©2017 AACR.

S1. PI3K pathway and mutations in cancer. S2. PI3K inhibitor chemical structures. S3. Effect of INPP4B siRNA on Akt signaling. S4. Effect of INPP4B siRNA on PI3K inhibitor GI50s. S5. Effect of CRISPR-mediated knockout of INPP4B in HCC70 cells on Akt signaling in response to PI3K-αI. S6. Effect of CRISPR-mediated knockout of INPP4B in HCC70 cells on PI3K inhibitor GI50s. S7. Effect of CRISPR-mediated knockout of INPP4B in BT549 cells on Akt signaling. S8. Effect of CRISPR-mediated knockdown of INPP4B in BT549 cells on PI3K inhibitor GI50s. S9. Effect of the pan PI3Ki on in vitro PI3K activity.

Supplementary Fig. S3 from Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor

Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species. [Mol Cancer Ther 2008;7(7):1880–9]

Supplementary Fig. S4 from Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor

Supplementary Fig. S1 from Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor

Nitidulidae trapping performed from 2018 to 2021 to characterize flight behaviors of potential vectors of the oak wilt pathogen yielded three new species records for Canada, six new species records for Ontario, and three new species records for Manitoba. The new records for Canada include Carpophilus (Ecnomorphus) corticinus reported from Ontario, C. (Myothorax) nepos reported from Ontario and Manitoba, and Glischrochilus (Librodor) obtusus reported from Ontario. In addition, the following species are first recorded in Ontario: Carpophilus (Ecnomorphus) antiquus, C. (Megacarpolus) sayi, Stelidota coenosa; and also in Manitoba: Carpophilus (Megacarpolus) lugubris and Cychramus adustus. Collection data is provided for the two provinces and national records.

Forced migrants suffer from significant psychological distress. However, they often prioritize urgent practical resettlement needs over mental health needs. The present study used a quasi-experimental design to compare pathways of treatment for survivors of torture (N = 369) from 42 different counties receiving care from a refugee health clinic. Random intercept ANOVAs were used to compare combined case management services and psychological treatment (CM-PT) to case management services only (CM) on changes in cultural adaptation and global functioning over time. Results showed that both groups improved on each outcome. Importantly, the CM-PT group endorsed greater improvements in cultural adaptation (b = 0.28, 95% CI 0.14, 0.41, p ≤ 0.001) and global functioning (b = 3.29, 95% CI 1.33, 5.25, p = 0.001) compared to the CM group. These findings suggest that treatment for survivors of torture should be multifaceted and include case management and psychological treatment. Case management services alone may be beneficial when socio-cultural and resource barriers exist for mental health treatment.

Background Vancomycin (VAN) is an efficacious therapy against Streptococcus. VAN area under the curve to minimum inhibitory concentration (AUC/MIC) is the preferred monitoring strategy for serious methicillin-resistant S. aureus infections but is not well elucidated for other bacterial pathogens such as Streptococcus. Methods This was a retrospective cohort study evaluating adult inpatients with streptococcal bacteremia treated with VAN definitive therapy from Jan 1, 2011 to Sept 30, 2021 at a tertiary care academic medical center. VAN AUC was retrospectively calculated using Bayesian software (ClinCalc). The primary outcome was treatment failure, defined as a composite of recurrent or persistent streptococcal bacteremia, 60-day all-cause readmission, or 60-day all-cause mortality. Secondary outcomes included time to bacteremia clearance, hospital length of stay (LOS), and nephrotoxicity. Data collected included demographics; comorbidities; severity of illness; streptococcal species and source; VAN initial trough and duration; and clinical outcomes. Classification and regression tree analysis (CART) was conducted to identify the AUC threshold predictive of clinical failure. Wilcoxon rank sum, Chi Square, or Fisher’s exact tests were utilized as appropriate to compare groups stratified by the CART-identified AUC threshold. Results Forty-six patients met inclusion criteria during the study timeframe. Eleven patients had a VAN AUC < 329 of which 8 (73%) experienced clinical failure, while 35 patients had a VAN AUC > 329 of which 12 (34%) experienced clinical failure (p=0.04). No significant differences in baseline or clinical characteristics were identified between groups. Median VAN initial trough was higher in the VAN AUC > 329 group (13.2 vs 6.2, p< 0.001). Median hospital LOS was longer in the VAN AUC > 329 group (15 vs 8 days, p=0.05) while median time to bacteremia clearance (29 vs 25 hrs, p=0.15) and nephrotoxicity incidence (13% vs 4%, p=1) were not significantly different. Conclusion Vancomycin AUC < 329 was predictive of clinical failure in patients with streptococcal bacteremia. Larger studies are needed before VAN AUC monitoring can be recommended for implementation in the management of streptococcal bacteremia. Disclosures All Authors: No reported disclosures.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. From the onset of the pandemic, rapid antigen tests have quickly proved themselves to be an accurate and accessible diagnostic platform. The initial (and still most commonly used antigen tests) for COVID-19 diagnosis were constructed using monoclonal antibodies (mAbs) specific to severe acute respiratory syndrome coronavirus (SARS-CoV) nucleocapsid protein (NP). These mAbs are able to bind SARS-CoV-2 NP due to high homology between the two viruses. However, since first being identified in 2019, SARS-CoV-2 has continuously mutated, and a multitude of variants have appeared. These mutations have an elevated risk of leading to possible diagnostic escape when using tests produced with SARS-CoV-derived mAbs. Here, we established a library of 18 mAbs specific to SARS-CoV-2 NP and used two of these mAbs (1CV7 and 1CV14) to generate a prototype antigen-detection lateral flow immunoassay (LFI). A side-by-side analysis of the 1CV7/1CV14 LFI and the commercially available BinaxNOW

Although historical records of introductions that trigger successful biological invasions are common, subsequent patterns of dispersal and colonisation routes are unclear. We use microsatellites to examine genetic population structuring of established invasive brown trout (Salmo trutta) populations in Newfoundland, Canada, for evidence of “natural” dispersal, human-mediated introductions, and colonisation routes. We also explored ancestry of contemporary populations relative to presumed progenitors. Results analysed using STRUCTURE, DAPC, a NJ tree and FST comparisons support records of historical introductions; current Newfoundland populations are largely descended from Scottish stock, with St. John’s the primary introduction site. Subsequent dispersal of these trout was facilitated principally by anadromy, largely consistent with a classic stepping-stone model, with significant isolation-by-distance. With one exception, dispersal along the north and south coasts of the Avalon peninsula appears to be natural and independent, involving stochastic processes resulting in unique outcomes for population composition. This study is a good example of dispersal patterns during a contemporary invasion underscoring the potential for non-anadromous founders to re-express anadromy, facilitating colonization of distant sites.

Background and AimsInitial use of drugs such as tobacco and alcohol may lead to subsequent more problematic drug use—the ‘gateway’ hypothesis. However, observed associations may be due to a shared underlying risk factor, such as trait impulsivity. We used bidirectional Mendelian randomization (MR) to test the gateway hypothesis.DesignOur main method was inverse-variance weighted (IVW) MR, with other methods included as sensitivity analyses (where consistent results across methods would raise confidence in our primary results). MR is a genetic instrumental variable approach used to support stronger causal inference in observational studies.Setting and participantsGenome-wide association summary data among European ancestry individuals for smoking initiation, alcoholic drinks per week, cannabis use and dependence, cocaine and opioid dependence (n = 1749–1 232 091).MeasurementsGenetic variants for exposure.FindingsWe found evidence of causal effects from smoking initiation to increased drinks per week [(IVW): β = 0.06; 95% confidence interval (CI) = 0.03–0.09; P = 9.44 × 10−06], cannabis use [IVW: odds ratio (OR) = 1.34; 95% CI = 1.24–1.44; P = 1.95 × 10−14] and cannabis dependence (IVW: OR = 1.68; 95% CI = 1.12–2.51; P = 0.01). We also found evidence of an effect of cannabis use on the increased likelihood of smoking initiation (IVW: OR = 1.39; 95% CI = 1.08–1.80; P = 0.01). We did not find evidence of an effect of drinks per week on other substance use outcomes, except weak evidence of an effect on cannabis use (IVW: OR = 0.55; 95% CI = 0.16–1.93; P-value = 0.35). We found weak evidence of an effect of opioid dependence on increased drinks per week (IVW: β = 0.002; 95% CI = 0.0005–0.003; P = 8.61 × 10−03).ConclusionsBidirectional Mendelian randomization testing of the gateway hypothesis reveals that smoking initiation may lead to increased alcohol consumption, cannabis use and cannabis dependence. Cannabis use may also lead to smoking initiation and opioid dependence to alcohol consumption. However, given that tobacco and alcohol use typically begin before other drug use, these results may reflect a shared risk factor or a bidirectional effect for cannabis use and opioid dependence.

Purpose Despite the increased awareness that all dialects are valid linguistic forms, perceptions of African American English (AAE) use are often negative in the general population. Students training for careers as speech-language pathologists (SLPs) are required to have coursework relating to cultural and linguistic diversity. However, little is known about the perceptions of AAE among students in SLP programs. Method Seventy-three students from 46 randomly selected university programs in the United States completed an online survey including explicit statements regarding the validity of AAE and a matched-guide task assessing participants' implicit perceptions of AAE. Participants were randomly assigned to one of four audio pairings that differed in terms of the dialect spoken and the formality of the conversational context. Participants rated the speaker on 11 attributes (e.g., literate/illiterate, rich/poor) using the Revised Speech Dialect Attitudinal Scale. Results Participants indicated positive opinions of statements on the validity of AAE. However, across three categories of personal attributes—sociointellectual, aesthetic, and dynamism—participants who heard the Mainstream American English recordings rated the speaker differently than recordings including AAE. Conclusions Students in SLP programs express positive opinions regarding AAE, and yet, they rate speakers who speak AAE lower in personal attributes. The results highlight the importance of expanding training for future SLPs to include not only explicit statements about the value of AAE but also activities addressing implicit perceptions of dialect use. We provide a brief discussion of how the current data can be implemented for such an activity. Lesson plans and materials are provided as supplemental materials. Supplemental Material https://doi.org/10.23641/asha.15241638

After initiating breastfeeding, some African American mothers find adjusting to the demands challenging and discontinue breastfeeding. To learn about decisions switching to formula, we conducted a secondary analysis of qualitative interviews with African American mothers ≥ 18 years old. Data were analyzed using thematic analysis guided by the social cognitive theory. We identified four key themes that reflect personal, behavioral, and environmental factors: (1) simplicity of formula, (2) diverse support networks, (3) early breastfeeding is most important, and (4) lack of access to breastfeeding support resources. To increase breastfeeding duration among African American mothers, it is essential for interventions to be comprehensive including various strategies such as education regarding the physical aspects of breastfeeding, exposure to African American breastfeeding mothers, and active involvement of support persons. More research among African American mothers is needed to identify effective opportunities for change in cultural, social, and structural systems that impede successful breastfeeding.

This introduction to this special issue of the Journal on Migration and Human Security discusses the background and focus of two meetings precursory to this collection, considers refugee resettlement and integration in the United States within the broader framework of the literature on migrant integration, and reflects on the role that population research can play in promoting successful and healthy refugee resettlement in the United States. Other contributions to the special issue are based on five of the presentations at a scientific workshop held in May 2019 in Washington, DC, entitled, “Forced Migration Research: From Theory to Practice in Promoting Migrant Well-Being.” A sixth article evolved from a virtual stakeholder meeting held as a follow-up activity in December 2020, entitled, “Refugee Resettlement in the United States: The Role of Migration Research in Promoting Migrant Well-being in a Post-Pandemic Era.” Both the workshop and the virtual meeting were hosted by the Committee on Population of the US National Academies of Sciences, Engineering, and Medicine, with dedicated support from the Robert Wood Johnson Foundation and the Andrew W. Mellon Foundation.

This paper summarizes the presentations and discussions of a virtual stakeholder meeting on Refugee Resettlement in the United States which built on the foundation of the May 2019 workshop represented in this special issue. With support from the Robert Wood Johnson Foundation and the Andrew W. Mellon Foundation and hosted by the Committee on Population (CPOP) of the US National Academies of Sciences, Engineering, and Medicine on Dec 1–2, 2020, 1 the meeting convened migration researchers, representatives of US voluntary resettlement agencies, and other practitioners to consider the role of migration research in informing programs serving refugees and migrants during the COVID-19 pandemic, continuing an emphasis on bringing global learning to those on the ground working with refugees. The goal of CPOP's work in this area has always been to build bridges between communities of research and practice and to create a dialogue for a shared agenda. We present the goals and framework for the 2020 meeting, followed by a summary of each of the four sessions and themes that emerged from these discussions. The paper ends by considering effective ways of amplifying the role of research in refugee policy and programs of refugee resettlement in the United States and how demographers and population researchers might contribute to this goal.

Background Adequate pain control in inflammatory bowel disease (IBD) can require opioids due to their high analgesic potency. The long-term use of opioids, however, is limited by the development of tolerance. This leads to reduced analgesic efficacy over time, resulting in escalating opioid dosing and thus increased risk of serious side effects. We previously demonstrated the safety and effectiveness of a novel pH-sensitive µ-opioid receptor (MOR) agonist, NFEPP, in a murine colitis pain model, but its tolerance potential with chronic administration is unknown. Purpose To assess the tolerance potential of NFEPP compared to its parent compound fentanyl during acute colitis in a preclinical mouse model. Method Acute colitis in C57BL/6 mice was induced using 2.5% dextran sulphate sodium for 5 days. NFEPP or fentanyl were then administered s.c. every 4 hours between 7am and 11pm over 5 days in daily increasing concentrations (0.4-1.5 mg/kg/d). Analgesic tolerance to opioids was assessed in conscious mice by measuring visceromotor responses (VMRs) to noxious colorectal distensions. Tolerance to the MOR agonist DAMGO in NFEPP or fentanyl treated mice was evaluated using patch-clamp recordings from dorsal root ganglion (DRG) neurons and extracellular recordings from lumbar splanchnic nerves that innervate the colon. Inflammation was assessed by macroscopic analyses, histological scoring and tissue-pH measurements of the inflamed colon. Group differences were analyzed using two-way ANOVA with Bonferroni′s or Tukey′s post-test (p-value Result(s) NFEPP significantly reduced VMRs before and after chronic NFEPP treatment (39% reduction, p Conclusion(s) Chronic administration of NFEPP during acute murine colitis does not lead to analgesic tolerance within the visceral nociceptive system, in contrast to its parent compound fentanyl. Please acknowledge all funding agencies by checking the applicable boxes below CCC Disclosure of Interest None Declared

Background Food and stress are common triggers of symptoms in IBS patients. We previously showed in a murine model of IBS that exposure to a food antigen during a period of psychological stress leads to visceral hypersensitivity in both the ileum and colon upon re-exposure to the food antigen. This was inhibited by blocking mast cells and histamine receptors, suggesting that mast cell activation is involved in this increased pain signaling. However, it is unknown if immunoglobulin E (IgE) is involved in the activation of mast cells leading to visceral hypersensitivity. Purpose Determine the role of IgE in the increased pain signaling in ileum and colon of mice re-exposed to ovalbumin after an initial exposure to ovalbumin during chronic stress. Method Balb/c mice underwent water avoidance stress (WAS) for 10 days and were exposed to ovalbumin (OVA) from days 2-10. Five weeks later, mice were re-exposed to ovalbumin for two weeks (WAS/OVA+OVA mice). Mice were injected with anti-mouse IgE or isotype control antibody (1 mg/kg, i.p.) just prior and during ovalbumin re-exposure. Ex-vivo extracellular afferent recordings from nerves innervating the ileum were obtained to assess changes in mechanosensitivity. Ileum and colonic supernatants were also collected. Dorsal root ganglion neurons (DRG) from control mice (n = 12) were incubated with ileal and colonic supernatants. The excitability of these neurons was assessed by measuring the rheobase (minimum current required to evoke an action potential; lower rheobase=increased excitability) using perforated patch clamp. Data were analyzed by unpaired t-test or two-way ANOVA with Sidak’s post hoc test. Result(s) WAS/OVA+OVA mice treated with anti-IgE antibody had decreased mechanosensitivity of ileal nerves following lumen distention compared to WAS/OVA+OVA mice treated with isotype control antibody (7.7 ± 0.65 vs 12.9 ± 1.04 Hz, p = 0.034, n = 9 and 8 mice, respectively). Ileal supernatants from anti-IgE treated WAS/OVA+OVA mice evoked lower excitability (higher rheobase) in DRG neurons than neurons incubated with supernatants from isotype control treated WAS/OVA+OVA mice (rheobase: 89.2 ± 4.7 vs 71.9 ± 5.1 pA, p= 0.018). Colonic supernatants showed similar effects of the anti-IgE treatment (rheobase: 95.5 ± 4.4 vs 76.7 ± 5.4 pA, p = 0.01). Conclusion(s) IgE is involved in the increased pain signaling observed in both ileum and colon induced by antigen re-exposure following an initial stress-food antigen interaction. This suggests that IgE-mediated mast cell activation in response to food antigens may be a mechanism of meal-induced pain in IBS patients. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Department of Medicine, Translational Medicine Grant, Queen's University Disclosure of Interest None Declared