Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria.

Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals. These preclinical data were then used to develop translational PK/PD models, which were scaled allometrically to humans to predict starting doses for first-in-human clinical studies for each disease. The predicted first-in-human doses for mRNA-3927, mRNA-3705, and mRNA-3210 were determined to be 0.3, 0.1, and 0.4 mg/kg, respectively.

Cost of Public Health Insurance for US-Born and Immigrant Adults.

Importance: The immigrant population in the US has low health insurance coverage. Surveys find that approximately one-half of the US population is opposed to public health insurance of immigrants, and there is a widely held belief that immigrants are a state fiscal liability. Objective: To estimate the cost of providing public health insurance to immigrants in the US. Design, Setting, and Participants: This serial cross-sectional study used restricted data from the 2011 to 2019 Medical Expenditure Panel Survey (and data from 2011-2020 in supplemental analyses). The data are nationally representative of the US civilian noninstitutionalized population. Participants included adults aged 19 to 64 years with family incomes below 138% of the Federal Poverty Level, the population that benefited from the Medicaid expansions. Data analysis was performed from November 2022 to August 2023. Exposures: State Medicaid expansion. Main Outcomes and Measures: The primary outcomes were insurance coverage, total health care expenditures, expenditures categorized by payment source (paid by self or family and paid by others), expenditures by major health care type (office based, inpatient, and prescription), and health care utilization (number of office-based visits, outpatient facility visits, emergency department visits, hospital discharges, dental care visits, home health clinician days, and prescription medicine refills). A difference-in-differences method was used to compare the health care cost and utilization by low-income, working-age US-born and immigrant adults in states that adopted the Patient Protection and Affordable Care Act (ACA) Medicaid expansions with the corresponding change in nonexpansion states before and after the policy implementation. Results: Among the study sample of 44 482 individuals (mean [SD] age, 38.5 [14.0] years; 25 221 female individuals [56.7%]; 34 052 [76.6%] US born), 46% of immigrant adults (1953 participants) and 70% of US-born adults (9396 participants) had insurance coverage in the pre-ACA period. Medicaid expansions increased insurance coverage of both groups by 7 percentage points (95% CI, 3 to 11 percentage points). The resulting change in health care increased total expenditures (self-paid plus insurer paid) by $660 (95% CI, $79 to $1242) and insurer-paid expenditures by $745 (95% CI, $141 to $1350) per US-born adult. For immigrant adults, the corresponding changes in total ($266; 95% CI, -$348 to $880) and insurer-paid ($308; 95% CI, -$352 to $968) expenditures were small and not statistically significant. Estimates suggest that providing insurance to immigrants costs the health care system approximately $3800 per person per year, less than one-half the corresponding cost ($9428 per person per year) for US-born adults. Conclusions and Relevance: These findings suggest that the direct cost of providing public health insurance to immigrants is less than that for the US born, and immigrants' health care utilization, upon coverage, remains comparatively modest, thus refuting the notion that providing insurance to immigrants imposes a heavy fiscal burden.

Risk factors for miscarriage in Syrian refugee women living in non-camp settings in Jordan: results from the Women ASPIRE cross-sectional study.

BACKGROUND: Syrian refugee women face health care disparities and experience worse pregnancy outcomes, including miscarriage. We investigated risk factors for miscarriage in Syrian refugee women living in non-camp settings in Jordan to identify targets for interventions. METHODS: We analyzed data from Women ASPIRE, a cross-sectional study of gendered physical and mental health concerns of 507 Syrian refugee women (≥ 18 years old) living in non-camp settings in Jordan. We recruited women using systematic clinic-based sampling from four clinics. We limited our analyses to women who had a history of pregnancy and whose most recent pregnancy was single, took place in Jordan, and ended in term live birth or miscarriage (N = 307). We grouped the women by the primary outcome (term live birth or miscarriage) and compared the sociodemographic and clinical characteristics of the two groups. We used Pearson's χ2 test or the Mann-Whitney U test to obtain unadjusted estimates and multivariable binomial logistic regression to obtain adjusted estimates. RESULTS: The most recent pregnancies of 262 women (85%) ended in term live birth and another 45 (15%) ended in miscarriage. Since crossing into Jordan, 11 women (4%) had not received reproductive health services. Of 35 women who were ≥ 35 years old, not pregnant, and did not want a (or another) child, nine (26%) did not use contraception. Of nine women who were ≥ 35 years old and pregnant, seven (78%) did not plan the pregnancy. The adjusted odds of miscarriage were higher in women who had been diagnosed with thyroid disease (aOR, 5.54; 95% CI, 1.56-19.07), had been of advanced maternal age (aOR, 5.83; 95% CI, 2.02-16.91), and had not received prenatal care (aOR, 36.33; 95% CI, 12.04-129.71). Each additional previous miscarriage predicted an increase in the adjusted odds of miscarriage by a factor of 1.94 (1.22-3.09). CONCLUSIONS: We identified several risk factors for miscarriage in Syrian refugee women living in non-camp settings in Jordan. The risk factors may be amenable to preconception and prenatal care.

Pandemic and prejudice: Results from a national survey experiment.

Do health and economic shocks exacerbate prejudice towards racial/ethnic minority groups? We investigate this question in the wake of the COVID-19 pandemic by collecting nationally representative survey data with an embedded experiment. Results show that priming COVID-19 salience has an immediate impact: compared to the control group, respondents in the treatment group reported increased prejudice towards East Asian and Hispanic colleagues. East Asians in the treatment group faced higher prejudicial responses from Americans living in counties with higher COVID-19 infections and those who lost jobs due to COVID-19, and fewer prejudicial responses in counties with a higher concentration of Asians. These results point to the salience of COVID-19 fueled health and economic insecurities in shaping prejudicial attitudes, specifically towards East Asians. County-level socioeconomic factors did not moderate the increased prejudicial attitudes toward Hispanics in the workplace. These findings highlight a dimension of prejudice, intensified during the pandemic, which has been largely underreported and therefore missing from the current discourse on this important topic.

Secondary Traumatic Stress, Depression, and Anxiety Symptoms Among Service Providers Working with Syrian Refugees in Istanbul, Turkey.

This paper examines the mental health of service providers working with Syrian refugees. Using the Professional Quality of Life framework, we hypothesize greater stress/less support from the work, person, client environment is associated with symptoms of STS, depression, and anxiety. We surveyed a sample of 104 service providers throughout Istanbul late 2018. Multivariable logistic regression examined associations between work (organizational support, caseload, supervision), person (perceived social support), client environment (trauma disclosure, percent Syrian refugees) on STS, depression, and anxiety. We found rates of moderate-to-severe STS to be 27.88%; depression 40.38%; and anxiety 29.81%. Our hypothesis was partially supported. Lower organizational support was associated with moderate-to-severe STS (aOR 0.91, 95% CI 0.84, 0.99) while lower social support with anxiety (aOR 0.89, 95% CI 0.81, 0.99). Caseload, supervision, trauma disclosure, percent refugees did not show significant associations. Organizations working with Syrian refugees may benefit from enhancing organizational support and promoting social support for staff.

Foreign-Trained Physicians in the United States: A Descriptive Profile.

More than a quarter of physicians in the United States are international medical graduates (IMGs). This statistic, although large, does not fully capture the importance of IMGs in certain specialties and locations. We provide a comprehensive profile of IMGs documenting where and in what specialties they work and how these distributions have changed over time. Estimates show that IMGs disproportionately work in densely populated, low-income communities with sicker residents and low physician density. IMGs are overrepresented in primary care and the lowest paying specialties, and their concentration in these specialties is growing. Calculations show that U.S. medical graduates exit the workforce at 2.5 times the exit rate of IMGs suggesting that in the near future IMGs will likely provide care for an increasingly larger share of Americans.

Mental health of clinic-attending Syrian refugee women in Jordan: associations between social ecological risks factors and mental health symptoms.

BACKGROUND: The mental health of refugee women is often affected by multiple risk factors in their social ecology. Assessing these risk factors is foundational in determining potential areas for intervention. We used the social ecological model to examine risk factors associated with self-reported mental health symptoms among clinic-attending Syrian refugee women in Jordan. We hypothesize that individual (older age, unmarried, have more children under 18, difficulty reading/writing with ease), interpersonal (intimate partner violence [IPV]), community and societal level risk factors (greater number of postmigration stressors), will be associated with depression, anxiety, and post-traumatic stress disorder (PTSD) symptoms. METHODS: We surveyed 507 women using a cross-sectional clinic-based systematic sampling approach between April and November 2018. We used multivariable regressions to examine associations between different risk factors in the social ecology on depression, anxiety, and PTSD. Additional multivariable regressions explored associations between specific postmigration stressors and mental health conditions. RESULTS: We found rates of depression among our sample to be 62.92%; anxiety 57.46%; and PTSD 66.21%. Our hypothesis was partially supported. At the individual level, age was directly associated with anxiety (aOR 1.04, 95% CI [1.02, 1.06]) and PTSD (aOR 1.03, 95% CI [1.01, 1.06]), while marriage decreased odds for depression (aOR 0.41, 95% CI [0.19, 0.92]) and PTSD (aOR 0.36, 95% CI [0.15, 0.87]). IPV was associated with depression (aOR 2.78, 95% CI [1.72, 4.47]); anxiety (aOR 3.30, 95% CI [2.06, 5.27]); and PTSD (aOR 5.49, 95% CI [3.09, 9.76]). Each additional community and societal risk factor (postmigration stressor) increased the odds for depression (aOR 1.32, 95% CI [1.22, 1.42]), anxiety (aOR 1.28, 95% CI [1.19, 1.39]), and PTSD (aOR 1.46, 95% CI [1.33, 1.60]). CONCLUSION: Understanding social ecological risk factors associated with mental health conditions of Syrian refugee women is vital to addressing their mental health needs. IPV and postmigration stressors are consistently impactful with all mental health conditions. IPV resulted in the largest odds increase for all mental health conditions. Multilevel interventions are needed to address mental health risk factors at multiple levels of the social ecology.

ATP-binding cassette (ABC) transporters in cancer: A review of recent updates.

The ATP-binding cassette (ABC) transporter superfamily is one of the largest membrane protein families existing in wide spectrum of organisms from prokaryotes to human. ABC transporters are also known as efflux pumps because they mediate the cross-membrane transportation of various endo- and xenobiotic molecules energized by ATP hydrolysis. Therefore, ABC transporters have been considered closely to multidrug resistance (MDR) in cancer, where the efflux of structurally distinct chemotherapeutic drugs causes reduced itherapeutic efficacy. Besides, ABC transporters also play other critical biological roles in cancer such as signal transduction. During the past decades, extensive efforts have been made in understanding the structure-function relationship, transportation profile of ABC transporters, as well as the possibility to overcome MDR via targeting these transporters. In this review, we discuss the most recent knowledge regarding ABC transporters and cancer drug resistance in order to provide insights for the development of more effective therapies.

Priming COVID-19 salience increases prejudice and discriminatory intent against Asians and Hispanics.

Mounting reports in the media suggest that the COVID-19 pandemic has intensified prejudice and discrimination against racial/ethnic minorities, especially Asians. Existing research has focused on discrimination against Asians and is primarily based on self-reported incidents or nonrepresentative samples. We investigate the extent to which COVID-19 has fueled prejudice and discrimination against multiple racial/ethnic minority groups in the United States by examining nationally representative survey data with an embedded vignette experiment about roommate selection (collected in August 2020; n = 5,000). We find that priming COVID-19 salience has an immediate, statistically significant impact: compared to the control group, respondents in the treatment group exhibited increased prejudice and discriminatory intent against East Asian, South Asian, and Hispanic hypothetical room-seekers. The treatment effect is more pronounced in increasing extreme negative attitudes toward the three minority groups than decreasing extreme positive attitudes toward them. This is partly due to the treatment increasing the proportion of respondents who perceive these minority groups as extremely culturally incompatible (Asians and Hispanics) and extremely irresponsible (Asians). Sociopolitical factors did not moderate the treatment effects on attitudes toward Asians, but prior social contact with Hispanics mitigated prejudices against them. These findings suggest that COVID-19-fueled prejudice and discrimination have not been limited to East Asians but are part of a broader phenomenon that has affected Asians generally and Hispanics as well.

Medicaid Expansions and Participation in Supplemental Security Income by Noncitizens.

Objectives. To estimate the effect of Medicaid expansion on noncitizens' and citizens' participation in the Supplemental Security Income (SSI) program. The Affordable Care Act (ACA) expanded Medicaid eligibility to cover low-income nonelderly adults without children, thus delinking their Medicaid participation from participation in the SSI program.Methods. Using data from the Social Security Administration for 2009 through 2018 (n = 1020 state-year observations) and the Current Population Survey for 2009 through 2019 (n = 78 776 respondents), we employed a difference-in-differences approach comparing SSI participation rates in US states that adopted Medicaid expansion with participation rates in nonexpansion states before and after ACA implementation.Results. Medicaid expansion reduced the SSI (disability) participation of nonelderly noncitizens by 12% and of nonelderly citizens by 2%. Estimates remained robust with administrative and survey data.Conclusions. Medicaid expansion caused a substantially larger decline in the SSI participation of noncitizens, who face more restrictive SSI eligibility criteria, than of citizens. Our estimates suggest an annual savings of $619 million in the federal SSI cost because of the decline in SSI participation among noncitizens and citizens.

Timing of social distancing policies and COVID-19 mortality: county-level evidence from the U.S.

Using county-level data on COVID-19 mortality and infections, along with county-level information on the adoption of non-pharmaceutical interventions (NPIs), we examine how the speed of NPI adoption affected COVID-19 mortality in the United States. Our estimates suggest that adopting safer-at-home orders or non-essential business closures 1 day before infections double can curtail the COVID-19 death rate by 1.9%. This finding proves robust to alternative measures of NPI adoption speed, model specifications that control for testing, other NPIs, and mobility and across various samples (national, the Northeast, excluding New York, and excluding the Northeast). We also find that the adoption speed of NPIs is associated with lower infections and is unrelated to non-COVID deaths, suggesting these measures slowed contagion. Finally, NPI adoption speed appears to have been less effective in Republican counties, suggesting that political ideology might have compromised their efficacy.

Sublingual insulin administration: application of hydroxypropyl beta-cyclodextrin and poloxamer188 as permeation enhancers.

The objective of this investigation is to investigate the feasibility of sublingual insulin administration. Insulin solutions formulated with permeation enhancers (HPßCD/poloxamer 188) and their in-vitro and in-vivo performances were evaluated. Thereafter, insulin fast-dissolving film was further developed to have similar properties, upon dissolving the film, of the optimized insulin solution. In-vitro performance was evaluated via effect of HPßCD and/or poloxamer 188 concentration across cellulose acetate membrane and porcine esophagus. In-vivo performance was evaluated via pharmacodynamic and pharmacokinetic profiles of insulin solution administered. Cumulative amounts of insulin permeated at 60 min formulated with HPßCD (5%), poloxamer 188 (0.5%), and their combination were 1.31, 3.23, and 4.99 IU/cm2, respectively, indicating an additive effect of combination of HPßCD and poloxamer 188. Insulin-induced hypoglycemic effect was observed for insulin solutions with combination of HPßCD and poloxamer 188 after sublingual administration to Sprague-Dawley rats. Microscopic evaluation of porcine oesophageal tissue indicates that HPßCD and poloxamer 188 are safe. Furthermore, the cumulative amount permeated across cellulose acetate membrane at 30 min was 1.13 and 1.00 IU/cm2 for insulin solution and fast-dissolving film, respectively, demonstrating to be similar. In conclusion, the use of HPßCD/poloxamer 188 is feasible for the development of sublingual insulin solutions/films.

How children's education affects caregiving: Evidence from parent's last years of life.

Using data from the Health and Retirement Study (1994-2012), we studied the association between adult children's education and financial and caregiving support they provided to their aging parents in the last years of the parents' life. We controlled for the circumstances of parents' death, their functional limitations, whether they were in long-term care or home-care settings in the last year of their life, and in some models, various measures of parents' self-reported health. Estimates suggest that having a college degree and above has a significantly positive association with monetary transfers and knowledge support children provide to their parents. Estimates remained robust in models that included parent fixed effects. Evidence of children's education on instrumental support to parents was nonlinear in that although some college education increased instrumental support, but, a college degree did not have a statistically significant effect. Gender did not play a moderating role in the relationship between offspring education and support towards parents.

Reducing poverty among children: Evidence from state policy simulations.

State approaches to reducing child poverty vary considerably. We exploit this state-level variation to estimate what could be achieved in terms of child poverty if all states adopted the most generous or inclusive states' policies. Specifically, we simulate the child poverty reductions that would occur if every state were as generous or inclusive as the most generous or inclusive state in four key policies: Supplemental Nutrition Assistance Program (SNAP), state Earned Income Tax Credits (EITC), Temporary Assistance for Needy Families (TANF), and state Child Tax Credits (CTC). We find that adopting the most generous or inclusive state EITC policy would have the largest impact on child poverty, reducing it by 1.2 percentage points, followed by SNAP, TANF, and lastly state CTC. If all states were as generous or inclusive as the most generous or inclusive state in all four policies, the child poverty rate would decrease by 2.5 percentage points, and five and a half million children would be lifted out of poverty.

Young adult poverty in historical perspective: The role of policy supports and early labor market experiences.

Recent research using an improved measure of poverty finds that poverty has fallen by nearly forty percent since the 1960s in the United States. But past research has not examined whether this finding holds across detailed demographic groups who might be more or less vulnerable to poverty. This paper helps fill that gap, focusing on one such vulnerable subgroup: young adults. Using the Current Population Survey, this paper examines long-term trends in young adult poverty in comparison to other groups. In contrast to almost all other groups, young adults have seen no decrease in poverty since the 1960s. We explore potential reasons for this fact, finding that young adults lack access to benefits from government programs, and are increasingly unmarried, living alone, and disconnected from the labor market, factors that leave young adults more vulnerable than other groups to poverty. The findings have implications for how antipoverty policies might assist this vulnerable group.

State dream acts and education, health and mental health of Mexican young adults in the U.S.

We investigate the education, health and mental health effects of state policies that allowed or explicitly banned tuition subsidy and financial aid to undocumented college students using the National Health Interview Survey (NHIS) for 1998-2013. Our analysis suggests that an explicit ban on tuition subsidy or enrollment in public colleges lowered college education of non-citizen Mexican young adults by 5.4-11.6 percentage points. We find some evidence that in-state tuition and access to financial aid improved self-reported health and reduced mental health distress, and ban on in-state-tuition/enrollment increased mental health distress among non-citizen Mexican young adults: estimated effects are generally significant in first-difference models and models that include state-specific cubic trends, and often insignificant in difference-in-difference models.

Missing Time with Parents: Son Preference among Asians in the United States.

We study prevalence of son preference in families of East and South Asian origin living in the U.S. by investigating parental time investments in children using American Time Use Surveys. Estimates show that East and South Asian mothers spend an additional hour of quality time per day with their young (aged 0-2 years) sons than with young daughters; son-preference in mothers' time allocation declines as children get older. East and South Asian fathers' time with young children is gender neutral. We find gender specialization in time with children aged 6-17 with fathers spending more time with sons and mothers spending more time with daughters.

Unhealthy assimilation or persistent health advantage? A longitudinal analysis of immigrant health in the United States.

Existing evidence on immigrant health assimilation, which is largely based on cross-sectional data, suggests that immigrants' initial health advantage erodes over time. This study uses longitudinal data to directly compare the self-rated health trajectories of immigrants and the native-born population. Data come from four panels of the Survey of Income and Program Participation (1996, 2001, 2004, and 2008), with each panel containing 2-4 years of health information. Results show that immigrants' self-rated health remained stable during the period under study, but there was a concomitant decline in health for the native-born population. This result pointed to a persistent health advantage of immigrants during the period under study. The pattern held for immigrants of different length of residence and was especially salient for those originally from Latin America and Asia. Our findings that immigrants maintain their health advantage do not support the pattern of unhealthy assimilation commonly reported in cross-sectional studies.

Health of newly arrived immigrants in Canada and the United States: Differential selection on health.

Canada and the U.S. are two major immigrant-receiving countries characterized by different immigration policies and health care systems. The present study examines whether immigrant health selection, or the "healthy immigrant effect", differs by destination and what factors may account for differences in immigrant health selection. We use 12 years of U.S. National Health Interview Survey and Canadian Community Health Survey data to compare the risks of overweight/obesity and chronic health conditions among new immigrants in the two countries. Results suggest a more positive health selection of immigrants to Canada than the U.S. Specifically, newly arrived U.S. immigrants are more likely to be overweight or obese and have serious chronic health conditions than their Canadian counterparts. The difference in overweight/obesity was explained by differences in source regions and educational levels of immigrants across the two countries. But this is not the case for serious chronic conditions. These results suggest that immigration-related policies can potentially shape immigrant health selection.

Progress on Poverty? New Estimates of Historical Trends Using an Anchored Supplemental Poverty Measure.

This study examines historical trends in poverty using an anchored version of the U.S. Census Bureau's recently developed Research Supplemental Poverty Measure (SPM) estimated back to 1967. Although the SPM is estimated each year using a quasi-relative poverty threshold that varies over time with changes in families' expenditures on a core basket of goods and services, this study explores trends in poverty using an absolute, or anchored, SPM threshold. We believe the anchored measure offers two advantages. First, setting the threshold at the SPM's 2012 levels and estimating it back to 1967, adjusted only for changes in prices, is more directly comparable to the approach taken in official poverty statistics. Second, it allows for a better accounting of the roles that social policy, the labor market, and changing demographics play in trends in poverty rates over time, given that changes in the threshold are held constant. Results indicate that unlike official statistics that have shown poverty rates to be fairly flat since the 1960s, poverty rates have dropped by 40 % when measured using a historical anchored SPM over the same period. Results obtained from comparing poverty rates using a pretax/pretransfer measure of resources versus a post-tax/post-transfer measure of resources further show that government policies, not market incomes, are driving the declines observed over time.