Regulation of Microprocessor assembly and localization via Pasha's WW domain in C. elegans.

Primary microRNA (pri-miRNA) transcripts are processed by the Microprocessor, a protein complex that includes the ribonuclease Drosha and its RNA binding partner DGCR8/Pasha. We developed a live, whole animal, fluorescence-based sensor that reliably monitors pri-miRNA processing with high sensitivity in C. elegans. Through a forward genetic selection for alleles that desilence the sensor, we identified a mutation in the conserved G residue adjacent to the namesake W residue of Pasha's WW domain. Using genome editing we also mutated the W residue and reveal that both the G and W residue are required for dimerization of Pasha and proper assembly of the Microprocessor. Surprisingly, we find that the WW domain also facilitates nuclear localization of Pasha, which in turn promotes nuclear import or retention of Drosha. Furthermore, depletion of Pasha or Drosha causes both components of the Microprocessor to mislocalize to the cytoplasm. Thus, Pasha and Drosha mutually regulate each other's spatial expression in C. elegans.

Comprehensive and Integrated Services in Specialty Mental Health Treatment Facilities in the US: Differences by the Racial/Ethnic Composition of the Facility's Clientele, 2020.

The integration of multiple ancillary services into mental health treatment settings may improve outcomes, but there are no national studies addressing whether comprehensive services are distributed equitably. We investigated whether the availability of a wide range of service types differs based on the facility's racial/ethnic composition. We used the 2020 National Mental Health Services Survey to identify twelve services offered in outpatient mental health treatment facilities (N = 1,074 facilities). We used logistic regression to model each of the twelve services, predicted by the percentage of a facility's clientele that was White, Black, and Hispanic, adjusted for covariates. Facilities with the highest proportions of Black and Hispanic clientele demonstrated the lowest predicted probabilities of offering comprehensive and integrated services. Our findings offer context around upstream factors that may, in part, drive treatment disparities. We orient our findings around frameworks of structural racism and inequities in mental healthcare.

County-level jail incarceration, community economic distress, rurality, and preterm birth among women in the US South.

Introduction: The USA has higher rates of preterm birth and incarceration than any other developed nation, with rates of both being highest in Southern states and among Black Americans, potentially due to rurality and socioeconomic factors. To test our hypothesis that prior-year county-level rates of jail admission, economic distress, and rurality were positively associated with premature birth rates in the county of delivery in 2019 and that the strength of these associations is greater for Black women than for White or Hispanic women, we merged five datasets to perform multivariable analysis of data from 766 counties across 12 Southern/rural states. Methods: We used multivariable linear regression to model the percentage of babies born premature, stratified by Black (Model 1), Hispanic (Model 2), and White (Model 3) mothers. Each model included all three independent variables of interest measured using data from the Vera Institute, Distressed Communities Index, and Index of Relative Rurality. Results: In fully fitted stratified models, economic distress was positively associated with premature births among Black (F = 33.81, p < 0.0001) and White (F = 26.50, p < 0.0001) mothers. Rurality was associated with premature births among White mothers (F = 20.02, p < 0.0001). Jail admission rate was not associated with premature births among any racial group, and none of the study variables were associated with premature births among Hispanic mothers. Conclusions: Understanding the connections between preterm birth and enduring structural inequities is a necessary scientific endeavor to advance to later translational stages in health-disparities research.

COVID-19 Vaccine Hesitancy and Experiences of Discrimination Among Black Adults.

Early in the COVID-19 vaccine rollout, Black adults consistently reported more hesitancy than White adults, but few studies have examined variation in hesitancy among Black adults or its associations with racial discrimination. Data were collected from Black Arkansas residents age 18 and older (n = 350) between July 12th and July 30th, 2021, as part of a larger survey of Arkansans (N = 1500). Participants were recruited through random digit dialing of both landline and cell phones, with oversampling of Black and Hispanic residents. Respondents reported COVID-19 vaccine hesitancy, sociodemographic information, influenza vaccination history, pandemic-related experiences, and experiences of racial discrimination. Almost half (48.9%) of Black adults in Arkansas were not hesitant towards COVID-19 vaccines, while the remainder reported some level of hesitancy. Nearly a quarter were very hesitant (22.4%), while fewer reported being somewhat (14.0%) and a little (14.7%) hesitant. Using an ordered logistic regression with partial proportional odds, we find odds of COVID-19 vaccine hesitancy decreased as age and influenza vaccination increased. Odds of COVID-19 vaccine hesitancy were 1.70 times greater for Black adults who experienced the death of a close friend/family member due to COVID-19 and 2.61 times greater for individuals reporting discrimination with police or in the courts. Within-group analysis revealed nearly half of Black adults did not report any COVID-19 vaccine hesitancy and heterogeneity among those who were hesitant. Findings suggest there may be an important link between racial discrimination in the criminal justice system and COVID-19 vaccine hesitancy among Black adults.

COVID-19 vaccine hesitancy and racial discrimination among US adults.

Vaccination is a critical preventive measure to reduce COVID-19 health risks. We utilize full information maximum likelihood (FIML) logistic regression to analyze COVID-19 vaccine hesitancy in a national sample of United States (US) adults (N = 2,022). Online survey data was collected between September 7th and October 3rd, 2021. Before weighting, the racial composition of the sample was as follows: Asian American (15.0 %), Black/African American (20.0 %), Hispanic/Latino (20.0 %), American Indian or Alaska Native (12.6 %), Native Hawaiian or Pacific Islander (12.5 %), and White (20.0 %). Informed by the Increasing Vaccination Model (IVM), we assessed the relationship between COVID-19 vaccine hesitancy and experiences of racial discrimination (Krieger's 9-item measure). Odds of COVID-19 vaccine hesitancy were greater for most younger age groups, women (OR = 1.96; 95 % CI[1.54, 2.49]), Black/African American respondents (OR = 1.68; 95 % CI[1.18, 2.39]), those with a high school education or less (OR = 1.46; 95 % CI[1.08, 1.98]), Independent (OR = 1.77; 95 % CI[1.34, 2.35]) or Republican political affiliation (OR = 2.69; 95 % CI[1.92, 3.79]), and prior COVID-19 infection (OR = 1.78; 95 % CI[1.29, 2.45]). Odds of COVID-19 vaccine hesitancy were 1.04 greater for every-one unit increase in lifetime experiences of racial discrimination (95 % CI[1.02, 1.05]). Odds of COVID-19 vaccine hesitancy were lower for Asian American respondents (OR = 0.682; 95 % CI[0.480, 0.969]), and those who had a primary care doctor had reduced odds of COVID-19 vaccine hesitancy (OR = 0.735; 95 % CI[0.542, 0.998). Our primary finding provides support for a link between experiences of racial discrimination and hesitancy towards a COVID-19 vaccine among US adults. We discuss implications for public health officials and future research.

Demographic and geographic shifts in the preferred route of methamphetamine administration among treatment cases in the US, 2010-2019.

BACKGROUND: Methamphetamine use disorder has increased rapidly in the past decade. Injecting is also increasing and has multifaceted implications for disease severity, overall health, and treatment outcomes, but less is known about where or among whom injecting has shifted the most. This national study assessed temporal changes in the preferred route of methamphetamine administration by race/ethnicity and within urban/rural geographies. METHODS: We used the Treatment Episode Dataset-Discharges (2010-2019) to identify outpatient treatment cases who reported methamphetamine as their primary drug of choice at admission (N = 531,799; 2010 n = 33,744; 2019 n = 81,885). We created a combined variable indicating race/ethnicity and the rural/urban location of treatment, and used logistic regression to model the predicted probability of cases reporting injection, smoking, or snorting as their preferred route of administration. We included an interaction term to determine differences over time (race/ethnicity/rurality*year). RESULTS: Across all years, smoking methamphetamine was the most common route of administration (66%), followed by injection (24%) and snorting (10%). Over time and among most sub-groups, the rates of injection increased while the rates of smoking decreased. Compared to 2010, the odds of injecting methamphetamine in 2019 were highest among Black cases in urban areas (aOR = 2.30, 95% CI = 1.76-3.00, p < 0.0001). CONCLUSION: Increasing methamphetamine injection was most pronounced among Black treatment cases in more urban areas, which is in contrast to the longstanding narrative that methamphetamine is a White and rural drug. Methamphetamine prevention, treatment, and harm reduction should target populations with high injection prevalence and growing incidence.

Homeless Opioid Treatment Clients Transitioning to Dependent and Independent Housing: Differential Outcomes by Race/Ethnicity.

Purpose: Homeless opioid treatment clients who transition into housing generally demonstrate better outcomes, but housing environments vary widely and may not benefit racial/ethnic minority populations equally. We sought to identify how race/ethnicity moderates the association between positive opioid treatment response and moving into dependent or independent living environments. Methods: We used the Treatment Episode Dataset-Discharges (2018-2019) to identify outpatient treatment clients who were homeless at admission and indicated heroin or other opioids as their primary drug of choice (n = 20,021). We defined positive treatment response as a reduction in opioid use between admission and discharge. We used multivariable logistic regression to model treatment response. We included an interaction between housing at discharge (remained homeless [reference], dependent living, or independent living) and race/ethnicity, and adjusted for relevant confounders. Results: Transitioning from homeless to dependent living was positively associated with treatment response among White (aOR = 3.57, 95% CI = 3.15-4.06), Hispanic (aOR = 2.11, 95% CI = 1.55-2.86), and Black clients (aOR = 1.79, 95% CI = 1.41-2.27), but no association was observed for homeless American Indian/Alaska Native clients. Transitioning from homeless to independent living was strongly associated with treatment response among all groups with the strongest association observed among White clients (aOR = 4.70, 95% CI = 4.26-5.19). Conclusions: Interventions aimed at improving OUD treatment outcomes among homeless clients should identify individual and structural factors that support moving into fully housed and independent living environments. Dependent living offers needed support during crises, but should be temporary and priority should be placed on independent, permanent, and autonomous living environments.

Dual roles for piRNAs in promoting and preventing gene silencing in C. elegans.

Piwi-interacting RNAs (piRNAs) regulate many biological processes through mechanisms that are not fully understood. In Caenorhabditis elegans, piRNAs intersect the endogenous RNA interference (RNAi) pathway, involving a distinct class of small RNAs called 22G-RNAs, to regulate gene expression in the germline. In the absence of piRNAs, 22G-RNA production from many genes is reduced, pointing to a role for piRNAs in facilitating endogenous RNAi. Here, however, we show that many genes gain, rather than lose, 22G-RNAs in the absence of piRNAs, which is in some instances coincident with RNA silencing. Aberrant 22G-RNA production is somewhat stochastic but once established can occur within a population for at least 50 generations. Thus, piRNAs both promote and suppress 22G-RNA production and gene silencing. rRNAs and histones are hypersusceptible to aberrant silencing, but we do not find evidence that their misexpression is the primary cause of the transgenerational sterility observed in piRNA-defective mutants.

Tailoring services in opioid treatment programs for patients involved in America's criminal justice system: national associations and variation by state and Medicaid expansion status.

BACKGROUND: Opioid treatment programs (OTPs) are the primary source of medication-assisted treatment (MAT) for many individuals with opioid use disorder, including poor and uninsured patients and those involved in the criminal justice (CJ) system. Substance use treatment services that are tailored to the unique needs of patients often produce better outcomes, but little national research has addressed characteristics associated with whether OTPs offer services specifically tailored to community members involved in the CJ system. Medicaid expansion under the Affordable Care Act has broadly strengthened MAT services, but the role of expansion in supporting MAT services that are specifically tailored towards CJ-involved populations remains unknown. Moreover, it is unknown whether the availability of tailored services varies between Medicaid expansion states. METHODS: We used the 2019 National Survey of Substance Abuse Treatment Services to identify OTPs in the US (n = 1679) and whether they offered services specifically tailored for CJ-involved patients. We used logistic regression to model the association between OTPs offering tailored services and state Medicaid expansion status, adjusted for state-level opioid overdose and community supervision rates. RESULTS: Nationally, only a quarter of OTPs offered services tailored to CJ populations, and the majority of OTPs (73%) were located in Medicaid expansion states. Compared to OTPs in non-expansion states, OTPs in expansion states demonstrated nearly double the odds of offering tailored services (adjusted odds ratio = 1.90, 95% confidence interval = 1.41-2.57, p < 0.0001). The predicted probability of offering tailored services varied by state; probability estimates for all expansion states were above the national mean, and estimates for all non-expansion states were below the national mean. CONCLUSION: Our findings reiterate the role of Medicaid in promoting the adoption of comprehensive OTP services for CJ-involved populations. However, the proportion of OTPs that offered tailored services was relatively low, pointing to the need to continually strengthen Medicaid services and coverage.

SNPC-1.3 is a sex-specific transcription factor that drives male piRNA expression in C. elegans.

Piwi-interacting RNAs (piRNAs) play essential roles in silencing repetitive elements to promote fertility in metazoans. Studies in worms, flies, and mammals reveal that piRNAs are expressed in a sex-specific manner. However, the mechanisms underlying this sex-specific regulation are unknown. Here we identify SNPC-1.3, a male germline-enriched variant of a conserved subunit of the small nuclear RNA-activating protein complex, as a male-specific piRNA transcription factor in Caenorhabditis elegans. SNPC-1.3 colocalizes with the core piRNA transcription factor, SNPC-4, in nuclear foci of the male germline. Binding of SNPC-1.3 at male piRNA loci drives spermatogenic piRNA transcription and requires SNPC-4. Loss of snpc-1.3 leads to depletion of male piRNAs and defects in male-dependent fertility. Furthermore, TRA-1, a master regulator of sex determination, binds to the snpc-1.3 promoter and represses its expression during oogenesis. Loss of TRA-1 targeting causes ectopic expression of snpc-1.3 and male piRNAs during oogenesis. Thus, sexually dimorphic regulation of snpc-1.3 expression coordinates male and female piRNA expression during germline development.

Widespread roles for piRNAs and WAGO-class siRNAs in shaping the germline transcriptome of Caenorhabditis elegans.

Piwi-interacting RNAs (piRNAs) and small interfering RNAs (siRNAs) are distinct classes of small RNAs required for proper germline development. To identify the roles of piRNAs and siRNAs in regulating gene expression in Caenorhabditis elegans, we subjected small RNAs and mRNAs from the gonads of piRNA and siRNA defective mutants to high-throughput sequencing. We show that piRNAs and an abundant class of siRNAs known as WAGO-class 22G-RNAs are required for proper expression of spermatogenic and oogenic genes. WAGO-class 22G-RNAs are also broadly required for transposon silencing, whereas piRNAs are largely dispensable. piRNAs, however, have a critical role in controlling histone gene expression. In the absence of piRNAs, histone mRNAs are misrouted into the nuclear RNAi pathway involving the Argonaute HRDE-1, concurrent with a reduction in the expression of many histone mRNAs. We also show that high-level gene expression in the germline is correlated with high level 22G-RNA production. However, most highly expressed genes produce 22G-RNAs through a distinct pathway that presumably involves the Argonaute CSR-1. In contrast, genes targeted by the WAGO branch of the 22G-RNA pathway are typically poorly expressed and respond unpredictably to loss of 22G-RNAs. Our results point to broad roles for piRNAs and siRNAs in controlling gene expression in the C. elegans germline.

henn-1/HEN1 Promotes Germline Immortality in Caenorhabditis elegans.

The germline contains an immortal cell lineage that ensures the faithful transmission of genetic and, in some instances, epigenetic information from one generation to the next. Here, we show that in Caenorhabditis elegans, the small RNA 3'-2'-O-methyltransferase henn-1/HEN1 is required for sustained fertility across generations. In the absence of henn-1, animals become progressively less fertile, becoming sterile after ∼30 generations at 25°C. Sterility in henn-1 mutants is accompanied by severe defects in germline proliferation and maintenance. The requirement for henn-1 in transgenerational fertility is likely due to its role in methylating and, thereby, stabilizing Piwi-interacting RNAs (piRNAs). However, despite being essential for piRNA stability in embryos, henn-1 is not required for piRNA stability in adults. Thus, we propose that methylation is important for the role of piRNAs in establishing proper gene silencing during early stages of development but is dispensable for their role in the proliferated germline.

Natural history of human papillomavirus and vaccinations in men: A literature review.

BACKGROUND AND AIMS: Infection with high-risk (HR) genotypes of the human papillomavirus (HPV) is necessary for and causative of almost all cervical cancers and their precursor condition, cervical intraepithelial neoplasia. These conditions have been sharply reduced by cervical cytology screening, and a further decrease is expected because of the recent introduction of prophylactic HPV vaccinations. While significant attention has been given to gynecologic HPV disease, men can be affected by HPV-related cancers of the anus, penis, and oropharynx. This literature review aims to address disparities in HPV-related disease in men, and certain HR male subpopulations, compared with women. DISCUSSION: Overall, immunocompetent men are far less likely than women to develop anogenital HPV-related cancers, despite harboring HR HPV infections at anogenital sites. On the other hand, men who have sex with men and men living with human immunodeficiency virus infection are at considerably higher risk of HPV-related disease. Historic rates of prophylactic HPV vaccination in males have trailed those of females due to numerous multilevel factors, although, in recent years, this sex gap in vaccination coverage has been closing. In the absence of routine HPV screening in males, therapeutic vaccinations have emerged as a potential treatment modality for preinvasive neoplasia and are in various phases of clinical testing. CONCLUSION: Successful reductions in HPV disease morbidity at the population level must acknowledge and target HPV infections in men.

Intimate Partner Violence-Related Fractures in the United States: An 8 Year Review.

BACKGROUND: Fractures associated with intimate partner violence (IPV) are devastating injuries that can have lifelong implications. With exception to the facial region, there are very limited epidemiological reports describing the types and location of IPV-related fractures. The objective of this study is to review a national database and describe trends associated with IPV-related fractures. METHODS: An analysis of all adults was performed using the National Trauma Data Bank from 2007 through 2014.Data including demographics, age, location of fracture, and drug/alcohol use were described and analyzed. FINDINGS: There were 1,352 records identified where the patient was diagnosed with an IPV-related fracture. Women accounted for 83% of the population and the mean age was 37.5 years. Approximately 30% of the population was diagnosed with vertebral, trunk, and rib fractures. Variances among fracture location were observed across age groups. Facial fractures were recorded more in the younger population (18-39 years) when compared to other age groups (40-59 years; 60+ years), p<0.0001. Alternatively, rib and femur fractures were more common among survivors aged 60+ when compared to the younger age groups, p<0.0001. INTERPRETATION: The ability to identify and respond to survivors of IPV in the healthcare setting is critically important. While facial fractures are common, they are not the only type of fractures that are seen. In many cases, healthcare professionals are the first line of defense in identifying suspected IPV cases. The findings of this paper build upon existing literature while also describing IPV-related fractures across the age spectrum.

HIV Risk Characteristics Associated with Violence Against Women: A Longitudinal Study Among Women in the United States.

BACKGROUND: Using data from HIV Prevention Trials Network 064, a multisite, observational cohort study conducted to estimate HIV incidence rates among women living in areas of high poverty and HIV prevalence in the United States, we examined the use of HIV risk characteristics to predict emotional abuse, physical violence, and forced sex. METHODS: Participants included 2099 women, 18-44 years of age, who reported unprotected vaginal or anal sex with a male partner and an additional personal or perceived male partner HIV risk characteristic in the past 6 months. Adjusting for time-varying covariates, generalized estimating equations were used to assess the ability of HIV risk characteristics to predict violence 6 months later. RESULTS: Reported analyses were limited to the 1980 study participants who reported having a male sex partner at that assessment. Exchanging sex, perceived partner concurrency, and perceived partner incarceration were significantly predictive of emotional abuse 6 months later (adjusted odds ratio [AOR]: 1.60; 1.59; 1.34, respectively). Prior sexually transmitted infection diagnosis, exchanging sex, and binge drinking were significantly predictive of physical violence 6 months later (AOR: 1.62; 1.71; 1.47, respectively). None of the variables measured was significantly predictive of forced sex. CONCLUSIONS: Strategies that address reducing violence against women should be studied further in the context of HIV prevention programs.

ALG-5 is a miRNA-associated Argonaute required for proper developmental timing in the Caenorhabditis elegans germline.

Caenorhabditis elegans contains 25 Argonautes, of which, ALG-1 and ALG-2 are known to primarily interact with miRNAs. ALG-5 belongs to the AGO subfamily of Argonautes that includes ALG-1 and ALG-2, but its role in small RNA pathways is unknown. We analyzed by high-throughput sequencing the small RNAs associated with ALG-5, ALG-1 and ALG-2, as well as changes in mRNA expression in alg-5, alg-1 and alg-2 mutants. We show that ALG-5 defines a distinct branch of the miRNA pathway affecting the expression of genes involved in immunity, defense, and development. In contrast to ALG-1 and ALG-2, which associate with most miRNAs and have general roles throughout development, ALG-5 interacts with only a small subset of miRNAs and is specifically expressed in the germline where it localizes alongside the piRNA and siRNA machinery at P granules. alg-5 is required for optimal fertility and mutations in alg-5 lead to a precocious transition from spermatogenesis to oogenesis. Our results provide a near-comprehensive analysis of miRNA-Argonaute interactions in C. elegans and reveal a new role for miRNAs in the germline.

Reducing Risky Sex among Rural African American Cocaine Users: A Controlled Trial.

Rural African American cocaine users experience high rates of STIs/HIV. This NIDA-funded trial tested an adapted evidence-based risk reduction program versus an active control condition. Participants were 251 African American cocaine users in rural Arkansas recruited from 2009-2011. Outcomes included condom use skills and self-efficacy, sexual negotiation skills, peer norms, and self-reported risk behavior. The intervention group experienced greater increases in condom use skills and overall effectiveness in sexual negotiation skills. Both groups reported reductions in trading sex, improvements in condom use self-efficacy, and increased use of specific negotiation skills. Implications and limitations are discussed.

Economic Context and HIV Vulnerability in Adolescents and Young Adults Living in Urban Slums in Kenya: A Qualitative Analysis Based on Scarcity Theory.

Urban slum adolescents and young adults have disproportionately high rates of HIV compared to rural and non-slum urban youth. Yet, few studies have examined youth's perceptions of the economic drivers of HIV. Informed by traditional and behavioral economics, we applied a scarcity theoretical framework to qualitatively examine how poverty influences sexual risk behaviors among adolescents and young adults. Focus group discussions with one hundred twenty youth in Kenyan's urban slums were transcribed, coded, and analyzed using interpretive phenomenology. Results indicated that slum youth made many sexual decisions considered rational from a traditional economics perspective, such as acquiring more sex when resources were available, maximizing wealth through sex, being price-sensitive to costs of condoms or testing services, and taking more risks when protected from adverse sexual consequences. Youth's engagement in sexual risk behaviors was also motivated by scarcity phenomena explained by behavioral economics, such as compensating for sex lost during scarce periods (risk-seeking), valuing economic gains over HIV risks (tunneling, bandwidth tax), and transacting sex as an investment strategy (internal referencing). When scarcity was alleviated, young women additionally described reducing the number of sex partners to account for non-economic preferences (slack). Prevention strategies should address the traditional and behavioral economics of the HIV epidemic.

Presentation and Management of Venomous Snakebites: Should All Patients Be Transferred to a Tertiary Referral Hospital?

Venomous snakebites may be difficult to manage because of the varied clinical presentations that may lead to uncertainty regarding the most appropriate medical and surgical management. Frequently, snakebite victims are referred from smaller rural hospitals to larger tertiary centers offering more specialized services and care. A retrospective chart review was performed using medical records from both adult and pediatric hospitals in a rural state over a 7-year period (January 2004 to January 2011) to investigate the utility of intensive care and specialized medical services offered at tertiary referral centers. The results demonstrated that presentation of venomous snakebites is the same in adults and children as well as the management. The results also demonstrated that the use of supportive care and antivenin alone was successful in the management of the vast majority of snakebites. Most snakebite victims recovered with nonsurgical care; thus surgical intervention is rarely warranted. These findings demonstrate that snakebite victims may not need referral to a tertiary center, if the primary local hospital has supportive care capacity and familiarity with antivenin usage.