Studying the Effect of MBNL1 and MBNL2 Loss in Skeletal Muscle Regeneration.

Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy. We used a BaCl2-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in Mbnl1∆E3/∆E3 and Mbnl2∆E2/∆E2 knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in Mbnl1 and Mbnl2 knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in Mbnl1∆E3/∆E3/ Mbnl2∆E2/+ mice showed increased histopathology but no deleterious reductions in MuSC numbers and only a slight increase in collagen deposition. These results suggest that factors beyond the loss of MBNL1/MBNL2 and the associated spliceopathy are likely to play a key role in the defects in skeletal muscle regeneration and deleterious effects on MuSCs that are seen in mouse models of RNA toxicity due to expanded CUG repeats.

Modeling muscle regeneration in RNA toxicity mice.

RNA toxicity underlies the pathogenesis of disorders such as myotonic dystrophy type 1 (DM1). Muscular dystrophy is a key element of the pathology of DM1. The means by which RNA toxicity causes muscular dystrophy in DM1 is unclear. Here, we have used the DM200 mouse model of RNA toxicity due to the expression of a mutant DMPK 3'UTR mRNA to model the effects of RNA toxicity on muscle regeneration. Using a BaCl2-induced damage model, we find that RNA toxicity leads to decreased expression of PAX7, and decreased numbers of satellite cells, the stem cells of adult skeletal muscle (also known as MuSCs). This is associated with a delay in regenerative response, a lack of muscle fiber maturation and an inability to maintain a normal number of satellite cells. Repeated muscle damage also elicited key aspects of muscular dystrophy, including fat droplet deposition and increased fibrosis, and the results represent one of the first times to model these classic markers of dystrophic changes in the skeletal muscles of a mouse model of RNA toxicity. Using a ligand-conjugated antisense (LICA) oligonucleotide ASO targeting DMPK sequences for the first time in a mouse model of RNA toxicity in DM1, we find that treatment with IONIS 877864, which targets the DMPK 3'UTR mRNA, is efficacious in correcting the defects in regenerative response and the reductions in satellite cell numbers caused by RNA toxicity. These results demonstrate the possibilities for therapeutic interventions to mitigate the muscular dystrophy associated with RNA toxicity in DM1.

"So let me give you money, you give me what I want": decision-making priorities around contraceptive method and source choice among young women in Kenya.

BACKGROUND: Many factors influence young women's choice of contraceptive methods and where to source them, yet less is known about whether one of these choices (method or source) is prioritized and the relationship between these choices. This study qualitatively explored decision-making around contraceptive method and source choice among young women in Kenya. METHODS: In August-September 2019, 30 in-depth interviews were conducted with women ages 18-24 who had used two or more contraceptive methods and resided in three counties: Nairobi, Mombasa or Migori. Participants were recruited from public and private health facilities and pharmacies. Interview guides captured information about decision-making processes for each contraceptive method the respondent had ever used. Responses were audio-recorded, transcribed, translated into English, coded, and analyzed thematically. RESULTS: The majority of respondents knew which method they wanted to use prior to seeking it from a source. This was true for all types of methods that women ever used. Of the small number of respondents who selected their source first, most were in the post-partum period or experiencing side effects and sought counseling at a source before choosing a method. CONCLUSIONS: This study highlights the importance of providing young women with high quality counseling that provides full information about contraceptive options and addresses that young women's needs vary along the reproductive health continuum of care. This will ensure that young women have information to inform future contraceptive decision-making prior to seeking care.

Systemic therapy in an RNA toxicity mouse model with an antisense oligonucleotide therapy targeting a non-CUG sequence within the DMPK 3'UTR RNA.

Myotonic dystrophy type 1 (DM1), the most common adult muscular dystrophy, is an autosomal dominant disorder caused by an expansion of a (CTG)n tract within the 3' untranslated region (3'UTR) of the dystrophia myotonica protein kinase (DMPK) gene. Mutant DMPK mRNAs are toxic, present in nuclear RNA foci and correlated with a plethora of RNA splicing defects. Cardinal features of DM1 are myotonia and cardiac conduction abnormalities. Using transgenic mice, we have demonstrated that expression of the mutant DMPK 3'UTR is sufficient to elicit these features of DM1. Here, using these mice, we present a study of systemic treatment with an antisense oligonucleotide (ASO) (ISIS 486178) targeted to a non-CUG sequence within the 3'UTR of DMPK. RNA foci and DMPK 3'UTR mRNA levels were reduced in both the heart and skeletal muscles. This correlated with improvements in several splicing defects in skeletal and cardiac muscles. The treatment reduced myotonia and this correlated with increased Clcn1 expression. Furthermore, functional testing showed improvements in treadmill running. Of note, we demonstrate that the ASO treatment reversed the cardiac conduction abnormalities, and this correlated with restoration of Gja5 (connexin 40) expression in the heart. This is the first time that an ASO targeting a non-CUG sequence within the DMPK 3'UTR has demonstrated benefit on the key DM1 phenotypes of myotonia and cardiac conduction defects. Our data also shows for the first time that ASOs may be a viable option for treating cardiac pathology in DM1.

Integrating private health facilities in government-led health systems: a case study of the public-private mix approach in Ethiopia.

BACKGROUND: Private health care facilities working in partnership with the public health sector is one option to create sustainable health systems and ensure health and well-being for all in low-income countries. As the second-most populous country in Africa with a rapidly growing economy, demand for health services in Ethiopia is increasing and one-quarter of its health facilities are privately owned. The Private Health Sector Program (PHSP), funded by the United States Agency for International Development, implemented a series of public-private partnership in health projects from 2004 to 2020 to address several public health priorities, including tuberculosis, malaria, HIV/AIDS, and family planning. We assessed PHSP's performance in leadership and governance, access to medicines, health management information systems, human resources, service provision, and finance. METHODS: The World Health Organization's health systems strengthening framework, which is organized around six health system building blocks, guided the assessment. We conducted 50 key informant interviews and a health facility assessment at 106 private health facilities supported by the PHSP to evaluate its performance. RESULTS: All six building blocks were addressed by the program and key informants shared that several policy and strategic changes were conducive to supporting the functioning of private health facilities. The provision of free medicines from the public pharmaceutical logistics system, relaxation of strict regulatory policies that restricted service provision through the private sector, training of private providers, and public-private mix guidelines developed for tuberculosis, malaria, and reproductive, maternal, newborn, child, and adolescent health helped increase the use of services at health facilities. CONCLUSIONS: Some challenges and threats to sustainability remain, including fragile partnerships between public and private bodies, resource constraints, mistrust between the public and private sectors, limited incentives for the private sector, and oversight of the quality of services. To continue with gains in the policy environment, service accessibility, and other aspects of the health system, the government and international communities must work collaboratively to address public-private partnerships in health areas that can be strengthened. Future efforts should emphasize a mechanism to ensure that the private sector is capable, incentivized, and supervised to deliver continuous, high-quality and equitable services.

MBNL1 overexpression is not sufficient to rescue the phenotypes in a mouse model of RNA toxicity.

Myotonic dystrophy type 1 (DM1) is caused by an expanded (CTG)n tract in the 3'UTR of the DM protein kinase (DMPK) gene. The RNA transcripts produced from the expanded allele sequester or alter the function of RNA-binding proteins (MBNL1, CUGBP1, etc.). The sequestration of MBNL1 results in RNA-splicing defects that contribute to disease. Overexpression of MBNL1 in skeletal muscle has been shown to rescue some of the DM1 features in a mouse model and has been proposed as a therapeutic strategy for DM1. Here, we sought to confirm if overexpression of MBNL1 rescues the phenotypes in a different mouse model of RNA toxicity. Using an inducible mouse model of RNA toxicity in which expression of the mutant DMPK 3'UTR results in RNA foci formation, MBNL1 sequestration, splicing defects, myotonia and cardiac conduction defects, we find that MBNL1 overexpression did not rescue skeletal muscle function nor beneficially affect cardiac conduction. Surprisingly, MBNL1 overexpression also did not rescue myotonia, though variable rescue of Clcn1 splicing and other splicing defects was seen. Additionally, contrary to the previous study, we found evidence for increased muscle histopathology with MBNL1 overexpression. Overall, we did not find evidence for beneficial effects from overexpression of MBNL1 as a means to correct RNA toxicity mediated by mRNAs containing an expanded DMPK 3'UTR.

Cardiac Pathology in Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.

Impact evaluation of scripted lesson plans for HIV-related content in a life orientation curriculum: results from two provinces in South Africa.

BACKGROUND: Young people under age 25 years are a key population at risk of unintended pregnancies, HIV and other sexually transmitted infections. School-based programming, focusing on youth under 17 years is strategic given that many in this age group are in school or are required to be in school and spend a considerable amount of their time at school. Prior evaluations of school-based HIV prevention programs for young people often employed weak study designs or lacked biomarkers (e.g., HIV or STI testing) to inform outcomes. METHODS: This study used longitudinal data collected in 2016 from a cohort of grade-8 girls from Mpumalanga and KwaZulu-Natal Provinces in South Africa. We followed them for 2 years to examine the impact of the South African Department of Basic Education's revised scripted lesson plans for the HIV and sexual content of a "life orientation" curriculum on knowledge, attitudes, condom use behaviors, pregnancy incidence, and genital herpes incidence. Schools were randomized to intervention and control arms. Multivariable analyses were undertaken using hazard modeling for incidence-based outcomes (genital herpes and pregnancy) and generalized linear latent and mixed modeling for outcomes measured at each time period (knowledge, attitudes, and condom use). RESULTS: At end line, 105 schools were included from the two provinces (44 from Mpumalanga and 61 from KwaZulu-Natal). Fifty-five were intervention and fifty were control schools. A total of 2802 girls were surveyed at both time periods (1477 intervention and 1325 control). At baseline, participating girls were about 13.6 years; by end line, they were about 2 years older. Longitudinal data demonstrated few differences between intervention and control groups on knowledge, attitudes, condom use, genital herpes, and pregnancy experience. Monitoring data demonstrated that the program was not implemented as intended. Our results demonstrated 7% incidence of genital herpes in the two-year follow-up period indicating sexual risk-taking among our cohort. CONCLUSIONS: We did not find significant effects of the revised life orientation curriculum on key outcomes; however, this may reflect poor implementation. Future HIV prevention programs for young people need to be implemented with fidelity to ensure they meet the crucial needs of the next generation. TRIAL REGISTRATION: This study has been registered at ClinicalTrials.gov . The trial registration number is: NCT04205721 . The trial was retrospectively registered on December 18, 2019.

Evaluations of Structural Interventions for HIV Prevention: A Review of Approaches and Methods.

Structural interventions alter the social, economic, legal, political, and built environments that underlie processes affecting population health. We conducted a systematic review of evaluations of structural interventions for HIV prevention in low- and middle-income countries (LMICs) to better understand methodological and other challenges and identify effective evaluation strategies. We included 27 peer-reviewed articles on interventions related to economic empowerment, education, and substance abuse in LMICs. Twenty-one evaluations included clearly articulated theories of change (TOCs); 14 of these assessed the TOC by measuring intermediary variables in the causal pathway between the intervention and HIV outcomes. Although structural interventions address complex interactions, no evaluation included methods designed to evaluate complex systems. To strengthen evaluations of structural interventions, we recommend clearly articulating a TOC and measuring intermediate variables between the predictor and outcome. We additionally recommend adapting study designs and analytic methods outside traditional epidemiology to better capture complex results, influences external to the intervention, and unintended consequences.

NKX2-5, a modifier of skeletal muscle pathology due to RNA toxicity.

RNA toxicity is implicated in a number of disorders; especially those associated with expanded repeat sequences, such as myotonic dystrophy (DM1). Previously, we have shown increased NKX2-5 expression in RNA toxicity associated with DM1. Here, we investigate the relationship between NKX2-5 expression and muscle pathology due to RNA toxicity. In skeletal muscle from mice with RNA toxicity and individuals with DM1, expression of Nkx2-5 or NKX2-5 and its downstream targets are significantly correlated with severity of histopathology. Using C2C12 myoblasts, we show that over-expression of NKX2-5 or mutant DMPK 3'UTR results in myogenic differentiation defects, which can be rescued by knockdown of Nkx2-5, despite continued toxic RNA expression. Furthermore, in a mouse model of NKX2-5 over-expression, we find defects in muscle regeneration after induced damage, similar to those seen in mice with RNA toxicity. Using mouse models of Nkx2-5 over-expression and depletion, we find that NKX2-5 levels modify disease phenotypes in mice with RNA toxicity.

A review of measures of women's empowerment and related gender constructs in family planning and maternal health program evaluations in low- and middle-income countries.

BACKGROUND: Evidence suggests that gender-integrated interventions, which actively seek to identify and integrate activities that address the role of gender norms and dynamics, improve family planning (FP) and maternal health (MH). To understand the link between the gender components of interventions and FP and MH outcomes, it is critical to examine the gender measures used in evaluations. METHODS: We conducted a systematic review of evaluations of gender-integrated FP and MH interventions in low- and middle-income countries. We examine characteristics of the interventions and their evaluations, and summarize women's empowerment and related gender measures. RESULTS: Out of 16 evaluation articles, five reported the theoretical or conceptual model that guided the intervention. Twelve described how gender was quantitatively measured and identified 13 women's empowerment and related gender constructs. Gender scales or indexes were used in five evaluations, three of which noted that their scales had been validated. Less than one third of articles reported examining the effect of gender on FP or MH. CONCLUSIONS: Evaluations of gender-integrated FP and MH interventions do not consistently describe how gender influences FP and MH outcomes or include validated gender measures within their studies. As a result, examining the pathways through which interventions empower women and the manner in which women's empowerment leads to changes in FP and MH outcomes remains a challenge. Valid measures of commonly reported women's empowerment and gender constructs, such as gender-equitable attitudes and women's decision-making power, must be adapted and used within evaluations to examine how empowerment and improvements in gender-related factors can produce positive FP and MH outcomes.

Evaluating the effects of CELF1 deficiency in a mouse model of RNA toxicity.

Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by an expanded (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The toxic RNA transcripts produced from the mutant allele alter the function of RNA-binding proteins leading to the functional depletion of muscleblind-like (MBNL) proteins and an increase in steady state levels of CUG-BP1 (CUGBP-ETR-3 like factor 1, CELF1). The role of increased CELF1 in DM1 pathogenesis is well studied using genetically engineered mouse models. Also, as a potential therapeutic strategy, the benefits of increasing MBNL1 expression have recently been reported. However, the effect of reduction of CELF1 is not yet clear. In this study, we generated CELF1 knockout mice, which also carry an inducible toxic RNA transgene to test the effects of CELF1 reduction in RNA toxicity. We found that the absence of CELF1 did not correct splicing defects. It did however mitigate the increase in translational targets of CELF1 (MEF2A and C/EBPß). Notably, we found that loss of CELF1 prevented deterioration of muscle function by the toxic RNA, and resulted in better muscle histopathology. These data suggest that while reduction of CELF1 may be of limited benefit with respect to DM1-associated spliceopathy, it may be beneficial to the muscular dystrophy associated with RNA toxicity.

Keeping it in the family: intergenerational transmission of violence in Cebu, Philippines.

While witnessing violence between parents is one of the most consistent correlates of experiencing intimate partner violence (IPV) in later life, little research exists in developing countries on the effects of witnessing interparental IPV on young adults' involvement with family violence. This study examines the relation between witnessing interparental IPV and young adults' subsequent use and experience with family intimidation and physical abuse (FIPA) in Cebu, Philippines. Using data from the Cebu Longitudinal Health and Nutrition Survey, recent use and experience of FIPA among 21-22 year old young adults was assessed through self-reports from the 2005 survey, and childhood witnessing of interparental IPV assessed from the 2002 survey. Multinomial logistic regression was used to examine the effect of witnessing interparental IPV on young adults' use and experience of FIPA. Among all young adults, witnessing paternal perpetration of IPV predicted using FIPA, and witnessing maternal perpetration predicted experiencing FIPA. Among young adult females only, witnessing reciprocal IPV between parents predicted experiencing FIPA. Witnessing paternal perpetration of IPV among young adult males, maternal perpetration among young adult females, and reciprocal interparental IPV among all young adults predicted young adults both using and experiencing FIPA. Violence prevention efforts should reach all family members through family centered interventions. School based curricula, which largely focus on intimate partner and peer violence, should recognize adolescents' use and experience of violence with family members, and design modules accordingly. Further research on gender differences in family violence is recommended.

Addressing Psychosocial Adversity Within the Patient-Centered Medical Home: Expert-Created Measurable Standards.

The Patient-Centered Medical Home (PCMH) may be improved by embedding identification and response for patients' experiences with psychosocial adversity, but how this might optimally occur in practice has not been well-specified. We sought input from an expert panel to define feasible elements that could adapt the PCMH to adequately respond to patients' experiences with psychosocial adversity. From December 2012 through September 2013, we used a Delphi process to systematically obtain expert opinions and reach consensus. We invited 37 experts to participate in three successive and iterative rounds of questionnaires, with each round based on aggregated, de-identified data from the prior round. We first asked experts to generate elements to adapt the PCMH, using the National Committee for Quality Assurance (NCQA's) established six PCMH standards as the foundation. We then asked the experts to rate these elements on a 5-point Likert scale, and finally specify what they considered the most and least valuable elements. Eighteen of the 37 (49 %) invited experts responded to the first survey, and constituted our sample. Experts identified 35 elements that fell under the six NCQA standards. The top rated elements included using a screening tool to identify adversity; training providers to address psychosocial adversity; having a team member with mental health expertise; providing culturally-competent care; and having written patient information related to adversity and coping. This study derived key elements that may enhance the PCMH's ability to improve patient outcomes by purposefully identifying and responding to their psychosocial adversity.

Changes in Children's Oral Health Status and Receipt of Preventive Dental Visits, United States, 2003-2011/2012.

INTRODUCTION: Oral health represents the largest unmet health care need for children, and geographic variations in children's receipt of oral health services have been noted. However, children's oral health outcomes have not been systematically evaluated over time and across states. This study examined changes in parent-reported children's oral health status and receipt of preventive dental visits in 50 states and the District of Columbia. METHODS: We used data from the 2003 and the 2011/2012 National Survey of Children's Health. National and state-level estimates of the adjusted prevalence of oral health status and preventive dental visits were calculated and changes over time examined. Multivariable logistic regression was used to compare outcomes across all states and the District of Columbia for each survey year. RESULTS: The percentage of parents who reported that their children had excellent or very good oral health increased from 67.7% in 2003 to 71.9% in 2011/2012. Parents who reported that their children had preventive dental visits increased from 71.5% in 2003 to 77.0% in 2011/2012. The prevalence of children with excellent or very good oral health status increased in 26 states, and the prevalence of children who received at least 1 preventive care dental visit increased in 45 states. In both years, there was more variation among states for preventive dental visits than for oral health status. CONCLUSIONS: State variation in oral health status and receipt of preventive dental services remained after adjusting for demographic characteristics. Understanding these differences is critical to addressing the most common chronic disease of childhood and achieving the oral health objectives of Healthy People 2020.

The context of violent disagreements between parents: a qualitative analysis from parents' reports.

BACKGROUND: Intimate partner violence (IPV) is a prevalent public health problem that affects millions of families. Much of what is known about IPV comes from quantitative studies that often "count" acts of IPV without exploring in depth the circumstances surrounding the violence, thereby leaving critical questions unanswered; existing qualitative studies tend to focus solely on women's perspectives. There is a dearth of dyadic qualitative research exploring the context of IPV in families with children, thus hindering the development of effective interventions for families experiencing IPV. METHODS: Seven heterosexual couples were recruited from a University-based family therapy clinic to participate in qualitative interviews. Couples were eligible if they had experienced severe verbal or any physical aggression during the past 4 months; had ≥ one child living in the household; were English-speaking; and were ≥ 18. Each individual was interviewed separately. Key topics explored included specific types of violence used by men and women; primary triggers and the context surrounding aggressive disagreements; degree to which the child(ren) were exposed; and perceived consequences for adults and children. RESULTS: All couples listed household responsibilities and parenting as key IPV triggers. Couples with infants reported that parenting disagreements were particularly heated, with women using aggression due to frustration about their partners' lack of support. Couples also described substance use, wanting to be heard, and prior violence histories as triggers or as the background context for IPV episodes. Children were present during IPV and often intervened in conflicts involving severe violence. Parents' perceptions of the effects of IPV on their children ranged from minimal to major emotional distress, with men describing more significant impact than women. CONCLUSIONS: When describing acute triggers, parents most commonly mentioned that arguments were instigated by concerns about the division of household labor and parenting, a finding that may have significant implications for intervention development; this was particularly notable for parents of infants. Our findings emphasize the need for innovative programs that help parents cope with the stresses of raising a family as well as programs that directly address the consequences of IPV for children.

Immunotherapy with biodegradable nanoparticles encapsulating the oligosaccharide galactose-alpha-1,3-galactose enhance immune tolerance against alpha-gal sensitization in a murine model of alpha-gal syndrome.

IgE antibodies against the mammalian oligosaccharide allergen galactose-α-1,3-galactose (αGal) can result in a severe allergic disease known as alpha-gal syndrome (AGS). This syndrome, acquired by tick bites that cause αGal sensitization, leads to allergic reactions after ingestion of non-primate mammalian meat and mammalian-derived products that contain αGal. Allergen-specific immunotherapies for this tickborne allergic syndrome are understudied, as are the immune mechanisms of allergic desensitization that induce clinical tolerance to αGal. Here, we reveal that prophylactic administration of αGal glycoprotein-containing nanoparticles to mice prior to tick protein-induced αGal IgE sensitization blunts the production of Th2 cytokines IL-4, IL-5, and IL-13 in an αGal-dependent manner. Furthermore, these effects correlated with suppressed production of αGal-specific IgE and hypersensitivity reactions, as measured by reduced basophil activation and histamine release and the systemic release of mast cell protease-1 (MCPT-1). Therapeutic administration of two doses of αGal-containing nanoparticles to mice sensitized to αGal had partial efficacy by reducing the Th2 cytokine production, αGal-specific IgE production, and MCPT-1 release without reducing basophil activation or histamine release. These data identify nanoparticles carrying encapsulated αGal glycoprotein as a potential strategy for augmenting αGal-specific immune tolerance and reveal diverse mechanisms by which αGal nanoparticles modify immune responses for established αGal-specific IgE-mediated allergic reactions.

B cells secrete functional antigen-specific IgG antibodies on extracellular vesicles.

B cells and the antibodies they produce are critical in host defense against pathogens and contribute to various immune-mediated diseases. B cells responding to activating signals in vitro release extracellular vesicles (EV) that carry surface antibodies, yet B cell production of EVs that express antibodies and their function in vivo is incompletely understood. Using transgenic mice expressing the Cre recombinase in B cells switching to IgG1 to induce expression of fusion proteins between emerald green fluorescent protein (emGFP) and the EV tetraspanin CD63 as a model, we identify emGFP expression in B cells responding to foreign antigen in vivo and characterize the emGFP+ EVs they release. Our data suggests that emGFP+ germinal center B cells undergoing immunoglobulin class switching to express IgG and their progeny memory B cells and plasma cells, also emGFP+, are sources of circulating antigen-specific IgG+ EVs. Furthermore, using a mouse model of influenza virus infection, we find that IgG+ EVs specific for the influenza hemagglutinin antigen protect against virus infection. In addition, crossing the B cell Cre driver EV reporter mice onto the Nba2 lupus-prone strain revealed increased circulating emGFP+ EVs that expressed surface IgG against nuclear antigens linked to autoimmunity. These data identify EVs loaded with antibodies as a novel route for antibody secretion in B cells that contribute to adaptive immune responses, with important implications for different functions of IgG+ EVs in infection and autoimmunity.

Men's controlling behaviors and women's experiences of physical violence in Malawi.

In the feminist paradigm, intimate partner violence (IPV) among heterosexual couples is gender asymmetric and largely a tactic of male control. However, research on the relationship between men's controlling behavior and physical violence against women is limited. This study examines whether having a controlling partner is associated with women's reports of experiencing physical violence in Malawi. Bivariate and multivariate analyses were conducted using data from 8,385 women who completed the domestic violence module of the Malawi 2004 Demographic and Health Survey. About 18 % of women reported they had experienced moderately severe physical violence and 1 % experienced very severe violence in the past 12 months. A third of women reported their partners had ever been controlling. Results from multivariable ordinal logistic regression showed that women who had controlling partners were significantly more likely to report experiencing physical violence. Other factors significantly associated with women's experience of physical violence included women who reported initiating physical violence against their partners, women's work status, partners' lower education level, and partners' alcohol consumption. Women with controlling partners were at increased risk of experiencing physical violence in the past year. However, women who reported initiating physical violence in the past year were nearly four times more likely to experience partner violence in the same time period. Future research should attempt to elucidate these two important risk factors for IPV.

Changes in children's oral health status and receipt of preventive dental visits, United States, 2003-2011/2012.

INTRODUCTION: Oral health represents the largest unmet health care need for children, and geographic variations in children's receipt of oral health services have been noted. However, children's oral health outcomes have not been systematically evaluated over time and across states. This study examined changes in parent-reported children's oral health status and receipt of preventive dental visits in 50 states and the District of Columbia. METHODS: We used data from the 2003 and the 2011/2012 National Survey of Children's Health. National and state-level estimates of the adjusted prevalence of oral health status and preventive dental visits were calculated and changes over time examined. Multivariable logistic regression was used to compare outcomes across all states and the District of Columbia for each survey year. RESULTS: The percentage of parents who reported that their children had excellent or very good oral health increased from 67.7% in 2003 to 71.9% in 2011/2012. Parents who reported that their children had preventive dental visits increased from 71.5% in 2003 to 77.0% in 2011/2012. The prevalence of children with excellent or very good oral health status increased in 26 states, and the prevalence of children who received at least 1 preventive care dental visit increased in 45 states. In both years, there was more variation among states for preventive dental visits than for oral health status. CONCLUSIONS: State variation in oral health status and receipt of preventive dental services remained after adjusting for demographic characteristics. Understanding these differences is critical to addressing the most common chronic disease of childhood and achieving the oral health objectives of Healthy People 2020.