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Hepatitis D virus (HDV) requires co-infection with hepatitis B virus (HBV). Human immunodeficiency virus (HIV) shares transmission routes with these viruses. Among 4,932 US women infected with or at-risk for HIV during 1994-2015, HBV surface antigen (HBsAg) positivity was more common in women with HIV (2.8% vs. 1.2%; p = 0.001); HDV was more common among participants enrolled during 2013-2015 (p = 0.0004) and those with resolved rather than active hepatitis C (1.9% vs. 0.5%; p = 0.02). Among HBsAg-positive women (n = 117), HDV antibody prevalence was 22% and did not vary by HIV status; HDV infection was associated with the presence of advanced fibrosis/cirrhosis at enrollment (adjusted odds ratio, 5.70; 95% confidence interval, 1.46-22.29). Our results demonstrate the importance of HDV testing in HBV-infected US women.

Policy research can reveal gaps and opportunities to enhance policy impact and implementation. In this study, we use a theoretically informed qualitative approach to investigate the implementation of two policies to promote breastfeeding in Vietnam. We conducted semi-structured interviews with national and local policy stakeholders (n = 26) in 2017. Interviews were audio-recorded, transcribed verbatim and then translated to English by certified translators. Transcript data were analysed using an integrated conceptual framework of policy implementation. Respondents identified several positive outcomes resulting from implementation of an extended maternity leave policy (Labour Code No. 10/2012/QH13) and further restrictions on marketing of breast milk substitutes (Decree No. 100/2014/ND-CP). Decree No. 100, in particular, was said to have reduced advertising of breast milk substitutes in mass media outlets and healthcare settings. Key implementation actors were national-level bureaucratic actors, local organizations and international partners. Findings reveal the importance of policy precedence and a broader set of policies to promote the rights of women and children to support implementation. Other facilitators were involvement from national-level implementing agencies and healthcare personnel and strength of government relationships and coordination with non-governmental and international organizations. Implementation challenges included insufficient funding, limited training to report violations, a cumbersome reporting process and pervasive misinformation about breast milk and breast milk substitutes. Limited reach for women employed in the informal labour sector and in rural communities was said to be a compatibility issue for the extended maternity leave policy in addition to the lack of impact on non-parental guardians and caretakers. Recommendations to improve policy implementation include designating a role for international organizations in supporting implementation, expanding maternity protections for all working women, building local-level policy knowledge to support enforcement, simplifying Decree No. 100 violation reporting processes and continuing to invest in interventions to facilitate a supportive policy environment in Vietnam.

IntroductionAlive and Thrive (A&T) implemented infant and young child feeding (IYCF) interventions in Bangladesh. We examine the sustained impacts on health workers' IYCF knowledge, service delivery, job satisfaction, and job readiness three years after the program's conclusion.MethodsWe use data from a cluster-randomized controlled trial design, including repeated cross-sectional surveys with health workers in 2010 (baseline, n = 290), 2014 (endline, n = 511) and 2017 (post-endline, n = 600). Health workers in 10 sub-districts were trained and incentivized to deliver intensified IYCF counseling, and participated in social mobilization activities, while health workers in 10 comparison sub-districts delivered standard counseling activities. Accompanying mass media and policy change activities occurred at the national level. The primary outcome is quality of IYCF service delivery (number of IYCF messages reportedly communicated during counseling); intermediate outcomes are IYCF knowledge, job satisfaction, and job readiness. We also assess the role of hypothesized modifiers of program sustainment, i.e. activities of the program: comprehensiveness of refresher trainings and receipt of financial incentives. Multivariable difference-in-difference linear regression models, including worker characteristic covariates and adjusted for clustering at the survey sampling level, are used to compare differences between groups (intervention vs. comparison areas) and over time (baseline, endline, post-endline).ResultsAt endline, health workers in intervention areas discussed significantly more IYCF topics than those in comparison areas (4.9 vs. 4.0 topics, p

Policy research can reveal gaps and opportunities to enhance policy impact and implementation. In this study, we use a theoretically informed qualitative approach to investigate implementation of two policies to promote breastfeeding in Vietnam. We conducted semi-structured interviews with national and local policy stakeholders (n=26) in 2017. Interviews were audio recorded and transcribed verbatim, then translated to English by certified translators. Transcript data were analyzed using an integrated conceptual framework of policy implementation. Respondents identified several positive outcomes to implementing an extended maternity leave policy (Labour Code No. 10/2012/QH13) and further restrictions on marketing of breast milk substitutes (Decree No. 100/2014/ND-CP). Decree No. 100, in particular, was said to have reduced advertising of breast milk substitutes in mass media outlets and health care settings. Key implementation actors were national-level bureaucratic actors, local organizations, and international partners. Findings reveal the importance of policy precedence and a broader set of policies to promote the rights of women and children to support implementation. Other facilitators were involvement from national level implementing agencies and healthcare personnel, and strength of government relationships and coordination with non-governmental and international organizations. Implementation challenges included insufficient funding, limited training to report violations, a cumbersome reporting process, and pervasive misinformation about breastmilk and breast milk substitutes. Limited reach for women employed in the informal labor sector and in rural communities was said to be a compatibility issue for the extended maternity leave policy in addition to the lack of impact on non-parental guardians and caretakers. Recommendations to improve policy implementation include designating a role for international organizations to support implementation, expanding maternity protections for all working women, building local-level policy knowledge to support enforcement, simplifying Decree No. 100 violation reporting processes, and continuing to invest in interventions to facilitate a supportive policy environment in Vietnam.

BackgroundCommunity health worker (CHW) motivation is an important factor related to health service quality and CHW program sustainability in low- and middle-income countries. Financial and non-financial motivators may influence CHW behavior through two dimensions of motivation: desire to perform and effort expended. The aim of this study was to explore how the removal of performance-based financial incentives impacted CHW motivation after formal funding ceased for Alive and Thrive (A&T), an infant and young child feeding (IYCF) program in Bangladesh.MethodsThis qualitative study included seven focus groups (n = 43 respondents) with paid supervisors of volunteer CHWs tasked with delivering interpersonal IYCF counseling services. Data were transcribed, translated into English, and then analyzed using both a priori themes and a grounded theory approach.ResultsResults suggest the removal of financial incentives was perceived to have negatively impacted CHWs' desire to perform in three primary ways: 1) a decreased desire to work without financial compensation, 2) changes in pre- and post-intervention motivation, and 3) household income challenges due to dependence on incentives. Removal of financial incentives was perceived to have negatively impacted CHWs' level of effort expended in four primary ways: 1) a reduction in CHW visits, 2) a reduction in quality of care, 3) CHW attrition, and 4) substitution of other income-generating activities.ConclusionsThis study provides new evidence regarding how removing performance-based financial incentives from a CHW program can negatively impact CHW motivation. The findings suggest that program decision makers should consider how to construct community health work programs such that CHWs may continue to receive performance-based compensation after the original funding ceases.

PURPOSE Few studies have determined whether clinician usage of a community health information exchange (HIE) directly improves patient care transitions. We hypothesized that lookup in the HIE by primary care physicians of patients recently released from the hospital would increase the time until hospital reuse. METHODS We identified a retrospective cohort of 8,216 hospital inpatients aged over 18 years that were discharged from January 1, 2021 through November 30, 2021 using the Paso del Norte Health Information Exchange, in El Paso County, Texas. All patients had a primary care physician visit within 30 days after hospital discharge, and we identified patients that were looked up in the HIE close to that visit. Of the cohort, 2,627 were rehospitalized and 3,809 visited an emergency department (ED) during the follow-up window. The remaining 1,780 patients were controls. We conducted survival analysis, censoring at the second ED or inpatient visit or end of the study window (January 31, 2022). The model was adjusted by ethnicity, gender, insurance, and age. RESULTS Lookup in the HIE was significantly associated with reducing the likelihood of visiting the ED by 53% and being rehospitalized by 61%. Lookup in the HIE was associated with an increased median time to use of the ED after inpatient discharge from 99 to 238 patient days. Ethnicity, insurance, gender, and age were also significant predictors of hospital reuse. CONCLUSIONS Increased utilization of community HIEs by primary care physicians on behalf of their recently discharged patients may dramatically increase the time until inpatient or ED reuse. Key words: care transitions; community health information exchange; family medicine; hospital readmission, INTRODUCTION The health care system in the United States is markedly fragmented, with patients moving through levels and types of care that benefit when seamless transfers of information from one [...]

BackgroundPoor early-life nutrition is a major barrier to good health and cognitive development, and is a global health priority. Alive & Thrive (A&T) was a multi-pronged initiative to improve infant and young child feeding behaviors. It aimed to achieve at-scale child health and nutrition improvements via a comprehensive approach that included nutrition counseling by health workers, policy change, social mobilization and mass media activities. This study evaluated the sustainability of activities introduced during A&T implementation (2009-2014) in Bangladesh and Vietnam.MethodsThis was a mixed methods study that used a quasi-experimental design. Quantitative data (surveys with 668 health workers, and 269 service observations) were collected in 2017; and analysis compared outcomes (primarily dose and fidelity of activities, and capacity) in former A&T intervention areas versus areas that did not receive the full A&T intervention. Additionally, we conducted interviews and focus groups with 218 stakeholders to explore their impressions about the determinants of sustainability, based on a multi-level conceptual framework.ResultsAfter program conclusion, stakeholders perceive declines in mass media campaigns, policy and advocacy activities, and social mobilization activities - but counseling activities were institutionalized and continued in both countries. Quantitative data show a persisting modest intervention effect: health workers in intervention areas had significantly higher child feeding knowledge, and in Bangladesh greater self-efficacy and job satisfaction, compared to their counterparts who did not receive the full package of A&T activities. While elements of the program were integrated into routine services, stakeholders noted dilution of the program focus due to competing priorities. Qualitative data suggest that some elements, such as training, monitoring, and evaluation, which were seen as essential to A&T's success, have declined in frequency, quality, coverage, or were eliminated altogether.ConclusionsThe inclusion of multiple activities in A&T and efforts to integrate the program into existing institutions were seen as crucial to its success but also made it difficult to sustain, particularly given unstable financial support and human resource constraints. Future complex programs should carefully plan for institutionalization in advance of the program by cultivating champions across the health system, and designing unique and complementary roles for all stakeholders including donors.

It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.

BackgroundTheoretical models and cross-sectional empirical studies of suicide indicate that anger is a factor that may help explain the association between posttraumatic stress disorder (PTSD) and suicide, but to date no longitudinal studies have examined this relationship. The current study used longitudinal data to examine whether changes in anger mediated the association between changes in PTSD symptomatology and suicidal ideation (SI).MethodsPost 9/11-era veterans (N = 298) were assessed at baseline, 6-months, and 12-month time points on PTSD symptoms, anger, and SI. Analyses covaried for age, sex, and depressive symptoms. Multilevel structural equation modeling was used to examine the three waves of data.ResultsThe effect of change in PTSD symptoms on SI was reduced from B = 0.02 (p = .008) to B = -0.01 (p = .67) when change in anger was added to the model. Moreover, the indirect effect of changes in PTSD symptoms on suicidal ideation via changes in anger was significant, B = 0.02, p = .034. The model explained 31.1% of the within-person variance in SI.LimitationsFocus on predicting SI rather than suicidal behavior. Sample was primarily male.ConclusionsFindings suggest that the association between PTSD and SI is accounted for, in part, by anger. This study further highlights the importance of anger as a risk factor for veteran suicide. Additional research on clinical interventions to reduce anger among veterans with PTSD may be useful in reducing suicide risk.

Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.

BackgroundSuboptimal healthcare quality may be a barrier to achieving child health improvements, yet little is known about the relationship between provider compliance with evidence-based practices and client behavior change. We assess provider compliance in the context of infant and young child feeding (IYCF) counseling, its relationship with client IYCF behaviors in Bangladesh, and explore its potential determinants.MethodsWe use data from a 2017 evaluation of an IYCF program that includes a health worker survey (n = 74), caregiver survey (n = 232), and direct service observation checklists of counseling sessions (n = 232 observations of 74 health workers). We assess the relationship between provider compliance with recommended IYCF counseling topics and behaviors (standardized to a 100-point scale) and three reported IYCF behaviors among clients using multi-level models with random effects at the health worker and sub-district (sampling) levels. We also evaluate whether health worker self-efficacy, satisfaction, and technical knowledge are associated with provider compliance.ResultsHealth worker compliance was significantly associated with reported exclusive breastfeeding for children under 6 months of age (adjusted odds ratio per 1 percentage point increase in counseling compliance score = 1.06, 95% CI 1.01, 1.12) and marginally associated with minimum dietary diversity (adjusted odds ratio per 1 percentage point increase in counseling compliance score = 1.05, 95% CI 1.00, 1.11). Counseling compliance was significantly and positively associated with both health worker self-efficacy and technical knowledge.ConclusionsWe find evidence for an association between health worker compliance and client health behaviors; however, small effect sizes suggest that behavior change is multifactorial and affected by factors beyond care quality. Improvements to technical quality of care may contribute to desired health outcomes; but policies and programs seeking to change health behaviors through counseling may also wish to target upstream factors such as self-efficacy, alongside technical skill-building and knowledge, for maximum impact.

The multienzyme catalytic phosphorylation of phosphatidylinositol (PI) in a supported lipid membrane platform is demonstrated for the first time. One-step treatment with PI 4-kinase IIIβ (PI4Kβ) yielded PI 4-phosphate (PI4P), while a multistep enzymatic cascade of PI4Kβ followed by PIP 5-kinase produced PI-4,5-bisphosphate (PI(4,5)P2 or PIP2). By employing quartz crystal microbalance with dissipation monitoring, we were able to track membrane association of kinase enzymes for the first time as well as detect PI4P and PI(4,5)P2 generation based on subsequent antibody binding to the supported lipid bilayers. Pharmacologic inhibition of PI4Kβ by a small molecule inhibitor was also quantitatively assessed, yielding an EC50 value that agrees well with conventional biochemical readout. Taken together, the development of a PI-containing supported membrane platform coupled with surface-sensitive measurement techniques for kinase studies opens the door to exploring the rich biochemistry and pharmacological targeting of membrane-associated phosphoinositides.

Type III phosphatidylinositol 4-kinase (PI4KIIIβ) is an essential enzyme in mediating membrane trafficking and is implicated in a variety of pathogenic processes. It is a key host factor mediating replication of RNA viruses. The design of potent and specific inhibitors of this enzyme will be essential to define its cellular roles and may lead to novel antiviral therapeutics. We previously reported the PI4K inhibitor PIK93, and this compound has defined key functions of PI4KIIIβ. However, this compound showed high cross reactivity with class I and III PI3Ks. Using structure-based drug design, we have designed novel potent and selective (>1000-fold over class I and class III PI3Ks) PI4KIIIβ inhibitors. These compounds showed antiviral activity against hepatitis C virus. The co-crystal structure of PI4KIIIβ bound to one of the most potent compounds reveals the molecular basis of specificity. This work will be vital in the design of novel PI4KIIIβ inhibitors, which may play significant roles as antiviral therapeutics.

We have used multiplexed high-throughput sequencing to characterize changes in small RNA populations that occur during viral infection in animal cells. Small RNA-based mechanisms such as RNA interference (RNAi) have been shown in plant and invertebrate systems to play a key role in host responses to viral infection. Although homologs of the key RNAi effector pathways are present in mammalian cells, and can launch an RNAi-mediated degradation of experimentally targeted mRNAs, any role for such responses in mammalian host-virus interactions remains to be characterized. Six different viruses were examined in 41 experimentally susceptible and resistant host systems. We identified virus-derived small RNAs (vsRNAs) from all six viruses, with total abundance varying from "vanishingly rare" (less than 0.1% of cellular small RNA) to highly abundant (comparable to abundant micro-RNAs "miRNAs"). In addition to the appearance of vsRNAs during infection, we saw a number of specific changes in host miRNA profiles. For several infection models investigated in more detail, the RNAi and Interferon pathways modulated the abundance of vsRNAs. We also found evidence for populations of vsRNAs that exist as duplexed siRNAs with zero to three nucleotide 3' overhangs. Using populations of cells carrying a Hepatitis C replicon, we observed strand-selective loading of siRNAs onto Argonaute complexes. These experiments define vsRNAs as one possible component of the interplay between animal viruses and their hosts.