Protocol for the ROSE sustainment (ROSES) study, a sequential multiple assignment randomized trial to determine the minimum necessary intervention to maintain a postpartum depression prevention program in prenatal clinics serving low-income women.

BACKGROUND: More research on sustainment of interventions is needed, especially return on investment (ROI) studies to determine cost-benefit trade-offs for effort required to sustain and how much is gained when effective programs are sustained. The ROSE sustainment (ROSES) study uses a sequential multiple assignment randomized (SMART) design to evaluate the effectiveness and cost-effectiveness of a stepwise approach to sustainment of the ROSE postpartum depression prevention program in 90 outpatient clinics providing prenatal care to pregnant women on public assistance. Postpartum depression (PPD) is common and can have lasting consequences. Outpatient clinics offering prenatal care are an opportune place to provide PPD prevention because most women visit while pregnant. The ROSE (Reach Out, Stay Strong, Essentials for mothers of newborns) program is a group educational intervention to prevent PPD, delivered during pregnancy. ROSE has been found to reduce cases of PPD in community prenatal settings serving low-income pregnant women. METHODS: All 90 prenatal clinics will receive enhanced implementation as usual (EIAU; initial training + tools for sustainment). At the first time at which a clinic is determined to be at risk for failure to sustain (i.e., at 3, 6, 9, 12, and 15 months), that clinic will be randomized to receive either (1) no additional implementation support (i.e., EIAU only), or (2) low-intensity coaching and feedback (LICF). If clinics receiving LICF are still at risk at subsequent assessments, they will be randomized to either (1) EIAU + LICF only, or (2) high-intensity coaching and feedback (HICF). Additional follow-up interviews will occur at 18, 24, and 30 months, but no implementation intervention will occur after 18 months. Outcomes include (1) percent sustainment of core program elements at each time point, (2) health impact (PPD rates over time at each clinic) and reach, and (3) ROI (costs and cost-effectiveness) of each sustainment step. Hypothesized mechanisms include sustainment of capacity to deliver core elements and engagement/ownership. DISCUSSION: This study is the first randomized trial evaluating the ROI of a stepped approach to sustainment, a critical unanswered question in implementation science. It will also advance knowledge of implementation mechanisms and clinical care for an at-risk population. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03267563 . Registered June 14, 2018.

Mast Cells and Innate Lymphoid Cells: Underappreciated Players in CNS Autoimmune Demyelinating Disease.

Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis, are autoimmune CNS inflammatory diseases. As a result of a breakdown in the relatively impermeable blood-brain barrier (BBB) in affected individuals, myelin-specific CD4+ and CD8+ T cells gain entry into the immune privileged CNS and initiate myelin, oligodendrocyte, and nerve axon destruction. However, despite the absolute requirement for T cells, there is increasing evidence that innate immune cells also play critical amplifying roles in disease pathogenesis. By modulating the character and magnitude of the myelin-reactive T cell response and regulating BBB integrity, innate cells affect both disease initiation and progression. Two classes of innate cells, mast cells and innate lymphoid cells (ILCs), have been best studied in models of allergic and gastrointestinal inflammatory diseases. Yet, there is emerging evidence that these cell types also exert a profound influence in CNS inflammatory disease. Both cell types are residents within the meninges and can be activated early in disease to express a wide variety of disease-modifying cytokines and chemokines. In this review, we discuss how mast cells and ILCs can have either disease-promoting or -protecting effects on MS and other CNS inflammatory diseases and how sex hormones may influence this outcome. These observations suggest that targeting these cells and their unique mediators can be exploited therapeutically.

Evidence for a neuroprotective microRNA pathway in amnestic mild cognitive impairment.

MicroRNAs (miRNAs) that regulate mRNA stability have been linked to amyloid production, tau phosphorylation, and inflammation in Alzheimer's disease (AD). However, whether cerebral miRNA networks are dysregulated during the earliest stages of AD remains underexplored. We performed miRNA expression analysis using frontal cortex tissue harvested from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild AD. Analysis revealed that the miRNA clusters miR-212/132 and miR-23a/23b were down-regulated in the frontal cortex of aMCI subjects. Both miR-212/132 and miR23a/b are predicted to destabilize the message for sirtuin 1 (sirt1); hence, down-regulation of either miR-212/132 or miR-23a/b in frontal cortex should promote sirt1 mRNA expression in this region. qPCR studies revealed that frontal cortex levels of sirt1 were increased in aMCI. Given the ability of frontal cortex to respond to the onset of dementia by neuronal reorganization, these data suggest that miRNA-mediated up-regulation of the sirt1 pathway represents a compensatory response to the onset of the disease. By contrast, qPCR analysis of inferior temporal cortex, an area affected early in the progression of AD, showed no changes in miR-212/132, miR-23a/b, or sirt1 transcripts in the same aMCI subjects. In vitro mechanistic studies showed that coordinated down-regulation of miR-212 and miR-23a increased sirt1 protein expression and provided neuroprotection from ß-amyloid toxicity in human neuronal cells. Taken together, these data suggest a novel miRNA-mediated neuroprotective pathway activated during the progression of AD that may be amenable to therapeutic manipulation.

Family-based interpersonal psychotherapy for depressed preadolescents: examining efficacy and potential treatment mechanisms.

OBJECTIVE: To conduct a randomized controlled trial to evaluate the preliminary efficacy of family-based interpersonal psychotherapy (FB-IPT) for treating depression in preadolescents (aged 7-12 years) as compared to child-centered therapy (CCT), a supportive and nondirective treatment that closely approximates the standard of care for pediatric depression in community mental health. METHOD: Preadolescents with depression (N = 42) were randomly assigned FB-IPT or CCT. Pre- and posttreatment assessments included clinician-administered measures of depression, parent- and child-reported depression and anxiety symptoms, and parent-child conflict and interpersonal impairment with peers. RESULTS: Preadolescents receiving FB-IPT had higher rates of remission (66.0% versus 31%), a greater decrease in depressive symptoms from pre- to posttreatment, and lower depressive symptoms at posttreatment (R(2) = 0.35, ΔR(2) = 0.22; B = -8.15, SE = 2.61, t[37] = -3.13, p = .002, F(2) = 0.28) than did preadolescents with depression receiving CCT. Furthermore, preadolescents in the FB-IPT condition reported significant reductions in anxiety and interpersonal impairment compared with preadolescents in the CCT condition. Changes in social and peer impairment from pre- to posttreatment were associated with preadolescents' posttreatment depressive symptoms. There was a significant indirect effect for decreased social impairment accounting for the association between the FB-IPT and preadolescents' posttreatment depressive symptoms. CONCLUSION: Findings indicate FB-IPT is an effective treatment for preadolescent depression and support further investigation of interpersonal mechanisms by which FB-IPT may reduce preadolescent depression. Clinical trial registration information-Phase II Study of Family Based Interpersonal Psychotherapy (FB-IPT) for Depressed Preadolescents; http://clinicaltrials.gov; NCT02054312.

A prospective study of parentally bereaved youth, caregiver depression, and body mass index.

OBJECTIVE: To examine the relationship between body mass index (BMI) in bereaved youth and nonbereaved controls 5 years after a parent's death. The study was conducted from August 9, 2002, through December 31, 2013. DESIGN: A prospective, longitudinal, controlled study of the effects of sudden parental death on youth. SETTING: Bereaved families were recruited through coroner records and by advertisement. Nonbereaved families were recruited using random-digit dialing and by advertisement. PARTICIPANTS: 123 parentally bereaved offspring were compared with 122 nonbereaved control offspring, all of whom were aged 11-25 years at the 5-year assessment. MAIN EXPOSURE: Bereavement status, type of parental death (accident, suicide, or sudden natural death), and history of depression in caregivers prior to parental death. OUTCOME MEASURES: BMI categories (normal, overweight, and obese), according to International Obesity Task Force guidelines for adults and Centers for Disease Control and Prevention guidelines for children, and DSM-IV psychiatric disorder in offspring and caregivers before and after time of parental death. RESULTS: Bereaved offspring were more likely to have a BMI in the obese range compared to nonbereaved controls (χ2(2) = 7.13, P < .01). There were no differences in BMI category by death type among bereaved offspring. Caregiver history of depression was a significant correlate of offspring obesity in nonbereaved youth but had a protective effect on the BMI of bereaved youth. CONCLUSIONS: Bereaved youth were more likely to be obese than nonbereaved youth 5 years after parental death, and caregiver history of depression was associated with increased risk for obesity in nonbereaved youth only. Future studies are necessary to identify mechanisms that increase risk for obesity in parentally bereaved youth.

Iκb-ζ plays an important role in the ERK-dependent dysregulation of malaria parasite GPI-induced IL-12 expression.

Plasmodium falciparum glycosylphosphatidylinositols (GPIs) have been proposed as malaria pathogenic factors based on their ability to induce proinflammatory responses in macrophages and malaria-like symptoms in mice. Parasite GPIs induce the production of inflammatory cytokines by activating the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways. Importantly, inhibition of the extracellular-signal-regulated kinase (ERK) pathway upregulates a subset of cytokines, including IL-12. We investigated the role of nuclear transcription factor, IκB-ζ, in the GPI-induced dysregulated expression of IL-12 on inhibition of the ERK pathway. GPIs efficiently induced the expression of IκB-ζ in macrophages regardless of whether cells were pretreated or untreated with ERK inhibitors, indicating that ERK has no role in IκB-ζ expression. However, on ERK inhibition followed by stimulation with GPIs, NF-κB binding to Il12b promoter κB site was markedly increased, suggesting that the ERK pathway regulates Il12b transcription. Knockdown of IκB-ζ using siRNA markedly reduced the GPI-induced IL-12 production and abrogated the dysregulated IL-12 production in ERK inhibited cells. Together these results demonstrate that ERK modulates IL-12 expression by regulating IκB-ζ-dependent binding of NF-κB transcription factors to Il12b gene promoter. Additionally, our finding that IκB-ζ can be knocked down efficiently in primary macrophages is valuable for studies aimed at gaining further insights into IκB-ζ function.

MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-induced production of tumor necrosis factor-{alpha} and interleukin-12 in macrophages.

Proinflammatory responses induced by Plasmodium falciparum glycosylphosphatidylinositols (GPIs) are thought to be involved in malaria pathogenesis. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2) in the regulation of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12, two of the major inflammatory cytokines produced by macrophages stimulated with GPIs. We show that MK2 differentially regulates the GPI-induced production of TNF-alpha and IL-12. Although TNF-alpha production was markedly decreased, IL-12 expression was increased by 2-3-fold in GPI-stimulated MK2(-/-) macrophages compared with wild type (WT) cells. MK2(-/-) macrophages produced markedly decreased levels of TNF-alpha than WT macrophages mainly because of lower mRNA stability and translation. In the case of IL-12, mRNA was substantially higher in MK2(-/-) macrophages than WT. This enhanced production is due to increased NF-kappaB binding to the gene promoter, a markedly lower level expression of the transcriptional repressor factor c-Maf, and a decreased binding of GAP-12 to the gene promoter in MK2(-/-) macrophages. Thus, our data demonstrate for the first time the role of MK2 in the transcriptional regulation of IL-12. Using the protein kinase inhibitors SB203580 and U0126, we also show that the ERK and p38 pathways regulate TNF-alpha and IL-12 production, and that both inhibitors can reduce phosphorylation of MK2 in response to GPIs and other toll-like receptor ligands. These results may have important implications for developing therapeutics for malaria and other infectious diseases.

Influence of source parameters on large-field electron beam profiles calculated using Monte Carlo methods.

The purpose of this paper was to study the source model for a Monte Carlo simulation of electron beams from a medical linear accelerator. In a prior study, a non-divergent Gaussian source with a full-width at half-maximum (FWHM) of 0.15 cm was successful in predicting relative dose distributions for electron beams with applicators. However, for large fields with the applicator removed, discrepancies were found between measured and calculated profiles, particularly in the shoulder region. In this work, the source was changed to a divergent Gaussian spatial distribution and the FWHM parameter was varied to produce better agreement with measured data. The influence of the FWHM source parameter on profiles was observed at multiple locations in the simulation geometry including in-air fluence profiles at a 95 cm source-to-surface distance (SSD), percent depth dose profiles and off-axis profiles (OARs) in a water phantom for two SSDs, 80 and 100 cm. For a 6 MeV 40 x 40 cm(2) OAR profile, discrepancies in the shoulder region were reduced from 15% to 4% using a FWHM value of 0.45 cm. The optimal FWHM values for the other energies were 0.45 cm for 9 MeV, 0.22 for 12 MeV, 0.25 for 16 MeV and 0.2 cm for 20 MeV. Although this range of values was larger than measured focal spot sizes reported by other researchers, using the increased FWHM values improved the fit at most locations in the simulation geometry, giving confidence that the model could be used with a variety of SSDs and field sizes.

Comprehensive evaluation of a commercial macro Monte Carlo electron dose calculation implementation using a standard verification data set.

A commercial electron dose calculation software implementation based on the macro Monte Carlo algorithm has recently been introduced. We have evaluated the performance of the system using a standard verification data set comprised of two-dimensional (2D) dose distributions in the transverse plane of a 15 X 15 cm2 field. The standard data set was comprised of measurements performed for combinations of 9-MeV and 20-MeV beam energies and five phantom geometries. The phantom geometries included bone and air heterogeneities, and irregular surface contours. The standard verification data included a subset of the data needed to commission the dose calculation. Additional required data were obtained from a dosimetrically equivalent machine. In addition, we performed 2D dose measurements in a water phantom for the standard field sizes, a 4 cm X 4 cm field, a 3 cm diameter circle, and a 5 cm X 13 cm triangle for the 6-, 9-, 12-, 15-, and 18-MeV energies of a Clinac 21EX. Output factors were also measured. Synthetic CT images and structure contours duplicating the measurement configurations were generated and transferred to the treatment planning system. Calculations for the standard verification data set were performed over the range of each of the algorithm parameters: statistical precision, grid-spacing, and smoothing. Dose difference and distance-to-agreement were computed for the calculation points. We found that the best results were obtained for the highest statistical precision, for the smallest grid spacing, and for smoothed dose distributions. Calculations for the 21EX data were performed using parameters that the evaluation of the standard verification data suggested would produce clinically acceptable results. The dose difference and distance-to-agreement were similar to that observed for the standard verification data set except for the portion of the triangle field narrower than 3 cm for the 6- and 9-MeV electron beams. The output agreed with measurements to within 2%, with the exception of the 3-cm diameter circle and the triangle for 6 MeV, which were within 5%. We conclude that clinically acceptable results may be obtained using a grid spacing that is no larger than approximately one-tenth of the distal falloff distance of the electron depth dose curve (depth from 80% to 20% of the maximum dose) and small relative to the size of heterogeneities. For judicious choices of parameters, dose calculations agree with measurements to better than 3% dose difference and 3-mm distance-to-agreement for fields with dimensions no less than about 3 cm.

Importance of UDP-glucuronosyltransferase 1A10 (UGT1A10) in the detoxification of polycyclic aromatic hydrocarbons: decreased glucuronidative activity of the UGT1A10139Lys isoform.

UDP-glucuronosyltransferase 1A10 (UGT1A10) is an extrahepatic enzyme expressed in aerodigestive tract tissues that exhibits significant glucuronidation activity against the important procarcinogenic benzo(a)pyrene (BaP) metabolite, BaP-trans-7,8-dihydrodiol (BPD), and the UGT1A10 codon 139 (Glu>Lys) polymorphism was previously implicated in risk for orolaryngeal cancer by Elahi et al. in their 2003 study. To better assess the potential role of UGT1A10 in risk for tobacco-related cancers, the glucuronidation activity of UGT1A10 was compared with that of other known UGT enzymes against selected polycyclic aromatic hydrocarbons, and the effects of the codon 139 polymorphism on UGT1A10 function were examined in vitro. UGT1A10 exhibited considerably more glucuronidation activity as determined by Vmax/Km against 3-hydroxy (OH)-BaP, 7-OH-BaP, 9-OH-BaP, and 1-OH-pyrene than any other UGT1A family member. Although a kinetic comparison using Vmax could not be performed against family 2B UGTs, UGT1A10 exhibited a 1.7- to 254-fold lower Km than active family 2B UGTs against 3-OH-BaP, 7-OH-BaP, and 1-OH-pyrene. A significantly (p < 0.01) higher Vmax/Km was observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against all four BaP metabolites tested (3-OH-BaP, 7-OH-BaP, 9-OH-BaP, and BPD). A similarly significant (p < 0.05) increase in Vmax/Km was observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against 1-OH-pyrene. Significant differences in Km were observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against 1-OH-pyrene (p < 0.05) and 3-OH-BaP (p < 0.01). Reverse transcription-polymerase chain reaction of total lung RNA showed low levels of UGT1A10 expression in human lung tissue. Together, these studies implicate UGT1A10 as an important detoxifier of polycyclic aromatic hydrocarbons in humans and that the UGT1A10 codon 139 polymorphism may be an important determinant in risk for tobacco-related cancers.

Dosimetric uncertainties of three-dimensional dose reconstruction from two-dimensional data in a multi-institutional study.

Inconsistencies in the treatment planning process leading to dosimetric uncertainties may affect conclusions drawn from interinstitutional radiation oncology clinical trials. The purpose of this study was to assess the dosimetric uncertainties resulting from the process of reconstructing three-dimensional dose distributions from two-dimensional treatment plan information provided by participating institutions in a randomized clinical trial. This study was based on American College of Radiology Protocol #427, Locally Advanced Multi-Modality Protocol; a multi-institutional phase II randomized study involving radiation therapy for patients with inoperable non-small cell lung cancer. Several sources of dosimetric uncertainty were identified and analyzed, including image quality of hard-copy computed tomography (CT) images, slice spacing of CT scans, treatment position, interpretations of target volumes by radiation oncologists, the contouring of normal anatomic structures, and the use of common beam models for all dose calculations. Each source of uncertainty was investigated using a set of plans, with the ideal characteristics of digital images with 3-mm axial slice spacing and a flat couch, consisting of eight cases from Vanderbilt University Medical Center with electronically transferred CT data. The target volume DVH values were dependent on the additional uncertainty introduced by differences in delineation of the target volumes by the participating radiation oncologists. The DVH values for the lungs and heart were dependent on image quality and treatment position. Esophagus DVH values were not dependent on any of the sources of uncertainty. None of the structure DVH values were dependent on slice thickness or variations in the contouring of normal anatomic structures. Reconstruction of three-dimensional dose distributions from two-dimensional treatment plan information may be useful in cases for which digital CT data is not available or for historical data review. However, dosimetric accuracy will depend on image quality of the treatment planning CT data and consistency in the delineation of tumor volumes.