Strengthening community-clinical linkages to reduce cardiovascular disease risk in rural NC: feasibility phase of the CHANGE study.

BACKGROUND: Community Health Workers (CHW) are recommended for delivery of interventions to prevent cardiovascular disease, but there is insufficient evidence to guide implementation of CHW interventions in rural, medically underserved areas. METHODS: Using a hybrid implementation-effectiveness design, we evaluated the implementation and effectiveness of an adapted, evidence-based cardiovascular disease risk reduction intervention among rural high-risk adults. CHWs at a community health center and local health department recruited, enrolled and counseled participants during 4 monthly home visits and 3 brief phone contacts. Participant data collection included pre- and post-intervention measurements of blood pressure, weight, and dietary and physical activity behaviors. We evaluated implementation with measures of intervention reach and delivery fidelity. Statistical analyses included descriptive statistics and paired t-tests. RESULTS: Study participants (n = 105) had a mean age of 62 years and included 88% Non-Hispanic Blacks and 82% females. Recruitment strategies resulted in the enrollment of 38% of interested and eligible participants who received 80% of the planned intervention visits and phone contacts. Mean differences in pre-/post-intervention measures showed significant mean reductions in blood pressure (- 5.4 mmHg systolic, p = .006; - 2.3 mmHg diastolic, p = .04) and body weight (- 3.8 lb., p = .02). Self-reported dietary and physical activity behaviors also improved significantly. CONCLUSION: This feasibility study demonstrated preliminary implementation and program effectiveness of a CHW-delivered intervention to reduce cardiovascular disease risk factors. Additionally, it identified areas for future refinements to strategies that strengthen community-clinical linkages with an integrated role of CHWs in rural health care delivery. If results from this feasibility study can be enhanced in a larger sample, there would be significant potential to positively impact the excess burden of chronic diseases that adversely impact rural, low-income, and medically underserved populations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03582696.

Reducing cardiovascular disease in a rural community.

In this case report, we describe the one-year formative phase of a five-year study to develop, implement, and test a community health worker (CHW)-delivered cardiovascular disease (CVD) prevention intervention. The purpose of the formative phase was to engage community partners in the adaptation of an existing evidence-based CVD prevention intervention to fit the needs and preferences of a rural, predominantly African-American community. The formative work was guided by a framework for adapting evidence-based interventions and involved engaging stakeholders in assessing the intervention's fit with the local context and then applying assessment findings to iteratively adapt the intervention's contents, materials, and delivery methods. Findings from the formative work were then applied to develop CHW position descriptions, workflow diagrams, and a training plan. Findings also were applied to adapt intervention materials and protocols to fit the needs of the community. This case report illustrates how community-engaged formative work can be applied to adapt an evidence-based intervention to fit community needs and resources.

Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL.

Chronic lymphocytic leukemia (CLL) -like monoclonal B-cell lymphocytosis (MBL) shares common immunophenotype and cytogenetic abnormalities with CLL, from which it is discriminated by a cutoff value of 5 × 10(9)/L circulating clonal B cells. However, the clonal size in MBL is extremely variable and allows discrimination of two distinct entities (high-count [HC] and low-count [LC]-MBL) based on a cutoff value of 0.5 × 10(9)/L clonal B cells. HC-MBL is associated with lymphocytosis and progresses to CLL requiring treatment at a rate of 1.1% per year, whereas LC-MBL is found in the general population only through high-sensitivity techniques and carries limited, if any, risk of progression. We performed an immunogenetic profiling of 333 cases with CLL-like MBL supplemented by detailed comparisons with CLL, focusing especially on CLL Rai stage 0 (CLL-0). LC- and HC-MBL had similar somatic hypermutation status, yet different IGHV gene repertoires and frequencies of B-cell receptor (BcR) stereotypy. In particular, stereotyped BcRs were infrequent in LC-MBL and were often not CLL specific. In contrast, HC-MBL exhibited clear immunogenetic similarities to CLL-0. These findings indicate that LC-MBL may not represent a true preleukemic condition, thus differing from HC-MBL/CLL-0 in which the identification of factors endowing malignant potential is strongly warranted.

A Hybrid Implementation-Effectiveness Study of a Community Health Worker-Delivered Intervention to Reduce Cardiovascular Disease Risk in a Rural, Underserved Non-Hispanic Black Population: The CHANGE Study.

PURPOSE: To evaluate the implementation and effectiveness of the Carolina Heart Alliance Networking for Greater Equity (CHANGE) Program, an adapted evidence-based cardiovascular disease risk reduction intervention delivered by Community Health Workers (CHW) to rural adults. DESIGN: Hybrid implementation-effectiveness study with a pre-post design. SETTING: North Carolina Federally Qualified Health Center and local health department in a rural, medically underserved area. SAMPLE: Participants (n = 255) included 87% Non-Hispanic Black with a mean age of 57 years; 84% had diagnosed hypertension, 55% had diabetes, and 65% had hypercholesterolemia. INTERVENTION: A CHW-delivered, low-intensity, 4-month behavioral lifestyle intervention promoting a southern-style Mediterranean dietary pattern and physical activity. MEASURES: We measured number and representativeness of participants reached and retained, intervention delivery fidelity, weight, blood pressure, and self-reported dietary and physical activity behaviors. ANALYSIS: Pre-post changes at 4 months were analyzed using paired t-tests. RESULTS: Study participants completed 90% of planned intervention contacts; 87% were retained. Intervention delivery fidelity measures showed participants receiving a mean of 3.5 counseling visits, 2.7 booster calls, and on average completing 1.7 modules, setting 1.8 goals, and receiving 1.3 referrals per visit. There were significant mean reductions in systolic (-2.5 mmHg, P < .05) and diastolic blood pressure (-2.1 mmHg, P < .01); the proportion of participants with systolic blood pressure <130 increased by 7 % points (P = .05), and diastolic pressure <80 by 9 percentage points (P < .01). Dietary behaviors improved significantly with average weekly servings of nuts increased by .5 serving (P < .0001), and fruits and vegetables by .8 daily serving (P < .0001). Physical activity also increased on average by 45 min./week (P < .001). Weight did not change significantly. CONCLUSIONS: The CHANGE program showed both implementation and program effectiveness and adds to the evidence supporting CHW-delivered lifestyle interventions to reduce CVD risk among rural, Non-Hispanic Black, and medically underserved populations.

Activation-induced cytidine deaminase expression and activity in the absence of germinal centers: insights into hyper-IgM syndrome.

Somatic hypermutation normally occurs as a consequence of the expression of activation-induced cytidine deaminase (AID) by Ag-activated, mature B cells during T cell-dependent germinal center responses. Nonetheless, despite their inability to express CD154 and initiate GC responses, patients with type 1 hyper-IgM syndrome (HIGM1) support populations of IgM(+)IgD(+)CD27(+) B cells that express mutated Ig genes. The origin of these mutated B cells is unknown; the IgM(+)IgD(+)CD27(+) cells do not express AID and appear to acquire mutations independent of stringent selection by Ag. Here, we demonstrate that immature/transitional 1 B cells from the bone marrow of CD154-deficient mice express AID and acquire Ig mutations that lack the hallmarks of antigenic selection via BCR signaling. Comparable levels of AID expression was found in developmentally immature B cells recovered from murine fetal liver and from human immature/transitional 1 B cells recovered from umbilical cord blood. AID expression in human fetal liver was also robust, approaching that of human tonsil tissue and the human germinal center B cell line, Ramos. These observations led us to conclude that AID expression in developing human B cells is the origin of the mutated IgM(+)IgD(+)CD27(+) B cells present in HIGM1 patients, and we propose that both mice and humans share a latent, AID-dependent pathway for the preimmune diversification of B lymphocytes that is more prominent in chicken, sheep, and rabbits.

Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes.

Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.

Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection.

BACKGROUND: The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4(+) T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells. METHODS AND FINDINGS: In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT) B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI) included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer's patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis. CONCLUSIONS: Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1. Please see later in the article for Editors' Summary.

Determinants of exhaled nitric oxide levels in healthy, nonsmoking African American adults.

BACKGROUND: Asthma is a significant cause of morbidity and mortality for African Americans. Fraction of exhaled nitric oxide (FeNO) levels are increased in patients with asthma, and airway levels of nitric oxide metabolites regulate airway inflammation and airway diameter. More needs to be known about the factors that regulate FeNO. There is a need for FeNO reference values for African Americans. OBJECTIVE: We sought to establish reference values and identify factors associated with FeNO levels in healthy African American adults. METHODS: FeNO levels were measured in 895 healthy, nonsmoking African Americans between the ages of 18 and 40 years. FeNO measurements were repeated in 84 subjects. Factors potentially associated with FeNO were measured, including blood pressure, height, weight, and serum total IgE, eosinophil cationic protein, C-reactive protein, and nitrate levels. Data on respiratory symptoms, including upper respiratory tract infection (URI) symptoms, were collected. Univariate and multivariate analyses of the relationship between these variables and FeNO levels were performed. RESULTS: In healthy, nonsmoking African Americans FeNO levels were stable during repeated measurements (intraclass correlation coefficient, 0.81). Sex (P < .0001), serum total IgE levels (P < .0001), and current URI symptoms (P = .0002) contributed significantly to FeNO variability but together accounted for less than 50% of the variation in FeNO levels. CONCLUSION: The high correlation between repeated measurements of FeNO and the low correlation coefficients of known factors associated with FeNO suggest that other factors might contribute substantially to variability of FeNO levels in African Americans.

Normative values for exhaled breath condensate pH and its relationship to exhaled nitric oxide in healthy African Americans.

BACKGROUND: Exhaled breath condensate (EBC) pH and exhaled nitric oxide (FeNO) have been proposed as markers of asthma severity. EBC pH values below 6.5 have been associated with asthma exacerbations. Protonation of airway nitrite occurs at low pH and may contribute to FeNO. OBJECTIVE: To establish normative EBC pH values and to determine the contribution of EBC pH to FeNO in healthy African Americans. METHODS: Two hundred seventy healthy African American subjects without asthma between 18 and 40 years old were evaluated. Subjects had simultaneous measurement of EBC pH, EBC nitrite, nitrate, and FeNO. RESULTS: The median EBC pH was 8.14 (interquartile range, 7.83-8.28). Of subjects, 11.9% had an EBC pH < or = 6.5. In subjects with EBC pH values below 6.5, there was an inverse correlation between EBC pH and FeNO (r(2) = 0.158; P = .0245; n = 32). In the entire cohort, there was a direct correlation between EBC pH and EBC nitrite (r(2) = 0.163; P < .0001), but there was no correlation between EBC nitrite and FeNO. In multivariate analyses, EBC pH and nitrite did not contribute significantly to FeNO variation while controlling for other confounders of FeNO. CONCLUSION: There was an increased prevalence (11.9%) of low EBC pH (less than 6.5) in healthy African American subjects compared with white subjects (<5%). EBC pH and nitrite were directly correlated, but there was no correlation between EBC nitrite and FeNO. FeNO correlated with EBC pH at pH values less than 6.5 in univariate but not multivariate analyses. This suggests that EBC pH and nitrite are not significant determinants of FeNO in healthy subjects.

School health implementation tools: a mixed methods evaluation of factors influencing their use.

BACKGROUND: The U.S. Centers for Disease Control and Prevention (CDC) develops tools to support implementation of evidence-based interventions for school health. To advance understanding of factors influencing the use of these implementation tools, we conducted an evaluation of state, school district, and local school staffs' use of four CDC tools to support implementation of physical activity, nutrition, health education, and parent engagement. Two frameworks guided the evaluation: Interactive Systems Framework (ISF) for Dissemination and Implementation and Consolidated Framework for Implementation Research (CFIR). METHODS: The evaluation applied a mixed methods, cross-sectional design that included online surveys (n = 69 state staff from 43 states), phone interviews (n = 13 state staff from 6 states), and in-person interviews (n = 90 district and school staff from 8 districts in 5 states). Descriptive analyses were applied to surveys and content analysis to interviews. RESULTS: The survey found that the majority of state staff surveyed was aware of three of the CDC tools but most were knowledgeable and confident in their ability to use only two. These same two tools were the ones for which states were most likely to have provided training and technical assistance in the past year. Interviews provided insight into how tools were used and why use varied, with themes organized within the ISF domain "support strategies" (e.g., training, technical assistance) and four CFIR domains: (1) characteristics of tools, (2) inner setting, (3) outer setting, and (4) individuals. Overall, tools were valued for the credibility of their source (CDC) and evidence strength and quality. Respondents reported that tools were too complex for use by school staff. However, if tools were adaptable and compatible with inner and outer setting factors, state and district staff were willing and able to adapt tools for school use. CONCLUSIONS: Implementation tools are essential to supporting broad-scale implementation of evidence-based interventions. This study illustrates how CFIR and ISF might be applied to evaluate factors influencing tools' use and provides recommendations for designing tools to fit within the multi-tiered systems involved in promoting, supporting, and implementing evidence-based interventions in schools. Findings have relevance for the design of implementation tools for use by other multi-tiered systems.

Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies.

Abstract Because of the importance of the phosphoinositide 3-kinase (PI3K)/AKT pathway in chronic lymphocytic leukemia (CLL), we evaluated in vitro cytotoxicity induced by perifosine, an AKT inhibitor, in CLL lymphocytes and found that the mean 50% effective dose (ED50) was 313 nM. We then performed a phase II trial of perifosine in patients with relapsed/refractory CLL to assess response, outcomes, toxicity and ex vivo correlative measures. After 3 months of treatment, six of eight patients showed stable disease, one achieved a partial response and one had progressive disease. Median event-free survival and overall survival in all patients treated were 3.9 and 9.7 months. Adverse events included hematologic, infectious/fever, pain, gastrointestinal and constitutional toxicities. Unexpectedly, AKT phosphorylation in CLL lymphocytes from treated patients was not correlated with response. Additionally, perifosine did not inhibit AKT phosphorylation in cultured CLL lymphocytes. Perifosine is cytotoxic to CLL cells in vitro, and largely induces stabilized disease in vivo, with an AKT-independent mechanism.

Racial differences in the association of CD14 polymorphisms with serum total IgE levels and allergen skin test reactivity.

BACKGROUND: The CD14 C-159T single nucleotide polymorphism (SNP) has been investigated widely as a candidate genetic locus in patients with allergic disease. There are conflicting results for the association of the CD14 C-159T SNP with total serum immunoglobulin E (IgE) levels and atopy. There are limited data regarding the association of the CD14 C-159T SNP in subjects of African ancestry. The aim of the study was to determine whether the C-159T SNP and other CD14 SNPs (C1188G, C1341T) were associated with total serum IgE levels and with allergy skin test results in nonatopic and atopic subjects; as well as in Caucasian and African American subjects. METHODS: A total of 291 participants, 18-40 years old, were screened to determine whether they were atopic and/or asthmatic. Analyses were performed to determine the association between CD14 C-159T, C1188G, or C1341T genotypes with serum IgE levels and with the number of positive skin tests among Caucasian or African American subjects. RESULTS: We found no significant association of serum total IgE level with CD14 C-159T, C1188G, or C1341T genotypes within nonatopic or atopic subjects. Subjects with CD14-159 T alleles had significantly more positive allergen skin tests than subjects without CD14-159 T alleles (P = 0.0388). There was a significant association between the CD14 1188 G allele, but not the CD14 1341 T allele, with the number of positive skin-test results in Caucasians, but not in African Americans. CONCLUSION: These results support a possible association between CD14 polymorphisms and atopy. CD14-159 T or CD14 1188 G alleles were associated with atopic disease. For subjects with CD14 1188 G alleles, the association with atopic disease was stronger in Caucasians compared to African Americans.

A TRPA1-dependent mechanism for the pungent sensation of weak acids.

Acetic acid produces an irritating sensation that can be attributed to activation of nociceptors within the trigeminal ganglion that innervate the nasal or oral cavities. These sensory neurons sense a diverse array of noxious agents in the environment, allowing animals to actively avoid tissue damage. Although receptor mechanisms have been identified for many noxious chemicals, the mechanisms by which animals detect weak acids, such as acetic acid, are less well understood. Weak acids are only partially dissociated at neutral pH and, as such, some can cross the cell membrane, acidifying the cell cytosol. The nociceptor ion channel TRPA1 is activated by CO(2), through gating of the channel by intracellular protons, making it a candidate to more generally mediate sensory responses to weak acids. To test this possibility, we measured responses to weak acids from heterologously expressed TRPA1 channels and trigeminal neurons with patch clamp recording and Ca(2+) microfluorometry. Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids. Notably, the degree of channel activation was predicted by the degree of intracellular acidification produced by each acid, suggesting that intracellular protons are the proximate stimulus that gates the channel. Responses to weak acids produced a Ca(2+)-independent inactivation that precluded further activation by weak acids or reactive chemicals, whereas preactivation by reactive electrophiles sensitized TRPA1 channels to weak acids. Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice. We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

Monoclonal B cell lymphocytosis.

Monoclonal B lymphocytosis (MBL) is an asymptomatic clinical syndrome wherein small B cell clones are detectable in the peripheral blood. MBL is common in the adult population, with an estimated prevalence of greater than 3% among individuals over age 50. Most MBLs have an immunophenotype similar to chronic lymphocytic leukemia (CLL). Recently, MBL has been shown to be a precursor state for CLL, though most MBLs presumably do not progress to CLL. Therefore, there has been considerable interest in the biology of MBL to better understand the mechanisms of CLL leukemogenesis. We have investigated immunoglobulin heavy chain gene usage and clonality in MBL. These investigations reveal that most MBLs use mutated heavy chains typically associated with good-risk CLL, and that MBLs are frequently oligoclonal, rather than monoclonal. Deletion of chromosome 13q14 is also commonly observed. These and other ongoing studies may help illuminate the pathogenesis of CLL.

Commentary: Comparison of current flow cytometry methods for monoclonal B cell lymphocytosis detection.

Monoclonal B cell lymphocytosis (MBL) is now recognized as the B-lymphocyte analogue of a monoclonal gammopathy of unknown significance. MBL can be the precursor of chronic lymphocytic leukemia or associated with non-Hodgkin's lymphoma. It may be associated with an autoimmune abnormality or be related to aging (immunosenescence). The combination of available new fluorochrome-conjugated monoclonal antibody reagents, multilaser instrumentation, and improved software tools have led to a new level of multicolor analysis of MBL. Presently, several centers, including the University of Salamanca (Spain), Duke University (Durham, NC), Mayo Clinic (Rochester, MN), and the National Cancer Institute (Bethesda, MD) in conjunction with the Genetics and Epidemiology of Familial chronic lymphocytic leukemia Consortium, the Food and Drug Administration (Bethesda, MD), and the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (Atlanta, GA) in collaboration with Saint Luke's Hospital (Kansas City, MO), the Università Vita-Salute San Raffaele in Milan (Italy), and Leeds Teaching Hospital (UK) are all actively conducting studies on MBL. This commentary is an updated summary of the current methods used in these centers. It is important to note the diversity of use in reagents, instruments, and methods of analysis. Despite this diversity, there is a consensus in what constitutes the diagnosis of MBL and its subtypes. There is also an emerging consensus on what the next investigative steps should be.