Longitudinal Analysis of the Relationship Between Social Isolation and Hypertension in Early Middle Adulthood.

BACKGROUND: Most studies have used cross-sectional or limited follow-up data to evaluate the relationship between social isolation (SI) and hypertension in older populations. The objective of this analysis was to examine the relationship between longitudinal SI and hypertension in a younger population. METHODS AND RESULTS: The present analysis used data from waves I to V of the National Longitudinal Study of Adolescent to Adult Health (1994-2018) and logistic regression models to describe the association of timing, duration, and transitional patterns of SI with hypertension in early middle adulthood. Models were adjusted for demographic variables and adolescent socioeconomic and health-related confounders. SI was higher across life stages among individuals with hypertension (adolescence: 38% versus 35%, young adulthood: 52% versus 44%, and early middle adulthood: 61% versus 52%). Individuals who were socially isolated in young adulthood or early middle adulthood had greater odds of hypertension in early middle adulthood than those who were not (odds ratio [OR], 1.30 [95% CI, 1.07-1.56]; OR, 1.42 [95% CI, 1.15-1.76], respectively). Early middle adulthood hypertension was significantly associated with persistent SI across all life stages and for those who moved into persistent SI after adolescence (OR, 1.40 [95% CI, 1.02-1.93]; OR, 1.61 [95% CI, 1.18-2.19], respectively). CONCLUSIONS: SI in young or early middle adulthood significantly increased the odds of hypertension, as did moving into SI and the accumulation of SI across life stages. Our analysis provides insights regarding timing for effective interventions to reduce hypertension earlier in the life course, which may prevent future adverse cardiovascular-related events.

An evaluation of programs to support new investigators at the National Institute of Allergy and Infectious Diseases: Striking a balance with funding for established investigators.

As the largest funder of basic biomedical research in the US, the National Institutes of Health (NIH) has an interest in maintaining a sustainable, productive workforce of investigators. Over the years, NIH has implemented several programs to attract early-stage investigators and other applicants without prior NIH support. The latest of these is the Next Generation Researchers Initiative. These programs have been shown to be successful in meeting NIH-wide goals but their success for any particular NIH institute or center (IC), and in any particular year, is determined by a variety of factors, some extrinsic to an IC's funding decision process. Each IC must balance support for new investigators with funding for productive ongoing programs of research. We examine historical trends in support of new investigators at the National Institute of Allergy and Infectious Diseases (NIAID) over a 22-year period, as well as trends in some major extrinsic influences on that support. The results indicate that NIH's new investigator programs have succeeded in maintaining a balance between the support for new NIAID investigators while also continuing to support an expanded pool of established investigators. The programs have been particularly effective in providing support to early-stage investigators.

Establishing how social capital is studied in relation to cardiovascular disease and identifying gaps for future research-A scoping review protocol.

INTRODUCTION: Though the relationship between social capital and health has been widely studied, the evidence of this relationship in cardiovascular disease is limited, with varied and inconsistent measures. This scoping review seeks to address this gap by answering the following questions: (1) How has social capital been characterized and measured in the literature related to cardiovascular disease? and (2) What gaps exist in the evaluation of the relationship between social capital and cardiovascular disease? MATERIALS AND METHODS: A scoping review will be used to answer the research questions. The scoping review will apply established methods described by Arksey and O'Malley, Levac and colleagues, and the Joanne Briggs Institute: (1) identifying the research question(s); (2) identifying relevant studies; (3) selecting the studies; (4) charting the data; and (5) collating, summarizing, and reporting the results. RESULTS: Our findings will be reported in accordance with the guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. DISCUSSION: The synthesis of this evidence base is intended to provide a framework for how social capital has been defined and measured in the cardiovascular literature, with additional guidance for future research and evaluation. The findings will be disseminated through peer-reviewed publication and presentations at relevant seminars.

Costs and effectiveness of a culturally tailored communication training program to increase cultural competence among multi-disciplinary care management teams.

BACKGROUND: Several studies have demonstrated that cultural competence improves patient-provider communication, which promotes adherence to established care plans and improves patient satisfaction and health outcomes. However, there is very little data available regarding the costs associated with the development and implementation of cultural competence training, or the cost-effectiveness of these programs. To that end, this evaluation aims to describe costs, program effectiveness, and cost-effectiveness of a culturally tailored communication training program to improve cultural competence among multi-disciplinary care management teams. METHODS: As part of a region-wide quality improvement initiative to reduce healthcare disparities among African American patients with uncontrolled hypertension, three multi-disciplinary care management teams were invited to participate in a two-part communication training program. A paired samples t-test was used to assess program effectiveness based on participant responses to a validated cultural competence self-assessment survey 2 weeks before and after the training program. A micro-costing approach was used to estimate programmatic costs for content development and delivery. Cost-effectiveness was then determined using the average cost-effectiveness ratio, and sensitivity analyses were conducted to assess the impact of participant mix on this result. RESULTS: All scores (n = 17) improved after training; however, only the culturally competent behaviors (CCB) subscale change was statistically significant (p = 0.02). Overall program costs were $5754.19. The average program cost per participant was $138.51, with an ACER of $337.83 per 1-unit increase in CCB score. Sensitivity analyses yielded a range of ACERs between $122.59 and $457.07, where all participants are support staff or nurses, respectively. CONCLUSIONS: Culturally tailored communication training increases how frequently participants demonstrate culturally competent behaviors and may be a cost-effective intervention for care management teams to address individual cultural competence. Detailed costs associated with cultural competence training are largely unavailable in the literature; as such, these data may serve as a financial framework for organizations considering the implementation of similar programs.

Regulation of estrogen receptor ß1 expression in breast cancer by epigenetic modification of the 5' regulatory region.

ERß1 is often down-regulated in breast cancer compared to normal breast but mechanisms surrounding this are unclear. We examined whether loss of heterozygosity (LOH) or methylation at ERß promoters (0N, 0K) and/or untranslated exon 0N were involved in ERß down-regulation in breast cancer tissues and cell lines and if treatment with the de-methylating agent 5-aza-deoxycytidine and/or the histone deacetylase inhibitor Trichostatin A could influence expression in vitro. We found no evidence of correlation between LOH at 14q22-24 (genomic locus containing ERß/ESR2), and ERß1 expression in primary breast cancers. A negative correlation between ERß1 mRNA expression and methylation status was observed for promoter 0N in BT-20, MDA-MB-453 and T47D cells. Promoter 0K was consistently unmethylated. In primary breast tumours, methylation of the untranslated exon 0N, downstream of promoter 0N, but not of promoter 0N itself, correlated with down-regulation of ERß. In MDA-MB-453 cells, treatment with 5-aza-deoxycytidine was sufficient to induce ERß1 expression from the 0N promoter while in BT-20 both agents were required. Examination of various sites on ESR2 highlighted epigenetic but not genetic regulation of ERß1. In particular methylation adjacent to promoter 0N was a key regulatory event for ERß1 silencing. A combination of de-methylating agents and histone deacetylase inhibitors fully restored ERß1 expression which may offer a novel therapeutic angle for breast cancer management.

Ischemia- reperfusion injury and its influence on the epigenetic modification of the donor kidney genome.

BACKGROUND: In clinical transplantation, ischemia-reperfusion injury (I/RI) causes damage to DNA. We hypothesize that one form of damage is the demethylation of methylated cytosines in the donor genome caused by the oxidative environment created first by ischemia, and subsequently by reperfusion on transplantation. This study contributes to the understanding of how the short-lived and transient ischemic insult may influence chronic pathological changes that occur in clinical transplantation in the long term. METHODS: A model of I/RI and chronic rejection; Fisher to Fisher kidney transplant rendered cold-ischemic for 4 hr before transplantation, to induce antigen-independent chronic nephropathy over a 6-month period, was used. Tissue was assessed by histopathology and methylation by pyrosequencing analysis. RESULTS: An epigenetic map of the rat renal C3 promoter was produced, which identified methylated Cytosine phospho Guanine (CpG) sites coincident to cytokine response elements and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) binding sites. Pyrosequencing analysis showed that the tissue that had undergone 4 hr ischemia and reperfusion developed aberrant demethylation of cytosines in putative regulatory sites within the C3 promoter. CONCLUSION: These findings may describe a newly recognized phenomena in the field of transplantation. Aberrant demethylation has long been linked to the development of tumors, and our data suggest a similar mechanism of gene dysregulation that may be initiated by I/RI with acute and chronic effects. These data may contribute to a further understanding of how the short lived and transient ischemic insult influences chronic pathological changes that occur even in the absence of major histocompatibility complex disparity in transplantation.

Formulation of the adenylate cyclase toxin of Bordetella pertussis as protein-coated microcrystals.

Adenylate cyclase toxin (CyaA) is an important virulence factor of Bordetella pertussis, the causative agent of whooping cough, and, in its detoxified form, a potential component of acellular pertussis vaccines. This study reports the application of a novel technology, formulation of CyaA as protein-coated microcrystals (PCMC), to improve the performance of CyaA as a vaccine component. CyaA is normally stored in a high urea concentration to prevent aggregation and to maintain stability of the protein. The aim of the work was to stabilise CyaA on a crystalline support to create a dry powder that could be reconstituted in aqueous buffer, free of urea. CyaA, formulated as PCMC with microcrystals of dl-valine, retained full adenylate cyclase (AC) and cell invasive (cytotoxic) activities after solubilistion in urea buffer. After storage as a dry powder at 37 degrees C for 2 weeks, the AC activity recovered from the CyaA-PCMC was only marginally reduced when solubilised in urea buffer. No AC activity was detected after attempts to solubilise CyaA-PCMC in aqueous buffer alone, in the absence of urea. Inclusion of various ionic, non-ionic or zwitterionic detergents in the aqueous buffer had little effect on recovery of CyaA activities. However, preparation of PCMC with CyaA plus calmodulin (CaM) or bovine serum albumin (BSA) or with both proteins allowed restoration of AC and cytotoxic activities of CyaA upon solubilisation in aqueous buffer. Incorporation of BSA and CaM with CyaA allowed essentially full recovery of AC activity but lower recovery of cytotoxicity. CyaA-CaM-BSA-PCMC, after reconstitution in aqueous buffer, induced a strong serum IgG response to CyaA when injected subcutaneously into mice.

A rapid and direct method for the determination of active site accessibility in proteins based on ESI-MS and active site titrations.

We have developed an electrospray ionisation mass spectrometry (ESI-MS) technique that can be applied to rapidly determine the number of intact active sites in proteins. The methodology relies on inhibiting the protein with an active-site irreversible inhibitor and then using ESI-MS to determine the extent of inhibition. We have applied this methodology to a test system: a serine protease, subtilisin Carlsberg, and monitored the extent of inhibition by phenylmethylsulfonyl fluoride (PMSF), an irreversible serine hydrolase inhibitor as a function of the changes in immobilisation and hydration conditions. Two types of enzyme preparation were investigated, lyophilised enzymes and protein-coated microcrystals (PCMC).

Protein-coated microcrystals for use in organic solvents: application to oxidoreductases.

Protein-coated microcrystals (PCMC), a biocatalyst preparation previously demonstrated to display substantially increased transesterification activity of proteases and lipases in organic solvents when compared to their as received counterparts [Kreiner M, Moore BD, Parker MC (2001) Chem. Commun. 12:1096--1097], was applied to oxidoreductases. Horse liver alcohol dehydrogenase (HLADH), catalase (CAT), soybean peroxidase and horseradish peroxidase were immobilised onto K(2)SO(4) crystals and dehydrated in a 1-step process, resulting in PCMC. These PCMC preparations showed enhanced activity in different organic solvents in most types of reactions tested. The highest activation was observed with HLADH (50-fold as active as enzyme as received) and CAT (25-fold).

DNA-coated microcrystals.

Coprecipitation leads to self-assembly of bioactive DNA on the surface of salt, sugar or amino-acid crystals and provides a rapid inexpensive immobilization method suitable for preparing dry-powder formulations of nucleic acids, useful for storage, imaging and drug delivery.

High-activity biocatalysts in organic media: solid-state buffers as the immobilisation matrix for protein-coated microcrystals.

Recently, we reported a new high-activity biocatalyst for use in organic media termed protein-coated microcrystals (PCMC) (Kreiner et al. [2001] Chem Commun 12:1096-1097). These novel particles consist of water-soluble micron-sized crystalline particles coated with the given biocatalyst(s) and are prepared in a one-step rapid dehydration process. In this study we extended the choice of immobilisation matrix from a simple inorganic salt, K(2)SO(4), to other compounds, both inorganic and zwitterionic, that act as solid-state buffers for biocatalysis in organic media. The catalytic activity of serine proteases subtilisin Carlsberg (SC) and alpha-chymotrypsin (CT) were significantly increased when coated onto the surface of solid-state buffers, as measured in acetonitrile/1wt% H(2)O. SC-PCMC with both organic and inorganic buffer carriers (Na-AMPSO, Na(2)CO(3), and NaHCO(3)) showed a 3-fold greater activity than that observed when using the unbuffered system (PCMC-SC/K(2)SO(4)). In comparison with freeze-dried preparations, this represents an approximately 3,000-fold increase in catalytic activity. Importantly, there is no improvement in catalytic activity upon external addition of any of the solid-state buffers to the reaction mixture. When acting in a solid-state buffer capacity, good buffering capacity was observed with SC-PCMC (3 wt% protein loading) prepared from a 1:1 mixture of AMPSO and AMPSO-Na. Alternatively, increasing the amount of solid-state buffer in the system allows improvement of the buffering. This can be achieved either by decreasing the protein loading of the SC/Na-AMPSO-PCMC or by addition of further external solid-state buffer to the reaction mixture. The catalytic activity of lipase-PCMC prepared from solid-state buffers was found less responsive to immobilisation.