Publications

Many HIV-positive pregnant women and infants are still not receiving optimal services, preventing the goal of eliminating mother-to-child transmission (MTCT) and improving maternal child health overall. A Rapid Results Initiative (RRI) approach was utilized to address key challenges in delivery of prevention of MTCT (PMTCT) services including highly active antiretroviral therapy (HAART) uptake for women and infants. The RRI was conducted between April and June 2011 at 119 health facilities in five districts in Nyanza Province, Kenya. Aggregated site-level data were compared at baseline before the RRI (Oct 2010-Jan 2011), during the RRI, and post-RRI (Jul-Sep 2011) using pre-post cohort analysis. HAART uptake amongst all HIV-positive pregnant women increased by 40% (RR 1.4, 95% CI 1.2-1.7) and continued to improve post-RRI (RR 1.6, 95% CI 1.4-1.8). HAART uptake in HIV-positive infants remained stable (RR 1.1, 95% CI 0.9-1.4) during the RRI and improved by 30% (RR 1.3, 95% CI 1.0-1.6) post-RRI. Significant improvement in PMTCT services can be achieved through introduction of an RRI, which appears to lead to sustained benefits for pregnant HIV-infected women and their infants.

BACKGROUND

Identification of low-income women with the rare but serious risk of hereditary cancer and their referral to appropriate services presents an important public health challenge. We report the results of formative research to reach thousands of women for efficient identification of those at high risk and expedient access to free genetic services. External validity is maximized by emphasizing intervention fit with the two end-user organizations who must connect to make this possible. This study phase informed the design of a subsequent randomized controlled trial.

METHODS

We conducted a randomized controlled pilot study (n = 38) to compare two intervention models for feasibility and impact. The main outcome was receipt of genetic counseling during a two-month intervention period. Model 1 was based on the usual outcall protocol of an academic hospital genetic risk program, and Model 2 drew on the screening and referral procedures of a statewide toll-free phone line through which large numbers of high-risk women can be identified. In Model 1, the risk program proactively calls patients to schedule genetic counseling; for Model 2, women are notified of their eligibility for counseling and make the call themselves. We also developed and pretested a family history screener for administration by phone to identify women appropriate for genetic counseling.

RESULTS

There was no statistically significant difference in receipt of genetic counseling between women randomized to Model 1 (3/18) compared with Model 2 (3/20) during the intervention period. However, when unresponsive women in Model 2 were called after 2 months, 7 more obtained counseling; 4 women from Model 1 were also counseled after the intervention. Thus, the intervention model that closely aligned with the risk program's outcall to high-risk women was found to be feasible and brought more low-income women to free genetic counseling. Our screener was easy to administer by phone and appeared to identify high-risk callers effectively. The model and screener are now in use in the main trial to test the effectiveness of this screening and referral intervention. A validation analysis of the screener is also underway.

CONCLUSION

Identification of intervention strategies and tools, and their systematic comparison for impact and efficiency in the context where they will ultimately be used are critical elements of practice-based research.

The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations.

BACKGROUND

Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress.

METHODOLOGY AND PRINCIPAL FINDINGS

Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M(77), thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-κB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes.

CONCLUSION

A novel N-terminal truncated intracellular isoform of MMP-2 is induced by oxidative stress. This isoform initiates a primary innate immune response that may contribute to progressive cardiac dysfunction in the setting of ischemia and systolic failure.

Fecal immunochemical tests for hemoglobin are replacing traditional guaiac fecal occult blood tests in population screening programs for many reasons. However, the many available fecal immunochemical test devices use a range of sampling methods, differ with regard to hemoglobin stability, and report hemoglobin concentrations in different ways. The methods for sampling, the mass of feces collected, and the volume and characteristics of the buffer used in the sampling device also vary among fecal immunochemical tests, making comparisons of test performance characteristics difficult. Fecal immunochemical test results may be expressed as the hemoglobin concentration in the sampling device buffer and, sometimes, albeit rarely, as the hemoglobin concentration per mass of feces. The current lack of consistency in units for reporting hemoglobin concentration is particularly problematic because apparently similar hemoglobin concentrations obtained with different devices can lead to very different clinical interpretations. Consistent adoption of an internationally accepted method for reporting results would facilitate comparisons of outcomes from these tests. We propose a simple strategy for reporting fecal hemoglobin concentration that will facilitate the comparison of results between fecal immunochemical test devices and across clinical studies. Such reporting is readily achieved by defining the mass of feces sampled and the volume of sample buffer (with confidence intervals) and expressing results as micrograms of hemoglobin per gram of feces. We propose that manufacturers of fecal immunochemical tests provide this information and that the authors of research articles, guidelines, and policy articles, as well as pathology services and regulatory bodies, adopt this metric when reporting fecal immunochemical test results.

The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold. Although LPS, zymosan, and turpentine decrease the hepatic expression of FGF21, they increase FGF21 expression in adipose tissue and muscle, suggesting that extrahepatic tissues account for the increase in serum FGF21. After LPS administration, the characteristic decrease in plasma ketone levels is accentuated in FGF21-/- mice, but this is not due to differences in expression of carnitine palmitoyltransferase 1α or hydroxymethyglutaryl-CoA synthase 2 in liver, because LPS induces similar decreases in the expression of these genes in FGF21-/- and control mice. However, in FGF21-/- mice, the ability of LPS to increase plasma free fatty acid levels is blunted. This failure to increase plasma free fatty acid could contribute to the accentuated decrease in plasma ketone levels because the transport of fatty acids from adipose tissue to liver provides the substrate for ketogenesis. Treatment with exogenous FGF21 reduced the number of animals that die and the rapidity of death after LPS administration in leptin-deficient ob/ob mice and to a lesser extent in control mice. FGF21 also protected from the toxic effects of cecal ligation and puncture-induced sepsis. Thus, FGF21 is a positive APR protein that protects animals from the toxic effects of LPS and sepsis.

BACKGROUND

As several studies have shown an association between periodontal disease and chronic kidney disease (CKD), regular dental care may be an important strategy for reducing the burden of CKD. Access to dental care may be limited in the US public health system.

METHODS

In this retrospective cohort study of 6,498 adult patients with (n = 2,235) and without (n = 4,263) CKD and at least 12 months of follow-up within the San Francisco Department of Public Health Community Health Network clinical databases, we examined the likelihood of having a dental visit within the observation period (2005-2010) using Cox proportional hazards models. To determine whether dental visits reflected a uniform approach to preventive service use in this setting, we similarly examined the likelihood of having an eye visit among those with diabetes, for whom regular retinopathy screening is recommended. We defined CKD status by average estimated glomerular filtration rate based on two or more creatinine measurements ≥ 3 months apart (no CKD, ≥ 60 ml/min/1.73 m2; CKD, < 60 ml/min/1.73 m2).

RESULTS

Only 11.0% and 17.4% of patients with and without CKD, respectively, had at least one dental visit. Those with CKD had a 25% lower likelihood of having a dental visit [HR = 0.75, 95% CI (0.64-0.88)] than those without CKD after adjustment for confounders. Among the subgroup of patients with diabetes, 11.8% vs. 17.2% of those with and without CKD had a dental visit, while 58.8% vs. 57.8% had an eye visit.

CONCLUSIONS

Dental visits, but not eye visits, in a US public healthcare setting are extremely low, particularly among patients with CKD. Given the emerging association between oral health and CKD, addressing factors that impede dental access may be important for reducing the disparate burden of CKD in this population.