Community-Based Antiretroviral Therapy (ART) Delivery for Female Sex Workers in Tanzania: 6-Month ART Initiation and Adherence.

We conducted an implementation science study of a community-based ART distribution program for HIV-positive female sex workers (FSW) whereby clients received ART services through community-based mobile and home-based platforms. We compared 6-month treatment-related outcomes in the community-based ART arm (N = 256) to the standard facility-based ART delivery arm (N = 253). Those in the intervention arm were more likely to have initiated ART (100.0% vs. 71.5%; p = 0.04), be currently taking ART at the 6-month visit (100.0% vs. 95.0%; p < 0.01), and less likely to have stopped taking ART for more than 30 days continuously (0.9% vs. 5.7%; p = 0.008) or feel high levels of internalized stigma (26.6% vs. 39.9%; p = 0.001). In the adjusted regression model, internalized stigma (adjusted OR [aOR]: 0.5; 95% CI 0.28-0.83) and receiving community-based ART (aOR: 208.6; 95% CI 12.5-3479.0) were significantly associated with ART initiation. Community-based ART distribution model can improve linkage to and adherence to ART over standard facility-based ART programs for FSWs.

Oscillatory mTOR inhibition and Treg increase in kidney transplantation.

Intracellular metabolic pathways dependent upon the mammalian target of rapamycin (mTOR) play a key role in immune-tolerance control. In this study, we focused on long-term mTOR-dependent immune-modulating effects in kidney transplant recipients undergoing conversion from calcineurin inhibitors (CNI) to mTOR inhibitors (everolimus) in a 1-year follow-up. The conversion to everolimus is associated with a decrease of neutrophils and of CD8(+) T cells. In addition, we observed a reduced production of interferon (IFN)-γ by CD8(+) T cells and of interleukin (IL)-17 by CD4(+) T lymphocytes. An increase in CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) [regulatory T cell [(Treg)] numbers was also seen. Treg increase correlated with a higher proliferation rate of this regulatory subpopulation when compared with the CD4(+) FoxP3(-) effector counterpart. Basal phosphorylation level of S6 kinase, a major mTOR-dependent molecular target, was substantially maintained in patients treated with everolimus. Moreover, oscillations in serum concentration of everolimus were associated with changes in basal and activation-dependent S6 kinase phosphorylation of CD4(+) and CD8(+) T cells. Indeed, T cell receptor (TCR) triggering was observed to induce significantly higher S6 kinase phosphorylation in the presence of lower everolimus serum concentrations. These results unveil the complex mTOR-dependent immune-metabolic network leading to long-term immune-modulation and might have relevance for novel therapeutic settings in kidney transplants.

Cost-benefit evaluation of a preventive intervention on the biological risk in health: the accidental puncture during the administration of insulin in the University Hospital "Federico II" of Naples.

BACKGROUND: The occupational exposure to biological risk is a frequent event that affects millions of workers in the health sector. Operators are exposed to accidental contact with blood and other potentially infectious biological materials with a frequency higher than that observed in the population (occupational exposure). The pathogens most frequently implicated are the human immunodeficiency virus (HIV), hepatitis C (HCV) and hepatitis B (HBV) viruses. The World Health Organization estimates that each year more than 3 million health workers hurt themselves with an object/edge definitely contaminated with at least one HIV (about 170,000 exposures), hepatitis B (approximately 2,000,000 exposures) and hepatitis C (approximately 900,000 exposures). In Italy approximately 100,000 percutaneous exposures/year are estimated to take place. The needlestick injuries in health care workers are, in large part, preventable by adopting measures such as the use of instrumental needlesticks Prevention Devices - NPDs. The adoption of the NPDs is extremely effective in reducing occupational exposure to biological risk (from 63 % to 100 % reduction). METHODS: The aim of this study was to evaluate whether the adoption of NPDs for insulin therapy is costeffective in terms of prevention of accidents by Biohazard, compared to administration of insulin with traditional methods (syringe + vial). The estimation is carried out both in the light of current legislation (European Directive 2010/32 and 81/08 Italian Law) and epidemiological data and cost of accidents (according to frequency) and alternative interventions. RESULTS: The evaluation of cost-effectiveness included the construction of an economic model that would allow the weighting of the costs of accidents that can occur following the administration of insulin therapy with traditional methods. The economic model was developed taking into account the international literature on the phenomenon of "accidental puncture" and allowed the financial quantification of the event. Then we calculated the cost of insulin therapy using the traditional methodology and the cost has been converted to the cost of insulin therapy when administered by NPDs. The period of the study was the year 2010. CONCLUSIONS: The data thus obtained were used to evaluate the benefits of implementing NPDs for insulin therapy, in terms not only of economic advantage but also of preventive efficacy and on the cost of the accident.

Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1.

Multiple myeloma (MM) is a deadly hematopoietic malignancy characterized by proliferation of malignant plasma cells in the bone marrow (BM) and bone disease. Interactions between myeloma and BM cells facilitate tumor progression and resistance to therapies. CXCR4 and its ligand Stromal cell-derived factor-1 (SDF-1) have a primary role in this process and are associated with poor prognosis. The Notch pathway is active in myeloma cells, resulting in increased proliferation, resistance to apoptosis and osteolytic activity. We hypothesized that the CXCR4/SDF-1 axis mediates the effects of Notch signals in myeloma cells. Here we show that Notch positively controls CXCR4/SDF-1 expression and functions in myeloma cell lines, and that forced CXCR4 activation partially rescues tumor cells from the outcomes of Notch inhibition. Additionally, we provide evidences that Notch blocking in vivo significantly reduces BM infiltration by human myeloma cells in mouse xenografts. This is the first evidence that a Notch-targeted approach effectively prevents MM cell migration, proliferation and resistance to apoptosis by reducing CXCR4 and SDF-1 levels.

Notch-directed microenvironment reprogramming in myeloma: a single path to multiple outcomes.

Multiple myeloma is a deadly hematopoietic malignancy. Despite therapeutic advances such as autologous stem cell transplantation and novel chemotherapeutics, multiple myeloma remains incurable. Multiple myeloma cell localization in the bone marrow and the cross-talk with the bone niche trigger dramatic alterations in the bone marrow microenvironment critical for tumor progression, resistance to therapies and osteolytic bone destruction. It does not surprise that the molecular bases of such fatal interaction are under examination as source of novel potential pharmacological targets. Among these, the Notch family of receptors and ligands has gained growing interest in the recent years because of their early deregulation in multiple myeloma and their ability to affect multiple features of the disease, including tumor cell growth, drug resistance, angiogenesis and bone lesions. This review will explore the evidences of Notch deregulation in multiple myeloma, the state of the art of the currently known roles of its signaling in the fatal interaction between multiple myeloma cells, extracellular matrix and cells in the bone marrow stroma. Finally, we will present recent findings concerning the arguments for or against a therapy addressed to Notch signaling inhibition in the cure of multiple myeloma.

Smoking vs other risk factors as the cause of smoking-attributable deaths: confounding in the courtroom.

CONTEXT: The surgeon general estimates that more than 400,000 deaths are attributable to smoking annually in the United States. The tobacco industry has criticized the surgeon general's estimates because they do not control for the lower educational and socioeconomic status of modern-day smokers. OBJECTIVE: To determine whether controlling for education, occupation, race, alcohol consumption, and various dietary factors, in addition to age and sex, substantially alters the relative and attributable risk estimates associated with tobacco smoking. DESIGN, SETTING, AND PARTICIPANTS: Nationwide American Cancer Society prospective cohort study of 974, 150 US adults aged 30 years or older, enrolled in 1982 and followed up through 1988. (The same study is used for the surgeon general and Centers for Disease Control and Prevention [CDC] estimates of smoking-attributable deaths in the United States.) MAIN OUTCOME MEASURES: Death from each of the chronic diseases considered in the CDC's estimate of smoking-attributable mortality (cancers of the lung, oropharynx, larynx, esophagus, pancreas, kidney, bladder, and cervix; ischemic heart disease, arterial disease, and other heart conditions; stroke; chronic obstructive pulmonary disease; and other respiratory conditions). Estimates adjusted for multiple covariates were compared with those adjusted for age only among current and former vs never smokers. RESULTS: Adjusting for multiple covariates slightly decreased the relative and attributable risk estimates for current smoking in both men and women, but slightly increased the estimates for former smoking in women. Multivariate adjustment decreased the overall estimate of deaths attributable to smoking in the United States by approximately 1%, from 401,109 to 396,741 per year. CONCLUSIONS: Our study suggests that federal estimates of deaths caused by smoking are not substantially altered by adjustment for behavioral and demographic factors associated with smoking beyond the current adjustment for age and sex. JAMA. 2000;284:706-712

Epidemiologic studies of fatal and nonfatal cardiovascular disease and ETS exposure from spousal smoking.

This article reviews the epidemiologic studies of the association of ischemic heart disease risk and environmental tobacco smoke (ETS) exposure from a spouse who smokes. Seventeen studies (nine cohort, eight case-control) comprising more than 485,000 lifelong nonsmokers and 7,345 coronary heart disease (CHD) events were included in a meta-analysis. Together, these studies include 36% more CHD events and 58% more study subjects than were available for review by the U. S. Occupational Safety and Health Administration (OSHA) in 1994. The relative risk (RR) for fatal or nonfatal coronary events among never smokers married to smokers, compared to those whose spouses did not smoke, was RR = 1.25 (95% confidence interval [95% CI], 1.17-1.33) across the combined studies. This association was statistically similar in men (RR = 1.24; 95% CI, 1.15-1.32) and women (RR = 1.23; 95% CI, 1.15-1.32); in studies of cohort (RR = 1.23; 95% CI, 1.15-1. 31) and case-control (RR = 1.47; 95% CI, 1.19-1.81) design; in the United States (RR =1.22; 95% CI, 1.13-1.30) and other countries (RR = 1.41; 95% CI, 1.21-1.65); and in studies of fatal (RR = 1.22; 95% CI, 1.14-1.30) and nonfatal (RR = 1.32; 95% CI, 1.04-1.67) heart disease. In three studies that presented data separately for nonsmokers married to current or former smokers, the association was stronger when the spouses continued to smoke (RR = 1.16, 1.06-1.28) than with former smokers (RR = 0.98; 95% CI, 0.89-1.08). The aggregate data are unlikely to be attributable to chance, publication bias, confounding, or misclassification of exposure. The evidence linking heart disease and ETS exposure from a spouse has become substantially stronger since OSHA first proposed including heart disease in its risk assessment of ETS in 1994.

Cigar smoking and death from coronary heart disease in a prospective study of US men.

CONTEXT: The prevalence of cigar smoking has increased rapidly in the United States since 1993. Although cigarette smoking is known to be an important cause of coronary heart disease (CHD) mortality, the relationship between cigar smoking and CHD mortality is unclear. OBJECTIVE: To determine whether cigar smoking increases risk of CHD mortality. DESIGN: Prospective cohort study with follow-up for mortality from 1982 through 1991. SETTING: United States. PARTICIPANTS: A total of 121 278 men, aged 30 years and older, in the American Cancer Society's nationwide Cancer Prevention Study II cohort who completed a baseline questionnaire on smoking history and other risk factors in 1982, had never smoked cigarettes or pipes, and had no diagnosed heart disease or diabetes at baseline. MAIN OUTCOME MEASURE: Death from CHD recorded as the underlying cause of death on the death certificate. RESULTS: There were 2508 deaths from CHD from 1982 through 1991. The association between cigar smoking and death from CHD was stronger among younger men and current rather than former smokers, as is observed with cigarette smoking. No increased risk was observed among current cigar smokers aged 75 years or older, or for former cigar smokers of any age. For men younger than 75 years who were current cigar smokers at baseline, the adjusted rate ratio for CHD mortality was 1.30 (95% confidence interval, 1.05-1.62). CONCLUSIONS: These results suggest that smoking cigars increases risk of early death from CHD. Any adverse effect of cigars on CHD is of particular importance given the rapidly rising prevalence of cigar smoking in the United States.

Reduction in the anti-adherence activity of Tamm-Horsfall protein with increasing concentration of calcium.

Tamm-Horsfall glycoprotein (THP), at concentrations occurring in normal urine, was demonstrated to show anti-adherence activity for type-1 fimbriated Escherichia coli. Urine also showed anti-adherence activity, and urine from which the THP was precipitated showed a significant drop in activity. The addition of calcium to the incubation medium with THP, at concentrations normally found in the urine, had no effect on the anti-adherence activity of THP. However, concentrations of calcium higher than those normally occurring in the urine significantly decreased the anti-adherence activity of THP. It is suggested that individuals with above normal concentrations of calcium in the urine may be at increased risk for urinary tract infections since the protective effect of THP is compromised.

Increased risk of urinary tract infection associated with the use of calcium supplements.

Since ions are known to influence the interaction between cells, we undertook an examination of the effect of various ions on bacterial adherence to uroepithelial cells. While most of the ions examined had no effect or decreased bacterial adherence, calcium ions significantly increased bacterial adherence. It was demonstrated, in vitro that as the concentration of calcium was increased to levels higher than normally found in the urine, there was a significant increase in bacterial adherence. It was also found that if the diet was supplemented with calcium there was an increase in the excretion of calcium in the urine and a corresponding increase in bacterial adherence when bacteria and uroepithelial cells were incubated in this urine. It is suggested that an excretion of excess calcium in the urine may lead to an increased bacterial adherence in vivo and an increased potential for urinary tract infections.