Tradeoff between the Brillouin and transverse mode instabilities in Yb-doped fiber amplifiers.

The Brillouin instability (BI) due to stimulated Brillouin scattering (SBS) and the transverse (thermal) mode instability (TMI) due to stimulated thermal Rayleigh scattering (STRS) limit the achievable power in high-power lasers and amplifiers. The pump power threshold for BI increases as the core diameter increases, but the threshold for TMI may decrease as the core diameter increases. In this paper, we use a multi-time-scale approach to simultaneously model BI and TMI, which gives us the ability to find the fiber diameter with the highest power threshold. We formulate the equations to compare the thresholds of the combined and individual TMI and BI models. At the pump power threshold and below, there is a negligible difference between the full and individual models, as BI and TMI are not strong enough to interact with each other. The highest pump threshold occurs at the optimal core size of 43 µm for the simple double-clad geometry that we considered. We found that both effects contribute equally to the threshold, and the full BI and TMI model yields a similar threshold as the BI or TMI model alone. However, once the reflectivity is sufficiently large, we find in the full BI and TMI model that BI may trigger TMI and reduce the TMI threshold to a value lower than is predicted in simulations with TMI alone. This result cannot be predicted by models that consider BI and TMI separately. Our approach can be extended to more complex geometries and used for their optimization.

Paracrine Regulation of Alveolar Epithelial Damage and Repair Responses by Human Lung-Resident Mesenchymal Stromal Cells.

COPD is characterized by irreversible lung tissue damage. We hypothesized that lung-derived mesenchymal stromal cells (LMSCs) reduce alveolar epithelial damage via paracrine processes, and may thus be suitable for cell-based strategies in COPD. We aimed to assess whether COPD-derived LMSCs display abnormalities. LMSCs were isolated from lung tissue of severe COPD patients and non-COPD controls. Effects of LMSC conditioned-medium (CM) on H2O2-induced, electric field- and scratch-injury were studied in A549 and NCI-H441 epithelial cells. In organoid models, LMSCs were co-cultured with NCI-H441 or primary lung cells. Organoid number, size and expression of alveolar type II markers were assessed. Pre-treatment with LMSC-CM significantly attenuated oxidative stress-induced necrosis and accelerated wound repair in A549. Co-culture with LMSCs supported organoid formation in NCI-H441 and primary epithelial cells, resulting in significantly larger organoids with lower type II-marker positivity in the presence of COPD-derived versus control LMSCs. Similar abnormalities developed in organoids from COPD compared to control-derived lung cells, with significantly larger organoids. Collectively, this indicates that LMSCs' secretome attenuates alveolar epithelial injury and supports epithelial repair. Additionally, LMSCs promote generation of alveolar organoids, with abnormalities in the supportive effects of COPD-derived LMCS, reflective of impaired regenerative responses of COPD distal lung cells.

Accurate and efficient modeling of the transverse mode instability in high energy laser amplifiers.

We study the transverse mode instability (TMI) in the limit where a single higher-order mode (HOM) is present. We demonstrate that when the beat length between the fundamental mode and the HOM is small compared to the length scales on which the pump amplitude and the optical mode amplitudes vary, TMI is a three-wave mixing process in which the two optical modes beat with the phase-matched component of the index of refraction that is induced by the thermal grating. This limit is the usual limit in applications, and in this limit TMI is identified as a stimulated thermal Rayleigh scattering (STRS) process. We demonstrate that a phase-matched model that is based on the three-wave mixing equations can have a large computational advantage over current coupled mode methods that must use longitudinal step sizes that are small compared to the beat length.

Abnormalities in reparative function of lung-derived mesenchymal stromal cells in emphysema.

Mesenchymal stromal cells (MSCs) may provide crucial support in the regeneration of destructed alveolar tissue (emphysema) in chronic obstructive pulmonary disease (COPD). We hypothesized that lung-derived MSCs (LMSCs) from patients with emphysema are hampered in their repair capacity, either intrinsically or due to their interaction with the damaged microenvironment. LMSCs were isolated from the lung tissue of controls and patients with severe emphysema and characterized at baseline. In addition, LMSCs were seeded onto control and emphysematous decellularized lung tissue scaffolds and assessed for deposition of extracellular matrix (ECM). We observed no differences in surface markers, differentiation/proliferation potential, and expression of ECM genes between control- and COPD-derived LMSCs. Notably, COPD-derived LMSCs displayed lower expression of FGF10 and HGF messenger RNA (mRNA) and hepatocyte growth factor (HGF) and decorin protein. When seeded on control decellularized lung tissue scaffolds, control- and COPD-derived LMSCs showed no differences in engraftment, proliferation, or survival within 2 wk, with similar ability to deposit new matrix on the scaffolds. Moreover, LMSC numbers and the ability to deposit new matrix were not compromised on emphysematous scaffolds. Collectively, our data show that LMSCs from patients with COPD compared with controls show less expression of FGF10 mRNA, HGF mRNA and protein, and decorin protein, whereas other features including the mRNA expression of various ECM molecules are unaffected. Furthermore, COPD-derived LMSCs are capable of engraftment, proliferation, and functioning on native lung tissue scaffolds. The damaged, emphysematous microenvironment as such does not hamper the potential of LMSCs. Thus, specific intrinsic deficiencies in growth factor production by diseased LMSCs may contribute to impaired alveolar repair in emphysema.

Mesenchymal Stromal Cells to Regenerate Emphysema: On the Horizon?

Mesenchymal stem or stromal cells (MSCs) are multipotent cells that play a pivotal role in various phases of lung development and lung homeostasis, and potentially also lung regeneration. MSCs do not only self-renew and differentiate into renew tissues, but also have anti-inflammatory and paracrine properties to reduce damage and to support tissue regeneration, constituting a promising cell-based treatment strategy for the repair of damaged alveolar tissue in emphysema. This review discusses the current state of the art regarding the potential of MSCs for the treatment of emphysema. The optimism regarding this treatment strategy is supported by promising results from animal models. Still, there are considerable challenges before effective stem cell treatment can be realized in emphysema patients. It is difficult to draw definitive conclusions from the available animal studies, as different models, dosage protocols, administration routes, and sources of MSCs have been used with different measures of effectiveness. Moreover, the regrowth potential of differentiated tissues and organs differs between species. Essential questions about MSC engraftment, retention, and survival have not been sufficiently addressed in a systematic manner. Few human studies have investigated MSC treatment for chronic obstructive pulmonary disease, demonstrating short-term safety but no convincing benefits on clinical outcomes. Possible explanations for the lack of beneficial effects on clinical outcomes could be the source (bone marrow), route, dosage, frequency of administration, and delivery (lack of a bioactive scaffold). This review will provide a comprehensive overview of the (pre)clinical studies on MSC effects in emphysema and discuss the current challenges regarding the optimal use of MSCs for cell-based therapies.

Compact, hydrophilic, lanthanide-binding tags for paramagnetic NMR spectroscopy.

The design, synthesis and evaluation of four novel lanthanide-binding tags for paramagnetic NMR spectroscopy are reported. Each tag is based on the ((2S,2'S,2''S,2'''S)-1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(propan-2-ol)) scaffold, featuring small chiral alcohol coordinating pendants to minimise the size and hydrophobic character of each tag. The tags feature different linkers of variable length for conjugation to protein via a single cysteine residue. Each tag's ability to induce pseudocontact shifts (PCS) was assessed on a ubiquitin A28C mutant. Two enantiomeric tags of particular note, C7 and C8, produced significantly larger Δχ-tensors compared to a previously developed tag, C1, attributed to the extremely short linker utilised, limiting the mobility of the bound lanthanide ion. The C7 and C8 tags' capacity to induce PCSs was further demonstrated on GB1 Q32C and 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) S112C/C80A mutants. Whilst factors such as the choice of lanthanide ion, pH and site of conjugation influence the size of the PCSs obtained, the tags represent a significant advance in the field.

Mycobacterium paratuberculosis is recognized by Toll-like receptors and NOD2.

Mycobacterium paratuberculosis has been suggested to be involved in the pathogenesis of Crohn's disease (CD). The importance of microorganisms in CD is supported by the association of CD with mutations in the intracellular pathogen recognition receptor (PRR) nucleotide-binding oligomerization domain 2 (NOD2). The aim of this study is to investigate the PRR involved in the recognition of M. paratuberculosis. Methods used include in vitro stimulation of transfected cell lines, murine macrophages, and human PBMC. M. paratuberculosis stimulated human TLR2 (hTLR2)-Chinese hamster ovary (CHO) cells predominantly and hTLR4-CHO cells modestly. Macrophages from TLR2 and TLR4 knockout mice produced less cytokines compared with controls after stimulation with M. paratuberculosis. TLR4 inhibition in human PBMC reduced cytokine production only after stimulation with live M. paratuberculosis. TLR-induced TNF-alpha, IL-1beta, and IL-10 production is mediated through MyD88, whereas Toll-IL-1R domain-containing adaptor inducing IFN-beta (TRIF) promoted the release of IL-1beta. hNOD2-human embryo kidney (HEK) cells, but not hNOD1-HEK cells, responded to stimulation with M. paratuberculosis. PBMC of individuals homozygous for the 3020insC NOD2 mutation showed a 70% defective cytokine response after stimulation with M. paratuberculosis. These results demonstrate that TLR2, TLR4, and NOD2 are involved in the recognition of M. paratuberculosis by the innate immune system.

Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells.

IL-23 is regarded as a major pro-inflammatory mediator in autoimmune disease, a role which until recently was ascribed to its related cytokine IL-12. IL-23, an IL-12p40/p19 heterodimeric protein, binds to IL-12Rbeta1/IL-23R receptor complexes. Mice deficient for p19, p40 or IL-12Rbeta1 are resistant to experimental autoimmune encephalomyelitis or collagen-induced arthritis. Paradoxically, however, IL-12Rbeta2- and IL-12p35-deficient mice show remarkable increases in disease susceptibility, suggesting divergent roles of IL-23 and IL-12 in modulating inflammatory processes. IL-23 induces IL-17, which mediates inflammation and tissue remodeling, but the role of IL-12 in this respect remains unidentified. We investigated the roles of exogenous (recombinant) and endogenous (macrophage-derived) IL-12 and IL-23, on IL-17-induction in human T-cells. IL-23 enhanced IL-17 secretion, as did IL-2, IL-15, IL-18 and IL-21. In contrast, IL-12 mediated specific inhibition of IL-17 production. These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion. These data therefore extend previous reports that had indicated unique functions for IL-23 and IL-12 due to distinct receptor expression and signal transduction complexes, and provide novel insights into the regulation of immunity, inflammation and immunopathology.

Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-gamma- and CD40L-mediated costimulation.

Macrophages (Mphi) comprise a heterogeneous population of cells with various immune and homeostatic functions. Recently, we have described type-1 and type-2 human monocyte-derived Mphi subsets. Although both support outgrowth of intracellular mycobacteria, Mphi-1 secretes interleukin (IL)-23/IL-12 and supports T helper cell type 1 (Th1) responses, whereas Mphi-2 fails to produce IL-23/IL-12, predominantly secretes IL-10, and inhibits Th1 function. Here, we further describe the phenotypic and functional profiles of Mphi-1 and Mphi-2 in response to microbial antigens and interferon-gamma (IFN-gamma) and CD40L as costimulatory T cell back-talk signals. Activated IL-23(+)/IL-12(+) Mphi-1 secreted IL-1beta, IL-18, IL-6, and tumor necrosis factor-alpha (TNF-alpha), as well as IL-8, monocyte chemoattractant protein-1 (MCP-1), IFN-inducible protein 10 (IP-10), Mphi inflammatory protein-1beta (MIP-1beta), regulated on activation, normal T expressed and secreted (RANTES), Mphi-derived chemokine (MDC), and (low levels of) pulmonary and activation-regulated chemokine and thymus and activation-regulated chemokine (TARC), corroborating their proinflammatory function. Regardless of the stimulus, Mphi-2 maintained their IL-10(+) signature cytokine profile and produced no or relatively low levels of IL-12p40, IL-1beta, IL-6, TNF-alpha, MDC, or TARC. It is remarkable that Mphi-2 secreted high levels of IL-8, MCP-1, IP-10, MIP-1beta, and RANTES, suggesting an active role for these cells in regulating cellular immunity and homeostasis. Mphi-1 and Mphi-2 expressed similar levels of Toll-like receptor and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as microbial pattern recognition receptors. Mphi-2, unlike Mphi-1 but like other nonclassical Mphi described previously, expressed CD163 and down-modulated human leukocyte antigen and costimulatory molecules specifically upon activation. These findings demonstrate how Mphi-1/Mphi-2 polarization can differentially skew the host response toward pro- or anti-inflammatory immune responses, respectively. This is likely to be relevant for host-pathogen interactions in chronic bacterial infections and provides a model for dissecting pro- and anti-inflammatory cascades.

NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis.

Infection with Mycobacterium tuberculosis is one of the leading causes of death worldwide. Recognition of M. tuberculosis by pattern recognition receptors is crucial for activation of both innate and adaptive immune responses. In the present study, we demonstrate that nucleotide-binding oligomerization domain 2 (NOD2) and Toll-like receptors (TLRs) are two nonredundant recognition mechanisms of M. tuberculosis. CHO cell lines transfected with human TLR2 or TLR4 were responsive to M. tuberculosis. TLR2 knock-out mice displayed more than 50% defective cytokine production after stimulation with mycobacteria, whereas TLR4-defective mice also released 30% less cytokines compared to controls. Similarly, HEK293T cells transfected with NOD2 responded to stimulation with M. tuberculosis. The important role of NOD2 for the recognition of M. tuberculosis was demonstrated in mononuclear cells of individuals homozygous for the 3020insC NOD2 mutation, who showed an 80% defective cytokine response after stimulation with M. tuberculosis. Finally, the mycobacterial TLR2 ligand 19-kDa lipoprotein and the NOD2 ligand muramyl dipeptide synergized for the induction of cytokines, and this synergism was lost in cells defective in either TLR2 or NOD2. Together, these results demonstrate that NOD2 and TLR pathways are nonredundant recognition mechanisms of M. tuberculosis that synergize for the induction of proinflammatory cytokines.

3-D Structure of multilaminar lysosomes in antigen presenting cells reveals trapping of MHC II on the internal membranes.

In late endosomes and lysosomes of antigen presenting cells major histocompatibility complex class II (MHC II) molecules bind peptides from degraded internalized pathogens. These compartments are called MHC class II compartments (MIICs), and from here peptide-loaded MHC II is transported to the cell surface for presentation to helper T-lymphocytes to generate an immune response. Recent studies from our group in mouse dendritic cells indicate that the MHC class II on internal vesicles of multivesicular late endosomes or multivesicular bodies is the main source of MHC II at the plasma membrane. We showed that dendritic cell activation triggers a back fusion mechanism whereby MHC II from the inner membranes is delivered to the multivesicular bodies' outer membrane. Another type of MIIC in B-lymphocytes and dendritic cells is more related to lysosomes and often appears as a multilaminar organelle with abundant MHC II-enriched internal membrane sheets. These multilaminar lysosomes have a functioning peptide-loading machinery, but to date it is not clear whether peptide-loaded MHC II molecules from the internal membranes can make their way to the cell surface and contribute to T cell activation. To obtain detailed information on the membrane organization of multilaminar lysosomes and investigate possible escape routes from the lumen of this organelle, we performed electron tomography on cryo-immobilized B-lymphocytes and dendritic cells. Our high-resolution 3-D reconstructions of multilaminar lysosomes indicate that their membranes are organized in such a way that MHC class II may be trapped on the inner membranes, without the possibility to escape to the cell surface.

Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria.

Macrophages (Mphi) play a central role as effector cells in immunity to intracellular pathogens such as Mycobacterium. Paradoxically, they also provide a habitat for intracellular bacterial survival. This paradoxical role of Mphi remains poorly understood. Here we report that this dual role may emanate from the functional plasticity of Mphi: Whereas Mphi-1 polarized in the presence of granulocyte-Mphi colony-stimulating factor promoted type 1 immunity, Mphi-2 polarized with Mphi colony-stimulating factor subverted type 1 immunity and thus may promote immune escape and chronic infection. Importantly, Mphi-1 secreted high levels of IL-23 (p40/p19) but no IL-12 (p40/p35) after (myco)bacterial activation. In contrast, activated Mphi-2 produced neither IL-23 nor IL-12 but predominantly secreted IL-10. Mphi-1 required IFN-gamma as a secondary signal to induce IL-12p35 gene transcription and IL-12 secretion. Activated dendritic cells produced both IL-12 and IL-23, but unlike Mphi-1 they slightly reduced their IL-23 secretion after addition of IFN-gamma. Binding, uptake, and outgrowth of a mycobacterial reporter strain was supported by both Mphi subsets, but more efficiently by Mphi-2 than Mphi-1. Whereas Mphi-1 efficiently stimulated type 1 helper cells, Mphi-2 only poorly supported type 1 helper function. Accordingly, activated Mphi-2 but not Mphi-1 down-modulated their antigen-presenting and costimulatory molecules (HLA-DR, CD86, and CD40). These findings indicate that (i) Mphi-1 and Mphi-2 play opposing roles in cellular immunity and (ii) IL-23 rather than IL-12 is the primary type 1 cytokine produced by activated proinflammatory Mphi-1. Mphi heterogeneity thus may be an important determinant of immunity and disease outcome in intracellular bacterial infection.

IL-12 receptor deficiency revisited: IL-23-mediated signaling is also impaired in human genetic IL-12 receptor beta1 deficiency.

IFN-gamma and IL-12 are crucial cytokines for cell-mediated immunity against intracellular pathogens. We have previously shown that human IL-12Rbeta1-deficiency leads to impaired IL-12 responsiveness and unusual susceptibility to infections due to mycobacteria and salmonellae. IL-23 is a cytokine with functions that partially overlap with those of IL-12. IL-23 consists of IL-12p40 and a novel p19 protein, and binds to a receptor complex comprising IL-12Rbeta1 and IL-23R. Thus, IL-12Rbeta1-deficiency may impair both IL-12- and IL-23 signaling, and both may contribute to the immunological phenotypes. To examine whether IL-12Rbeta1 is essential for IL-23 signaling in human T cells, we have studied IL-23 responsiveness of four IL-12Rbeta1-deficient individuals. Whereas IL-23 promoted IFN-gamma production by CD4(+) and CD8(+) T cells in controls, IL-12Rbeta1-deficient T cells lacked IL-23-induced IFN-gamma secretion, but responded normally to IL-2, IL-4, IL-15 and IL-18. We also show that induction of IFN-gamma production by IL-23 depends upon TCR-ligation and is enhanced by CD28-costimulation. Furthermore, IL-23 cooperates with IL-12 and IL-18 in promoting IFN-gamma production in controls, but not in patients. We conclude that IL-12Rbeta1-deficiency impairs IL-12- and IL-23-dependent signaling in human T cells. The syndrome caused by IL-12Rbeta1-deficiency thus needs to be reinterpreted as resulting from defective IL-12-as well as IL-23-mediated immunity.

Patterns of HIV risk and alcohol use among African-American crack abusers.

Although the association between heavy alcohol use and HIV risk has been studied in treatment populations, we know little about patterns of alcohol use and HIV risk among out-of-treatment African-American drug users. This study examines the extent to which alcohol use affects HIV risk in a sample of 495 African-American crack users who did not inject drugs. We present differences between levels of alcohol and crack use with regard to sexual practices (including sex while impaired), number of partners, frequency of sexual activity, and condom use. The findings suggest an intimate relationship between alcohol use, crack use, and sexual risks for HIV infection. Respondents who reported frequent use (15-30 days in the last 30 days) of alcohol, crack, or both displayed significantly greater risk than those who reported less than frequent use.

Symptoms of dependence, multiple substance use, and labor market outcomes.

The prevalence and costs of alcohol and drug disorders pose a serious social concern for policymakers. In this paper, we use data from the National Household Surveys on Drug Abuse (NHSDA) to estimate simple descriptive statistics and analysis of variance (ANOVA) models of the relationship between symptoms of dependence and labor market outcomes for alcohol, cigarettes, marijuana, and other illicit drugs. For men, we find that substance use with symptoms of dependence is associated with both lower employment rates and fewer hours of work. For women, we find that substance use with symptoms of dependence is associated with lower employment rates, but we find no consistent evidence of a relationship between symptoms of dependence and the number of hours worked. Finally, all of our point estimates are smaller in magnitude when we control for multiple substance use, suggesting that comorbidities play a critical role in the relationship between substance use and labor market outcomes. Our results suggest that policymakers and researchers should consider the full spectrum of substance use and dependence rather than focusing on the simple use of a single substance.

State-of-the-art methodologies in alcohol-related health services research.

Many of the failures to replicate clinical findings of treatment efficacy in more realistic field and community settings can be attributed to inappropriate research designs and other methodological shortcomings. In order to increase research designers' awareness of existing methodologies that may be better suited to answer the critical questions inherent in health services research on alcohol-related issues, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) convened an expert conference with three specific goals; (1) to identify the critical issues involved in alcohol services research; (2) to develop a primer that explicated each key area; and (3) to compile the resulting primers into an accessible resource for researchers, policy makers and consumers. The 9 papers in this special supplement are the product of that conference and are organized broadly around three phases of the research process: study design and implementation, data collection and use, and the analysis and interpretation of data. A final summary paper discusses the issues and offers a synthesis of key themes as well as some direction for the future.

Twenty-five strategies for improving the design, implementation and analysis of health services research related to alcohol and other drug abuse treatment.

While some aspects of addiction can be studied in laboratory or controlled settings, the study of long-term recovery management and the health services that support it requires going out into the community and dealing with populations and systems that are much more diverse and less under our control. This in turn raises many methodological challenges for the health service researchers studying alcohol and other drug abuse treatment. This paper identifies some of these challenges related to the design, measurement, implementation and effectiveness of health services research. It then recommends 25 strategies (and key primers) for addressing them: (1) identifying in advance all stakeholders and issues; (2) developing conceptual models of intervention and context; (3) identifying the population to whom the conclusions will be generalized; (4) matching the research design to the question; (5) conducting randomized experiments only when appropriate and necessary; (6) balancing methodological and treatment concerns; (7) prioritizing analysis plans and increasing design sensitivity, (8) combining qualitative and quantitative methods; (9) identifying the four basic types of measures needed; (10) identifying and using standardized measures; (11) carefully balancing measurement selection and modification; (12) developing and evaluating modified and new measures when necessary; (13) identifying and tracking major clinical subgroups; (14) measuring and analyzing the actual pattern of services received; (15) incorporating implementation checks into the design; (16) incorporating baseline measures into the intervention; (17) monitoring implementation and dosage as a form of quality assurance; (18) developing procedures early to facilitate tracking and follow-up of study participants; (19) using more appropriate representations of the actual experiment; (20) using appropriate and sensitive standard deviation terms; (21) partialing out variance due to design or known sources prior to estimating experimental effect sizes; (22) using dimensional, interval and ratio measures to increase sensitivity to change; (23) using path or structural equation models; (24) integrating qualitative and quantitative analysis into reporting; and (25) using quasi-experiments, economic or organizational studies to answer other likely policy questions. Most of these strategies have been tried and tested in this and other areas, but are not widely used. Improving the state of the art of health services research and bridging the gap between research and practice do not depend upon using the most advanced methods, but rather upon using the most appropriate methods.

Cross-phase modulation and multiwavelength adiabatic solitons.

In an experimental demonstration of four-channel, wavelength-division-multiplexed repeaterless transmission over 235 km, adiabatic soliton propagation allows for precise spectral characterization of cross-phase modulation effects during initial soliton collisions. Theoretical predictions of the spectral shifts that occur are verified for ultrashort solitons. The relationship between the frequency shift and the initial pulse separation is confirmed by measurement of the bit-error ratio as the pulse spacing is varied at the fiber input. Adiabatic expansion of narrow solitons may help to alleviate the channel restrictions that are required for prevention of soliton collisions at the fiber input.

A cluster analysis of not-in-treatment drug users at risk for HIV infection.

The purpose of the analysis described here was to classify not-in-treatment drug users participating in the National Institute on Drug Abuse (NIDA)-sponsored Cooperative Agreement study into several "homogeneous" HIV risk groups using cluster analysis. Data for this analysis (N=17,778) were collected at 19 study sites in the United States and Puerto Rico. Measures selected for the cluster analysis were limited to (a) current drug use and HIV risk behaviors, (b) mutually exclusive behaviors, (c) behaviors directly related to HIV risk, and (d) behaviors that were not statistically rare. Eight homogeneous HIV risk clusters were produced. Crack cocaine use was the most distinguishing feature of three clusters. Another three clusters were distinguishable by drug injection and needle use practices. Two additional clusters could not be grouped with either the crack- or the injection-dominant clusters. Prostitution was the most distinguishing risk behavior of one of these clusters, and extremely high drug injection frequencies and relative rates of risky needle use characterized the other. Composition of the clusters varied significantly by gender, race/ethnicity, educational attainment, and drug use characteristics. In addition, perceptions and behaviors initiated to reduce the chances of becoming infected with HIV varied by cluster. Subjects in the crack-predominant clusters reported low perceptions of the chances of getting AIDS. Perceptions of the chances of becoming infected with HIV among subjects in the injection-predominant clusters were strongly related to injection frequency. Seroprevalence was also related to cluster. Higher rates of HIV infection were evident among the injection-predominant clusters, and higher rates were related to frequency of injection and the rate of risky needle use. Among the crack-predominant clusters, the relationship between drug use and sexual behaviors and HIV infection was less clear.

Cluster analysis of HIV intervention outcomes among substance-abusing women.

The study described here presents an innovative approach to analyzing intervention outcomes among women substance abusers participating in a national HIV prevention research study funded by the National Institute on Drug Abuse. We used cluster analysis to divide the women in our sample (N=557) into four distinct subgroups predominantly characterized by differences in drug use, injecting risk, sexual behaviors, and drug and sexual risk combined. The four subgroups resulting from this process were primary crack-using women, primary needle-using women, high-frequency needle-using women, and women with multiple drug and sex risk behaviors. Our analysis focuses on changes in self-reported risk behaviors from baseline to 6-month follow-up. In general, the results clearly indicate that the women are heterogeneous; that is, the subgroups exhibit varying patterns of drug use, injecting risk, sexual behavior, and HIV seropositivity. Significant outcomes were found in many areas, indicating positive changes in risk behaviors. The two smaller subgroups of women--high-frequency needle users and those in the multiple-risk behavior subgroup--reported the highest rate of high-risk behaviors and seropositivity but also showed the greatest change at follow-up. A particularly important finding resulting from our analytical approach is that well over half the women in our sample were primary crack users (n=313). This finding is even more significant in light of the fact that the Cooperative Agreement specifically tried to include 70% or more participants who were injectors. Although the rate of HIV seropositivity is not as high for this crack-using subgroup as for the two smaller needle-using subgroups, a greater number of "women who are HIV positive" are in this primary crack-using subgroup than in all the other subgroups. Most of the crack-using women reported that they were not currently injecting drugs and never shared needles, but 10% were seropositive for HIV, suggesting that their risk comes primarily from sexual behaviors. Behaviors in this larger subgroup of women did not change as dramatically as those of women in the smaller subgroups; however, the women did show improvement in areas related to indirect risk (e.g., alcohol and crack use) and in several areas where change is most needed (e.g., trading sex for drugs and using condoms). The results demonstrate a promising alternative approach to analyzing substance abuse and HIV risk behaviors, and they suggest the need for further research on alternative interventions for women with different patterns of risk behaviors.