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Postsecondary education has never mattered more than it does presently. It is critical for adults, particularly for non-credentialed adults, to complete postsecondary pathways, ensuring they are prepared to compete in the global economy. Despite the well-documented benefits of a postsecondary degree, nearly one-fourth of adults in Louisiana have college experience, but no degree. Adult learners experience barriers to navigating higher education that negatively impact their ability to return and persist to graduation. Recognizing these challenges, the University of Louisiana System and their nine member institutions created Compete LA, a program designed to re-engage adult learners and create equitable academic pathways to obtaining a college degree. This chapter will serve as a case study by focusing on the creation and scaling of the Compete LA initiative. It will explore the characteristics of the team, the structural composition of the program, as well as the efforts to dismantle the systemic barriers that exist in higher education that make adult student re-entry challenging.

James S Kahn,1–3 Ronald M Witteles,3,4 Kenneth W Mahaffey,3–5 Sumbul A Desai,2,3 Errol Ozdalga,2,3 Paul A Heidenreich1,3 1Veterans Affairs Palo Alto Health Care System, Palo Alto, 2Division of Primary Care and Population Health, 3Department of Medicine, 4Division of Cardiovascular Medicine, 5Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, CA, USA Introduction: Satisfaction with training and with educational experiences represents important internal medicine (IM) programmatic goals. Graduates from IM residency programs are uniquely poised to provide insights into their educational and training experiences and to assess whether these experiences were satisfactory and relevant to their current employment. Methods: We surveyed former IM residents from the training program held during the years 2000–2015 at the Department of Medicine, Stanford University. The first part of the survey reviewed the IM residency program and the second part sought identifying data regarding gender, race, ethnicity, work, relationships, and financial matters. The primary outcome was satisfaction with the residency experience. Results: Of the 405 individuals who completed the Stanford IM residency program in the study period, we identified 384 (95%) former residents with a known email address. Two hundred and one (52%) former residents responded to the first part and 185 (48%) answered both the parts of the survey. The mean age of the respondents was 36.9 years; 44% were female and the mean time from IM residency was 6.1 (±4.3) years. Fifty-eight percent reported extreme satisfaction with their IM residency experience. Predictors associated with being less than extremely satisfied included insufficient outpatient experience, insufficient international experience, insufficient clinical research experience, and insufficient time spent with family and peers. Conclusion: The residents expressed an overall high satisfaction rate with their IM training. The survey results provided insights for improving satisfaction with IM residency training that includes diversifying and broadening IM training experiences. Keywords: internal medicine residency program, residents, training&nbsp

IMPORTANCE: Although lay health workers (LHWs) improve cancer screening and treatment adherence, evidence on whether they can enhance other aspects of care is limited. OBJECTIVE: To determine whether an LHW program can increase documentation of patients’ care preferences after cancer diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted from August 13, 2013, through February 2, 2015, among 213 patients with stage 3 or 4 or recurrent cancer at the Veterans Affairs Palo Alto Health Care System. Data analysis was by intention to treat and performed from January 15 to August 18, 2017. INTERVENTIONS: Six-month program with an LHW trained to assist patients with establishing end-of-life care preferences vs usual care. MAIN OUTCOMES AND MEASURES: The primary outcome was documentation of goals of care. Secondary outcomes were patient satisfaction on the Consumer Assessment of Health Care Providers and Systems “satisfaction with provider” item (on a scale of 0 [worst] to 10 [best possible]), health care use, and costs. RESULTS: Among the 213 participants randomized and included in the intention-to-treat analysis, the mean (SD) age was 69.3 (9.1) years, 211 (99.1%) were male, and 165 (77.5%) were of non-Hispanic white race/ethnicity. Within 6 months of enrollment, patients randomized to the intervention had greater documentation of goals of care than the control group (97 [92.4%] vs 19 [17.5%.]; P

He is one of my most memorable patients. Despite his passion and outrage, he recognized his own limitations and helplessness to right the wrongs he witnessed and endured.

The goal of this study was to compare the effectiveness of fish oil, fenofibrate, gemfibrozil, and atorvastatin on reducing triglyceride (TG) levels among a large cohort of HIV-infected patients in clinical care.Retrospective observational cohort study.The primary endpoint was absolute change in TG levels measured using the last TG value pretreatment and the first TG value posttreatment. A pre-post quasi-experimental design was used to estimate the change in TG because of initiating fish oil. Linear regression models examined the comparative effectiveness of treatment with fish oil versus gemfibrozil, fenofibrate, or atorvastatin for TG reduction. Models were adjusted for baseline differences in age, sex, race, CD4⁺ cell count, diabetes, body mass index, protease inhibitor use, and time between TG measures.A total of 493 patients (mean age, 46 years; 95% male) were included (46 patients receiving gemfibrozil; 80, fenofibrate; 291, atorvastatin; and 76, fish oil) with a mean baseline TG of 347 mg/dL. New use of fish oil decreased TG [ΔTG, -45 mg/dL; 95% confidence interval (CI): -80 to -11] in the pre-post study. Compared with fish oil (reference), fibrates were more effective (ΔTG, -66; 95% CI: -120 to -12) in reducing TG levels, whereas atorvastatin was not (ΔTG, -39; 95% CI: -86 to 9).In HIV-infected patients in routine clinical care, fish oil is less effective than fibrates (but not atorvastatin) at lowering TG values. Fish oil may still represent an attractive alternative for patients with moderately elevated TGs, particularly among patients who may not want or tolerate fibrates.

OBJECTIVE Laboratory monitoring is recommended during combination antiretroviral therapy (cART), but the pattern of detected abnormalities and optimal monitoring are unknown. We assessed laboratory abnormalities during initial cART in 2000-2010 across the United States. DESIGN Observational study in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort. METHODS Among patients with normal results within a year prior to cART initiation, time to first significant abnormality was assessed by Kaplan-Meier curves stratified by event type, with censoring at first of regimen change, loss to follow-up, or 104 weeks. Incidence rates of first events were estimated using Poisson regression; multivariable analyses identified associated factors. Results were stratified by time (16 weeks) from therapy initiation. RESULTS A total of 3470 individuals contributed 3639 person-years. Median age, pre-cART CD4, and follow-up duration were 40 years, 206 cells/μl, and 51 weeks, respectively. Incidence rates for significant abnormalities (per 100 person-years) in the first 16 weeks post-cART initiation were as follows: lipid=49 [95% confidence interval (CI) 41-58]; hematologic=44 (40-49); hepatic=24 (20-27); and renal=9 (7-11), dropping substantially during weeks 17-104 of cART to lipid=23 (18-29); hematologic=5 (4-6); hepatic=6 (5-8); and renal=2 (1-3) (all P

Importance Many organizations are adopting intensive outpatient care programs for high-need patients, yet little is known about their effectiveness in integrated systems with established patient-centered medical homes. Objective To evaluate how augmenting the Veterans Affairs (VA) medical home (Patient Aligned Care Teams [PACT]) with an Intensive Management program (ImPACT) influences high-need patients’ costs, health care utilization, and experience. Design, Setting, and Participants Randomized clinical trial at a single VA facility. Among 583 eligible high-need outpatients whose health care costs or hospitalization risk were in the top 5% for the facility, 150 were randomly selected for ImPACT; the remaining 433 received standard PACT care. Interventions The ImPACT multidisciplinary team addressed health care needs and quality of life through comprehensive patient assessments, intensive case management, care coordination, and social and recreational services. Main Outcomes and Measures Primary difference-in-difference analyses examined changes in health care costs and acute and extended care utilization over a 16-month baseline and 17-month follow-up period. Secondary analyses estimated the intervention’s effect on ImPACT participants (using randomization as an instrument) and for patients with key sociodemographic and clinical characteristics. ImPACT participants’ satisfaction and activation levels were assessed using responses to quality improvement surveys administered at baseline and 6 months. Results Of 140 patients assigned to ImPACT, 96 (69%) engaged in the program (mean [SD] age, 68.3 [14.2] years; 89 [93%] male; mean [SD] number of chronic conditions, 10 [4]; 62 [65%] had a mental health diagnosis; 21 [22%] had a history of homelessness). After accounting for program costs, adjusted person-level monthly health care expenditures decreased similarly for ImPACT and PACT patients (difference-in-difference [SE] −$101 [$623]), as did acute and extended care utilization rates. Among respondents to the ImPACT follow-up survey (n = 54 [56% response rate]), 52 (96%) reported that they would recommend the program to others, and pre-post analyses revealed modest increases in satisfaction with VA care (mean [SD] increased from 2.90 [0.72] to 3.16 [0.60]; P = .04) and communication (mean [SD] increased from 2.99 [0.74] to 3.18 [0.60]; P = .03). Conclusions and Relevance Intensive outpatient care for high-need patients did not reduce acute care utilization or costs compared with standard VA care, although there were positive effects on experience among patients who participated. Implementing intensive outpatient care programs in integrated settings with well-established medical homes may not prevent hospitalizations or achieve substantial cost savings. Trial Registration clinicaltrials.gov Identifier:NCT02932228

Background. The National HIV/AIDS Strategy proposes to scale-up post-exposure prophylaxis (PEP). Intensive risk reduction and adherence counseling appear to be effective but are resource intensive. Identifying simpler interventions that maximize the HIV prevention potential of PEP is critical. Methods. A randomized noninferiority study comparing 2 (standard) or 5 (enhanced) risk reduction counseling sessions was performed. Adherence counseling was provided in the enhanced arm. We measured changes in unprotected sexual intercourse acts at 12 months, compared with baseline; HIV acquisition; and PEP adherence. Outcomes were stratified by degree of baseline risk. Results. We enrolled 457 individuals reporting unprotected intercourse within 72 h with an HIV-infected or at-risk partner. Participants were 96% male and 71% white. There were 1.8 and 2.3 fewer unprotected sex acts in the standard and enhanced groups. The maximum potential risk difference, reflected by the upper bound of the 95% confidence interval, was 3.9 acts. The difference in the riskier subset may have been as many as 19.6 acts. The incidence of HIV seroconversion was 2.9% and 2.6% among persons randomized to standard and enhanced counseling, respectively, with a maximum potential difference of 3.4%. The absolute and maximal HIV seroconversion incidence was 9.9% and 20.4% greater in the riskier group randomized to standard, compared with enhanced, counseling. Adherence outcomes were similar, with noninferiority in the lower risk group and concerning differences among the higher-risk group. Conclusions. Risk assessment is critical at PEP initiation. Standard counseling is only noninferior for individuals with lower baseline risk; thus, enhanced counseling should be targeted to individuals at higher risk.

This issue includes a position paper from the American College of Physicians on the health care crisis of firearm-related injury and a research study assessing perceptions of the problem among phys...

Personal health records (PHRs) are information repositories; however, PHRs may be less available to persons in the safety net setting. We deployed a free, secure, internet-based PHR for persons receiving care at the AIDS/HIV clinic at San Francisco General Hospital. In our initial rollout, 221 persons registered for the PHR. Compared to the entire clinic, these initial users were more likely to be Caucasian, male, non-Hispanic, on antiretroviral medications, and have better control of their HIV infection. The median number of online sessions was 7 and the median session length was 4 min. Laboratory results were the most commonly accessed feature. Patients were satisfied with the PHR and more than 80% of users agreed that the PHR helped them manage their medical problems; however, some users were concerned that their health information was not accurate or secure. Patients in a safety net setting will access and use an online PHR.

Developing countries face steady growth in the prevalence of chronic diseases, along with a continued burden from communicable diseases. "Mobile" health, or m-health-the use of mobile technologies such as cellular phones to support public health and clinical care-offers promise in responding to both types of disease burdens. Mobile technologies are widely available and can play an important role in health care at the regional, community, and individual levels. We examine various m-health applications and define the risks and benefits of each. We find positive examples but little solid evaluation of clinical or economic performance, which highlights the need for such evaluation.

There is a gap between today's personal health records (PHRs) and what patients say they want and need from this electronic tool for managing their health information. Until that gap is bridged, it is unlikely that PHRs will be widely adopted. Current barriers to PHR adoption among patients include cost, concerns that information is not protected or private, inconvenience, design shortcomings, and the inability to share information across organizations. However, in the future, when these concerns are addressed, and health data are portable and understandable (in both content and format), PHRs will likely prove to be invaluable.

Objectives: To evaluate the documentation of advance directive (ADs) and physician orders for life-sustaining treatment (POLST) with acceptance of palliative care (PC) services referral among patients with cancer. Methods: We retrospectively reviewed veterans with advanced cancers at the Veterans Administration Palo Alto Health Care System. Chi-square tests estimated AD and POLST documentation and referral to PC. Logistic regression models estimated the odds of AD and POLST documentation and PC referral. Results: Two hundred and forty-six veterans were diagnosed with cancer. In all, 53% had a documented AD, 5% had a POLST, and 47% accepted referral to PC. The AD documentation was not associated with acceptance of PC. Discussion: We found no association of AD documentation and PC referral. Future studies should evaluate other factors that influence referral to these services.

Background. The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. Methods. HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. Results. Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus. Conclusions. As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

Objectives: To evaluate the cost-effectiveness of HIV postexposure prophylaxis (PEP) following sexual or injection-related exposures in 96 metropolitan statistical areas in the United States (MSA). Design: Empirical, model-based cost-effectiveness analysis. Methods: Epidemiological and population size estimates from the literature were combined with information about the distribution of exposure types, PEP completion rate, proportion of source partners known to be HIV infected, and PEP program costs obtained from a feasibility study of PEP in San Francisco to estimate the costeffectiveness of hypothetical PEP programs in each of the 96 MSA. The effectiveness of combination antiretroviral therapy following sexual or drug use-related exposures, which is presently not known, was assumed equal to the effectiveness of zidovudine monotherapy in the occupational setting. The main outcome measure was the cost– utility ratio, defined as the cost per quality-adjusted life year (QALY) saved by the PEP intervention. Results: The cost–utility ratios for the 96 MSA ranged from $4137 to $39 101 per QALY saved; only two of the ratios exceeded $30 000 per QALY saved. Combined across the 96 MSA, the hypothetical PEP programs would reach nearly 20 000 clients at a total cost of approximately $22 million. The overall cost–utility ratio across MSA was $12,567 per QALY saved. The majority of the HIV infections prevented by PEP were among men and women who reported receptive anal intercourse exposure. Conclusions: PEP following sexual or drug use-related exposures could be a costeffective complement to existing HIV-prevention efforts in most MSA across the United

Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation “set point” is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10 000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.

Primary HIV infection is a critical and highly dynamic time period in the course of HIV infection. The initial pathologic processes are important in determining long-term disease progression. In the absence of our ability to eradicate the virus, identifying individuals during primary HIV infection and performing interventions that optimize outcome are important to provide adequate care to a newly infected patient and, from a public health perspective, to identify sexual networks and provide a platform to reduce HIV exposures during a time of high viremia.

In a prospective open-label study, 41 male subjects received nelfinavir, zidovudine, and lamivudine stratified as either: early stage (ES; negative/indeterminate Western blot; n = 19) or late stage (LS; positive Western blot; n = 22) primary HIV-1 infection. Despite higher median baseline HIV-1 RNA levels and lower CD4(+) cell numbers in the ES subjects, a significantly greater decline in viral load (-3.46 vs. -2.83 log(10) copies/ml; p = 0.023) and increase in CD4(+) cell number (+85 vs. +41 cells/month increase, p = 0.01) were observed over the first 3 months of therapy such that both groups had comparable results at 1 year. The proportion with HIV-1 RNA50 copies/mL at 1 year was similar (9 of 19 ES subjects and 11 of 22 LS subjects by intention-to-treat analysis). Memory CD4(+) cell numbers, and activated CD4(+) percentages, were also significantly improved in ES subjects. Despite poorer prognostic markers at baseline ES subjects achieved responses similar to those of LS subjects after 1 year of treatment.

Whereas T-cell activation parameters of HIV disease have been extensively studied, the activation status of circulating monocytes has received less attention. Sixty-one subjects with primary HIV infection were evaluated by fluorescent-activated cell sorter (FACS) analysis at baseline (pretreatment) for CD4 T-cell count, CD4 T-cell apoptosis, and immune activation. A subset of 15 subjects with marked elevated (3 standard deviations above normal) monocyte DR expression had significantly reduced CD4 T-cell counts at baseline (p

6525 Background: Sustainable approaches to improve quality and safety of care of patients with advanced cancer while concurrently reducing costs is a growing national need. As part of the Veterans Administration Engagement of Patients with Advanced Cancer (EPAC) trial, we trained a lay health worker (LHW) to engage patients with stage 3 and 4 cancer in early advance care planning (ACP). The goal of this follow-up study was to examine the effect of the LHW intervention on patient-reported care experiences, healthcare utilization, and costs in the last 30 days of life for patients who died within 15 months of enrollment. Methods: We evaluated patient-reported experiences with decision-making, healthcare utilization, and total healthcare costs 30 days prior to death. A T-test was used to compare patient experiences with decision-making. To compare ED use and hospitalizations, we utilized an exact Poisson regression. A generalized linear model with gamma link-log function was used to compare total costs. The latter methods adjusted for length of follow-up. Results: In the 30 days prior to death, 60 patients died in each arm within 15 months of enrollment (difference not statistically significant). Patients in the intervention had significantly improved rates of ACP documentation (98% versus 18% p < 0.001), improved experiences with decision-making as measured by an index ranging from 0-5 with higher values representing more favorable experience (4.73 (SD 0.61) vs 4.15 (SD 1.02)) p < 0.001), higher utilization of hospice (77% vs 52%, p < 0.005), lower rates of any emergency department use (5% versus 45% p < 0.001) and any hospitalization (5% versus 43% p < 0.001), and significantly lower total costs of care ($1,048 versus $23,482 p < 0.001) compared to the patients randomized to the usual care arm. Conclusions: Integrating a LHW into oncology care to engage patients in early advance care planning resulted in significantly improved patient experience, decreased utilization and decreased total costs in the last month of life. LHWs may represent a sustainable resource to facilitate optimal patient-centered cancer care at the end-of-life. Clinical trial information: NCT02966509.

We employed a partnered research healthcare delivery redesign process to improve care for high-need, high-cost (HNHC) patients within the Veterans Affairs (VA) healthcare system.Health services researchers partnered with VA national and Palo Alto facility leadership and clinicians to: 1) analyze characteristics and utilization patterns of HNHC patients, 2) synthesize evidence about intensive management programs for HNHC patients, 3) conduct needs-assessment interviews with HNHC patients (n = 17) across medical, access, social, and mental health domains, 4) survey providers (n = 8) about care challenges for HNHC patients, and 5) design, implement, and evaluate a pilot Intensive Management Patient-Aligned Care Team (ImPACT) for a random sample of 150 patients.HNHC patients accounted for over half (52 %) of VA facility patient costs. Most (94 %) had three or more chronic conditions, and 60 % had a mental health diagnosis. Formative data analyses and qualitative assessments revealed a need for intensive case management, care coordination, transitions navigation, and social support and services. The ImPACT multidisciplinary team developed care processes to meet these needs, including direct access to team members (including after-hours), chronic disease management protocols, case management, and rapid interventions in response to health changes or acute service use. Two-thirds of invited patients (n = 101) enrolled in ImPACT, 87 % of whom remained actively engaged at 9 months. ImPACT is now serving as a model for a national VA intensive management demonstration project.Partnered research that incorporated population data analysis, evidence synthesis, and stakeholder needs assessments led to the successful redesign and implementation of services for HNHC patients. The rigorous design process and evaluation facilitated dissemination of the intervention within the VA healthcare system.Employing partnered research to redesign care for high-need, high-cost patients may expedite development and dissemination of high-value, cost-saving interventions.

A growing body of evidence highlights the importance of competent mentoring in academic research in the field of HIV, particularly for early stage investigators from diverse, underrepresented backgrounds. We describe the development and implementation of a 2-day intensive workshop to train mid-level and senior-level investigators conducting HIV-related clinical and translational research across multiple academic institutions on more effective mentoring, with an emphasis on techniques to foster mentees of diversity. The workshop was focused on training mentors in techniques designed to improve the effectiveness of the mentor-mentee relationship, and included didactic presentations, interactive discussions, and small-group problem-based learning activities. Mid-level or senior-level faculty involved or planning to be involved in significant mentorship activities related to HIV research were eligible. Surveys and formal actions plans allowed for workshop evaluation and laid the groundwork for subsequent workshops. Twenty-six faculty from 16 U.S.-based institutions participated, with good representation across discipline, gender, and race/ethnicity. The sessions were highly rated and discussions and evaluations revealed important barriers and facilitators to mentoring, challenges and solutions related to mentoring mentees from diverse backgrounds, and specific tools to enhance mentoring effectiveness. The Mentoring the Mentors training program for HIV researchers focusing on early career investigators of diversity was the first of its kind and was well attended, was rated highly, and provided guidance for improving the program in the future. This training program fills an important gap in the HIV researcher community and offers guidance for training mentors interested in diversity issues in settings outside of HIV.

In a nonrandomized study of nonoccupational postexposure prophylaxis (PEP), a cross-sectional evaluation of subjects who were the source of human immunodeficiency (HIV) exposure was performed to characterize partners of index subjects seeking nonoccupational PEP against HIV. Among 401 index subjects, 64 (16%) recruited a source subject. Those in a steady relationship and those who knew that the source subject was HIV antibody positive were more likely to recruit their source subject. Source subjects reported high rates of past (78%) and current (69%) antiretroviral use; 46% of those using antiretroviral drugs had detectable plasma HIV-1 RNA levels. Antiretroviral resistance was detected in many source subjects who reported any use of antiretrovirals and was rare among source subjects who reported no history of antiretroviral use. Clinicians often make treatment decisions on the basis of incomplete knowledge of the source subject's HIV status or antiretroviral treatment history. The treatment history, particularly nonuse of a class of antiretroviral drugs, can be used to predict drug resistance.

Although changing patterns in antimicrobial resistance in Streptococcus pneumoniae have prompted several surveillance initiatives in recent years, the frequency with which these studies are needed has not been addressed. To approach this issue, the extent to which resistance patterns change over a 1-year period was examined. In this study we analyzed S. pneumoniae antimicrobial susceptibility results produced in our laboratory with isolates obtained over 2 consecutive years (1997–1998 and 1998–1999) from the same 96 institutions distributed throughout the United States. Comparison of results revealed increases in resistant percentages for all antimicrobial agents studied except vancomycin. For four of the agents tested (penicillin, cefuroxime, trimethoprim-sulfamethoxazole, and levofloxacin), the increases were statistically significant ( P < 0.05). Resistance to the fluoroquinolone remained low in both years (0.1 and 0.6%, respectively); in contrast, resistance to macrolides was consistently greater than 20%, and resistance to trimethoprim-sulfamethoxazole increased from 13.3 to 27.3%. Multidrug resistance, concurrent resistance to three or more antimicrobials of different chemical classes, also increased significantly between years, from 5.9 to 11%. The most prevalent phenotype was resistance to penicillin, azithromycin (representative macrolide), and trimethoprim-sulfamethoxazole. Multidrug-resistant phenotypes that included fluoroquinolone resistance were uncommon; however, two phenotypes that included fluoroquinolone resistance not found in 1997–1998 were encountered in 1998–1999. This longitudinal surveillance study of resistance in S. pneumoniae revealed that significant changes do occur in just a single year and supports the need for surveillance at least on an annual basis, if not continuously.

The feasibility of providing postexposure prophylaxis (PEP) after sexual or injection drug use exposures to human immunodeficiency virus (HIV) was evaluated. PEP was provided within 72 h to individuals with exposures from partners known to have or to be at risk for HIV infection. PEP consisted of 4 weeks of antiretroviral medications and individually tailored risk-reduction and medication-adherence counseling. Among 401 participants seeking PEP, sexual exposures were most common (94%; n=375). Among sexual exposures, receptive (40%) and insertive (27%) anal intercourse were the most common sexual acts. The median time from exposure to treatment was 33 h. Ninety-seven percent of participants were treated exclusively with dual reverse-transcriptase inhibitors, and 78% completed the 4-week treatment. Six months after the exposure, no participant developed HIV antibodies, although a second PEP course for a subsequent exposure was provided to 12%. PEP, after nonoccupational HIV exposure, is feasible for persons at risk for HIV infection.

Recent advances in the ability to detect people at the early stages of HIV infection now permit the initiation of antiretroviral treatment before the full complement of antiviral immune responses has evolved. However, the influence of early treatment interventions on the developing anti-HIV immune response is unknown. This study investigates the impact of standard highly active antiretroviral therapy (HAART) during the primary stages of HIV infection on the plasma HIV-1 RNA level, CD4 + and CD8 + lymphocyte counts, and the CD8 + cell anti-HIV response. Individuals treated with HAART within 6 months of infection showed dramatic and rapid reductions in HIV-1 RNA levels along with modest increases in CD4 + cell number and decreases in CD8 + cell numbers. A significant reduction in the level of CD8 + cell noncytotoxic suppression of HIV replication was observed over time in most participants receiving HAART. Importantly, those individuals choosing not to receive therapy maintained low but detectable HIV-1 RNA levels and showed no reduction in their CD8 + cell antiviral response. These results suggest that either continued antigenic challenge is required to sustain CD8 + cell-mediated anti-HIV activity, or that HAART has some inhibitory effect on this important immunologic function during the early stages of infection.

The effects of early antiretroviral therapy on the peripheral CD8+ T-cell population were assessed by sequentially determining the T-cell receptor (TCR) repertoire complexity in a cohort of 15 individuals recently diagnosed with human immunodeficiency virus infection. Analysis was based on quantitative TCR variable B gene (TCRBV) usage and complementary-determining region 3 length assessment. Repertories were assessed at baseline and at weeks 2, 4, 12, 24, and 72 after initiation of therapy. Early administration of highly active antiretroviral therapy has a positive effect on the preservation and homeostasis of the CD8+ cell repertoire. Nevertheless, differences from average baseline and control TCR profiles and initial development of repertoire perturbations were observed. The findings suggest that additional therapeutic protocols will be required during primary infection to significantly prevent long-term erosion of the T-cell–mediated immune response.

Between 1981 and 1999, more than 110,00 cases of the acquired immunodeficiency syndrome (AIDS) have been reported in California, of whom nearly 70,000 patients have died. Since 1983, the University of California has funded basic, clinical, social, and behavioral research on the human immunodeficiency virus (HIV)/AIDS through the University wide AIDS ResearchProgram (UARP). Major accomplishments of UARP-supported research include the isolation and characterization of HIV, the detection and elimination of HIV in blood clotting factor VIII, and in early studies, the demonstration of the rapid production and turnover of HIV in the blood of infected persons. Together with its advisory group, the University wide Task Force on AIDS, UARP convenes an annual meeting that provides an opportunity for the exchange of new information on HIV/AIDS in California. Participants include bench scientists, clinicians, policymakers, outreach workers, community-based organizations, and members of affected communities. Most of the studies presented at the UARP conference are in their early stages and modestly funded. While some go on to receive larger federal grants, others are quickly integrated into new interventions or investigations. In this issue of wjm, we share highlights of the 3rd AnnualConference on AIDS Research inCalifornia.† The plenarytheme for the year 2000 was “Early Events and Intervention in HIVInfection.” Although the recent and ongoing advances in highly active antiretroviral therapy are well known, the meeting provided a fertile venue for presenting other innovative areas for treatment and prevention.

HIV-specific antibodies and CD8 + T cell antiviral responses were evaluated in three human immunodeficiency virus 1 (HIV-1) gp120 vaccine recipients who later became infected with HIV-1. Titers of ...

Eleven HIV-1 seronegative subjects previously injected with an HIV-1 p17 synthetic peptide vaccine (HGP-30) were given two booster immunizations to evaluate memory cell responses and the ability to boost cellular and humoral immune responses. Five of 11 subjects showed a significant increase in their antibody titres to HGP-30 or p17 and 6/11 had T-cell proliferation responses to either HGP-30 or p17. HIV-1 virus challenge studies in SCID mice demonstrated that 39 of 50 mice (78%) receiving PBMC from 5 of the HGP-30 immunized subjects were protected from infection with a different strain of HIV-1 compared to 4 of 30 mice (13%) that received PBMC from 3 non-immunized subjects (p < 0.001). These studies show that booster immunizations with HGP-30 vaccine are safe and non-toxic and induce protective cell mediated immune responses.

OBJECTIVE The primary objective was to compare the effects of dual or triple combinations of HIV-1 reverse transcriptase inhibitors with respect to survival. The time to new HIV disease progression or death, toxicities, the change in CD4 cells, and plasma HIV-1 RNA concentrations in a subset of study subjects were evaluated. DESIGN This was a multicenter randomized, double-blind, placebo-controlled study. SETTING The study was conducted among 42 adult AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation centers. PATIENTS 1313 HIV-infected patients with CD4 counts < or = 50 cells/mm3 participated in this study, which was conducted from June 1993 to June 1996. INTERVENTION Patients were randomized to one of four daily regimens containing 600 mg of zidovudine: zidovudine alternating monthly with 400 mg didanosine; zidovudine plus 2.25 mg of zalcitabine; zidovudine plus 400 mg of didanosine; or zidovudine plus 400 mg of didanosine plus 400 mg of nevirapine (triple therapy). MAIN OUTCOME MEASURES The main outcome was survival (i.e., time to death). RESULTS A significant difference in survival time was found between the four treatment groups, favoring those assigned to triple therapy (p = .02). A significant difference was also found in the delay of disease progression or death among the four treatment arms favoring the group assigned to triple therapy (p = .002). Baseline CD4 cell counts and plasma HIV-1 RNA concentrations as well as changes of CD4 counts at week 8 predicted survival for subjects in the virology substudy. CONCLUSIONS In the pre-protease inhibitor era, a combination of triple reverse transcriptase inhibitors prolonged life and delayed disease progression in AIDS patients with advanced immune suppression.

9-[2-( R )-(Phosphonomethoxy)propyl]adenine (PMPA) is a nucleotide analogue with potent antiretroviral activity in vitro and in simian models. A randomized, double-blind, placebo-controlled, dose-escalation clinical trial of intravenous PMPA monotherapy was conducted in 20 human immunodeficiency virus (HIV)-infected adults with CD4 cell counts of ≥200 cells/mm 3 and plasma HIV RNA levels of ≥10,000 copies/ml. Two dose levels were evaluated (1 and 3 mg/kg of body weight/day). Ten subjects were enrolled at each dose level (eight randomized to receive PMPA and two randomized to receive placebo). On day 1, a single dose of PMPA or placebo was administered by intravenous infusion. Beginning on study day 8, PMPA or placebo was administered once daily for an additional 7 consecutive days. All subjects tolerated dosing without significant adverse events. Mean peak serum PMPA concentrations were 2.7 ± 0.9 and 9.1 ± 2.1 μg/ml in the 1- and 3-mg/kg cohorts, respectively. Serum concentrations declined in a biexponential fashion, with a terminal half-life of 4 to 8 h. At 3 mg/kg/day, a single infusion of PMPA resulted in a 0.4 log 10 median decline in plasma HIV RNA by study day 8. Following 7 consecutive days of study drug administration thereafter, the median changes in plasma HIV RNA from baseline were −1.1, −0.6, and 0.1 log 10 in the 3-mg/kg/day, 1-mg/kg/day, and placebo dose groups, respectively. Following the final dose in the 3-mg/kg/day cohort, the reduction in HIV RNA was sustained for 7 days before returning toward baseline. Further studies evaluating an oral prodrug of PMPA are under way.

Combination treatments with agents that inhibit protease and reverse transcriptase of human immunodeficiency virus type 1 (HIV-1) decrease mortality and slow disease progression.1 The development of resistance to these drugs, however, limits the benefit of such treatments.2,3 There have been reports of the transmission of HIV-1 variants that are resistant to nucleoside and non-nucleoside inhibitors of reverse transcriptase.4–9 The transmission of HIV-1 variants that are resistant to protease inhibitors could represent an important emerging clinical and public health problem. We report a case of transmission of an HIV-1 variant with multiple mutations that conferred resistance to both protease . . .

This paper is devoted to the determination of the spin distribution in the spin triplet ground state of [Cu-2(t-Bupy)(4)(N-3)(2)](ClO4)(2), With t-Bupy = p-tert-butylpyridine. The crystal structure, previously solved at room temperature from X-ray diffraction, has been redetermined at 18 K from unpolarized neutron diffraction. The structure consists of binuclear cations in which Cu2+ ions are doubly bridged by azido groups in the 1,1-fashion, and noncoordinated perchlorate anions. The experimental spin distribution has been determined from polarized neutron diffraction (PND) at 1.6 K under 50 kOe. The spin populations have been found to be strongly positive on the Cu2+ ions, weakly positive on the terminal and bridging nitrogen atoms of the azido groups as well as on the nitrogen atoms of the t-Bupy ligands, and weakly negative on the central nitrogen atoms of the N-3(-) bridges. The PND results have been discussed. The spin distribution in [Cu-2(t-Bupy)(4)(N-3)2](ClO4)(2) has been analyzed as resulting from a spin delocalization from the Cu2+ ions toward the azido bridges, to which a spin polarization effect within the azido pi orbitals is superimposed. The experimental data have been compared to the results of DFT calculations. The spin density map is qualitatively reproduced; however, the DFT calculations overestimate the spin delocalization from the Cu2+ ions toward the peripheral and bridging ligands.

Some 3dn(4 ≤ n ≤ 7) transition metal compounds exhibit a cooperative transition between a low-spin (LS) and a high-spin (HS) state. This transition is abrupt and occurs with a thermal hysteresis, which confers a memory effect on the system. The intersite interactions and thus the cooperativity are magnified in polymeric compounds such as [Fe(Rtrz)3]A2·nH2O in which the Fe2+ions are triply bridged by 4-R-substituted-1,2,4-triazole molecules. Moreover, in these compounds, the spin transition is accompanied by a well-pronounced change of color between violet in the LS state and white in the HS state. The transition temperatures of these materials can be fine tuned, using an approach based on the concept of a molecular alloy. In particular, it is possible to design a compound for which room temperature falls in the middle of the thermal hysteresis loop. These materials have many potential applications, for example, as temperature sensors, as active elements of various types of displays, and in information storage and retrieval.

We conducted a longitudinal study of participants in phase I and II HIV vaccine safety and immunogenicity trials to examine changes in sexual risk behavior that are associated with risk of HIV transmission. The participants were 48 HIV-negative men and women enrolled in one of two placebo-controlled HIV vaccine trials conducted at San Francisco General Hospital. There was a significant increase in insertive unprotected anal intercourse (UAI) from 9% at baseline (trial entry), to 13% at the month 6 assessment, to 20% at the month 12 assessment (p = .02). The primary predictor of either insertive or receptive UAI during the vaccine trials was having engaged in this behavior prior to entry (p = .001). Higher-risk behavior was also seen among participants who were younger and had multiple sexual partners (each, p = .06) and who indicated that one of their reasons for participation in the vaccine trial was hope of protection from HIV infection (p = .07). These findings indicate that despite instructions otherwise, participants with a history of high-risk behavior or who express hope of protection from HIV infection by enrolling in vaccine trials may be candidates for more intensive risk-behavior counseling prior to and during their participation.

The present investigation shows the complementarity of neutron and X-ray diffraction studies. Neutron and X-ray diffraction experiments on a single crystal of Mn(cth)Cu(oxpn) (CF3SO3)(2) have been performed in order to study the nuclear structure and to

Recombinant human granulocyte-macrophage colony-stimulating factor (rHu GM-CSF) enhances bone marrow production of and stimulates granulocytes, macrophages, and eosinophils. Granulocyte-macrophage colony-stimulating factor may be used concomitantly with zidovudine in human immunodeficiency virus (HIV)-positive patients to minimize zidovudine-associated neutropenia. This open-label, randomized, placebo-controlled study was performed to evaluate the pharmacokinetic disposition of rHu GM-CSF in HIV-positive, asymptomatic patients in the absence and presence of concomitant zidovudine administration. Eight participants received rHu GM-CSF (5 micrograms/kg subcutaneously) daily for 4 days in combination with placebo or zidovudine (200 mg orally every 8 hours) in a randomized, crossover fashion, with each study period separated by a 3-day washout phase. Pharmacokinetic blood sampling was performed over 16 hours on days 1 and 4 of both treatment periods, and subsequent analysis of serum was performed using an enzyme-linked immunosorbent assay. Pharmacokinetic results of rHu GM-CSF at steady state (days 4 of periods I and II) in the absence (placebo) and presence of zidovudine included apparent total body clearance, half-life, and apparent volume of distribution, all of which were not significantly altered with concomitant administration of zidovudine. Mean pharmacokinetic results of rHu GM-CSF after the first dose (days 1 of periods I and II) were similar to steady-state values; however, total body clearance was significantly increased at steady state compared with the results of the first dose. Concurrent administration of zidovudine does not influence the pharmacokinetic disposition of rHu GM-CSF after single or multiple doses.

Human immunodeficiency virus (HIV)-1 RNA level in plasma was evaluated as a surrogate marker for disease progression in a clinical trial of advanced HIV-1 infection. Baseline HIV-1 RNA level was an independent predictor of disease progression (relative hazard [RH] for each doubling of HIV-1 RNA level, 1.26 ; 95% confidence interval [CI], 1.03-1.54 ; P =.02), after adjusting for the week 4 change in HIV-1 RNA level, baseline CD4 cell count, syncytium-inducing phenotype, clinical status at study entry, and therapy randomization. A 50% reduction in HIV-1 RNA level was associated with a 27% decrease in the adjusted risk of disease progression during the study (RH, 0.73 ; 95% CI, 0.52-1.02 ; P =.07). The partial validation of HIV-1 RNA as a predictor for clinical end points has implications for the use of HIV-1 RNA in clinical trials and practice.

The association of plasma human immunodeficiency virus type 1 (HIV-1) RNA level at study entry and over time with clinical progression was evaluated in 187 patients from AIDS Clinical Trials Group protocol 116A who had little or no prior zidovudine treatment. Three-fold-higher HIV-1 RNA levels at study entry and 3-fold increases by week 8 were associated with progression (relative hazard [RH], 1.67 ; 95% confidence limits [CL], 1.20, 2.32 ; and RH, 1.45 ; CL, 1.02, 2.05, respectively). Having 3-fold-higher CD4 cell count at entry was independently associated with a 52% reduction in risk for progression (adjusted RH, 0.48 ; CL, 0.33, 0.70). When stratified by length of prior zidovudine therapy, RNA level was predictive in drug-naive patients (adjusted RH, 1.87 ; CL, 1.23, 2.85) but not predictive in patients with up to 16 weeks of prior therapy (adjusted RH, 1.11 ; CL, 0.70, 1.76). Analysis suggests that the acquisition of mutations at HIV-1 reverse transcriptase codons 215 and 74 is associated with subsequent increases in HIV-1 RNA level (relative risk, 7.00 ; CL, 0.86, 56.90).