A systematic analysis of ultrastructural lesions in the Plasmodium coatneyi splenectomized rhesus macaque model of severe malaria.

Plasmodium falciparum remains one of the world's deadliest diseases and with ongoing concerns of evolving drug resistance, there is a need for continued refinement of the Plasmodium coatneyi infection model in macaques to study severe malaria. As such, the systemic ultrastructural lesions associated with P. coatneyi infection in splenectomized rhesus macaques was evaluated in 6 animals. Autopsy samples from multiple areas of the central nervous system (CNS), kidneys, heart, liver, and lungs of all 6 animals were processed for electron microscopy. A systematic analysis of the ultrastructural changes associated with the plasmodium was undertaken by multiple pathologists to ensure consensus. All tissues exhibited marked sequestration of infected red blood cells comprised either of cytoadherence to endothelium or rosette formation, associated with variable degrees of host cell damage in a range of tissues that in severe cases resulted in necrosis. This is the first complete systemic evaluation of ultrastructural tissue lesions in P. coatneyi-infected rhesus macaques, and the findings have important implications evaluating of the use of this model for the study of severe malaria caused by P. falciparum in humans.

Management of Latent Tuberculosis Infection Among Healthcare Workers: 10-Year Experience at a Single Center.

BACKGROUND: The risk of infection with Mycobacterium tuberculosis among healthcare workers (HCWs) is estimated to be higher than the general population. However, HCW acceptance and compliance with available latent tuberculosis infection (LTBI) treatment regimens has been problematic. Recently, regimens have become available that might improve HCW acceptance and compliance with LTBI treatment. METHODS: A retrospective single-center review of Employee Health and Wellness Services records of all HCWs diagnosed with LTBI was conducted. HCWs diagnosed with LTBI were offered 9-month isoniazid (INH), 4-month rifampin (RIF), weekly rifapentine/isoniazid (RPT/INH) for 12 weeks, or no treatment. Acceptance, completion rates, and side effects were reported for each regimen. Comparisons of regimens were assessed using Fisher exact test. RESULTS: Between 2005 and 2014, 363 of 927 (39%) HCWs diagnosed with LTBI accepted treatment. Of 363, 202 chose INH, 106 RIF, and 55 RPT/INH. Completion rates for each regimen were 58%, 80%, and 87%, respectively. HCWs were significantly more likely to have completed treatment with RIF (P < .0001) or RPT/INH (P < .0001) than INH. Rates of discontinuation owing to side effects were 35% for INH, 21% for RIF, and 10% for RPT/INH. Discontinuation of therapy due to side effects was significantly more frequent in the INH than the RPT/INH group (P = .0042). CONCLUSIONS: Completion of RIF and RPT/INH for LTBI in an HCW population is more likely than INH. Rates of discontinuation due to side effects were lower among those taking RPT/INH. Shorter LTBI treatment regimens should be more widely considered for HCWs in the United States.

Utilization of Electronic Health Record Events to Conduct a Tuberculosis Contact Investigation in a High-Risk Oncology Unit.

OBJECTIVE To describe the utilization of electronic medical data resources, including health records and nursing scheduling resources, to conduct a tuberculosis (TB) exposure investigation in a high-risk oncology unit. SETTING A 42-bed inpatient unit with a mix of surgical and medical patients at a large tertiary-care cancer center in New York City. PARTICIPANTS High-risk subjects and coworkers exposed to a healthcare worker (HCW) with cavitary smear positive lung TB. RESULTS During the 3-month exposure period, 270 patients were admitted to the unit; 137 of these (50.7%) received direct care from the index case HCW. Host immune status and intensity of exposure were used to establish criteria for postexposure testing, and 63 patients (45%) met these criteria for first-tier postexposure testing. No cases of active TB occurred. Among coworkers, 146 had significant exposure (ie, >8 hours cumulative). In the 22-month follow-up period after the exposure, no purified protein derivative or interferon gamma release assay conversions or active cases of TB occurred among exposed HCWs or patients. CONCLUSIONS Electronic medical records and employee scheduling systems are useful resources to conduct otherwise labor-intensive contact investigations. Despite the high-risk features of our index case, a highly vulnerable immunocompromised patient population, and extended proximity to coworkers, we did not find any evidence of transmission of active or latent tuberculosis infection among exposed individuals. Infect Control Hosp Epidemiol 2017;38:1235-1239.

HLA class II restriction of HIV-1 clade-specific neutralizing antibody responses in ethnic Thai recipients of the RV144 prime-boost vaccine combination of ALVAC-HIV and AIDSVAX(®) B/E.

Immune responses to vaccines may be influenced or associated with allelic variants of host genes such as those encoding human leucocyte antigens (HLA). We have molecularly determined the HLA class II DR and DQ gene, allele and haploype profiles in HIV-1 negative ethnic Thai recipients of an HIV-1 prime boost vaccine regimen, designed to induce neutralizing antibody (NAb) responses to HIV-1 CRF01_AE. Non-response to vaccine associated with DRB1*11 (3/32 responders vs. 7/13 non-responders, p(c)=0.027) and DRB1*16:02 (0/32 responders vs. 4/13 non-responders, p(c)=0.078) alleles. Furthermore, vaccine recipients with HLA-DQ heterodimers encoded by DQA1*05:01 and DQB1*03:01 alleles, were much less likely to produce NAb (p=0.009). These data suggest that the lack of response to a vaccine designed to induce clade-specific NAb to HIV-1 is associated with the presence of certain HLA class II alleles and heterodimers in some Southeast Asians.

Cancer surgeons' distress and well-being, II: modifiable factors and the potential for organizational interventions.

PURPOSE: We showed in a companion paper that the prevalence of burnout among surgical oncologists at a comprehensive cancer center was 42% and psychiatric morbidity 27%, and high quality of life (QOL) was absent for 54% of surgeons. Here we examine modifiable workplace factors and other stressors associated with burnout, psychiatric morbidity, and low QOL, together with interest in interventions to reduce distress and improve wellness. METHODS: Study-specific questions important for morale, QOL, and stressors associated with burnout were included in an anonymous Internet-based survey distributed to the surgical faculty at Memorial Sloan-Kettering Cancer Center. RESULTS: Among the 72 surgeons who responded (response rate of 73%), surgeons identified high stress from medical lawsuits, pressure to succeed in research, financial worries, negative attitudes to gender, and ability to cope with patients' suffering and death. Workplace features requiring greatest change were the reimbursement system, administrative support, and schedule. Work-life balance and relationship issues with spouse or partner caused high stress. Strongest correlations with distress were a desire to change communication with patients and the tension between the time devoted to work versus time available to be with family. Surgeons' preferences for interventions favored a fitness program, nutrition consultation, and increased socialization with colleagues, with less interest in interventions conventionally used to address psychological distress. DISCUSSION: Several opportunities to intervene at the organizational level permit efforts to reduce burnout and improve QOL.

Cancer surgeons' distress and well-being, I: the tension between a culture of productivity and the need for self-care.

BACKGROUND: Burnout is a prevalent and important occupational hazard among surgical oncologists. The well-being or distress experienced can have a significant effect on clinicians and their families, the quality of care provided to patients, and the success of the health care organization. METHODS: We aimed to measure the prevalence of burnout, psychiatric morbidity, and quality of life using standardized measures; characterize associated features; and ascertain the surgical faculty's views on potential interventions and obstacles to change. Additional questions about service commitment to well-being, use of annual leave, and attitudes about weekend surgical practice were constructed to guide future targeted interventions. RESULTS: Among the 72 surgeons who responded (response rate of 73%), we found that 42% of surgeons reported burnout and 27% psychiatric levels of distress, while 30% used alcohol and 13% used sleep medications as a possible means to cope. Only one third of surgeons reported high quality of life across physical, emotional, spiritual, and intellectual domains. DISCUSSION: Compared to general surgical practices, cancer surgeons achieved more personal fulfillment and made less use of distancing methods to cope with their patients. Institutional culture contributes to the nonuse of available annual leave, attitudes about weekend operating schedules, and missed opportunities for the leadership to attend to surgeons' well-being.

Serum levels of MIP-1beta and RANTES in HIV-1 subtype CRF01_AE infected patients with different rates of disease progression.

The beta-chemokines have been shown to inhibit HIV replication in vitro. To evaluate the role of serum beta-chemokines in disease progression and their anti-viral role in vivo, we determined serum levels of macrophage inflammatory protein-1beta (MIP-1beta) and regulated upon activation normal T-cell expressed and secreted (RANTES) of twenty HIV-1 subtype CRF01_AE infected patients: nine progressors (PRs, follow-up CD4+ cell count < 200/mm3 and progression to AIDS or death) and eleven slower progressors (SPs, asymptomatic and/or follow-up CD4+ cell counts > 350/mm3 at the end of follow-up) and determined their plasma viral loads. The subjects were followed for at least 36 months. All had initial CD4 values > 350 cells/mm3. In this longitudinal study, serum levels of MIP-1beta and RANTES in specimens obtained either early or later in the course of HIV infection did not differ significantly between progressors and slower progressors (p > 0.05). There were no significant changes in serum MIP-1beta and RANTES levels over time in either patient group (p > 0.05). No significant associations were observed between plasma viral loads and the measured beta-chemokines (r = -0.205, p = 0.21 for MIP-1beta and r = -0.12, p = 0.492 for RANTES). The results suggest these chemokines do not play a major systemic role in control of viremia or protection against the progression of HIV disease.

A phase 1/2 comparative vaccine trial of the safety and immunogenicity of a CRF01_AE (subtype E) candidate vaccine: ALVAC-HIV (vCP1521) prime with oligomeric gp160 (92TH023/LAI-DID) or bivalent gp120 (CM235/SF2) boost.

BACKGROUND: The development of an effective HIV-1 vaccine is critical to control the pandemic. A prime-boost HIV-1 vaccine trial assessing safety and immunogenicity was conducted in Thailand as part of an evaluation of candidate regimens for a phase 3 efficacy trial. METHODS: ALVAC-HIV (vCP1521), expressing circulating recombinant form 01_AE (CRF01_AE) gp120/subtype B LAI and subtype B Gag/Protease boosted with recombinant envelope oligomeric CRF01_AE gp160 (ogp160) or bivalent CRF01_AE/subtype B gp120 CM235/SF2, was evaluated in a phase 1/II trial of 130 HIV-negative Thai adults. RESULTS: One hundred forty volunteers were enrolled, and 130 completed all safety and immunogenicity visits. Reactogenicity was common but generally mild, and there was no significant difference in the adverse event rate between vaccine and placebo recipients (P = 0.26). There were 7 serious adverse events during the follow-up period, none of which were vaccine related. Cumulative HIV-specific, CD8-mediated, cytotoxic T-lymphocyte responses were observed in 11 (25%) of 44 subjects who received ALVAC boosted by bivalent gp120 and in 5 (11%) of 45 subjects who received ALVAC boosted by ogp160, but these differences were not statistically significant compared with those in placebo recipients (P = 0.62 and P = 0.37, respectively). HIV-specific lymphoproliferative responses were detected in 84% of subunit-boosted vaccine recipients and in 10% of placebo recipients. Neutralizing antibody responses to CRF01_AE and subtype B laboratory strains were seen in 95% of ogp160-boosted and 100% of gp120 B/E-boosted vaccinees, respectively. CONCLUSIONS: These 2 different prime-boost regimens seem to be safe and displayed cell-mediated immune responses consistent with those in other trials of canarypox vectors.

Molecular epidemiology of HIV Type 1 in preparation for a Phase III prime-boost vaccine trial in Thailand and a new approach to HIV Type 1 genotyping.

To characterize HIV-1 genotypes in candidate populations for a prime-boost phase III vaccine trial in Thailand, specimens from prevalent and incident HIV-1 infections from a family planning clinic population in Rayong Province and a community cohort in Chon Buri Province, collected from 1998 to 2001, were genotyped. A new multiregion hybridization assay, MHAbce, capable of distinguishing HIV-1 CRF01_AE, subtype B, and subtype C and their recombinants, was developed and applied to prevalent infections. Most incident and selected prevalent infections were studied by complete genome sequencing. By MHAbce, 168 of 194 prevalent infections were genotyped. Of these, 90.5% were CRF01_AE, 2.4% were subtype B, and 7.2% showed discordant or dual probe reactivity, indicative of recombination or dual infection, respectively. Among 23 incident infections, 20 were sequenced. Eighteen CRF01_AE, one subtype B, and one CRF01/B recombinant strains were seen. Two CRF01/B and one CRF01/C recombinant were identified among selected prevalent infections. These results indicate that incident and prevalent HIV-1 infections in Rayong and Chon Buri during 1998-2001 were 90% CRF01_AE, 3% subtype B, and 7% either recombinant or dual. This study frames the genetic diversity of HIV-1 in these cohorts in their preparatory phase for the ongoing ALVACHIV (vCP1521) prime, AIDSVAX B/E boost, phase III vaccine trial and will provide a benchmark for interpretation and analysis.

Behavioral and social issues among volunteers in a preventive HIV vaccine trial in Thailand.

Behavioral and social issues were investigated in 363 phase I/II preventive HIV-1 vaccine trial volunteers in Thailand. These issues included risk behavior, HIV knowledge, distress, and social consequences of vaccine trial participation. Data were collected at baseline and at 4-, 8-, and 12-month follow-up visits. Volunteers reported relatively low levels of risk behaviors at baseline and at follow-up. Overtly negative reactions from family or friends were reported by 5.9%. No experiences of discrimination in employment, health care, or insurance were reported. Mean levels of distress were low throughout the trial, and HIV-related knowledge was high, although it was common to consider the possibility of HIV transmission through casual contact. Findings add to the evidence that preventive HIV vaccine trials are feasible in Thailand.

A standardized regimen of antibiotics prevents infectious complications in skull base surgery.

OBJECTIVES/HYPOTHESIS: Craniofacial surgery has been associated with a significant improvement in disease outcome for patients with skull base neoplasms. Despite this improved survival, complications remain considerable. One major source of complications is infectious events. The current study was designed to evaluate a prospectively designed antibiotic regimen and its impact on the incidence and severity of infectious complications. This regimen was compared with a group of historic controls in which antibiotics were administered on an ad hoc basis. The specific objectives/hypothesis were to determine 1) the incidence and severity of infection in a group of patients treated with a nonstandardized antibiotic regimen undergoing craniofacial resection, and 2) whether the use of a prospectively designed, three-drug, broad spectrum antibiotic is associated with a reduced incidence and severity of infections. STUDY DESIGN: A single-arm, prospective antibiotic regimen consisting of ceftazidime, flagyl (metronidazole), and vancomycin (CMV) was compared with a historic control of patients treated with nonstandard antibiotic therapy (nonCMV), all of whom underwent craniofacial resection. Outcome measures focused on incidence of infection, severity of infection, and operative mortality. METHODS: In July 1990, a retrospective review (1973-1990) was performed of craniofacial resection. Beginning in July 1990, a prospective database (1990-2003) has been maintained. Demographics, prior therapy, anatomic site of origin and extent of disease, pathology, standard surgical data, and postoperative therapy were detailed. Antibiotic data were collected from chart review. Complications, focusing on infectious complications, were identified and categorized. Culture results and whether the inciting infection was sensitive or resistant to perioperative antibiotics were noted. Length of hospital stay was tabulated. Disease outcome, including incidence of postoperative mortality, was maintained for each patient. RESULTS: A total of 211 patients underwent craniofacial resection from 1973 to 2003. Major medical comorbidities were present in 53 (25%) patients, and 96 (46%) had prior therapy. The standardized antibiotic therapy (CMV) was used in 90 patients, and the nonstandardized antibiotics (nonCMV) were used in 107 patients. Free flap reconstruction was the sole surgical factor associated with a marked reduction in complications. Infectious wound complications were 11% within the CMV group versus 29% in the nonCMV regimen (P = .002). Moreover, the severity of infections was greatly diminished in the CMV group (P = .0001). With use of a multivariate analysis, the only factor which was predictive of infectious complications was the use of CMV. Patients who received nonCMV antibiotic therapy faced a risk of infection that was 2.5 times higher than those who received CMV. Hospital stay in days and operative mortality were both adversely affected by the use of nonCMV antibiotic therapy. CONCLUSIONS: The data supports the hypothesis that the use of a three-drug, broad spectrum antibiotic regimen in skull base surgery reduces the incidence of infectious complications and appears to reduce operative mortality. Broad spectrum coverage of Gram-positive, Gram-negative, and anaerobic pathogens leads to a marked reduction in infectious complications. Broad spectrum antibiotic coverage avoids many infectious complications and ultimately had a positive impact on patient outcome, quality of life, and, potentially, survival.

Antibody-dependent cell-mediated cytotoxic responses in participants enrolled in a phase I/II ALVAC-HIV/AIDSVAX B/E prime-boost HIV-1 vaccine trial in Thailand.

Antibody-dependent cell-mediated cytotoxicity (ADCC) was assessed in volunteers participating in an ALVAC-HIV (vCP1521)/AIDSVAX B/E gp120 prime-boost vaccine trial in Thailand. ADCC activity was measured using chromium release from gp120 subtype B- and CRF01_AE-coated targets in 95 vaccinees and 28 placebo recipients. There was a significant difference in the magnitude of the ADCC response to both targets between vaccinees and placebo recipients. The frequency of responders to subtype B and to CRF01_AE was 96% and 84% in the vaccine group versus 11% and 7% in the placebo group. The results demonstrate that this HIV vaccine is a potent inducer of ADCC activity and may be an additional protection of this prime-boost vaccine in preventing HIV disease.

The development of HIV research laboratories in the Royal Thai Army Medical Department.

The development of HIV research laboratories at the Armed Forces Research Institute of Medical Sciences (AFRIMS), Royal Thai Army Medical Department in supporting of HIV-1 vaccine trials in Thailand was implemented in 1991. The collaboration between AFRIMS, Royal Thai Army Medical Department, and the US Military HIV Research Program with the ultimate goal to conduct the HIV-1 vaccine trial phase III. The HIV serology lab was set up for surveillance program in military recruits. Then, there was a need to strengthen more on the existing laboratories by training personnel to cope with the confidentiality of the lab results, specimen processing and data management which are critical. Later on, the necessary laboratory for measuring of vaccine immunogenicity was developed, such as lymphoproliferation assay. Additionally, a molecular biology lab was also developed. The HIV research laboratory management must include an ability to deal with some problems, such as late specimen receiving, fluctuating of power supply, technical staffs maintained. Good laboratory practices and safety must be strictly implemented. Communication network among facilities also played an important role in HIV laboratory strengthening at AFRIMS.

Changes in HIV prevalence among young Thai men as defined by hepatitis C co-infection as a marker for mode of transmission.

To obtain a better understanding of the evolving HIV-1 epidemic in Thailand, we utilized antibody to hepatitis C virus (HCV) to indicate the mode of HIV-1 transmission. Although the proportion of men with HCV co-infection increased between 1995 and 2000, the prevalence was similar, whereas the prevalence of men not co- infected decreased (1.93-0.46%). This suggests that HIV-1 infection associated with parenteral transmission has been stable despite a dramatic reduction in the sexual transmission of HIV-1.

In vitro susceptibility of Thai seronegative donor CD8+ T lymphocytes to human immunodeficiency virus-1 (HIV-1) infection.

To determine whether CD8+ T lymphocytes from Thai donor cells are susceptible to HIV-1 infection, undepleted peripheral blood mononuclear cells (PBMC) and CD8-enriched PBMC were infected with HIV-1 Thai subtype B and CRF01_AE (E) primary isolates. Virus kinetics in HIV-1 infection of CD4+ and CD8+ T lymphocytes peaked at day 7 or 10 post infection (pi); the TCID50 used for cell infection was proportional to the level of p24 production in the cultures. We also found that the level of p24 antigen in the supernatants of infected undepleted PBMC was significantly higher than that of infected CD8-enriched PBMC. Interestingly, both single positive T lymphocytes (CD4+ and CD8+ T lymphocytes) as well as double positive CD4+/CD8+ T lymphocytes were infected with HIV-1. The double positive T lymphocytes in PBMC were found only in the presence of both CD4+ and CD8+ T lymphocytes. The majority of p24+/CD4-/CD8- T lymphocytes were HIV-1 infected CD4 down-modulated PBMC. This report provides direct evidence that single positive CD8+ T lymphocytes and double positive CD4+/ CD8+ T lymphocytes from Thai donors can be infected with HIV-1 subtypes B and E in vitro.