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Vaccine responses vary by geographic location. We have previously described how HIV-associated inflammation leads to fibrosis of secondary lymph nodes (LNs) and T cell depletion. We hypothesized that other infections may cause LN inflammation and fibrosis, in a process similar to that seen in HIV infection, which may lead to T cell depletion and affect vaccine responses. We studied LNs of individuals from Kampala, Uganda, before and after yellow fever vaccination (YFV) and found fibrosis in LNs that was similar to that seen in HIV infection. We found blunted antibody responses to YFV that correlated to the amount of LN fibrosis and loss of T cells, including T follicular helper cells. These data suggest that LN fibrosis is not limited to HIV infection and may be associated with impaired immunologic responses to vaccines. This may have an impact on vaccine development, especially for infectious diseases prevalent in the developing world., Introduction Vaccine responses are known to vary geographically. Bacillus Calmette-Guerin (BCG) for tuberculosis (TB) is perhaps the best known example of a vaccine for which efficacy rates vary according to [...]

Inappropriate antimicrobial use is common in the outpatient setting but often goes unaddressed by stewardship education. Residents might benefit from directed stewardship education. We conducted a needs assessment of resident knowledge, attitudes, and behaviors regarding antibiotic use and stewardship in outpatient continuity clinics. Internal medicine (IM) residents with continuity clinic at Minneapolis Veterans Affairs Health Care System were eligible. Antimicrobial prescriptions and number of visits were extracted from the Computerized Patient Record System (July 1, 2017–March 31, 2018). Antimicrobial rate (prescriptions per 1000 visits) was calculated for each resident. Results from a resident survey that included demographics, attitudes, and case-based multiple-choice knowledge questions were linked by unique identifier to antimicrobial rate. Prescription and visit data were available for 37 residents. Mean monthly antimicrobial rate was 51 prescriptions per 1000 visits (range 8–239). Surveys were completed by 19 residents (51%). Respondents were 32% female, 32% interns, and 11% international medical graduates. An online resource was most commonly used for prescribing guidance, whereas lectures and small group sessions for residents were rated as the most helpful educational modalities. Many respondents reported being unprepared to perform basic tasks related to antimicrobial stewardship. Median percentage correct was 57% of case-based knowledge questions (interquartile range 50%–71%). Antimicrobial rates among IM residents at a VA outpatient continuity clinic are low and vary by provider. Residents agree with key antimicrobial stewardship concepts but lack preparation in tasks related to antimicrobial stewardship. Knowledge regarding antimicrobial prescribing was low. [ABSTRACT FROM AUTHOR]

Young men who have sex with men (YMSM) are disproportionately affected by HIV in the United States. High-risk sexual behaviors are difficult to modify; thus, HIV pre-exposure prophylaxis (PrEP) with a daily pill is a promising prevention tool for this vulnerable population. We present a case of a young black MSM who was able to successfully access PrEP with the help of a community program but was not able to adhere to the regimen or engage in care. He ultimately acquired HIV infection. We review the existing literature and advocate for increased services and research to support youth's adherence to PrEP and engagement in HIV prevention programs, with a focus on YMSM of color. [ABSTRACT FROM AUTHOR]

Measures to prevent sexual mucosal transmission are critically needed, particularly to prevent transmission to young women at high risk in the microepidemics in South Africa that disproportionally contribute to the continued pandemic. To that end, microbicides containing anti-retroviral (ARV) agents have been shown to prevent transmission, but with efficacy limited both by adherence and pre-existing innate immune and inflammatory conditions in the female reproductive tract (FRT). Glycerol monolaurate (GML) has been proposed as a microbicide component to enhance efficacy by blocking these transmission-facilitating innate immune response to vaginal exposure. We show here in an especially rigorous test of protection in the SIV-rhesus macaque model of HIV-1 transmission to women, that GML used daily and before vaginal challenge protects against repeat high doses of SIV by criteria that include virological and immunological assays to detect occult infection. We also provide evidence for indirect mechanisms of action in GML-mediated protection. Developing a sustained formulation for GML delivery could contribute an independent, complementary protective component to an ARV-containing microbicide. [ABSTRACT FROM AUTHOR]

Background: Lymph nodes and gut-associated lymphatic tissue are important reservoirs of the human immunodeficiency virus (HIV). Little is known about these reservoirs in different geographic populations. We report the surgical outcomes of excisional lymph node and anorectal mucosal biopsies performed internationally and describe the lessons learned. Methods: Patients were recruited through the Joint Clinical Research Center (JCRC) in Kampala, Uganda, where procedures were performed. Studies were approved by the Institutional Review Boards of the JCRC and the University of Minnesota. Instruments and supplies were shipped to Uganda and prepared onsite. Drugs and skin preparations were purchased locally. Lymph nodes were removed through 1-3 cm incisions with ligatures on lymphovascular pedicles. Incisions were closed with subcuticular sutures and epidermal tape. Two to four pieces of anorectal mucosa were obtained through anoscopes using biopsy forceps. Results: One hundred thirty-eight lymph node biopsies and 98 anorectal mucosal biopsies were performed on 71 patients. Forty-one patients were HIV-positive. Many patients had multiple procedures. Two minor complications resulted: One hematoma and one lymphocele. Despite the cost of travel and lodging, cost per biopsy was lower in Uganda compared with the United States. Conclusion: Invasive clinical research can be performed with minimal morbidity in emerging nations with outcomes similar to those found in the United States, but with lower cost. [ABSTRACT FROM AUTHOR]

Background Lachancea fermentati is an environmental yeast that is also used in the fermentation of alcoholic drinks. It has not previously been described as a human pathogen although the closely related yeast Saccharomyces boulardii can cause fungemia. Here we report a case of L. fermentati acting as a pathogen in a septic patient with cultures positive from blood, peritoneal fluid, bile, and sputum. Case presentation A 36 year-old Caucasian man was hospitalized with acute alcoholic hepatitis complicated by Escherichia coli spontaneous bacterial peritonitis. Three days after admission, he developed new fevers with sepsis requiring mechanical ventilation and vasopressor support. He was found to have a bowel perforation. Cultures from blood, peritoneal fluid, and sputum grew a difficult-to-identify yeast. Micafungin was started empirically. On hospital day 43 the yeast was identified as L. fermentati with low minimum inhibitory concentrations (by Epsilometer test) to all antifungals tested. Micafungin was changed to fluconazole to complete a 3-month course of therapy. Serial peritoneal fluid cultures remained positive for 31 days. One year after his initial hospitalization the patient had ongoing cirrhosis but had recovered from fungemia. Conclusion This case demonstrates the need for clinicians to consider host factors when interpreting culture results with normally non-pathogenic organisms. In this immunocompromised host L. fermentati caused disseminated disease. We believe his hobby of brewing alcohol led to colonization with L. fermentati, which then resulted in invasive disease when the opportunity arose. [ABSTRACT FROM AUTHOR]

There is intense interest in developing curative interventions for HIV. How such a cure will be quantified and defined is not known. We applied a series of measurements of HIV persistence to the study of an HIV-infected adult who has exhibited evidence of cure after allogeneic hematopoietic stem cell transplant from a homozygous CCR5Δ32 donor. Samples from blood, spinal fluid, lymph node, and gut were analyzed in multiple laboratories using different approaches. No HIV DNA or RNA was detected in peripheral blood mononuclear cells (PBMC), spinal fluid, lymph node, or terminal ileum, and no replication-competent virus could be cultured from PBMCs. However, HIV RNA was detected in plasma (2 laboratories) and HIV DNA was detected in the rectum (1 laboratory) at levels considerably lower than those expected in ART-suppressed patients. It was not possible to obtain sequence data from plasma or gut, while an X4 sequence from PBMC did not match the pre-transplant sequence. HIV antibody levels were readily detectable but declined over time; T cell responses were largely absent. The occasional, low-level PCR signals raise the possibility that some HIV nucleic acid might persist, although they could also be false positives. Since HIV levels in well-treated individuals are near the limits of detection of current assays, more sensitive assays need to be developed and validated. The absence of recrudescent HIV replication and waning HIV-specific immune responses five years after withdrawal of treatment provide proof of a clinical cure. [ABSTRACT FROM AUTHOR]

PURPOSE: The aim of this study was to determine the biologic significance of tumor response and the prognostic value of molecular markers in a group of patients with rectal cancer treated with preoperative radiation therapy and radical surgery-. METHODS: Microsatellite instability, microvessel count, and immunohistochemistry for proliferating cell nuclear antigen, p53, p21, bcl-2, and vascular endothelial growth factor were performed in the preradiation biopsy specimen of 72 patients with rectal cancer treated by preoperative radiation therapy and radical curative surgery. Preoperative tumor stage by endorectal ultrasound was compared with pathology stage of the resected specimen. Mean follow-up was 50 months. RESULTS: Twenty-eight patients (39 percent) responded to radiation therapy. The response was complete in 8 (12 percent) and partial in 20 patients (27 percent). Tumors with positive nodes in the surgical specimen were less likely to have responded to preoperative radiation (P = 0.03). Only p21 expression was individually associated with response to radiation (56 vs. 30 percent; P = 0.03). Tumors that were p53-negative/p21- positive or p21-positive/bcl-2-positive were also more likely to respond to radiation (83 vs. 33 percent; P = 0.03 and 71 vs. 31 percent; P = 0.01, respectively). The tumor relapsed in 21 patients (29 percent): locally in 7 (10 percent) and distally in 14 (19 percent). Recurrence was associated with lack of response to radiation, female gender, distal tumor location, high proliferating cell nuclear antigen labeling index, and low microvessel count. Probability of survival was greater for patients with well or moderately differentiated tumors and tumors that responded completely to radiation. CONCLUSIONS; Tumor response to radiation is associated with improved tumor control and overall survival rate, and p21 expression is a marker of tumor radiosensitivity in patients with rectal cancer. Furthermore, a high proliferating cell nuclear antigen labeling index and a low microvessel count in the preradiation biopsy specimen may be prognostic indicators for tumor recurrence. [ABSTRACT FROM AUTHOR]

Background Antimicrobial stewardship is the coordinated approach to optimal use of antimicrobials. Directed stewardship may benefit resident physicians and improve outpatient antimicrobial prescribing. Methods Internal medicine residents as of July 1, 2017 (n = 37) with continuity clinic at the Minneapolis Veterans Affairs Health Care System were eligible. Antimicrobial prescriptions and number of patient visits per month were extracted from the Computerized Patient Record System. Antimicrobial rate was calculated for 9 baseline months (July 1, 2017–March 31, 2018) and 12 intervention months (April 1, 2018–March 31, 2019). Residents were divided into high and low prescribing groups based on baseline antimicrobial rate. The low prescribing group received one email with links to antimicrobial stewardship resources. The high prescribing group received the same email and one in person meeting with an infectious disease fellow to discuss antimicrobial prescribing. Results Prescription and visit data were available for 37 residents. The low and high prescribing interventions were administered to 17/17 (100%) and 12/20 (60%) participants, respectively. Remaining high prescribing participants (8, 40%) graduated and did not complete the intervention. During the intervention period, there were a total of 171 prescriptions and 4,018 visits, for an average antimicrobial rate of 43 prescriptions/1,000 visits compared with baseline rate of 51 (P = 0.09). Antimicrobial rate per month is shown in Figure 1. Conclusion An educational intervention did not significantly change antimicrobial prescribing rates in a VA resident clinic. Antimicrobial prescribing rates were much lower than expected, suggesting that weekly continuity clinic may not be an optimal setting for learning how to manage outpatient antimicrobials. Our study was small and conducted at a single site without evaluation of antimicrobial appropriateness. Further studies should explore the optimal setting for residents to gain outpatient antimicrobial prescribing experience. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies. Methods A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC). Results HIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days –8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem. Conclusions HIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs. [ABSTRACT FROM AUTHOR]

Background: HIV is produced in lymphoid tissues (LT) and stored on the follicular dendritic cell network in LT. When antiretroviral therapy is started, plasma viremia decays in 2 phases; the first within days of starting therapy and the second over weeks. Raltegravir (RAL), an integrase inhibitor, has been associated with only a single rapid phase of decay, and we speculated this may be due to higher intracellular concentration (IC) of RAL in LT. We have previously measured suboptimal ICs of antiretroviral therapy agents in LT, which were associated with slower decay of both vRNA+ cells and the follicular dendritic cell network pool., Setting: Outpatient clinic at the Joint Clinical Research Center in Kampala, Uganda., Methods: We compared the rate of decay in LT in people starting RAL with those starting efavirenz (EFV)., Results: There was no difference in the rate of virus decay in LT. The ratio of the ICs of RAL and EFV in lymph node to the concentration of drug that inhibits 95% of virus in blood was 1 log lower in lymph node for EFV and >3 logs lower for RAL., Conclusion: These data further highlight the challenges of drug delivery to LT in HIV infection and demonstrate that RAL is not superior to EFV as judged by direct measurements of the source of virus in LT.