A DNA prime-oral Listeria boost vaccine in rhesus macaques induces a SIV-specific CD8 T cell mucosal response characterized by high levels of α4β7 integrin and an effector memory phenotype

AbstractIn this study in Rhesus macaques, we tested whether IL-12 or IL-15 in a DNA prime-oral Listeria boost amplifies the SIV-Gag-specific CD8 mucosal response. SIV-specific CD8 T cells were demonstrated in the peripheral blood (PB) in all test vaccine groups, but not the control group. SIV-Gag-specific CD8 T cells in the PB expressed α4β7 integrin, the gut-homing receptor; a minor subset co-express αEβ7 integrin. SIV-Gag-specific CD8 T cells were also detected in the gut tissue, intraepithelial (IEL) and lamina propria lymphocytes (LPL) of the duodenum and ileum. These cells were characterized by high levels of β7 integrin expression and a predominance of the effector memory phenotype. Neither Il-12 nor IL-15 amplified the frequency of SIV-specific CD8 T cells in the gut. Thus, the DNA prime-oral Listeria boost strategy induced a mucosal SIV-Gag-specific CD8 T cell response characterized by expression of the α4β7 integrin gut-homing receptor

Variability in Rehabilitation Protocols after Superior Labrum Anterior Posterior Surgical Repair

Introduction. Rehabilitation after a superior labral anterior posterior (SLAP) repair is an important aspect of patient outcomes, however, no standardized rehabilitation protocol has been defined. The purpose of this paper is to assess the variability of rehabilitation after SLAP repair to understand the need for standardization to improve patient outcomes. Methods. Protocols for SLAP repairs were collected through a search for Academic Orthopedic Programs and a general google search using the terms “[Program Name (if applicable)] SLAP Repair Rehab Protocol”. Protocols were compared by sling, range of motion (ROM), physical therapy, return to sport (RTS), return to throwing, and biceps engagement/ biceps tenodesis recommendations. Protocols for non-operative or generalized shoulders were excluded.  Results. Sixty protocols were included. A total of 61.7% (37/60) recommended a sling for four to six weeks and 90% (54/60) included a full ROM recommendation, but time was variable. There were different exercises recommended, but pendulum swings were recommended by 53% (32/60), submaximal isometrics by 55% (33/60), and scapular strengthening by 65% (39/60). Of the sixty protocols, 33% (20/60) recommended return to sports in 24 weeks and 38.3% (23/60) recommended allowing throwing in 16 weeks. Conclusion. There was variability in protocols for SLAP repair, especially time until full ROM, RTS, and biceps strengthening. Time in sling and scapular strengthening were the least variable. A lack of specificity within protocols in what return to throwing meant for functional ability made it difficult to compare protocols. Considering the large number of Orthopedic programs, a relatively small number had published protocols. Further studies are needed to evaluate a standardized post-operative rehabilitation for SLAP repairs to improve outcomes

Correction: Lack of Mucosal Immune Reconstitution during Prolonged Treatment of Acute and Early HIV-1 Infection

BACKGROUND: During acute and early HIV-1 infection (AEI), up to 60% of CD4(+) T cells in the lamina propria of the lower gastrointestinal (GI) tract are lost as early as 2–4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART) is well established. However, the extent of immune reconstitution in the GI tract is unknown. METHODS AND FINDINGS: Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1–7 y of uninterrupted therapy). Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%–60% depletion of lamina propria lymphocytes despite 1–7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO(+) HLA-DR(+), returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4(+) T cell depletion despite therapy. Rare HIV-1 RNA–expressing cells were detected by in situ hybridization. CONCLUSIONS: Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T cell homing to the GI tract. Although clinically silent over the short term, the long-term consequences of the persistence of this lesion may emerge as the HIV-1–infected population survives longer owing to the benefits of HAART

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease

Stromal Down-Regulation of Macrophage CD4/CCR5 Expression and NF-κB Activation Mediates HIV-1 Non-Permissiveness in Intestinal Macrophages

Tissue macrophages are derived exclusively from blood monocytes, which as monocyte-derived macrophages support HIV-1 replication. However, among human tissue macrophages only intestinal macrophages are non-permissive to HIV-1, suggesting that the unique microenvironment in human intestinal mucosa renders lamina propria macrophages non-permissive to HIV-1. We investigated this hypothesis using blood monocytes and intestinal extracellular matrix (stroma)-conditioned media (S-CM) to model the exposure of newly recruited monocytes and resident macrophages to lamina propria stroma, where the cells take up residence in the intestinal mucosa. Exposure of monocytes to S-CM blocked up-regulation of CD4 and CCR5 expression during monocyte differentiation into macrophages and inhibited productive HIV-1 infection in differentiated macrophages. Importantly, exposure of monocyte-derived macrophages simultaneously to S-CM and HIV-1 also inhibited viral replication, and sorted CD4+ intestinal macrophages, a proportion of which expressed CCR5+, did not support HIV-1 replication, indicating that the non-permissiveness to HIV-1 was not due to reduced receptor expression alone. Consistent with this conclusion, S-CM also potently inhibited replication of HIV-1 pseudotyped with vesicular stomatitis virus glycoprotein, which provides CD4/CCR5-independent entry. Neutralization of TGF-β in S-CM and recombinant TGF-β studies showed that stromal TGF-β inhibited macrophage nuclear translocation of NF-κB and HIV-1 replication. Thus, the profound inability of intestinal macrophages to support productive HIV-1 infection is likely the consequence of microenvironmental down-regulation of macrophage HIV-1 receptor/coreceptor expression and NF-κB activation

Resistance to Type 1 Interferons is a Major Determinant of HIV-1 Transmission Fitness

Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC50) than did donor isolates, and their odds of replicating in CD4+ T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4+ T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response

What Do Patients Want? Survey of Patient Desires for Education in an Urban University Hospital

Introduction: This study examines the emergency department (ED) waiting room (WR) population’s knowledge about the ED process and hospital function and explores the types of educational materials that might appeal to patients and their companions in an ED waiting room. Our goal was to identify potential high-impact opportunities for patient education. Methods: A 32-question survey about demographics, usage of primary care physicians (PCP), understanding of the ED and triage process, desire to know about delays, health education and understanding of teaching hospitals was offered to all qualified individuals. Results: Five hundred and forty-four surveys were returned. Fifty-five percent reported having a PCP, of which 53% (29% of all WR patients) called a PCP prior to coming to the ED. It was found that 51.2% can define triage; 51% as an acuity assessment and 17% as a vital signs check. Sixty-nine percent knew why patients were seen according to triage priority. Seventy-two percent wanted to know about delays, yet only 25% wanted to know others’ wait times. People wanted updates every 41 minutes and only three percent wanted a physician to do this. Forty-one percent wanted information on how the ED functions, 60% via handouts and 43% via video. Information on updates and common medical emergencies is significantly more important than material on common illnesses, finding a PCP, or ED function (p<0.05). Median estimated time for medical workup ranged from 35 minutes for radiographs, to one hour for lab results, computed tomography, specialist consult, and admission. Sixty-nine percent knew the definition of a teaching hospital and of those, 87% knew they were at a teaching hospital. Subgroup analysis between racial groups showed significantly reduced knowledge of the definitions of triage and teaching hospitals and significantly increased desire for information on ED function in minority groups (p<0.05). Conclusion: The major findings in this study were that many visitors would like handouts about ED function and medical emergencies over other topics. Additionally, the knowledge of functions such as triage and teaching hospitals were 70% and 69%, respectively. This was reduced in non-Caucasian ethnicities, while there was an increased desire for information on ED function relative to Caucasians. This research suggests increasing updates and educational materials in the waiting room could impact the waiting room and overall hospital experience. [West J Emerg Med. 2014;15(7):-0.

What Do Patients Want? Survey of Patient Desires for Education in an Urban University Hospital

Introduction: This study examines the emergency department (ED) waiting room (WR) population’s knowledge about the ED process and hospital function and explores the types of educational materials that might appeal to patients and their companions in an ED waiting room. Our goal was to identify potential high-impact opportunities for patient education.Methods: A 32-question survey about demographics, usage of primary care physicians (PCP), understanding of the ED and triage process, desire to know about delays, health education and understanding of teaching hospitals was offered to all qualified individuals.Results: Five hundred and forty-four surveys were returned. Fifty-five percent reported having a PCP, of which 53% (29% of all WR patients) called a PCP prior to coming to the ED. It was found that 51.2% can define triage; 51% as an acuity assessment and 17% as a vital signs check. Sixty-nine percent knew why patients were seen according to triage priority. Seventy-two percent wanted to know about delays, yet only 25% wanted to know others’ wait times. People wanted updates every 41 minutes and only three percent wanted a physician to do this. Forty-one percent wanted information on how the ED functions, 60% via handouts and 43% via video. Information on updates and common medical emergencies is significantly more important than material on common illnesses, finding a PCP, or ED function (p&lt;0.05). Median estimated time for medical workup ranged from 35 minutes for radiographs, to one hour for lab results, computed tomography, specialist consult, and admission. Sixty-nine percent knew the definition of a teaching hospital and of those, 87% knew they were at a teaching hospital. Subgroup analysis between racial groups showed significantly reduced knowledge of the definitions of triage and teaching hospitals and significantly increased desire for information on ED function in minority groups (p&lt;0.05).Conclusion: The major findings in this study were that many visitors would like handouts about ED function and medical emergencies over other topics. Additionally, the knowledge of functions such as triage and teaching hospitals were 70% and 69%, respectively. This was reduced in non-Caucasian ethnicities, while there was an increased desire for information on ED function relative to Caucasians. This research suggests increasing updates and educational materials in the waiting room could impact the waiting room and overall hospital experience. [West J Emerg Med. 2014;15(7):-0.