HIV-1 prophylactic vaccine comprised of topical DermaVir prime and protein boost elicits cellular immune responses and controls pathogenic R5 SHIV162P3

Topical DNA vaccination (DermaVir) facilitates antigen presentation to naive T cells. DermaVir immunization in mice, using HIV-1 Env and Gag, elicited cellular immune responses. Boosting with HIV-1 gp120 Env and p41 Gag augmented Th1 cytokine levels. Intramuscular DNA administration was less efficient in priming antigen-specific cytokine production and memory T cells. In rhesus macaques, DermaVir immunization induced Gag- and Env-specific Th1 and Th2 cytokines and generation of memory T cells. Boosting of DermaVir-primed serum antibody levels was noted following gp140(SHIV89.6P)/p27(SIV) immunization. Rectal challenge with pathogenic R5-tropic SHIV162P3 resulted in control of plasma viremia (4/5 animals) that was reflected in jejunum, colon and mesenteric lymph nodes. An inverse correlation was found between Gag- and Env-specific central memory T cell responses on the day of challenge and plasma viremia at set point. Overall, the topical DermaVir/protein vaccination yields central memory T cell responses and facilitates control of pathogenic SHIV infection.     

Overexpression of carcinoma and embryonic cytotrophoblast cell-specific Mig-7 induces invasion and vessel-like structure formation

Molecular requirements for carcinoma cell interactions with the microenvironment are critical for disease progression but are poorly understood. Integrin alpha v beta 5, which senses the extracellular matrix, is important for carcinoma cell dissemination in vivo. alpha v beta 5 signaling induces Mig-7, a novel human gene product that is apparently carcinoma-specific. We hypothesized that Mig-7 expression facilitates tumor cell dissemination by increasing invasion and vasculogenic mimicry. Results show that embryonic cytotrophoblasts up-regulated Mig-7 expression before they acquired an invasive phenotype capable of pseudovasculogenesis. Mig-7 protein primarily co-localized with vasculogenic mimicry markers factor VIII-associated antigen, vascular endothelial-cadherin, and laminin 5 gamma 2 chain domain III fragment in lymph node metastases. Overexpression of Mig-7 increased gamma 2 chain domain III fragments known to contain epidermal growth factor (EGF)-like repeats that can activate EGF receptor. Interestingly, EGF also induced Mig-7 expression. Carcinoma cell adhesion to laminins was significantly reduced by Mig-7 expression. Remarkably, in two-dimensional and three-dimensional Matrigel cultures, Mig-7 expression caused invasion and vessel-like structures. Melanoma cells, which were previously characterized to invade aggressively and to undergo vasculogenic mimicry, expressed Mig-7. Taken together, these data suggest that Mig-7 expression allows cells to sense their environment, to invade, and to form vessel-like structures through a novel relationship with laminin 5 gamma 2 chain domain III fragments.     

A histological survey of green fluorescent protein expression in 'green' mice: implications for stem cell research

AIMS: The transgenic enhanced green fluorescent protein (EGFP) expressing 'green' mouse (C57BL/6-TgN(ACTbEGFP)1Osb) is a widely used tool in stem cell research, where the ubiquitous nature of EGFP expression is critical to track the fate of single or small groups of transplanted haematopoietic stem cells (HSC). Our aim was to investigate this assumed ubiquitous expression by performing a detailed histological survey of EGFP expression in these mice. METHODS: Fluorescent microscopy of frozen tissue sections was used to perform a detailed histological survey of the pattern of EGFP expression in these mice. Flow cytometry was also used to determine the expression pattern in blood and bone marrow. RESULTS: Three patterns of EGFP expression were noted. In most tissues there was an apparently stochastic variegation of the transgene, with individual cell types demonstrating highly variable rates of EGFP expression. Certain specific cell types such as pancreatic ductal epithelium, cerebral cortical neurones and glial cells and glomerular mesangial cells consistently lacked EGFP expression, while others, including pancreatic islet cells, expressed EGFP only at extremely low levels, barely distinguishable from background. Lastly, in the colon and stomach the pattern of EGFP expression was suggestive of clonal inactivation. Only cardiac and skeletal muscle showed near ubiquitous expression. CONCLUSIONS: These findings raise questions regarding the 'ubiquitous' expression of EGFP in these transgenic mice and suggest caution in relying overly on EGFP alone as an infallible marker of donor cell origin.     

Arguments Used in Public Comments to Support or Oppose the US Department of Agriculture’s Minimum Stocking Requirements: A Content Analysis

Background

In 2016, the US Department of Agriculture (USDA)’s Supplemental Nutrition Assistance Program (SNAP) Retailer Rule proposed several changes for SNAP-authorized retailers, including: requiring retailers to have at least 85% of their food sales come from items that are not cooked or heated on site before or after purchase; requiring stores to stock seven varieties of qualifying foods from four staple food groups; requiring stores to carry perishable foods in three of the four staple groups; requiring stores to carry six units of qualifying foods at all times (depth of stock); disqualifying multiple ingredient foods and accessory foods from counting toward depth of stock requirements.

Steroid-sparing maintenance immunosuppression is safe and effective after simultaneous liver-kidney transplantation

Optimization of maintenance immunosuppression (mIS) regimens in the transplant recipient requires a balance between sufficient potency to prevent rejection and avoidance of excessive immunosuppression to prevent toxicities and complications. The optimal regimen after simultaneous liver-kidney (SLK) transplantation remains unclear, but small single-center reports have shown success with steroid-sparing regimens. We studied 4184 adult SLK recipients using the Scientific Registry of Transplant Recipients, from March 1, 2002, to February 28, 2017, on tacrolimus-based regimens at 1 year post-transplant. We determined the association between mIS regimen and mortality and graft failure using Cox proportional hazard models. The use of steroid-sparing regimens increased post-transplant, from 16.1% at discharge to 88.0% at 5 years. Using multi-level logistic regression modeling, we found center-level variation to be the major contributor to choice of mIS regimen (ICC 44.5%; 95% CI: 36.2%-53.0%). In multivariate analysis, use of a steroid-sparing regimen at 1 year was associated with a 21% decreased risk of mortality compared to steroid-containing regimens (aHR 0.79, P = .01) and 20% decreased risk of liver graft failure (aHR 0.80, P = .01), without differences in kidney graft loss risk (aHR 0.92, P = .6). Among SLK recipients, the use of a steroid-sparing regimen appears to be safe and effective without adverse effects on patient or graft survival.     

Changes in Burnout and Satisfaction With Work-Life Integration in Physicians and the General US Working Population Between 2011 and 2017

ObjectiveTo evaluate the prevalence of burnout and satisfaction with work-life integration among physicians and other US workers in 2017 compared with 2011 and 2014.Participants and MethodsBetween October 12, 2017, and March 15, 2018, we surveyed US physicians and a probability-based sample of the US working population using methods similar to our 2011 and 2014 studies. A secondary survey with intensive follow-up was conducted in a sample of nonresponders to evaluate response bias. Burnout and work-life integration were measured using standard tools.ResultsOf 30,456 physicians who received an invitation to participate, 5197 (17.1%) completed surveys. Among the 476 physicians in the secondary survey of nonresponders, 248 (52.1%) responded. A comparison of responders in the 2 surveys revealed no significant differences in burnout scores (P=.66), suggesting that participants were representative of US physicians. When assessed using the Maslach Burnout Inventory, 43.9% (2147 of 4893) of the physicians who completed the MBI reported at least one symptom of burnout in 2017 compared with 54.4% (3680 of 6767) in 2014 (P<.001) and 45.5% (3310 of 7227) in 2011 (P=.04). Satisfaction with work-life integration was more favorable in 2017 (42.7% [2056 of 4809]) than in 2014 (40.9% [2718 of 6651]; P<.001) but less favorable than in 2011 (48.5% [3512 of 7244]; P<.001). On multivariate analysis adjusting for age, sex, relationship status, and hours worked per week, physicians were at increased risk for burnout (odds ratio, 1.39; 95% CI, 1.26-1.54; P<.001) and were less likely to be satisfied with work-life integration (odds ratio, 0.77; 95% CI, 0.70-0.85; P<.001) than other working US adults.ConclusionBurnout and satisfaction with work-life integration among US physicians improved between 2014 and 2017, with burnout currently near 2011 levels. Physicians remain at increased risk for burnout relative to workers in other fields.     

Health care costs and costs associated with changes in work productivity among persons with systemic lupus erythematosus

Objective

To estimate health care costs and costs associated with changes in work productivity among persons with systemic lupus erythematosus (SLE) in the US.

Methods

Data were derived from the University of California, San Francisco Lupus Outcomes Study. Participants provided information on their health care resource use and employment. Cost estimates were derived for both direct health care costs and costs related to changes in work productivity. Direct health care costs included costs for hospitalizations, emergency department services, physician visits, outpatient surgical procedures, dialysis, and medications. Productivity costs were estimated by measuring changes in hours of work productivity since diagnosis of SLE; these estimates were also compared with normal US population data.

Results

For the total population of participants, the mean annual direct cost was $12,643 (2004 US dollars). The mean annual productivity cost for subjects of employment age (≥18 and <65 years) was $8,659. The mean annual total cost (direct and productivity) for subjects of employment age was $20,924. Regression results showed that greater disease activity, longer disease duration, and worse physical and mental health were significant predictors of higher direct costs; older age predicted lower direct costs. Older age, greater disease activity, and worse physical and mental health status were significant predictors of higher costs due to changes in work productivity.

Conclusion

Both direct health care costs and costs associated with changes in work productivity are substantial and both represent important contributors to the total costs associated with SLE.     

Survey of patient and physician influences and decision-making regarding CT utilization for minor head injury

Objective

Assess factors that influence both the patient and the physician in the setting of minor head injury in adults and the decision-making process around CT utilization.

Methods

This is a convenience sample survey study of adult minor head injury patients (GCS 15) and their physicians regarding factors influencing the decision to use CT to evaluate for intra-cranial haemorrhage. Once a head CT was ordered and before the results were known, both the patient and physician were given a one-page survey asking questions about their concern for injury and rationale for CT use. CT results and surveys were then recorded in a centralized database and analyzed.

Results

584 subjects were enrolled over the 27-month study period. The rate of any intra-cranial haemorrhage was 3.3%. Both the physicians (6% pre-test estimate) and the patients (22% pre-test estimate) over-estimated risk for haemorrhage. Clinical decision rules were not met in 46% of cases where CT was used. Physicians listed an average of 5 factors from a list of 9 that influenced their decision to order CT. Patients listed an average of 1.7 factors influencing their decision to present to the Emergency Department for evaluation. Many patients felt cost (45%) and low risk stratification (34%) should weigh heavily in the decision to use CT. If asked to limit CT utilization, physicians were able to identify a group with less than 2% risk of injury.

Conclusions

Patients with low risk of intra-cranial injury continue to be evaluated by CT. Physician decision-making around the use of CT to evaluate minor head injury is multi-factorial. Shared decision-making between the patient and the physician in a low risk minor head injury encounter shows promise as a method to reduce CT utilization in this low risk cohort.