Ultra‐short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients

We conducted an adaptive design single‐center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra‐short‐term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)‐nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R?). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12‐week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first‐line DAA therapy; and two after retreatment with second‐line DAA). At a median follow‐up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4‐day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%‐20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R ? transplants.     

Genetic Background Modifies the Effects of Type 2 Cannabinoid Receptor Deficiency on Bone Mass and Bone Turnover

Cannabinoid receptors and their ligands play significant roles in regulating bone metabolism. Previous studies of type 1 cannabinoid receptor-deficient mice have shown that genetic background influences the skeletal phenotype. Here, we investigated the effects of genetic background on the skeletal phenotype of mice with type 2 cannabinoid receptor deficiency (Cnr2 ^?/?). We studied Cnr2 ^?/? mice on a CD1 background and compared the findings with those previously reported in Cnr2 ^?/? C57BL/6 mice. Young female Cnr2 ^?/? CD1 mice had low bone turnover and high trabecular bone mass compared with wild-type (WT), contrasting with the situation in Cnr2 ^?/? C57BL/6 mice where trabecular bone mass has been reported to be similar to WT. The Cnr2 ^?/? CD1 mice lost more trabecular bone at the tibia with age than WT due to reduced bone formation, and at 12 months there was no difference in trabecular bone volume between genotypes. This differs from the phenotype previously reported in C57BL/6 Cnr2 ^?/? mice, where bone turnover is increased and bone mass reduced with age. There were no substantial differences in skeletal phenotype between Cnr2 ^?/? and WT in male mice. Cortical bone phenotype was similar in Cnr2 ^?/? and WT mice of both genders. Deficiency of Cnr2 has site- and gender-specific effects on the skeleton, mainly affecting trabecular bone, which are influenced by genetic differences between mouse strains. Further evaluation of the pathways responsible might yield new insights into the mechanisms by which cannabinoid receptors regulate bone metabolism.     

Bamboo leaf-based carbon dots for efficient tumor imaging and therapy

In this study, carbon dots synthesized from bamboo leaf cellulose were used simultaneously as a staining agent and for doxorubicin delivery to target cancer cells. Owing to their nontoxic properties, the production of carbon dots from bamboo leaves is a green approach involving optimized application of bamboo tree waste. For multifunctional applications, the carbon dots were modified with 4-carboxybenzylboronic acid and doxorubicin to improve target specificity and drug delivery to HeLa tumor cells. The resulting modified carbon dots were characterized using different analytical techniques, which showed that they were biocompatible, nontoxic, and highly stable over a wide range of pH values and at high ionic strengths. Furthermore, in vitro confocal microscopy studies demonstrated their blue fluorescence and cellular pathway for entering HeLa cells via folate receptor-mediated endocytosis. Cell viability data and flow cytometry results also confirmed the selective uptake of the carbon dots by HeLa cells, which significantly enhanced cell cytotoxicity.

In this study, carbon dots synthesized from bamboo leaf cellulose were used simultaneously as a staining agent and for doxorubicin delivery to target cancer cells.     

Rosiglitazone and pulmonary oedema: an acute dose-dependent effect on human endothelial cell permeability

AIMS/HYPOTHESIS: Peripheral and pulmonary oedema has emerged as the most common drug-related side effect of rosiglitazone in clinical practice, but the underlying mechanisms are not clear. Fluid retention and changes in vascular tone could contribute to oedema formation, but the interpretation of clinical and in vivo studies is particularly difficult and the direct effects of thiazolidinediones on endothelial barrier function have not been previously reported. METHODS: Human pulmonary artery endothelial cells were seeded and grown on 0.4 microm collagen-coated filters to form a tight monolayer (transendothelial electrical resistance 9-11 ohms.cm(-2) after 2-3 days). Transendothelial albumin flux (expressed as the percentage clearance of albumin relative to control) was measured using Evans blue-labelled albumin after exposure to rosiglitazone 1-100 micromol/l for 1 h to 48 h, and after removal of drug from the monolayer. RESULTS: Incubation of pulmonary artery endothelial cells with rosiglitazone for 4 h produced immediate concentration-dependent increases in transendothelial albumin flux: e.g., relative to control (100%), 113%+/-13% (1 micromol/l), 215%+/-37% (10 micromol/l, p=0.01) and 461%+/-96% (100 micromol/l, p=0.002) (n=12). There was no effect after 1 h. The acute hyperpermeability response to rosiglitazone, maximal after 4 h, was fully reversible after washing the monolayer. After incubation for 24 to 48 h the effect of rosiglitazone on pulmonary endothelial permeability tended to subside: e.g., 210%+/-59% (24 h) for rosiglitazone 100 micromol/l (p=0.06). CONCLUSION/INTERPRETATION: Exposure to high-therapeutic concentrations of rosiglitazone causes a reversible fourfold increase in pulmonary endothelial permeability which could be clinically relevant especially at higher doses and at times of peak plasma drug concentration.     

Augmentation of post transplant immunity: antigen encounter at the time of hematopoietic stem cell transplantation enhances antigen-specific donor T-cell responses in the post transplant repertoire

After transplant, the immune system is reconstituted by cells derived from both hematopoietic stem cells and peripheral expansion from differentiated donor T cells. After transplant, immune function is poor despite transplantation of mature lymphocytes from immune-competent donors. We tested the hypothesis that early antigen encounter at the time of cell transplant would improve the desired donor T-cell responses. Two independent models of peptide-specific T-cell responses were studied. The model for CD4 cells employed T cells from transgenic (Tg) DO11.11 mice that constitutively express the T-cell receptor for the class II-restricted ovalbumin peptide 323-339. The model for CD8 cells employed non-Tg H2-Db-restricted T-cell responses to the influenza nucleoprotein peptide 366-374. As measured both functionally and by direct imaging of T cells using clonotypic reagents, encounter with specific antigen at the time of T-cell transplantation led to clonal expansion of donor T cells and preservation of donor T-cell function in the post transplant immune environment. Antigen-specific donor T-cell function was poor if antigen encounter was delayed or omitted. Severe parent>F1 graft-versus-host reactions blocked the effect of early antigen exposure. Vaccination of transplant recipients against microbial or leukemia antigens may be worthy of study.     

Get Screened: A Randomized Trial of the Incremental Benefits of Reminders, Recall, and Outreach on Cancer Screening

BACKGROUND

Rates of breast cancer (BC) and colorectal cancer (CRC) screening are particularly low among poor and minority patients. Multifaceted interventions have been shown to improve cancer-screening rates, yet the relative impact of the specific components of these interventions has not been assessed. Identifying the specific components necessary to improve cancer-screening rates is critical to tailor interventions in resource limited environments.

OBJECTIVE

To assess the relative impact of various components of the reminder, recall, and outreach (RRO) model on BC and CRC screening rates within a safety net practice.

DESIGN

Pragmatic randomized trial.

PARTICIPANTS

Men and women aged 50–74 years past due for CRC screen and women aged 40–74 years past due for BC screening.

INTERVENTIONS

We randomized 1,008 patients to one of four groups: (1) reminder letter; (2) letter and automated telephone message (Letter + Autodial); (3) letter, automated telephone message, and point of service prompt (Letter + Autodial + Prompt); or (4) letter and personal telephone call (Letter + Personal Call).

MAIN MEASURES

Documentation of mammography or colorectal cancer screening at 52 weeks following randomization.

KEY RESULTS

Compared to a reminder letter alone, Letter + Personal Call was more effective at improving screening rates for BC (17.8 % vs. 27.5 %; AOR 2.2, 95 % CI 1.2–4.0) and CRC screening (12.2 % vs. 21.5 %; AOR 2.0, 95 % CI 1.1–3.9). Compared to letter alone, a Letter + Autodial + Prompt was also more effective at improving rates of BC screening (17.8 % vs. 28.2 %; AOR 2.1, 95 % CI 1.1–3.7) and CRC screening (12.2 % vs. 19.6 %; AOR 1.9, 95 % CI 1.0–3.7). Letter + Autodial was not more effective than a letter alone at improving screening rates.

CONCLUSIONS

The addition of a personal telephone call or a patient-specific provider prompt were both more effective at improving mammogram and CRC screening rates compared to a reminder letter alone. The use of automated telephone calls, however, did not provide any incremental benefit to a reminder letter alone.     

An evaluation of the effects of susceptibility changes on the water chemical shift method of temperature measurement in human peripheral muscle

Divergencies between chemical shift measurements of temperature and directly measured values using optical sensors have been studied in vivo in human peripheral muscle with the assistance of a variety of experimental and theoretical techniques. These include the modeling of both thermal and susceptibility changes using two- and three-dimensional finite element methods, as well as the use of multi-wavelength near infrared observations. The conclusion of these studies is that a simple temperature calibration is not accessible, with results affected by the complex response of the tissue itself.