Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells

The adoptive transfer of donor T cells that have been genetically modified to recognize leukemia could prevent or treat leukemia relapse after allogeneic HSCT (allo-HSCT). However, adoptive therapy after allo-HSCT should be performed with T cells that have a defined endogenous TCR specificity to avoid GVHD. Ideally, T cells selected for genetic modification would also have the capacity to persist in vivo to ensure leukemia eradication. Here, we provide a strategy for deriving virus-specific T cells from CD45RA(-)CD62L(+)CD8(+) central memory T (T(CM)) cells purified from donor blood with clinical grade reagents, and redirect their specificity to the B-cell lineage marker CD19 through lentiviral transfer of a gene encoding a CD19-chimeric Ag receptor (CAR). Virus-specific T(CM) were selectively transduced by exposure to the CD19 CAR lentivirus after peptide stimulation, and bi-specific cells were subsequently enriched to high purity using MHC streptamers. Activation of bi-specific T cells through the CAR or the virus-specific TCR elicited phosphorylation of downstream signaling molecules with similar kinetics, and induced comparable cytokine secretion, proliferation, and lytic activity. These studies identify a strategy for tumor-specific therapy with CAR-modified T cells after allo-HSCT, and for comparative studies of CAR and TCR signaling.     

Breastfeeding Practices Among First-Time Mothers and Across Multiple Pregnancies

To investigate maternal characteristics associated with breastfeeding initiation and success. Women enrolled in the Mothers Outcomes After Delivery study reported breastfeeding practices 5?C10?years after a first delivery. Women were classified as successful breastfeeding initiators, unsuccessful initiators, or non-initiators. For the first birth, demographic and obstetrical characteristics were compared across these three breastfeeding groups. For multiparous women, agreement in breastfeeding status between births was evaluated. Multivariate regression analysis was used to identify characteristics associated with non-initiation and unsuccessful breastfeeding across all births. Of 812 participants, 740 (91%) mothers tried to breastfeed their first child and 593 (73%) reported breastfeeding successfully. In a multivariate analysis, less educated women were less likely to initiate breastfeeding (odds ratio (OR) for non-initiation 1.97; 95% confidence interval (CI) 1.23, 3.14). There was a notable decrease in breastfeeding initiation with increasing birth order: compared to the first birth, the odds for non-initiation after a second delivery almost doubled (OR 1.83, 95% CI 1.42, 2.35) and the odds for non-initiation after a third delivery were further increased (OR 2.44, 95% CI 1.56, 3.82). Successful breastfeeding in a first pregnancy was a predictor of subsequent breastfeeding initiation and success. Specifically, women who did not attempt breastfeeding or who reported unsuccessful attempts to breastfeed at first birth were unlikely to initiate breastfeeding at later births. Cesarean delivery was not associated with breastfeeding initiation (OR 1.01; 95% CI 0.68, 1.48) or success (OR 1.33; 95% CI 0.92, 1.94). Breastfeeding practices after a first birth are a significant predictor of breastfeeding in subsequent births.     

Clostridium difficile

Clostridium difficile is the leading cause of healthcare‐associated infectious diarrhea. Although C difficile is part of normal flora in some healthy individuals, patients with selective risk factors are often vulnerable to the toxigenic potential of this virulent healthcare pathogen. The spectrum of C difficile infection (CDI) is highly variable, ranging from mild to severe illness, presenting with single to multiple disease recurrences. Current approaches to treatment are based on severity of illness, number of recurrences, and clinical presentation. Oral vancomycin and metronidazole have formed the foundation for treatment of CDI, but therapeutic failures are commonly reported, especially involving hypervirulent clones. Alternative therapies, including newer antimicrobials, probiotics, immunotherapy, and fecal transplantation, have all met with varying degrees of efficacy. Although toxigenic culture (TC) testing from anaerobic culture remains the gold standard, newer technologies, including enzyme immunoassay, common antigen (glutamate dehydrogenase) testing, and real‐time polymerase chain reaction (PCR) are less time‐consuming and rapid. However, TC and PCR have reported high specificity and sensitivity when compared with other laboratory tests. Because of the significant morbidity and mortality associated with CDI, a high index of suspicion is warranted. Prevention and eradication of CDI require a multidisciplinary approach, including early disease recognition through appropriate surveillance, implementation of effective contact isolation strategies, adherence to environmental controls, judicious hand hygiene, evidence‐based treatment, and management that includes antibiotic stewardship, continuous education of healthcare workers, and administrative support.     

Direct conversion of testosterone to dihydrotestosterone glucuronide in man.

Tritiated testosterone and [14C]dihydrotestosterone (DHT) were administered by constant iv infusion into five young and five elderly men undergoing diagnostic cardiac catheterization. The radioactivity concentrations of free and conjugated DHT in arterial and hepatic vein blood samples were then determined. The analysis of the 3H:14C ratio of free DHT in arterial and hepatic vein blood showed that in both groups, the 3H:14C ratio of free DHT was the same in arterial and hepatic vein blood, indicating that splanchnic tissue is not the source of blood DHT from testosterone. This is in agreement with data that the transfer constant across the liver ([rho]T-DHT SD) was undetectable. In both young and elderly men, a significant increase of the 3H concentration of DHT glucuronide in hepatic vein blood was observed, indicating that the splanchnic compartment could be the site of production of DHT glucuronide. The 3H:14C ratio of DHT glucuronide was much higher than that of free DHT in both groups, suggesting that DHT glucuronide is derived from the blood testosterone pool, and most of the DHT from testosterone seems to be conjugated before mixing with blood DHT. This study indicates that a large fraction of DHT produced in the liver from testosterone is efficiently conjugated or further metabolized, and this results in the lack of splanchnic production of free DHT in men.     

Clinical Outcomes and Survivorship of Lateral Unicompartmental Knee Arthroplasty: Does Surgical Approach Matter?

Background

Lateral unicompartmental knee arthroplasty (UKA) has been shown to be an effective procedure to treat isolated lateral compartment osteoarthritis with excellent long-term survivorship. Whether a medial parapatellar approach or a lateral parapatellar approach is superior in lateral UKA is unknown. The purpose of this study was to determine if there is a difference in intermediate-term clinical outcomes in patients undergoing lateral UKA through a lateral vs medial parapatellar approach.

Efficacy of a beta-lactamase inhibitor combination for serious intraabdominal infections.

A double-blind trial was conducted in 385 patients with suspected bacterial intra-abdominal infections to compare the efficacy and safety of ampicillin-sulbactam with cefoxitin. Patients were randomized to receive either 3 g ampicillin-sulbactam (2 g ampicillin-1 g sulbactam), or 2 g cefoxitin, every 6 hours. To be evaluable, patients had to demonstrate positive culture evidence of peritoneal infection at the time of operation. A total of 197 patients were evaluable for clinical efficacy. The two treatment groups were comparable in demographic features and in the presence of risk factors for infection. Clinical success (absence of infection and of adverse drug reaction) was observed in 86% of patients in the ampicillin-sulbactam group and 78% in the cefoxitin group. Eradication of infection occurred in 88% of the ampicillin-sulbactam group and 79% of the cefoxitin group. There were no differences in the nature or frequency of side effects observed in the two groups. Ampicillin-sulbactam demonstrated no difference in safety or efficacy when compared with cefoxitin in the treatment of serious intra-abdominal infections of bacterial origin.