Thymic-derived CD25Recent reports have shown that Tregs proliferate and retain their antigen-dependent suppressive functions when the APCs are antigen-loaded mature dendritic cells (DCs) (16-18). When Tregs specific for a pancreatic islet ␤ cell antigen are stimulated by DCs together with IL-2, the expanded antigen-specific T cells regulate the development of autoimmune diabetes in nonobese diabetic mice and do so much more effectively than polyclonal populations (18). From the perspective of suppressing unwanted immune reactions, preferential expansion of antigen-specific Tregs will also avoid complications likely to be incurred if therapeutic T cells were contaminated with Tregs that suppress resistance to infections and tumors.We will show here that DCs expand alloantigen-specific Tregs from polyclonal starting populations, which initially have little specific suppressive activity. The DCs prove to be much more effective than a standard source of spleen APCs in expanding Tregs and maintaining high Foxp3 expression. When function is tested, DC-expanded Tregs exert more potent and antigenspecific suppression of transplantation immunity.

Background Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Methods This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7–14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7–14 days after completing therapy in the MITT population. Results Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, −5.3% [95% confidence interval {CI}, −11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, −3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively. Conclusions Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients. Clinical Trials Registration NCT02493764.

On screening 192 men and women aged 35-64 were identified as having two or more of the following risk factors: blood pressure > 140/90 mm Hg, plasma cholesterol concentration > 6-3 mmol/l (243 6 mg/100 ml), and current smoking habit ) 10 cigarettes a day. They were randomly allocated to a group for modification of behaviour or to serve as controls. Both groups were given health education leaflets containing advice to stop smoking, to reduce animal fats in the diet, and on the importance of reducing blood pressure. In addition, the treatment group had group sessions of one hour a week for eight weeks in which they were taught breathing exercises, relaxation, and meditation and about managing stress. It had previously been found that after eight weeks and eight months there was a significantly greater reduction in both systolic and diastolic blood pressures in the group taught to relax compared with the control group. After four years of follow up these differences in blood pressure were maintained. Plasma cholesterol concentration and the number of cigarettes smoked were lower in the treatment group at eight weeks and eight months but not

Incidental cardiac irradiation was associated with subsequent symptomatic cardiac events, particularly ACS/CHF, and symptomatic cardiac events were associated with inferior survival. These results support the minimization of cardiac doses among patients with inoperable NSCLC receiving standard-dose CRT.

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In the phase III RESTORE‐IMI 2 study (ClinicalTrials.gov: NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all‐cause mortality at day 28 and favorable clinical response at the early follow‐up visit in adult participants with gram‐negative hospital‐acquired bacterial pneumonia/ventilator‐associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE‐IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to <150 ml/min), renal impairment (mild, CrCl ≥60 to <90 ml/min; moderate, CrCl ≥30 to <60 ml/min; or severe, CrCl ≥15 to <30 ml/min), and end‐stage renal disease (CrCl <15 ml/min). At the recommended IMI/REL dosing regimens across renal categories, greater than 90% of patients in all renal function groups were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at a minimum inhibitory concentration breakpoint of ≤2 μg/ml, regardless of ventilation status. This modeling and simulation analysis supports use of the recommended IMI/REL dosing regimens, adjusted based on renal function, in patients with HABP/VABP.

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