Carbapenem Antibiotics for the Empiric Treatment of Nosocomial Pneumonia: A Systematic Review and Meta-analysis.

BACKGROUND: Previous meta-analyses suggested that treating hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), with empiric carbapenems was associated with lower mortality rates but higher rates of clinical failure for pseudomonal pneumonia. This study was an updated meta-analysis with sensitivity analyses and meta-regression to better understand the impact of carbapenem use in HAP/VAP. RESEARCH QUESTION: What is the efficacy of carbapenems for empiric treatment of nosocomial pneumonia? STUDY DESIGN AND METHODS: Databases were searched for randomized controlled studies evaluating empiric treatment for HAP and/or VAP, and studies were included comparing carbapenem- vs non-carbapenem-containing regimens. The primary outcome was all-cause mortality. Secondary outcomes included subgroup stratification and resistance development. RESULTS: Of 9,140 references, 20 trials enrolling 5,489 patients met inclusion criteria. For mortality, carbapenem use had a risk ratio (RR) of 0.84 (95% CI, 0.74-0.96; P = .01). Stratified according to VAP proportion (< 33%, 33%-66%, and > 66%), RRs were 0.95 (95% CI, 0.77-1.17; P = .66), 0.78 (95% CI, 0.57-1.07; P = .13), and 0.81 (95% CI, 0.65-0.99; P = .04), respectively. Stratified according to severity, only groups with Acute Physiology and Chronic Health Evaluation II scores < 14 and between 14 and 17 showed mortality benefit (RRs of 0.64 [95% CI, 0.45-0.92; P = .01] and 0.77 [95% CI, 0.61-0.97; P = .03]). Meta-regression did not show an association between Pseudomonas prevalence and mortality (P = .44). Carbapenem use showed a trend toward developing resistance (RR, 1.40; 95% CI, 0.95-2.06; P = .09) and a 96% probability of resistance emergence. INTERPRETATION: Carbapenem-based empiric regimens were associated with lower mortality rates compared with non-carbapenems, largely driven by trials of VAP. The mortality effect was not observed in trials with high disease severity and was not associated with Pseudomonas. The mortality difference was observed mainly in studies that used ceftazidime as control. There was a trend toward increasing resistance associated with carbapenems. TRIAL REGISTRY: International Prospective Register of Systematic Reviews; No. CRD42018093602; URL: https://www.crd.york.ac.uk/prospero/.

Traumatic brain injury among men in an urban homeless shelter: observational study of rates and mechanisms of injury.

BACKGROUND: Little empiric research has investigated the interrelationship between homelessness and traumatic brain injury. The objectives of this study were to determine the rate, mechanisms and associated outcomes of traumatic brain injury among men in an urban homeless shelter. METHODS: We recruited participants from an urban men's shelter in Toronto, Ontario. Researchers administered the Brain Injury Screening Questionnaire, a semistructured interview screening tool for brain injury. Demographic information and detailed histories of brain injuries were obtained. Participants with positive and negative screening results were compared, and the rates and mechanisms of injury were analyzed by age group. RESULTS: A total of 111 men (mean age 54.2 ± standard deviation 11.5 yr; range 27-81 yr) participated. Nearly half (50 [45%]) of the respondents had a positive screening result for traumatic brain injury. Of these, 73% (35/48) reported experiencing their first injury before adulthood (< 18 yr), and 87% (40/46) reported a first injury before the onset of homelessness. Among those with a positive screening result, 33 (66%) reported sustaining at least one traumatic brain injury by assault, 22 (44%) by sports or another recreational activity, 21 (42%) by motor vehicle collision and 21 (42%) by a fall. A positive screening result was significantly associated with a lifetime history of arrest or mental illness and a parental history of substance abuse. INTERPRETATION: Multiple mechanisms contributed to high rates of traumatic brain injury within a sample of homeless men. Assault was the most common mechanism, with sports and recreation, motor vehicle collisions and falls also being reported frequently by the participants. Injury commonly predated the onset of homelessness, with most participants experiencing their first injury in childhood. Additional research is needed to understand the complex interactions among homelessness, traumatic brain injury, mental illness and substance use.

A critical role for mast cells and mast cell-derived IL-6 in TLR2-mediated inhibition of tumor growth.

Several TLR agonists are effective in tumor immunotherapy, but their early innate mechanisms of action, particularly those of TLR2 agonists, are unclear. Mast cells are abundant surrounding solid tumors where they are often protumorigenic and enhance tumor angiogenesis. However, antitumor roles for mast cells have also been documented. The impact of mast cells may be dependent on their activation status and mediator release in different tumors. Using an orthotopic melanoma model in wild-type C57BL/6 and mast cell-deficient Kit(W-sh/W-sh) mice and a complementary Matrigel-tumor model in C57BL/6 mice, mast cells were shown to be crucial for TLR2 agonist (Pam(3)CSK(4))-induced tumor inhibition. Activation of TLR2 on mast cells reversed their well-documented protumorigenic role. Tumor growth inhibition after peritumoral administration of Pam(3)CSK(4) was restored in Kit(W-sh/W-sh) mice by local reconstitution with wild-type, but not TLR2-deficient, mast cells. Mast cells secrete multiple mediators after Pam(3)CSK(4) activation, and in vivo mast cell reconstitution studies also revealed that tumor growth inhibition required mast cell-derived IL-6, but not TNF. Mast cell-mediated anticancer properties were multifaceted. Direct antitumor effects in vitro and decreased angiogenesis and recruitment of NK and T cells in vivo were observed. TLR2-activated mast cells also inhibited the growth of lung cancer cells in vivo. Unlike other immune cells, mast cells are relatively radioresistant making them attractive candidates for combined treatment modalities. This study has important implications for the design of immunotherapeutic strategies and reveals, to our knowledge, a novel mechanism of action for TLR2 agonists in vivo.