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Background Pneumonia is the most common infection after out-of-hospital cardiac arrest (OHCA) occurring in up to 65% of patients who remain comatose after return of spontaneous circulation. Preventing infection after OHCA may (1) reduce exposure to broad-spectrum antibiotics, (2) prevent hemodynamic derangements due to local and systemic inflammation, and (3) prevent infection-associated morbidity and mortality. Methods The ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arrest (PROTECT) trial is a randomized, placebo-controlled, single-center, quadruple-blind (patient, treatment team, research team, outcome assessors), non-commercial, superiority trial to be conducted at Maine Medical Center in Portland, Maine, USA. Ceftriaxone 2 g intravenously every 12 h for 3 days will be compared with matching placebo. The primary efficacy outcome is incidence of early-onset pneumonia occurring < 4 days after mechanical ventilation initiation. Concurrently, T cell-mediated inflammation bacterial resistomes will be examined. Safety outcomes include incidence of type-one immediate-type hypersensitivity reactions, gallbladder injury, and C lostridioides difficile -associated diarrhea. The trial will enroll 120 subjects over approximately 3 to 4 years. Discussion The PROTECT trial is novel in its (1) inclusion of OHCA survivors regardless of initial heart rhythm, (2) use of a low-risk antibiotic available in the USA that has not previously been tested after OHCA, (3) inclusion of anti-inflammatory effects of ceftriaxone as a novel mechanism for improved clinical outcomes, and (4) complete metagenomic assessment of bacterial resistomes pre- and post-ceftriaxone prophylaxis. The long-term goal is to develop a definitive phase III trial powered for mortality or functional outcome. Trial registration ClinicalTrials.gov NCT04999592 . Registered on August 10, 2021.

Due to their autosynchronous roles in shaping the anti-tumor immune response, complex immune regulatory networks acting both locally within the tumor microenvironment as well as in its draining lymph nodes play critical roles in the cancer immunotherapy response. We describe herein a thermosensitive co-polymer hydrogel system formed from biocompatible polymers gelatin and Pluronic ® F127 that are widely used in humans to enable the sustained release of a nitric oxide donor and antibody blocking immune checkpoint cytotoxic T-lymphocyte-associated protein-4 for efficient and durable anti-tumor immunotherapy. By virtue of its unique gel formation and degradation properties that sustain drug retention at the tumor tissue site for triggered release by the tumor microenvironment and formation of in situ micelles optimum in size for lymphatic uptake, this rationally designed thermosensitive hydrogel facilitates modulation of two orthogonal immune signaling networks relevant to the regulation of the anti-tumor immune response to improve local and abscopal effects of cancer immunotherapy. Nitric oxide exerts a multitude of physiological functions and has also been exploited for anticancer therapies. Here the authors report the design of a micelle-releasing thermosensitive hydrogel system for the concomitant locoregional and lymphatic delivery of a nitric oxide donor and an anti-CTLA4 antibody, showing anti-tumor immune responses in preclinical cancer models.

Vancomycin is a glycopeptide antibiotic that is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus . Nephrotoxicity, which is usually reversible, is the most serious common adverse effect of vancomycin. Vancomycin-associated nephrotoxicity prolongs hospital stays, imposes a need for additional antibiotics and, in rare circumstances, dialysis treatment, and increases medical costs and mortality. Risk factors for nephrotoxicity include the dose and duration of vancomycin treatment, serum trough concentration, patient characteristics, and concomitant receipt of nephrotoxins. Contemporary guidelines recommend targeting vancomycin trough concentrations of ≥10 mg/L to prevent resistance and trough concentrations of 15–20 mg/L to optimize outcomes. There is significant correlation between vancomycin trough serum concentrations and the incidence of vancomycin-associated nephrotoxicity; however, evidence of an association between trough concentrations and efficacy is less convincing. Routine monitoring of serum vancomycin concentrations consumes time and limited healthcare resources and may not be cost effective. The use of alternative antibacterial agents that do not require monitoring would free up pharmacy resources. This time could then be devoted to initiatives such as pharmacist-led antibiotic stewardship programs that are known to reduce antibiotic use and promote improved patient outcomes.

Cultivation of corn and soybeans in the United States reached record high levels following the biofuels boom of the late 2000s. Debate exists about whether the expansion of these crops caused conversion of grasslands and other carbon-rich ecosystems to cropland or instead replaced other crops on existing agricultural land. We tracked crop-specific expansion pathways across the conterminous US and identified the types, amount, and locations of all land converted to and from cropland, 2008-2012. We found that crop expansion resulted in substantial transformation of the landscape, including conversion of long-term unimproved grasslands and land that had not been previously used for agriculture (cropland or pasture) dating back to at least the early 1970s. Corn was the most common crop planted directly on new land, as well as the largest indirect contributor to change through its displacement of other crops. Cropland expansion occurred most rapidly on land that is less suitable for cultivation, raising concerns about adverse environmental and economic costs of conversion. Our results reveal opportunities to increase the efficacy of current federal policy conservation measures by modifying coverage of the 2014 US Farm Bill Sodsaver provision and improving enforcement of the US Renewable Fuels Standard.

Despite millions of dogs entering and exiting shelters annually, little is known about dog behavior long-term after adoption. Entering a shelter is stressful for dogs which may inhibit or exaggerate behavior. There is a common public sentiment that dogs have a “honeymoon period” after adoption where dogs do not show their full repertoire of behaviors, both positive and negative, until getting more comfortable in their new home. The aim of this prospective observational cohort study was to identify prevalence of and changes in behavior issues in dogs throughout the first six months following adoption. The owners of ninety-nine dogs adopted from five Ohio shelters between October 1, 2020 and June 1, 2021 were surveyed 7, 30, 90, and 180 days after adoption, using the Canine Behavioral Assessment & Research Questionnaire (C-BARQ). Owners were also asked about household changes that may affect behavior. Estimated age, sex, weight, length of shelter stay, shelter intake reason, use of gastrointestinal, antibiotic, and psychotropic medications in the shelter, whether the animal had been previously returned to the shelter, and whether the owner was a first-time dog owner, were evaluated as predictors in a mixed effect regression model of different behavior measures over time. At various timepoints, dogs showed high prevalence for stranger-directed aggression (81.7%), owner-directed aggression (32.3%), dog-directed aggression (75%), familiar dog aggression (37.8%), stranger directed fear (58.2%), nonsocial fear (95.8%), dog directed fear (80.0%) and separation-related behaviors (92.6%). Over 180 days, stranger-directed aggression, excitability, touch sensitivity, training difficulty, and chasing increased, while separation-related behaviors, attachment and attention-seeking decreased. Owners reported high satisfaction with their dogs’ behavior. Use of psychotropic medications in the shelter was predictive of stranger-directed aggression and touch sensitivity at home. These findings help veterinarians and shelter professionals council owners on potential behavior changes after adoption.

Respiratory macrophage subpopulations exhibit unique phenotypes depending on their location within the respiratory tract, posing a challenge to in vitro macrophage model systems. Soluble mediator secretion, surface marker expression, gene signatures, and phagocytosis are among the characteristics that are typically independently measured to phenotype these cells. Bioenergetics is emerging as a key central regulator of macrophage function and phenotype but is often not included in the characterization of human monocyte-derived macrophage (hMDM) models. The objective of this study was to expand the phenotype characterization of naïve hMDMs, and their M1 and M2 subsets by measuring cellular bioenergetic outcomes and including an expanded cytokine profile. Known markers of M0, M1 and M2 phenotypes were also measured and integrated into the phenotype characterization. Peripheral blood monocytes from healthy volunteers were differentiated into hMDM and polarized with either IFN-γ + LPS (M1) or IL-4 (M2). As expected, our M0, M1, and M2 hMDMs exhibited cell surface marker, phagocytosis, and gene expression profiles indicative of their different phenotypes. M2 hMDMs however were uniquely characterized and different from M1 hMDMs by being preferentially dependent on oxidativte phosphorylation for their ATP generation and by secreting a distinct cluster of soluble mediators (MCP4, MDC, and TARC). In contrast, M1 hMDMs secreted prototypic pro-inflammatory cytokines (MCP1, eotaxin, eotaxin-3, IL12p70, IL-1α, IL15, TNF-β, IL-6, TNF-α, IL12p40, IL-13, and IL-2), but demonstrated a relatively constitutively heightened bioenergetic state, and relied on glycolysis for ATP generation. These data are similar to the bioenergetic profiles we previously observed in vivo in sputum (M1) and BAL (M2)-derived macrophages in healthy volunteers, supporting the notion that polarized hMDMs can provide an acceptable in vitro model to study specific human respiratory macrophage subtypes.

Despite growing recognition of neglectful, abusive, and disrespectful treatment of women during childbirth in health facilities, there is no consensus at a global level on how these occurrences are defined and measured. This mixed-methods systematic review aims to synthesize qualitative and quantitative evidence on the mistreatment of women during childbirth in health facilities to inform the development of an evidence-based typology of the phenomenon. We searched PubMed, CINAHL, and Embase databases and grey literature using a predetermined search strategy to identify qualitative, quantitative, and mixed-methods studies on the mistreatment of women during childbirth across all geographical and income-level settings. We used a thematic synthesis approach to synthesize the qualitative evidence and assessed the confidence in the qualitative review findings using the CERQual approach. In total, 65 studies were included from 34 countries. Qualitative findings were organized under seven domains: (1) physical abuse, (2) sexual abuse, (3) verbal abuse, (4) stigma and discrimination, (5) failure to meet professional standards of care, (6) poor rapport between women and providers, and (7) health system conditions and constraints. Due to high heterogeneity of the quantitative data, we were unable to conduct a meta-analysis; instead, we present descriptions of study characteristics, outcome measures, and results. Additional themes identified in the quantitative studies are integrated into the typology. This systematic review presents a comprehensive, evidence-based typology of the mistreatment of women during childbirth in health facilities, and demonstrates that mistreatment can occur at the level of interaction between the woman and provider, as well as through systemic failures at the health facility and health system levels. We propose this typology be adopted to describe the phenomenon and be used to develop measurement tools and inform future research, programs, and interventions.

The use of peripheral nerve blocks for anesthesia and postoperative analgesia has increased significantly in recent years. Adjuvants are frequently added to local anesthetics to prolong analgesia following peripheral nerve blockade. Numerous randomized controlled trials and meta-analyses have examined the pros and cons of the use of various individual adjuvants. To systematically review adjuvant-related randomized controlled trials and meta-analyses and provide clinical recommendations for the use of adjuvants in peripheral nerve blocks. Randomized controlled trials and meta-analyses that were published between 1990 and 2014 were included in the initial bibliographic search, which was conducted using Medline/PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Only studies that were published in English and listed block analgesic duration as an outcome were included. Trials that had already been published in the identified meta-analyses and included adjuvants not in widespread use and published without an Investigational New Drug application or equivalent status were excluded. Sixty one novel clinical trials and meta-analyses were identified and included in this review. The clinical trials reported analgesic duration data for the following adjuvants: buprenorphine (6), morphine (6), fentanyl (10), epinephrine (3), clonidine (7), dexmedetomidine (7), dexamethasone (7), tramadol (8), and magnesium (4). Studies of perineural buprenorphine, clonidine, dexamethasone, dexmedetomidine, and magnesium most consistently demonstrated prolongation of peripheral nerve blocks. Buprenorphine, clonidine, dexamethasone, magnesium, and dexmedetomidine are promising agents for use in prolongation of local anesthetic peripheral nerve blocks, and further studies of safety and efficacy are merited. However, caution is recommended with use of any perineural adjuvant, as none have Food and Drug Administration approval, and concerns for side effects and potential toxicity persist.

BackgroundImmune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as checkpoint-inhibitor pneumonitis (CIP). Literature estimates for CIP incidence are inconsistent. Real-world adherence to guidelines, clinical course, and healthcare utilization in the treatment of CIP has not been described in large cohorts.MethodsA combined claims and electronic health record database (TriNetX) was used to identify 13,113 patients with lung cancer treated with programmed cell death receptor/ligand 1 (PD-1/PD-L1) inhibitors, and a propensity score-matched control cohort treated with chemotherapy or targeted therapies. The attributable risk of CIP was calculated in the first 12 months after therapy by comparing the incidence of diagnosis codes for pneumonitis/pneumonia between cohorts. Cases of CIP, identified by the most specific code for drug-induced respiratory conditions, were further analyzed for medication usage, rates of diagnostic bronchoscopy, ICI discontinuation rates, and usage of hospital services compared with patients receiving PD-1/PD-L1 inhibitors who did not develop CIP.ResultsThe attributable risk of pneumonitis to PD-1/PD-L1 inhibitors was 2.49% (95% CI, 1.50% to 3.47%). Median time to onset in the CIP subcohort was 3.9 months (IQR, 2.1–7.3 months). Steroid and antibiotic use increased dramatically after a pneumonitis diagnosis, and 70.2% of patients permanently discontinued ICI therapy. Compared with controls, patients with CIP had more than a threefold increased risk of needing critical care (relative risk 3.59, 95% CI, 2.31 to 5.57) and an increased risk of mortality (HR 2.34, 95% CI, 1.47 to 3.71).ConclusionsIn a large claims-based analysis, PD-1/PD-L1 inhibitors increase the risk of pneumonitis in patients with lung cancer by 2.49%. Cases of CIP are associated with high healthcare utilization, discontinuation of ICIs, and mortality.

To date there has been very little scholarship that (1) traces the color-blind rhetoric of liberal or progressive communities, or (2) emphasizes the mainstream, color-blind rhetoric of far-right conservative movements. This article compares the racial politics at two ends of the U.S. political spectrum in order to demonstrate how color-blind ideology constitutes the dominant framework for understanding and discussing race and racial inequality in the United States. This racial ideology transcends political party and ideology, but also motivates individuals to do identity work constructing themselves as transcending racism. Grounded in a racial formations framework, I compare two distinct political locations, one consisting of liberal Democrats and progressives in a diverse urban community and the other among Tea Party organizers in one state, in order to demonstrate the similarities in racial discourse and identities, despite differing political orientations and goals.