Does Single Dose Epinephrine Improve Outcomes for Patients with Out-of-Hospital Cardiac Arrest and Bystander CPR or a Shockable Rhythm?

BACKGROUND: A single dose epinephrine protocol (SDEP) for out-of-hospital cardiac arrest (OHCA) achieves similar survival to hospital discharge (SHD) rates as a multidose epinephrine protocol (MDEP). However, it is unknown if a SDEP improves SHD rates among patients with a shockable rhythm or those receiving bystander cardiopulmonary resuscitation (CPR). METHODS: This pre-post study, spanning 11/01/2016-10/29/2019 at 5 North Carolina EMS systems, compared pre-implementation MDEP and post-implementation SDEP in patients ≥18 years old with non-traumatic OHCA. Data on initial rhythm type, performance of bystander CPR, and the primary outcome of SHD were sourced from the Cardiac Arrest Registry to Enhance Survival. We compared SDEP vs MDEP performance in each rhythm (shockable and non-shockable) and CPR (bystander CPR or no bystander CPR) subgroup using Generalized Estimating Equations to account for clustering among EMS systems and to adjust for age, sex, race, witnessed arrest, arrest location, AED availability, EMS response interval, and presence of a shockable rhythm or receiving bystander CPR. The interaction of SDEP implementation with rhythm type and bystander CPR was evaluated. RESULTS: Of 1690 patients accrued (899 MDEP, 791 SDEP), 19.2% (324/1690) had shockable rhythms and 38.9% (658/1690) received bystander CPR. After adjusting for confounders, SHD was increased after SDEP implementation among patients with bystander CPR (aOR 1.61, 95%CI 1.03-2.53). However, SHD was similar in the SDEP cohort vs MDEP cohort among patients without bystander CPR (aOR 0.81, 95%CI 0.60-1.09), with a shockable rhythm (aOR 0.96, 95%CI 0.48-1.91), and with a non-shockable rhythm (aOR 1.26, 95%CI 0.89-1.77). In the adjusted model, the interaction between SDEP implementation and bystander CPR was significant for SHD (p = 0.002). CONCLUSION: Adjusting for confounders, the SDEP increased SHD in patients who received bystander CPR and there was a significant interaction between SDEP and bystander CPR. Single dose epinephrine protocol and MDEP had similar SHD rates regardless of rhythm type.

Integrating biological knowledge for mechanistic inference in the host-associated microbiome.

Advances in high-throughput technologies have enhanced our ability to describe microbial communities as they relate to human health and disease. Alongside the growth in sequencing data has come an influx of resources that synthesize knowledge surrounding microbial traits, functions, and metabolic potential with knowledge of how they may impact host pathways to influence disease phenotypes. These knowledge bases can enable the development of mechanistic explanations that may underlie correlations detected between microbial communities and disease. In this review, we survey existing resources and methodologies for the computational integration of broad classes of microbial and host knowledge. We evaluate these knowledge bases in their access methods, content, and source characteristics. We discuss challenges of the creation and utilization of knowledge bases including inconsistency of nomenclature assignment of taxa and metabolites across sources, whether the biological entities represented are rooted in ontologies or taxonomies, and how the structure and accessibility limit the diversity of applications and user types. We make this information available in a code and data repository at: https://github.com/lozuponelab/knowledge-source-mappings. Addressing these challenges will allow for the development of more effective tools for drawing from abundant knowledge to find new insights into microbial mechanisms in disease by fostering a systematic and unbiased exploration of existing information.

Inhibition of superoxide and iNOS augment cutaneous nitric oxide-dependent vasodilation in non-Hispanic black young adults.

We assessed the combined effect of superoxide and iNOS inhibition on microvascular function in non-Hispanic Black and non-Hispanic White participants (n = 15 per group). Participants were instrumented with four microdialysis fibers: (1) lactated Ringer's (control), (2) 10 µM tempol (superoxide inhibition), (3) 0.1 mM 1400 W (iNOS inhibition), (4) tempol + 1400 W. Cutaneous vasodilation was induced via local heating and NO-dependent vasodilation was quantified. At control sites, NO-dependent vasodilation was lower in non-Hispanic Black (45 ± 9% NO) relative to non-Hispanic White (79 ± 9% NO; p < 0.01; effect size, d = 3.78) participants. Tempol (62 ± 16% NO), 1400 W (78 ± 12% NO) and tempol +1400 W (80 ± 13% NO) increased NO-dependent vasodilation in non-Hispanic Black participants relative to control sites (all p < 0.01; d = 1.22, 3.05, 3.03, respectively). The effect of 1400 W (p = 0.04, d = 1.11) and tempol +1400 W (p = 0.03, d = 1.22) was greater than tempol in non-Hispanic Black participants. There was no difference between non-Hispanic Black and non-Hispanic White participants at 1400 W or tempol + 1400 W sites. These data suggest iNOS has a greater effect on NO-dependent vasodilation than superoxide in non-Hispanic Black participants.

Fc-silent anti-TIGIT antibodies potentiate anti-tumor immunity without depleting regulatory T cells.

TIGIT is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance anti-tumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand whether there is therapeutic benefit from Fcγ receptor (FcγR) binding. Here, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with anti-PD-1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of Phase I solid tumor cancer patients treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two Phase I solid tumor cancer patients in whom peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence of pharmacological activity and anti-tumor efficacy of anti-TIGIT antibodies lacking the ability to engage FcγR.

Otterly diverse - A high diversity of Dracunculus species (Spirurida: Dracunculoidea) in North American river otters (Lontra canadensis).

The genus Dracunculus contains numerous species of subcutaneous parasites of mammals and reptiles. In North America, there are at least three mammal-infecting species of Dracunculus. Reports of Dracunculus infections have been reported from river otters (Lontra canadensis) since the early 1900s; however, little is known about the species infecting otters or their ecology. Most reports of Dracunculus do not have a definitive species identified because females, the most common sex found due to their larger size and location in the extremities of the host, lack distinguishing morphological characteristics, and few studies have used molecular methods to confirm identifications. Thus, outside of Ontario, Canada, where both D. insignis and D. lutrae have been confirmed in otters, the species of Dracunculus in river otters is unknown. In the current study, molecular characterization of nematodes from river otters revealed a high diversity of Dracunculus species. In addition to confirming D. insignis infections, two new clades were detected. One clade was a novel species in any host and the other was a clade previously detected in Virginia opossums (Didelphis virginiana) from the USA and a domestic dog from Spain. No infections with D. lutrae were detected and neither new lineage was genetically similar to D. jaguape, which was recently described from a neotropical otter (Lontra longicaudis) from Argentina. These data also indicate that Dracunculus spp. infections in otters are widespread throughout Eastern North America. Currently the life cycles for most of the Dracunculus spp. infecting otters are unknown. Studies on the diversity, life cycle, and natural history of Dracunculidae parasites in wildlife are important because the related parasite, D. medinensis (human Guinea worm) is the subject of an international eradication campaign and there are increasing reports of these parasites in new geographic locations and new hosts, including new species in humans and domestic dogs.

PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors.

Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

Longitudinal Aortic Root Dilatation in Collegiate American-Style Football Athletes.

Background Clinically relevant aortic dilatation (>40 mm) and increased cardiovascular risk are common among retired professional American-style football athletes. Among younger athletes, the effect of American-style football participation on aortic size is incompletely understood. We sought to determine changes in aortic root (AR) size and associated cardiovascular phenotypes across the collegiate career. Methods and Results This was a multicenter, longitudinal repeated-measures observational cohort study of athletes across 3 years of elite collegiate American-style football participation. A total of 247 athletes (119 [48%] Black, 126 [51%] White, 2 [1%] Latino; 91 [37%] linemen, 156 [63%] non-linemen) were enrolled as freshmen and studied at pre- and postseason year 1, postseason year 2 (N=140 athletes), and postseason year 3 (N=82 athletes). AR size was measured with transthoracic echocardiography. AR diameter increased over the study period from 31.7 (95% CI, 31.4-32.0) to 33.5 mm (95% CI, 33.1-33.8; P<0.001). No athlete developed an AR ≥40 mm. Athletes also demonstrated increased weight (cumulative mean Δ, 5.0 [95% CI, 4.1-6.0] kg, P<0.001), systolic blood pressure (cumulative mean Δ, 10.6 [95% CI, 8.0-13.2] mm Hg, P<0.001), pulse wave velocity (cumulative mean Δ, 0.43 [95% CI, 0.31-0.56] m/s, P<0.001), and left ventricular mass index (cumulative mean Δ, 21.2 [95% CI, 19.2-23.3] g/m2, P<0.001), and decreased E' velocity (cumulative mean Δ, -2.4 [95%CI, -2.9 to -1.9] cm/s, P<0.001). Adjusting for height, player position, systolic blood pressure, and diastolic blood pressure, higher weight (ß=0.030, P=0.003), pulse wave velocity (ß=0.215, P=0.02), and left ventricular mass index (ß=0.032, P<0.001) and lower E' (ß=-0.082, P=0.001) were associated with increased AR diameter. Conclusions Over the collegiate American-style football career, athletes demonstrate progressive AR dilatation associated with cardiac and vascular functional impairment. Future studies delineating aortic outcomes are necessary to determine whether AR dilation is indicative of maladaptive vascular remodeling in this population.

Intravenous Immunoglobulin: Mechanism of Action in Autoimmune and Inflammatory Conditions.

Intravenous immunoglobulin (IVIG) is the mainstay of therapy for humoral immune deficiencies and numerous inflammatory disorders. Although the use of IVIG may be supplanted by several targeted therapies to cytokines, the ability of polyclonal normal IgG to act as an effector molecule as well as a regulatory molecule is a clear example of the polyfunctionality of IVIG. This article will address the mechanism of action of IVIG in a number of important conditions that are otherwise resistant to treatment. In this commentary, we will highlight mechanistic studies that shed light on the action of IVIG. This will be approached by identifying effects that are both common and disease-specific, targeting actions that have been demonstrated on cells and processes that represent both innate and adaptive immune responses.

Contribution of sensory nerves to cutaneous reactive hyperaemia in non-Hispanic Black and White young adults.

NEW FINDINGS: What is the central question of this study? Does cutaneous sensory nerve-mediated vasodilatation differ between non-Hispanic Black and White young adults? What is the main finding and its importance? The magnitude of cutaneous reactive hyperaemia is lower in non-Hispanic Black relative to non-Hispanic White young adults, but the overall sensory nerve contribution is the same, suggesting that sensory nerve function is similar in both non-Hispanic Black and White young adults. ABSTRACT: The aim of this study was to assess cutaneous sensory nerve function, independent of nitric oxide, in non-Hispanic Black and White young adults. We tested the hypothesis that cutaneous reactive hyperaemia and sensory nerve-mediated vasodilatation would be lower in non-Hispanic Black young adults relative to non-Hispanic White young adults. Twenty-four participants who self-identified as non-Hispanic Black (n = 12) or non-Hispanic White (n = 12) were recruited. All participants underwent three bouts of reactive hyperaemia. An index of skin blood flow was measured continuously using laser-Doppler flowmetry at a control site and at a site treated with topical 4% lignocaine to inhibit sensory nerve function. Peak reactive hyperaemia was lower in non-Hispanic Black relative to non-Hispanic White participants (P < 0.001). Total reactive hyperaemia was lower in non-Hispanic Black [mean (SD); control, 4085 (955)%CVCmax  s; lignocaine, 2127 (639) percent maximal cutaneous vascular conductance * seconds, %CVCmax  s] relative to non-Hispanic White [control: 6820 (1179)%CVCmax  s; lignocaine, 3573 (712)%CVCmax  s] participants (P < 0.001 for both sites). There was no difference between groups for the calculated contribution of sensory nerves to either the peak [non-Hispanic Black, 25 (14)%; non-Hispanic White, 19 (13)%] or total reactive hyperaemic response [non-Hispanic Black, 48 (10)%; non-Hispanic White, 47 (10)%]. These data suggest that cutaneous reactive hyperaemia is lower in non-Hispanic Black young adults, but the sensory nerve contribution is similar in non-Hispanic Black and White young adults.

Effects of biological sex and oral contraceptive pill use on cutaneous microvascular endothelial function and nitric oxide-dependent vasodilation in humans.

The purpose of this study was to evaluate in vivo endothelial function and nitric oxide (NO)-dependent vasodilation between women in either menstrual or placebo pill phases of their respective hormonal exposure [either naturally cycling (NC) or using oral contraceptive pills (OCPs)] and men. A planned subgroup analysis was then completed to assess endothelial function and NO-dependent vasodilation between NC women, women using OCP, and men. Endothelium-dependent and NO-dependent vasodilation were assessed in the cutaneous microvasculature using laser-Doppler flowmetry, a rapid local heating protocol (39°C, 0.1 °C/s), and pharmacological perfusion through intradermal microdialysis fibers. Data are represented as means ± standard deviation. Men displayed greater endothelium-dependent vasodilation (plateau, men: 71 ± 16 vs. women: 52 ± 20%CVCmax, P < 0.01), but lower NO-dependent vasodilation (men: 52 ± 11 vs. women: 63 ± 17%NO, P = 0.05) compared with all women. Subgroup analysis revealed NC women had lower endothelium-dependent vasodilation (plateau, NC women: 48 ± 21%CVCmax, P = 0.01) but similar NO-dependent vasodilation (NC women: 52 ± 14%NO, P > 0.99), compared with men. Endothelium-dependent vasodilation did not differ between women using OCP and men (P = 0.12) or NC women (P = 0.64), but NO-dependent vasodilation was significantly greater in women using OCP (74 ± 11%NO) than both NC women and men (P < 0.01 for both). This study highlights the importance of directly quantifying NO-dependent vasodilation in cutaneous microvascular studies. This study also provides important implications for experimental design and data interpretation.NEW & NOTEWORTHY This study supports differences in microvascular endothelial function and nitric oxide (NO)-dependent vasodilation between women in low hormone phases of two hormonal exposures and men. However, when separated into subgroups of hormonal exposure, women during placebo pills of oral contraceptive pill (OCP) use have greater NO-dependent vasodilation than naturally cycling women in their menstrual phase and men. These data improve knowledge of sex differences and the effect of OCP use on microvascular endothelial function.

Endothelin A receptor inhibition increases nitric oxide-dependent vasodilation independent of superoxide in non-Hispanic Black young adults.

Young non-Hispanic Black adults have reduced microvascular endothelial function compared with non-Hispanic White counterparts, but the mechanisms are not fully elucidated. The purpose of this study was to investigate the effect of endothelin-1 A receptor (ETAR) and superoxide on cutaneous microvascular function in young non-Hispanic Black (n = 10) and White (n = 10) adults. Participants were instrumented with four intradermal microdialysis fibers: 1) lactated Ringer's (control), 2) 500 nM BQ-123 (ETAR antagonist), 3) 10 µM tempol (superoxide dismutase mimetic), and 4) BQ-123 + tempol. Skin blood flow was assessed via laser-Doppler flowmetry (LDF), and each site underwent rapid local heating from 33°C to 39°C. At the plateau of local heating, 20 mM l-NAME [nitric oxide (NO) synthase inhibitor] was infused to quantify NO-dependent vasodilation. Data are means ± standard deviation. NO-dependent vasodilation was decreased in non-Hispanic Black compared with non-Hispanic White young adults (P < 0.01). NO-dependent vasodilation was increased at BQ-123 sites (73 ± 10% NO) and at BQ-123 + tempol sites (71 ± 10%NO) in non-Hispanic Black young adults compared with control (53 ± 13%NO, P = 0.01). Tempol alone had no effect on NO-dependent vasodilation in non-Hispanic Black young adults (63 ± 14%NO, P = 0.18). NO-dependent vasodilation at BQ-123 sites was not statistically different between non-Hispanic Black and White (80 ± 7%NO) young adults (P = 0.15). ETAR contributes to reduced NO-dependent vasodilation in non-Hispanic Black young adults independent of superoxide, suggesting a greater effect on NO synthesis rather than NO scavenging via superoxide.NEW & NOTEWORTHY Endothelin-1 A receptors (ETARs) have been shown to reduce endothelial function independently and through increased production of superoxide. We show that independent ETAR inhibition increases microvascular endothelial function in non-Hispanic Black young adults. However, administration of a superoxide dismutase mimetic alone and in combination with ETAR inhibition had no effect on microvascular endothelial function suggesting that, in the cutaneous microvasculature, the negative effects of ETAR in non-Hispanic Black young adults are independent of superoxide production.

Nuclear PTEN's Functions in Suppressing Tumorigenesis: Implications for Rare Cancers.

Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect pediatric and adult populations. Originally discovered and characterized as a negative regulator of the cytoplasmic, pro-oncogenic phosphoinositide-3-kinase (PI3K) pathway, PTEN is also localized to the nucleus where it can exert tumor-suppressive functions in a PI3K pathway-independent manner. Cancers can usurp the tumor-suppressive functions of PTEN to promote oncogenesis by disrupting homeostatic subcellular PTEN localization. The objective of this review is to describe the changes seen in PTEN subcellular localization during tumorigenesis, how PTEN enters the nucleus, and the spectrum of impacts and consequences arising from disrupted PTEN nuclear localization on tumor promotion. This review will highlight the immediate need in understanding not only the cytoplasmic but also the nuclear functions of PTEN to gain more complete insights into how important PTEN is in preventing human cancers.

Microvascular endothelial function following cessation of long-term oral contraceptive pill use: A case report.

NEW FINDINGS: What is the main observation in this case? The main observation of this case report is substantial improvement in cutaneous microvascular endothelial function after cessation of long-term use of a fourth-generation oral contraceptive pill. This improvement appears independent of relative changes in the contribution of nitric oxide. What insights does it reveal? Our findings suggest that cessation of long-term, fourth-generation oral contraceptive pill use improves endothelial function within 20 months of cessation. ABSTRACT: The purpose of this case report was to evaluate in vivo endothelial function and nitric oxide (NO)-dependent vasodilatation before and after the cessation of long-term (11-12 years) fourth-generation oral contraceptive pill (OCP) use in one young, healthy and premenopausal woman. This retrospective analysis includes data from six experimental visits: three visits during months 133-144 of fourth-generation OCP use and three visits 19-22 months after OCP cessation. Endothelium-dependent and NO-dependent vasodilatation were assessed in the cutaneous microvasculature using laser-Doppler flowmetry, a rapid local heating protocol (39°C, 0.1°C/s) and pharmacological perfusion through intradermal microdialysis fibres. The participant had consistent medical history and lifestyle behaviours throughout both hormonal exposures. Data are presented as the mean (SD). Endothelium-dependent vasodilatation was 42 (10)% of site-specific maximal cutaneous vascular conductance (CVCmax ) during OCP use and 63 (10)%CVCmax after OCP cessation (49% increase). Nitric oxide-dependent vasodilatation was 70 (5)% contribution of NO during OCP use and 60 (15)%NO after OCP cessation (15% reduction). Baseline blood flow was greater after OCP cessation, but maximal blood flow was reduced. Data from this case report support a substantial increase in cutaneous microvascular endothelial function assessed via local heating after cessation of long-term use of a fourth-generation OCP, which does not appear to be attributable to increased NO bioavailability. Overall, these data suggest an improvement in endothelial and microvascular function after the cessation of long-term use of a fourth-generation OCP.

Molecular Profiling of Peanut under Raw, Roasting, and Autoclaving Conditions Using High-Resolution Magic Angle Spinning and Solution 1H NMR Spectroscopy.

Higher rates of peanut allergy have been observed in countries that commonly roast peanuts prior to consumption. Despite the importance of understanding the role of thermal processing in allergy and on peanut composition, studies toward generating signatures that identify molecular contents following processing are scant. Here, we identified spectral signatures to track changes and differences in the molecular composition of peanuts under raw, roasted, and high-pressure and high-temperature autoclaved conditions. We analyzed both the solid flesh of the seed and solutions derived from soaking peanuts using High-Resolution Magic Angle Spinning (HR-MAS) and solution 1H Nuclear Magnetic Resonance (NMR) spectroscopy, respectively. The NMR spectra of intact peanuts revealed triglycerides as the dominant species, assigned on the basis of multiplets at 4.1 and 4.3 ppm, and corresponding defatted flours revealed the presence of sugars. Sucrose assigned based on a doublet at 5.4 ppm (anomeric proton), and triglycerides were the most abundant small molecules observed, with little variation between conditions. Soaked peanut solutions were devoid of lipids, and their resulting spectra matched the profiles of defatted peanuts. Spectral signatures resulting from autoclaving differed strikingly between those from raw and roasted peanuts, with considerable line-broadening in regions corresponding to proteins and amino-acid side chains, from 0.5 to 2.0 ppm and 6.5 to 8.5 ppm. Taken together, by using complementary NMR methods to obtain a fingerprint of the molecular components in peanuts, we demonstrated that autoclaving led to a distinct composition, likely resulting from the hydrolytic cleavage of proteins, the most important molecule of the allergic reaction.

An Update on Female Urethral Stricture Disease.

PURPOSE OF REVIEW: To provide an overview of female urethral stricture disease and updates on surgical outcomes. RECENT FINDINGS: In a large retrospective case series, women reported significant improvements in urinary symptoms and quality of life following treatment of their urethral stricture. Both vaginal flap and buccal mucosal graft urethroplasty have higher short- and long-term success rates than urethral dilation. Female urethral stricture disease is rare and surgical reconstruction has the highest likelihood of long-term success. Due to the complexity of reconstruction, referral to a reconstructive trained urologist should be considered.