Differences in Out-of-Hospital Cardiac Arrest Outcomes Among 5 Racial/Ethnic Groups.

OBJECTIVE: Out-of-hospital cardiac arrest (OHCA) is a major health problem and one of the leading causes of death in adults older than 40. Multiple prior studies have demonstrated survival disparities based on race/ethnicity, but most of these focus on a single racial/ethnic group. This study evaluated OHCA variables and outcomes among on 5 racial/ethnic groups. METHODS: This is a retrospective review of data for adult patients in the Cardiac Arrest Registry to Enhance Survival (CARES) from 3 racially diverse urban counties in the San Francisco Bay Area from May 2009 to October 2021. Stratifying by 5 racial/ethnic groups, we evaluated patient survival outcomes based on patient demographics, emergency medical services response location, cardiac arrest characteristics, and hospital interventions. Adjusted risk ratios were calculated for survival to hospital discharge, controlling for sex, age, response locations, median income of response location, arrest witness, shockable rhythm, and bystander cardiopulmonary resuscitation as well as clustering by census tract. RESULTS: There were 10,757 patient entries analyzed: 42% White, 24% Black, 18% Asian, 9.3% Hispanic, 6.0% Pacific Islander, 0.7% American Indian/Alaska Native, and 0.1% multiple races selected; however, only the first 5 racial/ethnic groups had sufficient numbers for comparison. The adjusted risk ratio for survival to hospital discharge was lower among the 4 racial/ethnic groups compared with the White reference group: Black (0.79, p = 0.003), Asian (0.78 p = 0.004), Hispanic (0.79, p = 0.018), and Pacific Islander (0.78, p = 0.041) groups. The risk difference for positive neurologic outcome was also lower among all 4 racial/ethnic groups compared with the White reference group. CONCLUSIONS: The Black, Asian, Hispanic, and Pacific Islander groups were less likely to survive to hospital discharge from OHCA when compared with the White reference group. No variables were associated with decreased survival across any of these 4 groups.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

The Aortic Team Model and Collaborative Decision Pathways for the Management of Complex Aortic Disease: Clinical Practice Update From the Canadian Cardiovascular Society/Canadian Society of Cardiac Surgeons/Canadian Society for Vascular Surgery/Canadian Association for Interventional Radiology.

Disease of the aortic arch, descending thoracic, or thoracoabdominal aorta necessitates dedicated expertise across medical, endovascular, and surgical specialties. Cardiologists, cardiac surgeons, vascular surgeons, interventional radiologists, and others have expertise and skills that aid in the management of patients with complex aortic disease. No specialty is uniformly expert in all aspects of required care. Because of this dispersion of expertise across specialties, an aortic team model approach to decision-making and treatment is advocated. A nonhierarchical partnership across specialties within an interdisciplinary aortic clinic ensures that all treatment options are considered and promotes shared decision-making between the patient and all aortic experts. Furthermore, regionalization of care for aortic disease of increased complexity assures that the breadth of treatment options is available and that favourable volume-outcome ratios for high-risk procedures are maintained. An awareness of best practice care pathways for patient referrals for preventative management, acute care scenarios, chronic care scenarios, and pregnancy might facilitate a more organized management schema for aortic disease across Canada and improve lifelong surveillance initiatives.

Aortic arch endovascular branch and fenestrated repair: Initial Canadian experience with novel technology.

Objective: The objective is to describe the initial Canadian experience using novel aortic arch branched endograft technologies. Methods: We performed a retrospective consecutive case series of all patients undergoing aortic arch branched repair with newly available endograft technology since 2020 at our site. We describe the patient characteristics, treatment characteristics, and postoperative outcomes. Results: Eleven patients received arch branched endografts, indicated for penetrating aortic ulcer in seven patients (64%), arch degeneration after prior aortic dissection repair in three (27%), and acute aortobronchial fistula in one patient (9%). Their average age was 72 ± 7 years. Complete arch repair from zone 0 to 4 was performed in six cases (55%); the remaining repairs landed proximally in zones 1 or 2. Seven repairs used a single retrograde facing inner branch (thoracic branch endoprosthesis; W.L. Gore & Associates), three used double antegrade inner branch (Bolton Relay; Terumo Interventional Systems), and one emergent case used double in situ fenestrations. Seven repairs (64%) used an adjunctive extra-anatomic bypass to complete great vessel perfusion, two of which were created during a prior aortic repair. Inferior vena cava balloon inflow occlusion during deployment was used in all cases. No mortalities, transient or permanent spinal cord paralysis, myocardial infarction, dialysis dependence, venous thromboembolism, or bleeding requiring reintervention occurred. No patient undergoing elective arch branch repair experienced a stroke. The one patient undergoing emergent repair did suffer a stroke. The median length of stay was 5 days (interquartile range, 2-8 days). Two endoleaks developed: a type Ia endoleak successfully treated with a Palmaz stent (Cordis) during the index admission, and a type II endoleak with ongoing sac regression on postoperative follow-up. Postoperatively, one patient suffered a suspected aortic graft infection that was treated with lifelong antibiotics. During a mean radiographic follow-up of 7.2 months, no cases of branch vessel instability (ie, no migration, reintervention, arterial rupture, intraluminal thrombus, occlusion, stenosis, or kinking of the branch grafts) developed. Three patients experienced sac regression of >5 mm, and no patient experienced continued postoperative dilation. Conclusions: To the best of our knowledge, this is the largest reported Canadian volume of aortic arch repair using novel branched or fenestrated technology. The series demonstrates that a multidisciplinary program and properly selected patients can yield excellent results using endovascular repair for complex aortic arch pathology.

Four decades of regional wet deposition, local bulk deposition, and stream-water chemistry show the influence of nearby land use on forested streams in Central Appalachia.

Hydrologic monitoring began on two headwater streams (<1 km2) on the University of Kentucky's Robinson Forest in 1971. We evaluated stream-water (1974-2013) and bulk-deposition (wet + dust) (1984-2013) chemistry in the context of regional wet-deposition patterns that showed decreases in both sulfate and nitrate concentrations as well as proximal surface-mine expansion. Decadal time steps (1974-83, 1984-93, 1994-2003, 2004-2013) were used to quantify change. Comparison of the first two decades showed similarly decreased sulfate (minimum flow-adjusted annual-mean concentration of ≈13.5 mg/L in 1982 to 8.8 mg/L in 1992) and increased pH (6.6-6.8) in both streams, reflecting contemporaneous changes in both bulk and wet deposition. In contrast, concentrations of nitrate (0.14 to >0.25 mg/L) and base cations increased between these two decades, coinciding with expansion of surface mining between 1985 and 1995. In 2004, stream-water pH (6.7 in 2004), sulfate (9.2 mg/L), and nitrate (>0.11 mg/L) were similar to 1982, despite wet-deposition concentrations being lower. Base-cation concentrations were higher in the stream adjacent to ongoing surface mining relative to the stream situated near the middle of the experimental forest. However, pH decreased to approximately 5.7 by 2013 for both streams, which, combined with a shift in dominant cations from calcium to magnesium and potassium, indicates that the soil-buffering capacity of this landscape has been exceeded. Ratios of bulk deposition and stream-water concentrations indicate enrichment of sulfate (1.7-25.2) and cations (0.5-64.8), but not nitrogen (0.1-5.6), indicating that the Forest is not nitrogen saturated and that ongoing changes in water-quality are sulfate driven. When concentrations were adjusted to account for changes in streamflow (climate) over the 4 decades, external influences (land management/regulation) explained most change. The amount and direction of change differed among constituents, both between consecutive decades and between the first and last decades, reflecting the influence of localized surface mining even as regional wet deposition continued to improve due to the Clean Air Act. The implication is that localized stressors have the potential to out-pace the benefits of national environmental policies for communities that depend on local water-resources in similar environments.

A Systematic Review of Total Endovascular Aortic Arch Repair: A Promising Technology.

BACKGROUND: Total endovascular aortic arch repair (TEAAR) represents an emerging alternative for the treatment of aortic arch disease in patients at prohibitive risk for open surgery. A systematic review of TEAAR was performed to delineate early outcomes with this new technology. METHODS: All studies (excluding single-patient case reports) of CE-certified "custom made" or "off-the-shelf" zone 0 stent graft deployments were included. The primary search of Medline, Embase, CINAHL, and the Cochrane CENTRAL registry was supplemented with searches of Web of Science, ClinicalTrials.gov, and conference abstracts (within last 3 years), and a hand search of citations within relevant articles. Articles underwent 2-stage screening by 2 independent reviewers before inclusion. RESULTS: Fifteen relevant investigations were identified. Indications for TEAAR were chronic arch dissection with degenerative aneurysmal disease (54%, 148/273), pure arch aneurysm (41%, 112/273), penetrating atherosclerotic ulcer (2%, 5/273), and type IA endoleak from a zone 2 thoracic endograft (1%, 3/273). Double-branch (70%, 192/273), triple-branch (19%, 53/273), and single-branch (into innominate artery; 10%, 28/273) devices were used. Adjunct left carotid-subclavian bypass occurred in 90% of double- and single-branch procedures. Procedural success with TEAAR was 93% (95% CI 85.8%-96.3%). The proportion of all-cause mortality was 16% (95% CI 8%-26%), stroke 14% (8%-24%), peripheral vascular events 7% (1%-33%), and myocardial infarction 4% (2%-7%). Endoleaks were identified in 13% (7%-25%) of the study population. CONCLUSIONS: TEAAR represents an emerging option for the management of aortic arch disease wth high procedural success rates and acceptable early outcomes in a high-risk patient population.

The Aortic Team Model for the Management of the Distal Arch, Descending Thoracic and Thoracoabdominal Aorta: Appraisal at 3 Years.

BACKGROUND: This study aimed to assess feasibility, logistical challenges, and clinical outcomes associated with the implementation of an Aortic Team model for the management of distal arch, descending thoracic and thoracoabdominal aortic disease. METHODS: An Aortic Team care pathway was implemented in November 2019. Working as a unit, two cardiac surgeons, two vascular surgeons, an interventional radiologist, a cardiologist, and an anesthesiologist collectively determined care decisions via multispecialty presence at an Aortic Clinic. Cardiac and vascular surgeons operated in tandem for open procedures. Interventional radiology participated alongside cardiac and vascular for endovascular procedures. Cardiology aided in medical therapies for heritable and degenerative disease, and had a lead role for genetics and high-risk pregnancy referrals. The model spanned three hospitals. Clinical outcomes at 3 years were assessed. RESULTS: There were 35 descending thoracic and thoracoabdominal surgeries and 77 thoracic endovascular aortic repairs. Endoarch devices were used in 7 cases (Gore Thoracic Branch Endoprosthesis, 4, Terumo RelayBranch, 3) and an endothoracoabdominal device in 4 cases (Cook Zenith t-branch). The Aortic Clinic acquired 456 patients, with yearly increases (54 patients [year 1], 181 patients [year 2], 221 patients [year 3]). For surgery, mortality was 8.6% (3/35), permanent paralysis 5.7% (2/35), stroke 8.6% (3/35), permanent dialysis 0%, and reinterventions 8.6% (3/35). For endovascular cases, mortality was 3.9% (3/77), permanent paralysis 3.9% (3/77), stroke 5.2% (4/77), permanent dialysis 1.3% (1/77), and reinterventions 16.9% (13/77). CONCLUSION: An Aortic Team model is feasible and ensures all treatment options are considered. Conventional open thoracoabdominal procedures showed acceptable outcomes. Endoarch technology shows early promise.

Bovine Tuberculosis Epidemiology in Cameroon, Central Africa, Based on the Interferon-Gamma Assay.

Despite sub-Saharan Africa (SSA) accounting for ~20% of the global cattle population, prevalence estimates and related risk factors of bovine tuberculosis (bTB) are still poorly described. The increased sensitivity of the IFN-γ assay and its practical benefits suggest the test could be useful to investigate bTB epidemiology in SSA. This study used a population-based sample to estimate bTB prevalence, identify risk factors and estimate the effective reproductive rate in Cameroonian cattle populations. A cross-sectional study was conducted in the North West Region (NWR) and the Vina Division (VIN) of Cameroon in 2013. A regional stratified sampling frame of pastoral cattle herds produced a sample of 1,448 cattle from 100 herds. In addition, a smaller cross-sectional study sampled 60 dairy cattle from 46 small-holder co-operative dairy farmers in the NWR. Collected blood samples were stimulated with bovine and avian purified protein derivatives, with extracted plasma screened using the IFN-γ enzyme-linked immunosorbent assay (Prionics Bovigam®). Design-adjusted population prevalences were estimated, and multivariable mixed-effects logistic regression models using Bayesian inference techniques identified the risk factors for IFN-γ positivity. Using the IFN-γ assay, the prevalence of bTB in the dairy cattle was 21.7% (95% CI: 11.2-32.2). The design-adjusted prevalence of bTB in cattle kept by pastoralists was 11.4% (95% CI: 7.6-17.0) in the NWR and 8.0% (95% CI: 4.7-13.0) in the VIN. A within-herd prevalence estimate for pastoralist cattle also supported that the NWR had higher prevalence herds than the VIN. Additionally, the estimates of the effective reproductive rate R t were 1.12 for the NWR and 1.06 for the VIN, suggesting different transmission rates within regional cattle populations in Cameroon. For pastoral cattle, an increased risk of IFN-γ assay positivity was associated with being male (OR = 1.89; 95% CI:1.15-3.09), increasing herd size (OR = 1.02; 95% CI:1.01-1.03), exposure to the bovine leucosis virus (OR = 2.45; 95% CI: 1.19-4.84) and paratuberculosis (OR = 9.01; 95% CI: 4.17-20.08). Decreased odds were associated with contacts at grazing, buffalo (OR = 0.20; 95% CI: 0.03-0.97) and increased contact with other herds [1-5 herds: OR = 0.16 (95% CI: 0.04-0.55); 6+ herds: OR = 0.18 (95% CI: 0.05-0.64)]. Few studies have used the IFN-γ assay to describe bTB epidemiology in SSA. This study highlights the endemic situation of bTB in Cameroon and potential public health risks from dairy herds. Further work is needed to understand the IFN-γ assay performance, particularly in the presence of co-infections, and how this information can be used to develop control strategies in the SSA contexts.

Bovine Tuberculosis Antemortem Diagnostic Test Agreement and Disagreement in a Naturally Infected African Cattle Population.

The interferon-gamma (IFN-γ) assay and single comparative cervical skin test (SCITT) are used to estimate bovine tuberculosis (bTB) prevalence globally. Prevalence estimates of bTB, caused by Mycobacterium bovis, are poorly quantified in many Sub-Saharan African (SSA) cattle populations. Furthermore, antemortem diagnostic performance can vary at different stages of bTB pathogenesis and in different cattle populations. In this study, we aim to explore the level of agreement and disagreement between the IFN-γ assay and SCITT test, along with the drivers for disagreement, in a naturally infected African cattle population. In, 2013, a pastoral cattle population was sampled using a stratified clustered cross-sectional study in Cameroon. A total of 100 pastoral cattle herds in the North West Region (NWR) and the Vina Division (VIN) were sampled totalling 1,448 cattle. Individual animal data and herd-level data were collected, and animals were screened using both the IFN-γ assay and SCITT. Serological ELISAs were used to detect exposure to immunosuppressing co-infections. Agreement analyses were used to compare the performance between the two bTB diagnostic tests, and multivariable mixed-effects logistic regression models (MLR) were developed to investigate the two forms of IFN-γ assay and SCITT binary disagreement. Best agreement using the Cohen's κ statistic, between the SCITT (>2 mm) and the IFN-γ assay implied a 'fair-moderate' agreement for the NWR [κ = 0.42 (95%CI: 0.31-0.53)] and 'poor-moderate' for the VIN [κ = 0.33 (95% CI: 0.18-0.47)]. The main test disagreement was the animals testing positive on the IFN-γ assay and negative by the SCITT. From MLR modeling, adults (adults OR: 7.57; older adults OR = 7.21), females (OR = 0.50), bovine leucosis (OR = 2.30), and paratuberculosis positivity (OR = 6.54) were associated with IFN-γ-positive/SCITT-negative disagreement. Subsets to investigate diagnostic test disagreement for being SCITT-positive and IFN-γ-negative also identified that adults (adults OR = 15.74; older adults OR = 9.18) were associated with IFN-γ-negative/SCITT-positive disagreement. We demonstrate that individual or combined use of the IFN-γ assay and SCITT can lead to a large variation in bTB prevalence estimates. Considering that animal level factors were associated with disagreement between the IFN-γ assay and SCITT in this study, future work should further investigate their impact on diagnostic test performance to develop the approaches to improve SSA prevalence estimates.

Seroepidemiology of Crimean-Congo Haemorrhagic Fever among cattle in Cameroon: Implications from a One Health perspective.

BACKGROUND: Crimean-Congo Haemorrhagic Fever (CCHF) is a tick-borne viral zoonotic disease distributed across several continents and recognized as an ongoing health threat. In humans, the infection can progress to a severe disease with high fatality, raising public health concerns due to the limited prophylactic and therapeutic options available. Animal species, clinically unaffected by the virus, serve as viral reservoirs and amplifier hosts, and can be a valuable tool for surveillance. Little is known about the occurrence and prevalence of Crimean-Congo Haemorrhagic Fever Virus (CCHFV) in Cameroon. Knowledge on CCHFV exposure and the factors associated with its presence in sentinel species are a valuable resource to better understand transmission dynamics and assess local risks for zoonotic disease emergence. METHODS AND FINDINGS: We conducted a CCHFV serological survey and risk factor analysis for animal level seropositivity in pastoral and dairy cattle in the North West Region (NWR) and the Vina Division (VD) of the Adamawa Region in Cameroon. Seroprevalence estimates were adjusted for sampling design-effects and test performance. In addition, explanatory multivariable logistic regression mixed-effects models were fit to estimate the effect of animal characteristics, husbandry practices, risk contacts and ecological features on the serological status of pastoral cattle. The overall seroprevalence was 56.0% (95% CI 53.5-58.6) and 6.7% (95% CI 2.6-16.1) among pastoral and dairy cattle, respectively. Animals going on transhumance had twice the odds of being seropositive (OR 2.0, 95% CI 1.1-3.8), indicating that animal movements could be implicated in disease expansion. From an ecological perspective, absolute humidity (OR 0.6, 95% CI 0.4-0.9) and shrub density (OR 2.1, 95% CI 1.4-3.2) were associated with seropositivity, which suggests an underlying viral dynamic connecting vertebrate host and ticks in a complex transmission network. CONCLUSIONS: This study demonstrated high seroprevalence levels of CCHFV antibodies in cattle in Cameroon indicating a potential risk to human populations. However, current understanding of the underlying dynamics of CCHFV locally and the real risk for human populations is incomplete. Further studies designed using a One Health approach are required to improve local knowledge of the disease, host interactions and environmental risk factors. This information is crucial to better project the risks for human populations located in CCHFV-suitable ecological niches.

The HPK1 Inhibitor A-745 Verifies the Potential of Modulating T Cell Kinase Signaling for Immunotherapy.

Hematopoietic progenitor kinase 1 (HPK1) is an MAP4K family member within the Ste20-like serine/threonine branch of the kinome. HPK1 expression is limited to hematopoietic cells and has a predominant role as a negative regulator of T cell function. Because of the central/dominant role in negatively regulating T cell function, HPK1 has long been in the center of interest as a potential pharmacological target for immune therapy. The development of a small molecule HPK1 inhibitor remains challenging because of the need for high specificity relative to other kinases, including additional MAP4K family members, that are required for efficient immune cell activation. Here, we report the identification of the selective and potent HPK1 chemical probe, A-745. In unbiased cellular kinase-binding assays, A-745 demonstrates an excellent cellular selectivity binding profile within pharmacologically relevant concentrations. This HPK1 selectivity translates to an in vitro immune cell activation phenotype reminiscent of Hpk1-deficient and Hpk1-kinase-dead T cells, including augmented proliferation and cytokine production. The results from this work give a path forward for further developmental efforts to generate additional selective and potent small molecule HPK1 inhibitors with the pharmacological properties for immunotherapy.

A cadaveric model for transesophageal echocardiography transducer placement training: A pilot study.

BACKGROUND: Transesophageal echocardiography (TEE) is used in the emergency department to guide resuscitation during cardiac arrest. Insertion of a TEE transducer requires manual skill and experience, yet in some residency programs cardiac arrest is uncommon, so some physicians may lack the means to acquire the manual skills to perform TEE in clinical practice. For other infrequently performed procedural skills, simulation models are used. However, there is currently no model that adequately simulates TEE transducer insertion. The aim of this study is to evaluate the feasibility and efficacy of using a cadaveric model to teach TEE transducer placement among novice users. METHODS: A convenience sample of emergency medicine residents was enrolled during a procedure education session using cadavers as tissue models. A pre-session assessment was used to determine prior knowledge and confidence regarding TEE manipulation. Participants subsequently attended a didactic and hands-on education session on TEE placement. All participants practised placing the TEE transducer until they were able to pass a standardized assessment of technical skill (SATS). After the educational session, participants completed a post-session assessment. RESULTS: Twenty-five residents participated in the training session. Mean assessment of knowledge improved from 6.2/10 to 8.7/10 (95% confidence interval [CI] of knowledge difference 1.6-3.2, P<0.001) and confidence improved from 1.6/5 to 3.1/5 (95% CI of confidence difference 1.1-2.0, P<0.001). There was no relationship between training level and the delta in knowledge or confidence. CONCLUSIONS: In this pilot study, the use of a cadaveric model to teach TEE transducer placement methods among novice users is feasible and improves both TEE manipulation knowledge and confidence levels.

The Efficacy of a Brief Educational Training Session in Point-of-Care Pediatric Hip Ultrasound.

BACKGROUND: Pediatric limp is a common presenting complaint to emergency departments. Despite this, diagnosis can be difficult in young patients with no history of trauma. Ultrasound can be used to identify a hip effusion, which may be the etiology of limp in pediatric patients. Brief educational training sessions have successfully been used to introduce novice ultrasound users to point-of-care (POC) ultrasound; however, the education of POC hip ultrasound is underexplored, and the efficacy of educational training sessions in this domain remains unknown. OBJECTIVE: To evaluate the feasibility and efficacy of using a brief educational training session to teach novice ultrasound users to identify hip anatomy and effusions. METHODS: Medical and physician assistant students were enrolled during an ultrasound education conference. A pretest evaluated prior knowledge, experience, and confidence level regarding POC hip ultrasound. Students attended a brief didactic session and then completed an objective structured assessment of technical skill as well as a posttest. RESULTS: Twenty-eight students naive to hip ultrasound participated in this study. Levels of training included medical and physician assistant students. Mean test scores increased from the pretest (4.8 of 9, SD = 1.6) to the posttest (7.9 of 9, SD = 0.72) (P < 0.001). Average objective structured assessment of technical skill was 4.6 of 5 (SD, 0.75; 95% confidence interval, 4.3-4.9). After the sessions, confidence levels in identifying landmarks, joint space, and a joint effusion significantly increased (P < 0.001). CONCLUSIONS: Pediatric hip ultrasound knowledge, performance, skills, and confidence improved as demonstrated by novice ultrasound users after a brief educational training session. Our study shows that a brief, targeted educational intervention was a feasible and effective method of introducing pediatric POC hip ultrasound to novices.

Effects of Left Ventricular Versus Traditional Chest Compressions in a Traumatic Pulseless Electrical Activity Model.

BACKGROUND: Prehospital cardiopulmonary resuscitation has commonly been considered ineffective in traumatic cardiopulmonary arrest because traditional chest compressions do not produce substantial cardiac output. However, recent evidence suggests that chest compressions located over the left ventricle (LV) produce greater hemodynamics when compared to traditional compressions. We hypothesized that chest compressions located directly over the LV would result in an increase in return of spontaneous circulation (ROSC) and hemodynamic variables, when compared to traditional chest compressions, in a swine model of traumatic pulseless electrical activity (PEA). METHODS: Transthoracic echocardiography was used to mark the location of the aortic root (traditional compressions) and the center of the LV on animals (n = 34) that were randomized to receive chest compressions in one of the two locations. Animals were hemorrhaged to mean arterial pressure <20 to simulate traumatic PEA. After 5 minutes of PEA, basic life support (BLS) with mechanical cardiopulmonary resuscitation was initiated and performed for 10 minutes followed by advanced life support for an additional 10 minutes. Hemodynamic variables were averaged over the final 2 minutes of BLS and advanced life support periods. RESULTS: Six of the LV group (35%) achieved ROSC compared to eight of the traditional group (47%) (P = .73). There was an increase in aortic systolic blood pressure (P < .01), right atrial systolic blood pressure (P < .01), and right atrial diastolic blood pressure (P = .02) at the end of BLS in the LV group compared to the traditional group. CONCLUSIONS: In our swine model of traumatic PEA, chest compressions performed directly over the LV improved blood pressures during BLS but not ROSC.

Zone 0 Aortic Arch Reconstruction Using the RelayBranch Thoracic Stent Graft.

Endovascular therapies have had a considerable impact on contemporary management of thoracic aortic disease. Still, with the anatomic challenges of the aortic arch, endovascular experience with devices that traverse the arch and deploy in the Zone 0 position remains limited. We report the first Canadian experience with the RelayBranch Thoracic Stent Graft (Terumo Aortic, Sunrise, FL) with Zone 0 deployment for total endovascular aortic arch repair in a patient at very high risk for redo open surgery. We demonstrate safe deployment of the device and successful treatment of a type 1A endoleak. Features of the RelayBranch design that mitigate challenges of arch deployment are also discussed.

Les traitements endovasculaires ont eu un impact considérable sur la gestion contemporaine des pathologies de l'aorte thoracique. Pourtant, en raison des contraintes anatomiques de la crosse aortique, l'expérience endovasculaire avec des dispositifs qui traversent la crosse et se déploient dans la zone 0 reste limitée. Nous rapportons la première expérience canadienne de l'endoprothèse thoracique RelayBranch avec déploiement (Terumo Aortic, Sunrise, FL) en zone 0 pour une réparation endovasculaire totale de la crosse aortique chez un patient présentant un risque très élevé de reprise de chirurgie ouverte. Nous décrivons le déploiement en toute sécurité du dispositif et le traitement réussi d'une endofuite de type 1A. Enfin, nous examinons les caractéristiques du système RelayBranch qui limitent les difficultés liées au déploiement du dispositif dans la crosse aortique.

Enterocutaneous Fistula and Abscess Diagnosed with Point-of-care Ultrasound.

CASE PRESENTATION: A 64-year-old female with history of umbilical hernia repair with mesh 18 years prior, cystocele, and diabetes mellitus presented with 10 days of abdominal and flank pain. The patient was tachycardic, normotensive, afebrile, and had an erythematous, tender, protuberant abdominal wall mass. Point-of-care ultrasound (POCUS) revealed an irregular, heterogeneous extraperitoneal fluid collection with intraperitoneal communication; these findings were consistent with an abscess and infected mesh with evidence for intraperitoneal extension. The diagnosis of enterocutaneous fistula (ECF) with infected mesh and abdominal wall abscess was confirmed with computed tomography and the patient was admitted for antibiotics and source control. DISCUSSION: A rare complication of hernia repair with mesh, ECF typically occurs later than more common complications including cellulitis, hernia recurrence, and bowel obstruction. In the emergency department, POCUS is commonly used to evaluate for abscess; in other settings, comprehensive ultrasound is used to evaluate for complications after hernia repair with mesh. However, to date there is no literature reporting POCUS diagnosis of ECF or mesh infection. This case suggests that distant surgery should not preclude consideration of mesh infection and ECF, and that POCUS may be useful in evaluating for these complications.

Balancing Properties with Carboxylates: A Lead Optimization Campaign for Selective and Orally Active CDK9 Inhibitors.

Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration. Here, we report the lead optimization of a series of azaindole-based inhibitors. To overcome early challenges with promiscuity and cardiovascular toxicity, carboxylates were introduced into the pharmacophore en route to compounds such as 14 and 16. These CDK9 inhibitors demonstrated a reduced toxicity, adequate pharmacokinetic properties, and a robust in vivo efficacy in mice upon oral dosing.