Right ventricular failure (RVF) increases morbidity and mortality. The RECOVER RIGHT study evaluated the safety and efficacy of a novel percutaneous right ventricular assist device, the Impella RP ...(Abiomed, Danvers, MA), in a prospective, multicenter trial.
Thirty patients with RVF refractory to medical treatment received the Impella RP device at 15 United States institutions. The study population included 2 cohorts: 18 patients with RVF after left ventricular assist device (LVAD) implantation (Cohort A) and 12 patients with RVF after cardiotomy or myocardial infarction (Cohort B). The primary end point was survival to 30 days or hospital discharge (whichever was longer). Major secondary end points included indices of safety and efficacy.
The patients (77% male) were a mean age of 59 ± 15 years, 53% had diabetes, 88.5% had a history of congestive heart failure, and 37.5% had renal dysfunction. Patients were on an average of 3.2 inotropes/pressors. Device delivery was achieved in all but 1 patient. Hemodynamics improved immediately after initiation of Impella RP support, with an increase in cardiac index from 1.8 ± 0.2 to 3.3 ± 0.23 liters/min/m(2) (p < 0.001) and a decrease in central venous pressure from 19.2 ± 4 to 12.6 ± 1 mm Hg (p < 0.001). Patients were supported for an average of 3.0 ± 1.5 days (range, 0.5-7.8 days). The overall survival at 30 days was 73.3%. All patients discharged were alive at 180 days.
In patients with life-threatening RVF, the novel percutaneous Impella RP device was safe, easy to deploy, and reliably resulted in immediate hemodynamic benefit. These data support its probable benefit in this gravely ill patient population.
Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlates closely with mortality. The origin of ...these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2+CD150+CD48− LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. This subset has 4-fold higher proliferation rates than CCR2−CD150+CD48− LSK cells, displays a myeloid differentiation bias, and dominates the migratory HSPC population. We further demonstrate that the myeloid translocation gene 16 (Mtg16) regulates CCR2+ HSPC emergence. Mtg16−/− mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury and identify potential therapeutic targets to modulate leukocyte output after MI.
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•CCR2 expression identifies an HSPC subset that responds vigorously to ischemia•Myeloid translocation gene 16 (Mtg16) is necessary for the emergence of CCR2+ HSPCs•Absence of CCR2+ HSPCs associates with compromised infarct healing•CCR2+CD150+CD48− LSKs preferentially migrate outside of the bone marrow
Blood leukocyte levels predict mortality following myocardial infarction (MI), but the cellular mechanisms leading to this increase are unclear. Dutta et al. show that CCR2 expression defines an upstream subset of HSPCs that proliferate, migrate, and generate myeloid cells following ischemic injury, and their absence is associated with decreased healing.
Mixed-chirality peptide macrocycles such as cyclosporine are among the most potent therapeutics identified to date, but there is currently no way to systematically search the structural space spanned ...by such compounds. Natural proteins do not provide a useful guide: Peptide macrocycles lack regular secondary structures and hydrophobic cores, and can contain local structures not accessible with L-amino acids. Here, we enumerate the stable structures that can be adopted by macrocyclic peptides composed of L- and D-amino acids by near-exhaustive backbone sampling followed by sequence design and energy landscape calculations. We identify more than 200 designs predicted to fold into single stable structures, many times more than the number of currently available unbound peptide macrocycle structures. Nuclear magnetic resonance structures of 9 of 12 designed 7- to 10-residue macrocycles, and three 11- to 14-residue bicyclic designs, are close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide macrocycles and vastly increase the available starting scaffolds for both rational drug design and library selection methods.
Abstract Naturally generated lipid nanoparticles termed extracellular vesicles (EVs) hold significant promise as engineerable therapeutic delivery vehicles. However, active loading of protein cargo ...into EVs in a manner that is useful for delivery remains a challenge. Here, we demonstrate that by rationally designing proteins to traffic to the plasma membrane and associate with lipid rafts, we can enhance loading of protein cargo into EVs for a set of structurally diverse transmembrane and peripheral membrane proteins. We then demonstrate the capacity of select lipid tags to mediate increased EV loading and functional delivery of an engineered transcription factor to modulate gene expression in target cells. We envision that this technology could be leveraged to develop new EV-based therapeutics that deliver a wide array of macromolecular cargo.
Abstract DPANN archaea are a diverse group of microorganisms characterised by small cells and reduced genomes. To date, all cultivated DPANN archaea are ectosymbionts that require direct cell contact ...with an archaeal host species for growth and survival. However, these interactions and their impact on the host species are poorly understood. Here, we show that a DPANN archaeon ( Candidatus Nanohaloarchaeum antarcticus) engages in parasitic interactions with its host ( Halorubrum lacusprofundi ) that result in host cell lysis. During these interactions, the nanohaloarchaeon appears to enter, or be engulfed by, the host cell. Our results provide experimental evidence for a predatory-like lifestyle of an archaeon, suggesting that at least some DPANN archaea may have roles in controlling host populations and their ecology.
Surgery in patients with Kommerell diverticulum (KD) is controversial. Although the presence of symptoms is an accepted indication, the KD itself may be a risk factor for dissection and rupture, ...although size criteria for operation are undefined.
A retrospective review of 19 adult patients who underwent surgical treatment of KD between March 2004 and June 2013 was performed. Mean age was 48 years (range, 32 to 68 years). Fifteen patients were female, 15 were symptomatic, and 13 had a right aortic arch. Sixteen patients with aberrant subclavian artery underwent a two-stage procedure involving subclavian-common carotid artery transposition or bypass followed by aortic resection, including origin of the KD, with interposition graft reconstruction. Aortic resection was performed with left heart bypass (n = 10) or deep hypothermic circulatory arrest (n = 9).
There were no deaths or strokes. Complications after aberrant subclavian artery revascularization were transient ptosis (n = 3), graft occlusion (n = 1), recurrent laryngeal nerve injury (n = 1),phrenic nerve injury (n = 1), and reintubation (n = 1). Complications after aortic resection were intraoperative type A dissection (n = 1), phrenic nerve injury (n = 1), chylothorax (n = 1), and transient neurologic dysfunction (n = 1). Mean hospital stay after aberrant subclavian artery revascularization was 2 ± 2 days and after aortic resection, 6.4 ± 2.4 days. Of 18 available pathology specimens, all 18 showed medial degeneration. Mean follow-up was 3.3 years.
This is the largest reported single-center experience with the surgical management of KD in adults, verifying its safety and efficacy. The high percentage of KD with medial degeneration suggests asymptomatic patients with an enlarged KD also may benefit from resection.
The ability to communicate is the most fundamental educational outcome leading to academic success (Kearns et al., 2015). This is no different for students with disabilities. Students with autism ...spectrum disorders (ASD), however, demonstrate difficulty with spontaneous communication and use of functional language throughout a variety of settings (Centers for Disease Control; CDC, 2020), including academic contexts. Embedded instruction (Jimenez & Kamei, 2015) and systematic prompting (Doyle et al.,1988) have been used as strategies to improve skill acquisition for students with ASD. This study provides support to the existing literature by combining two previously evidence-based practices to increase the verbal behavior of students with autism during reading instruction. A single-subject multiple probe design across three elementary school students with ASD was used to analyze the outcomes of the use of embedded trials and systematic prompting on tacted and intraverbal responses to story questions. In addition, the content and accuracy of the responses were recorded. All students increased their ability to accurately respond and provide verbalizations about a text at the completion of the study. Limitations and future research were discussed regarding implementation of technology, distance learning, and implications due to COVID-19.
We present the discovery of TOI-1518b—an ultra-hot Jupiter orbiting a bright star (V = 8.95). The transiting planet is confirmed using high-resolution optical transmission spectra from EXPRES. It is ...inflated, with Rp = 1.875 ± 0.053 RJ, and exhibits several interesting properties, including a misaligned orbit (240.34 (+0.93, -0.98) degrees) and nearly grazing transit (b=0.9036 (+0.0061, -0.0053)). The planet orbits a fast-rotating F0 host star (Teff ≃ 7300 K) in 1.9 days and experiences intense irradiation. Notably, the TESS data show a clear secondary eclipse with a depth of 364 ± 28 ppm and a significant phase-curve signal, from which we obtain a relative day–night planetary flux difference of roughly 320 ppm and a 5.2σ detection of ellipsoidal distortion on the host star. Prompted by recent detections of atomic and ionized species in ultra-hot Jupiter atmospheres, we conduct an atmospheric cross-correlation analysis. We detect neutral iron (5.2σ), at K(p) = 157 (+68, -44) km/s and V(sys) = -16 (+2, -4), adding another object to the small sample of highly irradiated gas-giant planets with Fe detections in transmission. Detections so far favor particularly inflated gas giants with radii ≳1.78 R(J), which may be due to observational bias. With an equilibrium temperature of T(eq) = 2492 ± 38 K and a measured dayside brightness temperature of 3237 ± 59 K (assuming zero geometric albedo), TOI-1518b is a promising candidate for future emission spectroscopy to probe for a thermal inversion.
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