High-Grade Prostate Cancer: Favorable Results in the Modern Era Regardless of Initial Treatment

Purpose. We performed a retrospective study to determine the outcome of a modern cohort of patients with high-grade (Gleason score ≥ 8) prostate cancer treated with radical prostatectomy, radiation therapy, or hormone therapy. Methods. We identified 404 patients in the South Texas Veteran's Healthcare System Tumor Registry diagnosed with high grade prostate cancer between 1998 and 2008. Mean follow-up was 4.62 ± 2.61 years. End points were biochemical failure-free survival, overall survival, metastasis-free survival, and cancer-specific survival. Results. 5-year overall survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 88.9%, 76.3%, and 58.9%, respectively. 5-year metastasis-free survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 96.8%, 96.6%, and 88.4%, respectively, and 5-year cancer-specific survival was 97.2%, 100%, and 89.9%, respectively. Patients with a Gleason score of 10 and pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year biochemical failure-free and cancer-specific survival. Patients with a pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year overall survival. Discussion. Even for patients with high-grade disease, the outcome is not as dire in the modern era regardless of primary treatment modality chosen. While there is room for improvement, we should not have a nihilistic impression of how these patients will respond to treatment

Global Three-Dimensional Radiation Magnetohydrodynamic Simulations of Accretion onto a Stellar Mass Black Hole at Sub- and Near-critical Accretion Rates

We present global 3D radiation magnetohydrodynamical simulations of accretion onto a 6.62 solar mass black hole with quasi-steady state accretion rates reaching 0.016 to 0.9 times the critical accretion rate, which is defined as the accretion rate to power the Eddington luminosity assuming a 10% radiative efficiency, in different runs. The simulations show no sign of thermal instability over hundreds of thermal timescales at 10 $r_{\rm g}$. The energy dissipation happens close to the mid-plane in the near-critical runs and near the disk surface in the low accretion rate run. The total radiative luminosity inside $\sim$20 $r_{\rm g}$ is about 1% to 30% the Eddington limit, with a radiative efficiency of about 6% and 3%, respectively, in the sub- and near-critical accretion regimes. In both cases, self-consistent turbulence generated by the magnetorotational instability (MRI) leads to angular momentum transfer, and the disk is supported by magnetic pressure. Outflows from the central low-density funnel with a terminal velocity of $\sim$0.1$c$ are seen only in the near-critical runs. We conclude that these magnetic pressure dominated disks are thermally stable and thicker than the $\alpha$ disk, and the effective temperature profiles are much flatter than that in the $\alpha$ disks. The magnetic pressure of these disks are comparable within an order of magnitude with the previous analytical magnetic pressure dominated disk model.Comment: 17 pages, 13 figures, 3 tables, accepted for publication in Ap

Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling in intestinal epithelial cells

Intestinal nematode parasites can cross the epithelial barrier, causing tissue damage and release of danger-associated molecular patterns (DAMPs) that may promote host protective type 2 immunity. We investigate whether adenosine binding to the A2B adenosine receptor (A2BAR) on intestinal epithelial cells (IECs) plays an important role. Specific blockade of IEC A2BAR inhibits the host protective memory response to the enteric helminth, Heligmosomoides polygyrus bakeri (Hpb), including disruption of gran-uloma development at the host-parasite interface. Memory T cell development is blocked during the primary response, and transcriptional analyses reveal profound impairment of IEC activation. Extracel-lular ATP is visualized 24 h after inoculation and is shown in CD39-deficient mice to be critical for the adenosine production mediating the initiation of type 2 immunity. Our studies indicate a potent adeno-sine-mediated IEC pathway that, along with the tuft cell circuit, is critical for the activation of type 2 immunity

Retrospective screening of routine respiratory samples revealed undetected community transmission and missed intervention opportunities for SARS-CoV-2 in the United Kingdom.

In the early phases of the SARS coronavirus type 2 (SARS-CoV-2) pandemic, testing focused on individuals fitting a strict case definition involving a limited set of symptoms together with an identified epidemiological risk, such as contact with an infected individual or travel to a high-risk area. To assess whether this impaired our ability to detect and control early introductions of the virus into the UK, we PCR-tested archival specimens collected on admission to a large UK teaching hospital who retrospectively were identified as having a clinical presentation compatible with COVID-19. In addition, we screened available archival specimens submitted for respiratory virus diagnosis, and dating back to early January 2020, for the presence of SARS-CoV-2 RNA. Our data provides evidence for widespread community circulation of SARS-CoV-2 in early February 2020 and into March that was undetected at the time due to restrictive case definitions informing testing policy. Genome sequence data showed that many of these early cases were infected with a distinct lineage of the virus. Sequences obtained from the first officially recorded case in Nottinghamshire - a traveller returning from Daegu, South Korea - also clustered with these early UK sequences suggesting acquisition of the virus occurred in the UK and not Daegu. Analysis of a larger sample of sequences obtained in the Nottinghamshire area revealed multiple viral introductions, mainly in late February and through March. These data highlight the importance of timely and extensive community testing to prevent future widespread transmission of the virus.Whole genome sequencing of SARS-CoV-2 was funded by COG-UK; COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research and Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute

Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure

AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD

The TESS Grand Unified Hot Jupiter Survey. I. Ten TESS Planets

We report the discovery of ten short-period giant planets (TOI-2193A b, TOI-2207 b, TOI-2236 b, TOI-2421 b, TOI-2567 b, TOI-2570 b, TOI-3331 b, TOI-3540A b, TOI-3693 b, TOI-4137 b). All of the planets were identified as planet candidates based on periodic flux dips observed by NASA's Transiting Exoplanet Survey Satellite (TESS). The signals were confirmed to be from transiting planets using ground-based time-series photometry, high angular resolution imaging, and high-resolution spectroscopy coordinated with the TESS Follow-up Observing Program. The ten newly discovered planets orbit relatively bright F and G stars ($G < 12.5$,~$T_\mathrm{eff}$ between 4800 and 6200 K). The planets' orbital periods range from 2 to 10~days, and their masses range from 0.2 to 2.2 Jupiter masses. TOI-2421 b is notable for being a Saturn-mass planet and TOI-2567 b for being a ``sub-Saturn'', with masses of $0.322\pm 0.073$ and $0.195\pm 0.030$ Jupiter masses, respectively. In most cases, we have little information about the orbital eccentricities. Two exceptions are TOI-2207 b, which has an 8-day period and a detectably eccentric orbit ($e = 0.17\pm0.05$), and TOI-3693 b, a 9-day planet for which we can set an upper limit of $e < 0.052$. The ten planets described here are the first new planets resulting from an effort to use TESS data to unify and expand on the work of previous ground-based transit surveys in order to create a large and statistically useful sample of hot Jupiters.Comment: 44 pages, 15 tables, 21 figures; revised version submitted to A

Plastid phylogenomic insights into relationships of all flowering plant families

Background Flowering plants (angiosperms) are dominant components of global terrestrial ecosystems, but phylogenetic relationships at the familial level and above remain only partially resolved, greatly impeding our full understanding of their evolution and early diversification. The plastome, typically mapped as a circular genome, has been the most important molecular data source for plant phylogeny reconstruction for decades. Results Here, we assembled by far the largest plastid dataset of angiosperms, composed of 80 genes from 4792 plastomes of 4660 species in 2024 genera representing all currently recognized families. Our phylogenetic tree (PPA II) is essentially congruent with those of previous plastid phylogenomic analyses but generally provides greater clade support. In the PPA II tree, 75% of nodes at or above the ordinal level and 78% at or above the familial level were resolved with high bootstrap support (BP ≥ 90). We obtained strong support for many interordinal and interfamilial relationships that were poorly resolved previously within the core eudicots, such as Dilleniales, Saxifragales, and Vitales being resolved as successive sisters to the remaining rosids, and Santalales, Berberidopsidales, and Caryophyllales as successive sisters to the asterids. However, the placement of magnoliids, although resolved as sister to all other Mesangiospermae, is not well supported and disagrees with topologies inferred from nuclear data. Relationships among the five major clades of Mesangiospermae remain intractable despite increased sampling, probably due to an ancient rapid radiation. Conclusions We provide the most comprehensive dataset of plastomes to date and a well-resolved phylogenetic tree, which together provide a strong foundation for future evolutionary studies of flowering plants

A second planet transiting LTT 1445A and a determination of the masses of both worlds

K.H. acknowledges support from STFC grant ST/R000824/1.LTT 1445 is a hierarchical triple M-dwarf star system located at a distance of 6.86 pc. The primary star LTT 1445A (0.257 M⊙) is known to host the transiting planet LTT 1445Ab with an orbital period of 5.36 days, making it the second-closest known transiting exoplanet system, and the closest one for which the host is an M dwarf. Using Transiting Exoplanet Survey Satellite data, we present the discovery of a second planet in the LTT 1445 system, with an orbital period of 3.12 days. We combine radial-velocity measurements obtained from the five spectrographs, Echelle Spectrograph for Rocky Exoplanets and Stable Spectroscopic Observations, High Accuracy Radial Velocity Planet Searcher, High-Resolution Echelle Spectrometer, MAROON-X, and Planet Finder Spectrograph to establish that the new world also orbits LTT 1445A. We determine the mass and radius of LTT 1445Ab to be 2.87 ± 0.25 M⊕ and 1.304-0.060+0.067 R⊕, consistent with an Earth-like composition. For the newly discovered LTT 1445Ac, we measure a mass of 1.54-0.19+0.20 M⊕ and a minimum radius of 1.15 R⊕, but we cannot determine the radius directly as the signal-to-noise ratio of our light curve permits both grazing and nongrazing configurations. Using MEarth photometry and ground-based spectroscopy, we establish that star C (0.161 M⊙) is likely the source of the 1.4 day rotation period, and star B (0.215 M⊙) has a likely rotation period of 6.7 days. We estimate a probable rotation period of 85 days for LTT 1445A. Thus, this triple M-dwarf system appears to be in a special evolutionary stage where the most massive M dwarf has spun down, the intermediate mass M dwarf is in the process of spinning down, while the least massive stellar component has not yet begun to spin down.Publisher PDFPeer reviewe