Abstract
Multiplanet systems are valuable arenas for investigating exoplanet architectures and comparing planetary siblings. TOI-1246 is one such system, with a moderately bright K dwarf (
V
= 11.6,
...K
= 9.9) and four transiting sub-Neptunes identified by TESS with orbital periods of 4.31, 5.90, 18.66, and 37.92 days. We collected 130 radial velocity observations with Keck/HIRES and TNG/HARPS-N to measure planet masses. We refit the 14 sectors of TESS photometry to refine planet radii (2.97 ± 0.06
R
⊕
, 2.47 ± 0.08
R
⊕
, 3.46 ± 0.09
R
⊕
, and 3.72 ± 0.16
R
⊕
) and confirm the four planets. We find that TOI-1246 e is substantially more massive than the three inner planets (8.1 ± 1.1
M
⊕
, 8.8 ± 1.2
M
⊕
, 5.3 ± 1.7
M
⊕
, and 14.8 ± 2.3
M
⊕
). The two outer planets, TOI-1246 d and TOI-1246 e, lie near to the 2:1 resonance (
P
e
/
P
d
= 2.03) and exhibit transit-timing variations. TOI-1246 is one of the brightest four-planet systems, making it amenable for continued observations. It is one of only five systems with measured masses and radii for all four transiting planets. The planet densities range from 0.70 ± 0.24 to 3.21 ± 0.44 g cm
−3
, implying a range of bulk and atmospheric compositions. We also report a fifth planet candidate found in the RV data with a minimum mass of 25.6 ± 3.6
M
⊕
. This planet candidate is exterior to TOI-1246 e, with a candidate period of 93.8 days, and we discuss the implications if it is confirmed to be planetary in nature.
Plasmodium malariae is widely distributed across the tropics, causing symptomatic malaria in humans with a 72-hour fever periodicity, and may present after latency periods lasting up to many decades. ...Delayed occurrence of symptoms is observed in humans using chemoprophylaxis, or patients having received therapies targeting P. falciparum intraerythrocytic asexual stages, but few investigators have addressed the biological basis of the ability of P. malariae to persist in the human host. To investigate these interesting features of P. malariae epidemiology, we assembled, here, an extensive case series of P. malariae malaria patients presenting in non-endemic China, Sweden, and the UK who returned from travel in endemic countries, mainly in Africa. Out of 378 evaluable P. malariae cases, 100 (26.2%) reported using at least partial chemoprophylaxis, resembling the pattern seen with the relapsing parasites P. ovale spp. and P. vivax. In contrast, for only 7.5% of imported UK cases of non-relapsing P. falciparum was any chemoprophylaxis use reported. Genotyping of parasites from six patients reporting use of atovaquone-proguanil chemoprophylaxis did not reveal mutations at codon 268 of the cytb locus of the P. malariae mitochondrial genome. While travellers with P. malariae malaria are significantly more likely to report prophylaxis use during endemic country travel than are those with P. falciparum infections, atovaquone-proguanil prophylaxis breakthrough was not associated with pmcytb mutations. These preliminary studies, together with consistent observations of the remarkable longevity of P. malariae, lead us to propose re-examination of the dogma that this species is not a relapsing parasite. Further studies are needed to investigate our favoured hypothesis, namely that P. malariae can initiate a latent hypnozoite developmental programme in the human hepatocyte: if validated this will explain the consistent observations of remarkable longevity of parasitism, even in the presence of antimalarial prophylaxis or treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Symptomatic chronic subdural hematoma (CSDH) will become an increasingly common presentation in neurosurgical practice as the population ages, but quality evidence is still lacking to guide the ...optimal management for these patients. The British Neurosurgical Trainee Research Collaborative (BNTRC) was established by neurosurgical trainees in 2012 to improve research by combining the efforts of trainees in each of the United Kingdom (UK) and Ireland's neurosurgical units (NSUs). The authors present the first study by the BNTRC that describes current management and outcomes for patients with CSDH throughout the UK and Ireland. This provides a resource both for current clinical practice and future clinical research on CSDH.
Data on management and outcomes for patients with CSDH referred to UK and Ireland NSUs were collected prospectively over an 8-month period and audited against criteria predefined from the literature: NSU mortality < 5%, NSU morbidity < 10%, symptomatic recurrence within 60 days requiring repeat surgery < 20%, and unfavorable functional status (modified Rankin Scale score of 4-6) at NSU discharge < 30%.
Data from 1205 patients in 26 NSUs were collected. Bur-hole craniostomy was the most common procedure (89%), and symptomatic recurrence requiring repeat surgery within 60 days was observed in 9% of patients. Criteria on mortality (2%), rate of recurrence (9%), and unfavorable functional outcome (22%) were met, but morbidity was greater than expected (14%). Multivariate analysis demonstrated that failure to insert a drain intraoperatively independently predicted recurrence and unfavorable functional outcome (p = 0.011 and p = 0.048, respectively). Increasing patient age (p < 0.00001), postoperative bed rest (p = 0.019), and use of a single bur hole (p = 0.020) independently predicted unfavorable functional outcomes, but prescription of high-flow oxygen or preoperative use of antiplatelet medications did not.
This is the largest prospective CSDH study and helps establish national standards. It has confirmed in a real-world setting the effectiveness of placing a subdural drain. This study identified a number of modifiable prognostic factors but questions the necessity of some common aspects of CSDH management, such as enforced postoperative bed rest. Future studies should seek to establish how practitioners can optimize perioperative care of patients with CSDH to reduce morbidity as well as minimize CSDH recurrence. The BNTRC is unique worldwide, conducting multicenter trainee-led research and audits. This study demonstrates that collaborative research networks are powerful tools to interrogate clinical research questions.
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes ...(T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10
) and candidate genes from knockout mice (P = 5.2 × 10
). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
Little information exists on the incidence of complications after acellular human dermis implantation in two-stage tissue expander breast reconstruction. The purpose of this study was to evaluate the ...incidence of postoperative adverse events and identify significant predictors of complications in acellular human dermis tissue expander breast reconstruction.
This study accrued all patients from January of 2004 through April of 2008 undergoing two-stage immediate tissue expander breast reconstruction using acellular human dermis. A total of 153 expanders were placed. Complications were assessed. Univariate and multivariate logistic regression modeling was performed. Comparison of complication rates using the traditional (non-acellular human dermis) technique from concurrent (2004 to 2008) and consecutive time periods (2001 to 2003) for 2910 and 1170 expanders, respectively, is provided.
A total of 153 expanders were implanted in 96 women: 39 unilateral and 57 bilateral. Eleven (7.2 percent) were removed due to infection (n = 5, 3.3 percent), exposure (n = 4, 2.6 percent), or patient preference (n = 2, 1.3 percent). Other complications included cellulitis (3.9 percent), seroma (7.2 percent), hematoma (2.0 percent), mastectomy flap necrosis (4.6 percent), and leak/failed expansion (0.0 percent); 92.8 percent were successfully expanded and exchanged for a permanent implant. Eleven seromas (7.2 percent) were identified; nine underwent aspiration. None of these resulted in infection or reconstructive failure. Univariate analysis revealed age, body mass index, axillary dissection, and postoperative chemotherapy to be associated with reconstructive failure (p < 0.05). Multivariate analysis revealed that age, body mass index, and axillary dissection are independent risk factors for developing complications (p < 0.05).
Acellular human dermis is a useful adjunct for intraoperative pocket development in immediate tissue expander reconstruction but can result in an increased risk of complications, in particular, seroma and reconstructive failure.
Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense ...mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including ...type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10
). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (R
= -0.22, P = 5.5 × 10
), T2D (R
= -0.27, P = 1.1 × 10
) and coronary artery disease (R
= -0.30, P = 6.5 × 10
). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10
). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas. There is currently no consensus on the optimum ...management of WHO grade II meningiomas. In this study, we identified the calcium binding extracellular matrix glycoprotein, Fibulin-2, via mass-spectrometry-based proteomics, assessed its expression in grade I and II meningiomas and explored its potential as a grade II biomarker. A total of 87 grade I and 91 grade II different meningioma cells, tissue and plasma samples were used for the various experimental techniques employed to assess Fibulin-2 expression. The tumours were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the central nervous system (CNS). Mass spectrometry proteomic analysis identified Fibulin-2 as a differentially expressed protein between grade I and II meningioma cell cultures. Fibulin-2 levels were further evaluated in meningioma cells using Western blotting and Real-time Quantitative Polymerase Chain Reaction (RT-qPCR); in meningioma tissues via immunohistochemistry and RT-qPCR; and in plasma via Enzyme-Linked Immunosorbent Assay (ELISA). Proteomic analyses (
< 0.05), Western blotting (
< 0.05) and RT-qPCR (
< 0.01) confirmed significantly higher Fibulin-2 (FBLN2) expression levels in grade II meningiomas compared to grade I. Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients. This study suggests that elevated Fibulin-2 might be a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.
We report the discovery of a warm sub-Saturn, TOI-257b (HD 19916b), based on data from NASA’s Transiting Exoplanet Survey Satellite (TESS). The transit signal was detected by TESS and confirmed to be ...of planetary origin based on radial velocity observations. An analysis of the TESS photometry, the MINERVA-Australis, FEROS, and HARPS radial velocities, and the asteroseismic data of the stellar oscillations reveals that TOI-257b has a mass of M(P) = 0.138 ± 0.023 M(J) (43.9 ± 7.3 Mꚛ), a radius of R(P) = 0.639 ± 0.013 R(J) (7.16 ± 0.15 Rꚛ), bulk density of 0.65 (+0.12,−0.11) (cgs), and period 18.38818 (+0.00085,−0.00084) days. TOI-257b orbits a bright (V = 7.612 mag) somewhat evolved late F-type star with M⁎ = 1.390 ± 0.046 M(sun), R⁎ = 1.888 ± 0.033 R(sun), T(eff) = 6075 ± 90 K, and 𝜈sin 𝑖 = 11.3 ± 0.5 km/s. Additionally, we find hints for a second non-transiting sub-Saturn mass planet on a ∼71 day orbit using the radial velocity data. This system joins the ranks of a small number of exoplanet host stars (∼100) that have been characterized with asteroseismology. Warm sub-Saturns are rare in the known sample of exoplanets, and thus the discovery of TOI-257b is important in the context of future work studying the formation and migration history of similar planetary systems.
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