749 research outputs found
Long-term surgical and patient-reported outcomes of Hirschsprung Disease
Background: Information is needed regarding the complex relationships between long-term functional outcomes and health-related quality of life (HRQoL) in Hirschsprung's Disease (HSCR). We describe longterm outcomes across multiple domains, completing a core outcome set through to adulthood. Methods: HSCR patients operated at a single center over a 35-year period (1978-2013) were studied. Patients completed detailed questionnaires on bowel and urologic function, and HRQOL. Patients with learning disability (LD) were excluded. Outcomes were compared to normative data. Data are reported as median [IQR] or mean (SD). Results: 186 patients (median age 28 [18-32] years; 135 males) completed surveys. Bowel function was reduced (BFS 17 [14-19] vs. 19 [19-20], p < 0.0001;eta(2) = 0.22). Prevalence and severity of fecal soiling and fecal awareness improved with age ( p < 0.05 for both). Urinary incontinence was more frequent than controls, most of all in 13-26y females (65% vs. 31%, p = 0.003). In adults, this correlated independently with constipation symptoms (OR 3.18 [1.4-7.5], p = 0.008). HRQoL outcomes strongly correlated with functional outcome: 42% of children demonstrated clinically significant reductions in overall PedsQL score, and poor bowel outcome was strongly associated with impaired QOL (B = 22.7 [12.7- 32.7], p < 0.001). In adults, GIQLI scores were more often impacted in patients with extended segment disease. SF-36 scores were reduced relative to population level data in most domains, with large effect sizes noted for females in General Health (g = 1.19) and Social Wellbeing (g = 0.8). Conclusion: Functional impairment is common after pull-through, but bowel function improves with age. Clustering of poor functional outcomes across multiple domains identifies a need for early recognition and long-term support for these patients. (C) 2021 Elsevier Inc. All rights reserved.Peer reviewe
Homologous recombination DNA repair defects in PALB2-associated breast cancers
Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast
cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define
the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display biallelic
inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic
PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel
sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, largescale
state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the
genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic
mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic
mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation
sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was
significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-
associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast
majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.. The
authors thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses
and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up
Study (which has received funding from the NHMRC, the National Breast Cancer
Foundation, Cancer Australia, and the National Institute of Health (USA)) for their
contributions to this resource, and the many families who contribute to kConFab.
Research reported in this paper was supported in part by the Breast Cancer Research
Foundation and the Sarah Jenkins Fund, a Cancer Center Support Grant of the
National Institutes of Health/National Cancer Institute (grant No. P30CA008748; MSK),
a grant of the Ministry of Health of the Czech Republic (NV15-29959A), Charles
University projects PROGRES Q28/LF1 and SVV2019/260367, an HIR Grant UM.C/HlR/
MOHE/06 from the Ministry of Higher Education, Malaysia, and the National Health
and Medical Research Council, Australia (NHMRC, Project Grant APP1029974).
kConFab is supported by a grant from the National Breast Cancer Foundation, and
previously by the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New
South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of
Western Australia. W.D.F. was funded in part by Susan G Komen. A.L. was supported
by the China Scholarship Council. T.N.-D. is an Early Career Fellow of the National
Breast Cancer Foundation and M.S. is a NHMRC Senior Research Fellow of the
National Health and Medical Research Council. M.T. was funded by the National
Institute for Health Research (NIHR) Cambridge Biomedical Research Centre,
Addenbrooke’s Hospital and European Union Seventh Framework Program
(2007–2013)/European Research Council (310018). S.P. was supported by the Swiss
National Science Foundation (Ambizione grant number: PZ00P3_168165). J.S.R-F. is
partly funded by the Breast Cancer Research Foundation and Britta Weigelt by Cycle
for Survival
Publishing and sharing multi-dimensional image data with OMERO
Imaging data are used in the life and biomedical sciences to measure the molecular and structural composition and dynamics of cells, tissues, and organisms. Datasets range in size from megabytes to terabytes and usually contain a combination of binary pixel data and metadata that describe the acquisition process and any derived results. The OMERO image data management platform allows users to securely share image datasets according to specific permissions levels: data can be held privately, shared with a set of colleagues, or made available via a public URL. Users control access by assigning data to specific Groups with defined membership and access rights. OMERO’s Permission system supports simple data sharing in a lab, collaborative data analysis, and even teaching environments. OMERO software is open source and released by the OME Consortium at www.openmicroscopy.org
Thymic epithelial cell fate and potency in early organogenesis assessed by single cell transcriptional and functional analysis
During development, cortical (c) and medullary (m) thymic epithelial cells (TEC) arise from the third pharyngeal pouch endoderm. Current models suggest that within the thymic primordium most TEC exist in a bipotent/common thymic epithelial progenitor cell (TEPC) state able to generate both cTEC and mTEC, at least until embryonic day 12.5 (E12.5) in the mouse. This view, however, is challenged by recent transcriptomics and genetic evidence. We therefore set out to investigate the fate and potency of TEC in the early thymus. Here using single cell (sc) RNAseq we identify a candidate mTEC progenitor population at E12.5, consistent with recent reports. Via lineage-tracing we demonstrate this population as mTEC fate-restricted, validating our bioinformatics prediction. Using potency analyses we also establish that most E11.5 and E12.5 progenitor TEC are cTEC-fated. Finally we show that overnight culture causes most if not all E12.5 cTEC-fated TEPC to acquire functional bipotency, and provide a likely molecular mechanism for this changed differentiation potential. Collectively, our data overturn the widely held view that a common TEPC predominates in the E12.5 thymus, showing instead that sublineage-primed progenitors are present from the earliest stages of thymus organogenesis but that these early fetal TEPC exhibit cell-fate plasticity in response to extrinsic factors. Our data provide a significant advance in the understanding of fetal thymic epithelial development and thus have implications for thymus-related clinical research, in particular research focussed on generating TEC from pluripotent stem cells
Thymic epithelial cell fate and potency in early organogenesis assessed by single cell transcriptional and functional analysis
Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial
Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989
Quantum state preparation and macroscopic entanglement in gravitational-wave detectors
Long-baseline laser-interferometer gravitational-wave detectors are operating
at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within
a broad frequency band. Such a low classical noise budget has already allowed
the creation of a controlled 2.7 kg macroscopic oscillator with an effective
eigenfrequency of 150 Hz and an occupation number of 200. This result, along
with the prospect for further improvements, heralds the new possibility of
experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical
behavior of objects in the realm of everyday experience - using
gravitational-wave detectors. In this paper, we provide the mathematical
foundation for the first step of a MQM experiment: the preparation of a
macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum
state, which is possible if the interferometer's classical noise beats the SQL
in a broad frequency band. Our formalism, based on Wiener filtering, allows a
straightforward conversion from the classical noise budget of a laser
interferometer, in terms of noise spectra, into the strategy for quantum state
preparation, and the quality of the prepared state. Using this formalism, we
consider how Gaussian entanglement can be built among two macroscopic test
masses, and the performance of the planned Advanced LIGO interferometers in
quantum-state preparation
Searching for a Stochastic Background of Gravitational Waves with LIGO
The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed
the fourth science run, S4, with significantly improved interferometer
sensitivities with respect to previous runs. Using data acquired during this
science run, we place a limit on the amplitude of a stochastic background of
gravitational waves. For a frequency independent spectrum, the new limit is
. This is currently the most sensitive
result in the frequency range 51-150 Hz, with a factor of 13 improvement over
the previous LIGO result. We discuss complementarity of the new result with
other constraints on a stochastic background of gravitational waves, and we
investigate implications of the new result for different models of this
background.Comment: 37 pages, 16 figure
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