89 research outputs found
Sex Differences in rt-PA Utilization at Hospitals Treating Stroke: The National Inpatient Sample.
BACKGROUND AND PURPOSE: Sex and race disparities in recombinant tissue plasminogen activator (rt-PA) use have been reported. We sought to explore sex and race differences in the utilization of rt-PA at primary stroke centers (PSCs) compared to non-PSCs across the US.
METHODS: Data from the National (Nationwide) Inpatient Sample (NIS) 2004-2010 was utilized to assess sex differences in treatment for ischemic stroke in PSCs compared to non-PSCs.
RESULTS: There were 304,152 hospitalizations with a primary diagnosis of ischemic stroke between 2004 and 2010 in the analysis: 75,160 (24.7%) patients were evaluated at a PSC. A little over half of the patients evaluated at PSCs were female (53.8%). A lower proportion of women than men received rt-PA at both PSCs (6.8 vs. 7.5%, pâ\u3câ0.001) and non-PSCs (2.3 vs. 2.8%, pâ\u3câ0.001). After adjustment for potential confounders the odds of being treated with rt-PA remained lower for women regardless of presentation to a PSC (OR 0.87, 95% CI 0.81-0.94) or non-PSC (OR 0.88, 95% CI 0.82-0.94). After stratifying by sex and race, the lowest absolute treatment rates were observed in black women (4.4% at PSC, 1.9% at non-PSC). The odds of treatment, relative to white men, was however lowest for white women (PSC ORâ=â0.85, 95% CI 0.78-0.93; non-PSC ORâ=â0.80, 95% CI 0.75-0.85). In the multivariable model, sex did not modify the effect of PSC certification on rt-PA utilization (p-value for interactionâ=â0.58).
CONCLUSION: Women are less likely to receive rt-PA than men at both PSCs and non-PSCs. Absolute treatment rates are lowest in black women, although the relative difference in men and women was greatest for white women
Protein Requirements of Pre-Menopausal Female Athletes: Systematic Literature Review
This systematic literature review aimed to determine the protein requirements of pre-menopausal (e.g., 18–45 years) female athletes and identify if the menstrual cycle phase and/or hormonal contraceptive use influence protein requirements. Four databases were searched for original research containing pre-menopausal female athletes that ingested protein alongside exercise. The Academy of Nutrition and Dietetics Quality Criteria Checklist was used to determine study quality. Fourteen studies, which included 204 recreationally active or competitive females, met the eligibility criteria for inclusion in this review, and all were assessed as positive quality. The estimated average requirement (EAR) for protein intake of pre-menopausal recreational and/or competitive female athletes is similar for those undertaking aerobic endurance (1.28–1.63 g/kg/day), resistance (1.49 g/kg/day) and intermittent exercise (1.41 g/kg/day) of ~60–90 min duration. The optimal acute protein intake and influence of menstrual cycle phase or hormonal contraceptive use on protein requirements could not be determined. However, pre- and post-exercise protein intakes of 0.32–0.38 g/kg have demonstrated beneficial physiological responses in recreational and competitive female athletes completing resistance and intermittent exercise. The protein requirements outlined in this review can be used for planning and assessing protein intakes of recreational and competitive pre-menopausal female athletes
Competing in hot conditions at the Tokyo Olympic Games : Preparation strategies used by Australian race walkers
Introduction: The Tokyo 2021 Olympic Games was anticipated to expose athletes to the most challenging climatic conditions experienced in the history of the modern Olympic Games. This study documents strategies executed by Australian endurance athletes during the team holding camp and Olympic Games experiences, including (1) baseline physiological data, training data, and heat acclimation/acclimatization practices; (2) pre- and in-race cooling and nutritional strategies, and (3) Olympic Games race performance data.
Methods: Six athletes (three males, three females; age 24 ± 4 years; VO2max 63.2 ± 8.7 mLâ
kgâ1â
minâ1; sum of 7 skinfolds 53.1 ± 23.4 mm) were observed prior to and during the team holding camp held in Cairns, QLD, Australia. Athletes completed 6â7 weeks of intermittent heat acclimation training, utilizing a combination of 2â4 passive and active acclimation sessions per week. Active acclimation was systematically increased via exposure time, exercise intensity, temperature, and humidity. In the team holding camp, athletes undertook a further 23 heat acclimatization training sessions over 18 days in a continuous fashion. Hyperhydration (using sodium and glycerol osmolytes), and internal and external pre-and in-race cooling methods were also utilized. A low energy availability intervention was implemented with two athletes, as a strategy to periodize ideal race body composition. Race performance data and environmental conditions from the 2021 Olympic Games were also documented.
Results: The highest values for aerobic capacity were 63.6 mLâ
kgâ1â
minâ1 for female race walkers and 73.7 mLâ
kgâ1â
minâ1 for males. Training volume for the six athletes was the highest in the second week of the team holding camp, and training intensity was lowest in the first week of the team holding camp. Performance outcomes included 6th place in the womenâs 20 km event (1:30:39), which was within 2% of her 20 km personal best time, and 8th place in the menâs 50 km event (3:52:01), which was a personal best performance time.
Conclusion: Periodized training, heat acclimation/acclimatization, cooling and nutritional strategies study may have contributed to the race outcomes in Olympic Games held hot, humid conditions, for the race walkers within this observational study
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Rescue of the MERTK phagocytic defect in a human iPSC disease model using translational read-through inducing drugs.
Inherited retinal dystrophies are an important cause of blindness, for which currently there are no effective treatments. In order to study this heterogeneous group of diseases, adequate disease models are required in order to better understand pathology and to test potential therapies. Induced pluripotent stem cells offer a new way to recapitulate patient specific diseases in vitro, providing an almost limitless amount of material to study. We used fibroblast-derived induced pluripotent stem cells to generate retinal pigment epithelium (RPE) from an individual suffering from retinitis pigmentosa associated with biallelic variants in MERTK. MERTK has an essential role in phagocytosis, one of the major functions of the RPE. The MERTK deficiency in this individual results from a nonsense variant and so the MERTK-RPE cells were subsequently treated with two translational readthrough inducing drugs (G418 & PTC124) to investigate potential restoration of expression of the affected gene and production of a full-length protein. The data show that PTC124 was able to reinstate phagocytosis of labeled photoreceptor outer segments at a reduced, but significant level. These findings represent a confirmation of the usefulness of iPSC derived disease specific models in investigating the pathogenesis and screening potential treatments for these rare blinding disorders
Sex Differences in rt-PA Utilization at Hospitals Treating Stroke: The National Inpatient Sample
Background and purposeSex and race disparities in recombinant tissue plasminogen activator (rt-PA) use have been reported. We sought to explore sex and race differences in the utilization of rt-PA at primary stroke centers (PSCs) compared to non-PSCs across the US.MethodsData from the National (Nationwide) Inpatient Sample (NIS) 2004â2010 was utilized to assess sex differences in treatment for ischemic stroke in PSCs compared to non-PSCs.ResultsThere were 304,152 hospitalizations with a primary diagnosis of ischemic stroke between 2004 and 2010 in the analysis: 75,160 (24.7%) patients were evaluated at a PSC. A little over half of the patients evaluated at PSCs were female (53.8%). A lower proportion of women than men received rt-PA at both PSCs (6.8 vs. 7.5%, pâ<â0.001) and non-PSCs (2.3 vs. 2.8%, pâ<â0.001). After adjustment for potential confounders the odds of being treated with rt-PA remained lower for women regardless of presentation to a PSC (OR 0.87, 95% CI 0.81â0.94) or non-PSC (OR 0.88, 95% CI 0.82â0.94). After stratifying by sex and race, the lowest absolute treatment rates were observed in black women (4.4% at PSC, 1.9% at non-PSC). The odds of treatment, relative to white men, was however lowest for white women (PSC ORâ=â0.85, 95% CI 0.78â0.93; non-PSC ORâ=â0.80, 95% CI 0.75â0.85). In the multivariable model, sex did not modify the effect of PSC certification on rt-PA utilization (p-value for interactionâ=â0.58).ConclusionWomen are less likely to receive rt-PA than men at both PSCs and non-PSCs. Absolute treatment rates are lowest in black women, although the relative difference in men and women was greatest for white women
Combined approaches, including long-read sequencing, address the diagnostic challenge of HYDIN in primary ciliary dyskinesia
Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence homology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN. We have used a combined approach of SR-NGS with bioinformatic masking of HYDIN2, and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of HYDIN as a cause of PCD. Bioinformatic masking of HYDIN2 after SR-NGS facilitated the detection of biallelic HYDIN variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected HYDIN deletions in 2 families, where SR-NGS had detected a single heterozygous HYDIN variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic HYDIN variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported HYDIN cohort to date and highlights previous underdiagnosis of HYDIN-associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.</p
In Vivo T Cell Costimulation Blockade with Abatacept for Acute Graft-versus-Host Disease Prevention: A First-in-Disease Trial
AbstractWe performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days â1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4+ T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4+ Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P < .01). The ABA patients demonstrated a low rate of aGVHD, despite robust immune reconstitution, with 2 of 10 patients diagnosed with grade II-IV aGVHD before day +100, no deaths from infection, no day +100 TRM, and with 7 of 10 evaluable patients surviving (median follow-up, 16 months). These results suggest that costimulation blockade with abatacept can significantly affect CD4+ T cell proliferation and activation post-transplantation, and may be an important adjunct to standard immunoprophylaxis for aGVHD in patients undergoing unrelated-donor HCT
HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus
Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme
Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort
Background Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests.Methods The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries.Results Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results.Conclusions This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening
The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe
The preponderance of matter over antimatter in the early Universe, the
dynamics of the supernova bursts that produced the heavy elements necessary for
life and whether protons eventually decay --- these mysteries at the forefront
of particle physics and astrophysics are key to understanding the early
evolution of our Universe, its current state and its eventual fate. The
Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed
plan for a world-class experiment dedicated to addressing these questions. LBNE
is conceived around three central components: (1) a new, high-intensity
neutrino source generated from a megawatt-class proton accelerator at Fermi
National Accelerator Laboratory, (2) a near neutrino detector just downstream
of the source, and (3) a massive liquid argon time-projection chamber deployed
as a far detector deep underground at the Sanford Underground Research
Facility. This facility, located at the site of the former Homestake Mine in
Lead, South Dakota, is approximately 1,300 km from the neutrino source at
Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino
charge-parity symmetry violation and mass ordering effects. This ambitious yet
cost-effective design incorporates scalability and flexibility and can
accommodate a variety of upgrades and contributions. With its exceptional
combination of experimental configuration, technical capabilities, and
potential for transformative discoveries, LBNE promises to be a vital facility
for the field of particle physics worldwide, providing physicists from around
the globe with opportunities to collaborate in a twenty to thirty year program
of exciting science. In this document we provide a comprehensive overview of
LBNE's scientific objectives, its place in the landscape of neutrino physics
worldwide, the technologies it will incorporate and the capabilities it will
possess.Comment: Major update of previous version. This is the reference document for
LBNE science program and current status. Chapters 1, 3, and 9 provide a
comprehensive overview of LBNE's scientific objectives, its place in the
landscape of neutrino physics worldwide, the technologies it will incorporate
and the capabilities it will possess. 288 pages, 116 figure
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