1,970 research outputs found
The mapping class group and the Meyer function for plane curves
For each d>=2, the mapping class group for plane curves of degree d will be
defined and it is proved that there exists uniquely the Meyer function on this
group. In the case of d=4, using our Meyer function, we can define the local
signature for 4-dimensional fiber spaces whose general fibers are
non-hyperelliptic compact Riemann surfaces of genus 3. Some computations of our
local signature will be given.Comment: 24 pages, typo adde
Probing temperature- and solvent-dependent protein dynamics using terahertz time-domain spectroscopy
The effect of temperature on the terahertz-frequency-range material properties of lyophilized and single-crystal hen egg-white lysozyme has been measured using terahertz time-domain spectroscopy, with the results presented and discussed in the context of protein and solvent dynamical and glass transitions. Lyophilized hen egg-white lysozyme was measured over a temperature range from 4 to 290 K, and a change in the dynamical behaviour of the sample at around 100 K was observed through a change in the terahertz absorption spectrum. Additionally, the effect of cryoprotectants on the temperature-dependent absorption coefficient is studied, and it is demonstrated that terahertz time-domain spectroscopy is capable of resolving the true glass transition temperature of single-crystal hen egg-white lysozyme at 150 K, which is in agreement with literature values measured using differential scanning calorimetry
What to do with diabetes therapies when HbA1c lowering is inadequate:add, switch, or continue? A MASTERMIND study
This is the author accepted manuscript. The final version is available from BioMed Central via the DOI in this record.Background: It is unclear what to do when people with type 2 diabetes have had no or a
limited glycemic response to a recently introduced medication. Intra-individual HbA1c
variability can obscure true response. Some guidelines suggest stopping apparently
ineffective therapy, but no studies have addressed this issue.
Methods: In a retrospective cohort analysis using the UK Clinical Practice Research Datalink
(CPRD), we assessed the outcome of 55,530 patients with type 2 diabetes starting their
second or third non-insulin glucose lowering medication, with a baseline HbA1c >58mmol/mol
(7.5%). For those with no HbA1c improvement or a limited response at 6 months (HbA1c fall
<5.5mmol/mol [0.5%]) we compared HbA1c 12 months later in those who continued their
treatment unchanged, switched to new treatment, or added new treatment.
Results: An increase or a limited reduction in HbA1c was common, occurring in 21.9%
(12,168/55,230), who had a mean HbA1c increase of 2.5mmol/mol (0.2%). After this limited
response, continuing therapy was more frequent (n=9,308; 74%) than switching (n=1,177; 9%)
or adding (n=2,163; 17%). Twelve months later, in those who switched medication HbA1c fell
(-6.8mmol/mol [-0.6%], 95%CI -7.7, -6.0) only slightly more than those who continued
unchanged (-5.1 mmol/mol [-0.5%], 95%CI -5.5, -4.8). Adding another new therapy was
associated with a substantially better reduction (-12.4mmol/mol [-1.1%], 95%CI -13.1, -11.7).
Propensity score matched subgroups demonstrated similar results.
Conclusions: Where glucose lowering therapy does not appear effective on initial HbA1c
testing, changing agents does not improve glycemic control. The initial agent should be
continued with another therapy added.Medical Research Council (MRC)National Institute for Health Research (NIHR
Are the new drugs better? Changing UK prescribing of Type 2 diabetes medications and effects on HbA1c and weight, 2010 to 2016
This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Aim: The availability of new glucoseâlowering drugs has changed UK National Institute of Clinical Excellence Type 2 diabetes guidelines, but there has been little evaluation of realâworld use of these drugs, or of the populationâlevel impact of their use. We examined changes in UK prescribing for patients starting secondâ and thirdâline medications, and populationâlevel trends in glycaemic response and weight change.
Methods: We extracted incident secondâ and thirdâline oral prescription records for patients with Type 2 diabetes in the UKârepresentative Clinical Practice Research Datalink, 2010 to 2016 (n = 68,902). Each year we calculated the proportion of each drug prescribed as the percentage of the total prescribed. We estimated annual mean sixâmonth HbA1c response and weight change using linear regression, standardised for clinical characteristics.
Results: Use of Dipeptidyl peptidaseâ4 (DPP4) inhibitors has increased markedly to overtake sulfonylureas as the most commonly prescribed secondâline drug in 2016 (43% vs 34% of total prescriptions compared with 18% v 59% in 2010). Use of sodiumâglucose coâtransporterâ2 (SGLT2) inhibitors has increased rapidly to 14% of secondâline and 27% of thirdâline prescriptions in 2016. Mean HbA1c response at six months was stable over time (2016: 13.5 (95% confidence interval 12.8, 14.1) mmol/mol vs 2010: 13.9 (13.6;14.2) mmol/mol, p = 0.21). We found mean weight loss at six months in 2016, in contrast to 2010 where there was mean weight gain (2016: â1.2 (â0.9; â1.5) kg vs 2010: +0.4 (+0.3; +0.5) kg, p < 0.001).
Conclusion: The pattern of drug prescribing to manage patients with Type 2 diabetes has changed rapidly in the United Kingdom. Increasing use of DPP4 inhibitors and SGLT2 inhibitors has not resulted in improved glycaemic control but has improved the body weight of patients starting secondâ and thirdâline therapy.
Acknowledgement: This abstract is submitted on behalf of the MASTERMIND consortium
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Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment
Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor and has a very poor prognosis, with only around 5% of patients surviving for a period of 5 years or more after diagnosis. Despite aggressive multimodal therapy, consisting mostly of a combination of surgery, radiotherapy, and temozolomide chemotherapy, tumors nearly always recur close to the site of resection. For the past 15 years, very little progress has been made with regards to improving patient survival. Although immunotherapy represents an attractive therapy modality due to the promising pre-clinical results observed, many of these potential immunotherapeutic approaches fail during clinical trials, and to date no immunotherapeutic treatments for GBM have been approved. As for many other difficult to treat cancers, GBM combines a lack of immunogenicity with few mutations and a highly immunosuppressive tumor microenvironment (TME). Unfortunately, both tumor and immune cells have been shown to contribute towards this immunosuppressive phenotype. In addition, current therapeutics also exacerbate this immunosuppression which might explain the failure of immunotherapy-based clinical trials in the GBM setting. Understanding how these mechanisms interact with one another, as well as how one can increase the anti-tumor immune response by addressing local immunosuppression will lead to better clinical results for immune-based therapeutics. Improving therapeutic delivery across the blood brain barrier also presents a challenge for immunotherapy and future therapies will need to consider this. This review highlights the immunosuppressive mechanisms employed by GBM cancers and examines potential immunotherapeutic treatments that can overcome these significant immunosuppressive hurdles
Rates of Low-Value Service in Australian Public Hospitals and the Association With Patient Insurance Status.
Importance: Low-value services have limited or no benefit to patients. Rates of low-value service in public hospitals may vary by patient insurance status, given that there may be different financial incentives for treatment of privately insured patients. Objective: To assess the variation in rates of 5 low-value services performed in Australian public hospitals according to patient funding status (ie, private or public). Design, Setting, and Participants: This retrospective cross-sectional study analyzed New South Wales public hospital data from January 2013 to June 2018. Patients included in the sample were over age 18 years and eligible to receive low-value services based on diagnoses and concomitant procedures. Data analysis was conducted from June to December 2020. Main Outcomes and Measures: Hospital-specific rates of low-value knee arthroscopic debridement, vertebroplasty for osteoporotic spinal fractures, hyperbaric oxygen therapy, oophorectomy with hysterectomy, and laparoscopic uterine nerve ablation for chronic pelvic pain were measured. For each measure, rates within each public hospital were compared by patient funding status descriptively and using multilevel models. Results: A total of 219âŻ862 inpatients were included in analysis from 58 public hospitals across the 5 measures. A total of 38âŻ365 (22âŻ904 [59.7%] women; 12âŻ448 [32.4%] aged 71-80 years) were eligible for knee arthroscopic debridement for osteoarthritis; 2520 (1924 [76.3%] women; 662 [26.3%] aged 71-80 years), vertebroplasty for osteoporotic spinal fractures; 162âŻ285 (82âŻ046 [50.6%] women; 28âŻ255 [17.4%] aged 61-70 years), hyperbaric oxygen therapy; 15âŻ916 (7126 [44.8%] aged 41-50 years), oophorectomy with hysterectomy; and 776 (327 [42.1%] aged 18-30 years), uterine nerve ablation for chronic pelvic pain. Overall rates of low-value services varied considerably between measures, with the lowest rate for hyperbaric oxygen therapy (0.3 procedures per 1000 inpatients [47 of 158âŻ220 eligible inpatients]) and the highest for vertebroplasty (30.8 procedures per 1000 eligible patients [77 of 2501 eligible inpatients]). There was significant variation in rates between hospitals, with a few outlying hospitals (ie, <10), particularly for knee arthroscopy (range from 1.8 to 21.0 per 1000 eligible patients) and vertebroplasty (range from 13.1 to 70.4 per 1000 eligible patients), with higher numerical rates of low-value services among patients with private insurance than for those without. However, there was no association overall between patient insurance status and low-value services. Overall differences in rates among those with and without private insurance by individual procedure type were not statistically significant. Conclusions and Relevance: There was significant variation in rates of low-value services in public hospitals. While there was no overall association between private insurance and rate of low-value services, private insurance may be associated with low-value service rates in some hospitals. Further exploration of factors specific to local hospitals and practices are needed to reduce this unnecessary care
Threonine 57 is required for the post-translational activation of Escherichia coli aspartate α-decarboxylase.
Aspartate α-decarboxylase is a pyruvoyl-dependent decarboxylase required for the production of ÎČ-alanine in the bacterial pantothenate (vitamin B5) biosynthesis pathway. The pyruvoyl group is formed via the intramolecular rearrangement of a serine residue to generate a backbone ester intermediate which is cleaved to generate an N-terminal pyruvoyl group. Site-directed mutagenesis of residues adjacent to the active site, including Tyr22, Thr57 and Tyr58, reveals that only mutation of Thr57 leads to changes in the degree of post-translational activation. The crystal structure of the site-directed mutant T57V is consistent with a non-rearranged backbone, supporting the hypothesis that Thr57 is required for the formation of the ester intermediate in activation
Observational Properties of Jets in Active Galactic Nuclei
Parsec scale jet properties are shortly presented and discussed.
Observational data are used to derive constraints on the jet velocity and
orientation, the presence of velocity structures, and the connection between
the pc and kpc scale. Two peculiar sources with limb-brightened jets: 1144+35
and Mkn 501 are discussed in detail.Comment: 13 pages with 7 figures. To appear in "Virtual Astrophysical Jets"
APSS, Kluwer Academic Publisher - Massaglia, Bodo, Rossi eds - in pres
Managing healthcare budgets in times of austerity: the role of program budgeting and marginal analysis
Given limited resources, priority setting or choice making will remain a reality at all levels of publicly funded healthcare across countries for many years to come. The pressures may well be even more acute as the impact of the economic crisis of 2008 continues to play out but, even as economies begin to turn around, resources within healthcare will be limited, thus some form of rationing will be required. Over the last few decades, research on healthcare priority setting has focused on methods of implementation as well as on the development of approaches related to fairness and legitimacy and on more technical aspects of decision making including the use of multi-criteria decision analysis. Recently, research has led to better understanding of evaluating priority setting activity including defining âsuccessâ and articulating key elements for high performance. This body of research, however, often goes untapped by those charged with making challenging decisions and as such, in line with prevailing public sector incentives, decisions are often reliant on historical allocation patterns and/or political negotiation. These archaic and ineffective approaches not only lead to poor decisions in terms of value for money but further do not reflect basic ethical conditions that can lead to fairness in the decision-making process. The purpose of this paper is to outline a comprehensive approach to priority setting and resource allocation that has been used in different contexts across countries. This will provide decision makers with a single point of access for a basic understanding of relevant tools when faced with having to make difficult decisions about what healthcare services to fund and what not to fund. The paper also addresses several key issues related to priority setting including how health technology assessments can be used, how performance can be improved at a practical level, and what ongoing resource management practice should look like. In terms of future research, one of the most important areas of priority setting that needs further attention is how best to engage public members
The GATA1s isoform is normally down-regulated during terminal haematopoietic differentiation and over-expression leads to failure to repress MYB, CCND2 and SKI during erythroid differentiation of K562 cells
Background: Although GATA1 is one of the most extensively studied haematopoietic transcription factors little is currently known about the physiological functions of its naturally occurring isoforms GATA1s and GATA1FL in humansâparticularly whether the isoforms have distinct roles in different lineages and whether they have non-redundant roles in haematopoietic differentiation. As well as being of general interest to understanding of haematopoiesis, GATA1 isoform biology is important for children with Down syndrome associated acute megakaryoblastic leukaemia (DS-AMKL) where GATA1FL mutations are an essential driver for disease pathogenesis.
<p/>Methods: Human primary cells and cell lines were analyzed using GATA1 isoform specific PCR. K562 cells expressing GATA1s or GATA1FL transgenes were used to model the effects of the two isoforms on in vitro haematopoietic differentiation.
<p/>Results: We found no evidence for lineage specific use of GATA1 isoforms; however GATA1s transcripts, but not GATA1FL transcripts, are down-regulated during in vitro induction of terminal megakaryocytic and erythroid differentiation in the cell line K562. In addition, transgenic K562-GATA1s and K562-GATA1FL cells have distinct gene expression profiles both in steady state and during terminal erythroid differentiation, with GATA1s expression characterised by lack of repression of MYB, CCND2 and SKI.
<p/>Conclusions: These findings support the theory that the GATA1s isoform plays a role in the maintenance of proliferative multipotent megakaryocyte-erythroid precursor cells and must be down-regulated prior to terminal differentiation. In addition our data suggest that SKI may be a potential therapeutic target for the treatment of children with DS-AMKL
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