Inverted/reverse hexagonal (HII) phases are of special interest in several fields of research, including nanomedicine. We used molecular dynamics (MD) simulation to study HII systems composed of ...dioleoylphosphatidylethanolamine (DOPE) and palmitoyloleoylphosphatidylethanolamine (POPE) at several hydration levels and temperatures. The effect of the hydration level on several HII structural parameters, including deuterium order parameters, was investigated. We further used MD simulations to estimate the maximum hydrations of DOPE and POPE HII lattices at several given temperatures. Finally, the effect of acyl chain unsaturation degree on the HII structure was studied via comparing the DOPE with POPE HII systems. In addition to MD simulations, we used deuterium nuclear magnetic resonance (2H NMR) and small-angle X-ray scattering (SAXS) experiments to measure the DOPE acyl chain order parameters, lattice plane distances, and the water core radius in HII phase DOPE samples at several temperatures in the presence of excess water. Structural parameters calculated from MD simulations are in excellent agreement with the experimental data. Dehydration decreases the radius of the water core. An increase in hydration level slightly increased the deuterium order parameter of lipids acyl chains, whereas an increase in temperature decreased it. Lipid cylinders undulated along the cylinder axis as a function of hydration level. The maximum hydration levels of PE HII phases at different temperatures were successfully predicted by MD simulations based on a single experimental measurement for the lattice plane distance in the presence of excess water. An increase in temperature decreases the maximum hydration and consequently the radius of the water core and lattice plane distances. Finally, DOPE formed HII structures with a higher curvature compared to POPE, as expected. We propose a general protocol for constructing computational HII systems that correspond to the experimental systems. This protocol could be used to study HII systems composed of molecules other than the PE systems used here and to improve and validate force field parameters by using the target data in the HII phase.
•Developing a model for creating master operating theatre timetables that include multiple factors.•Smoothing of expected bed usage, taking account of variations in bed availability.•The use of ...operating theatre types allowing for multiple non-nested types.•The inclusion of surgeons’ preference scoring of available operating theatre slots.
Operating theatres and surgeons are among the most expensive resources in any hospital, so it is vital that they are used efficiently. Many European hospitals implement block scheduling, where each surgeon is assigned blocks of time in specific operating theatres on a cyclic basis. This paper proposes a model that assists hospitals in creating new master theatre timetables, which take account of reducing the maximum number of beds required, surgeons’ availability, surgeons’ preferences, variations in types of theatre and their suitability for different types of surgery, limited equipment availability, and the ability to vary the length of the cycle over which the timetable is repeated. The weightings given to each of these factors can be altered, thereby allowing exploration of a variety of possible timetables. Novel features of the model include consideration of surgeons’ preferences for slots, smoothing of bed usage during the generation of master theatre timetables and the use of operating theatres with the potential for the same theatre to be belong to multiple non-nested types. These new features are considered in combination with a range of other factors that have been considered in previous studies on the development of master theatre timetables.
Guidelines of care for the management of acne vulgaris Zaenglein, Andrea L., MD; Pathy, Arun L., MD; Schlosser, Bethanee J., MD, PhD ...
Journal of the American Academy of Dermatology,
05/2016, Letnik:
74, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Acne is one of the most common disorders treated by dermatologists and other health care providers. While it most often affects adolescents, it is not uncommon in adults and can also be seen in ...children. This evidence-based guideline addresses important clinical questions that arise in its management. Issues from grading of acne to the topical and systemic management of the disease are reviewed. Suggestions on use are provided based on available evidence.
Objective
To define patterns of prescription and factors associated with choice of pharmacotherapy for gestational diabetes mellitus (GDM), namely metformin, glyburide and insulin, during a period of ...evolving professional guidelines.
Desing
Cross‐sectional study.
Setting
US commercial insurance beneficiaries from Market‐Scan (late 2015 to 2018).
Study design
We included women with GDM, singleton gestations, 15–51 years of age on pharmacotherapy. The exposure was pharmacy claims for metformin, glyburide and insulin.
Main outcomes
Pharmacotherapy for GDM with either oral agent, metformin or glyburide, compared with insulin as the reference, and secondarily, consequent treatment modification (addition and/or change) to metformin, glyburide or insulin.
Results
Among 37 762 women with GDM, we analysed data from 10 407 (28%) with pharmacotherapy, 21% with metformin (n = 2147), 48% with glyburide (n = 4984) and 31% with insulin (n = 3276). From late 2015 to 2018, metformin use increased from 17 to 29%, as did insulin use from 26 to 44%, whereas glyburide use decreased from 58 to 27%. By 2018, insulin was the most common pharmacotherapy for GDM; metformin was more likely to be prescribed by 9% compared with late 2015/16, but glyburide was less likely by 45%. Treatment modification occurred in 20% of women prescribed metformin compared with 2% with insulin and 8% with glyburide.
Conclusions
Insulin followed by metformin has replaced glyburide as the most common pharmacotherapy for GDM among a privately insured US population during a time of evolving professional guidelines. Further evaluation of the relative effectiveness and safety of metformin compared with insulin is needed.
Tweetable
Insulin followed by metformin has replaced glyburide as the most common pharmacotherapy for gestational diabetes mellitus in the USA.
Tweetable
Insulin followed by metformin has replaced glyburide as the most common pharmacotherapy for gestational diabetes mellitus in the USA.
Linked article This article is commented on by AB Caughey, p. 484 in this issue. To view this mini commentary visit https://doi.org/10.1111/1471-0528.16961.
High frequency of BRAF mutations in nevi Meltzer, Paul S; Pollock, Pamela M; Harper, Ursula L ...
Nature genetics,
01/2003, Letnik:
33, Številka:
1
Journal Article
Recenzirano
To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi ...samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract PRM-151, recombinant human Pentraxin-2 (PTX-2) also referred to as serum amyloid P (SAP), is under development for treatment of fibrosis. A First-in-Human (FIH) trial was performed to assess ...the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects (PRM-151:placebo; 2:1). SAP levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous SAP. At a dose level of 10 mg/kg, at which a physiologic plasma level of SAP was reached, two additional healthy volunteers and three pulmonary fibrosis (PF) patients were enrolled enabling comparison of the pharmacokinetic SAP profile between healthy volunteers and PF patients. In addition, the percentage of fibrocytes (CD45+/Procollagen-1+ cells) in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two pulmonary fibrosis patients non-specific, transient skin reactions (urticaria and erythema) were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma SAP levels at dose levels of 5, 10, and 20 mg/kg. The estimated t1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and PF patients. PRM-151 administration resulted in a 30–50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in PF patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.
The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4
T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and ...cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4
T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8
T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.
Globally, priority areas for biodiversity are relatively well known, yet few detailed plans exist to direct conservation action within them, despite urgent need. Madagascar, like other globally ...recognized biodiversity hot spots, has complex spatial patterns of endemism that differ among taxonomic groups, creating challenges for the selection of within-country priorities. We show, in an analysis of wide taxonomic and geographic breadth and high spatial resolution, that multitaxonomic rather than single-taxon approaches are critical for identifying areas likely to promote the persistence of most species. Our conservation prioritization, facilitated by newly available techniques, identifies optimal expansion sites for the Madagascar government's current goal of tripling the land area under protection. Our findings further suggest that high-resolution multitaxonomic approaches to prioritization may be necessary to ensure protection for biodiversity in other global hot spots.
Understanding the functional connections between genes, proteins, metabolites and mineral ions is one of biology's greatest challenges in the postgenomic era. We describe here the use of mineral ...nutrient and trace element profiling as a tool to determine the biological significance of connections between a plant's genome and its elemental profile. Using inductively coupled plasma spectroscopy, we quantified 18 elements, including essential macro- and micronutrients and various nonessential elements, in shoots of 6,000 mutagenized M2 Arabidopsis thaliana plants. We isolated 51 mutants with altered elemental profiles. One mutant contains a deletion in FRD3, a gene known to control iron-deficiency responses in A. thaliana. Based on the frequency of elemental profile mutations, we estimate 2-4% of the A. thaliana genome is involved in regulating the plant's nutrient and trace element content. These results demonstrate the utility of elemental profiling as a useful functional genomics tool.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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