Evaluating glucose‐lowering treatment in older people with diabetes : lessons from the IMPERIUM trial

Understanding the benefits and risks of treatments to be used by older individuals (≥65 years old) is critical for informed therapeutic decisions. Glucose‐lowering therapy for older patients with diabetes should be tailored to suit their clinical condition, comorbidities and impaired functional status, including varying degrees of frailty. However, despite the rapidly growing population of older adults with diabetes, there are few dedicated clinical trials evaluating glucose‐lowering treatment in older people. Conducting clinical trials in the older population poses multiple significant challenges. Despite the general agreement that individualizing treatment goals and avoiding hypoglycaemia is paramount for the therapy of older people with diabetes, there are conflicting perspectives on specific glycaemic targets that should be adopted and on use of specific drugs and treatment strategies. Assessment of functional status, frailty and comorbidities is not routinely performed in diabetes trials, contributing to insufficient characterization of older study participants. Moreover, significant operational barriers and problems make successful enrolment and completion of such studies difficult. In this review paper, we summarize the current guidelines and literature on conducting such trials, as well as the learnings from our own clinical trial (IMPERIUM) that assessed different glucose‐lowering strategies in older people with type 2 diabetes. We discuss the importance of strategies to improve study design, enrolment and attrition. Apart from summarizing some practical advice to facilitate the successful conduct of studies, we highlight key gaps and needs that warrant further research

Teacher interventions in small group work in secondary mathematics and science lessons

Collaborative problem solving, when students work in pairs or small groups on a curriculum-related task, has become an increasingly common feature of classroom education. This paper reports a study of a topic which has received relatively little attention: how teachers can most usefully intervene when students are working in a group, but have encountered some sort of problem. The data used comes from a large scale interventional study of mathematics and science teaching in secondary schools in south east England, in which interactions between teachers and students were recorded in their usual classrooms. We identify the typical problem situations which lead to teachers’ interventions, and describe the different ways teachers were observed to intervene. We examine the different types of intervention, and consider how effective they are in helping group work proceed in a productive manner. Finally, we offer some conclusions about the practical implications of these findings.This is the final version of the article. It was first available from Taylor & Francis via http://dx.doi.org/10.1080/09500782.2015.112536

Destabilization of dark states and optical spectroscopy in Zeeman-degenerate atomic systems

We present a general discussion of the techniques of destabilizing dark states in laser-driven atoms with either a magnetic field or modulated laser polarization. We show that the photon scattering rate is maximized at a particular evolution rate of the dark state. We also find that the atomic resonance curve is significantly broadened when the evolution rate is far from this optimum value. These results are illustrated with detailed examples of destabilizing dark states in some commonly-trapped ions and supported by insights derived from numerical calculations and simple theoretical models.Comment: 14 pages, 10 figure

Glycaemic outcomes of an Individualised treatMent aPproach for oldER vulnerable patIents: A randomised, controlled stUdy in type 2 diabetes Mellitus (IMPERIUM).

AIM: To compare the glycaemic outcomes of 2 glucose-lowering treatment strategies in vulnerable (moderately ill and/or frail) patients aged ≥65 years with type 2 diabetes whose individual HbA1c targets were not met with diet/exercise and/or oral antihyperglycaemic medications (OAMs). METHODS: The primary endpoint of this study was a composite of achieving/maintaining individualised HbA1c targets without 'clinically significant' hypoglycaemia (severe hypoglycaemia or repeated hypoglycaemia causing interruption of patients' activities or blood glucose <54 mg/dL). Strategy-A comprised glucose-dependent therapies (N = 99) with a non-sulphonylurea OAM and a glucagon-like peptide-1 receptor agonist as the first injectable. Strategy-B comprised non-glucose-dependent therapies (N = 93) with sulphonylurea as the preferred OAM and insulin glargine as the first injectable. RESULTS: There was no significant difference between Strategies A and B in percentages of patients achieving the primary endpoint (64.5% vs 54.9%; P=0.190). Mean incidences (A vs B) of total (10.2% vs 53.8%), documented symptomatic (5.1% vs 36.6%), and asymptomatic (8.2% vs 32.3%) hypoglycaemia were lower for Strategy-A (P<0.001 each). Proportions of patients achieving/maintaining HbA1c target (A, 63.3% vs B, 55.9%) were similar. CONCLUSIONS: Similar proportions of older, vulnerable aged ≥65 years patients with type 2 diabetes achieved/maintained glycaemic treatment goals without clinically significant hypoglycaemia with Strategies A or B. However, Strategy-A resulted in lower risk of total, documented symptomatic, and asymptomatic hypoglycaemia. These results identify an approach of potential clinical benefit in this age group and will inform future clinical research in older patients with type 2 diabetes. This trial is registered with ClinTrials.gov, number NCT02072096

The combined use of cross-section analysis and other stratigraphic recording systems in the cleaning of two panel paintings from the fifteenth- and sixteenth-century

Cross sections are frequently used in the stratigraphic study of pictorial structures. Thanks to cross sections, it is possible to study and record original and non-original strata that may provide important information regarding the artist's technique and later restoration processes. This information helps conservators design different strategies in processes such as cleaning. However, it is often in cleaning where the advantages and limitations of cross sections become obvious. When dealing with a complex structure, cross sections may not be enough to record in a comprehensive and accurate manner all the strata removed during cleaning. In some cases, the conservator may obtain during cleaning a great amount of stratigraphic information that is not visible in the cross sections. Therefore, it may be necessary to resort to other recording systems, such as the stratigraphic unit recording sheet and the stratigraphic diagram, which are frequently used in archaeological stratigraphy. This article demonstrates how cross-section analysis was combined with stratigraphic study during the cleaning of two panel paintings to gain an improved understanding of their complicated layer structure.Barros García, JM.; Reina De La Torre, A.; Pérez Marín, E. (2014). The combined use of cross-section analysis and other stratigraphic recording systems in the cleaning of two panel paintings from the fifteenth- and sixteenth-century. Studies in Conservation. 60(4):245-252. doi:10.1179/2047058414Y.0000000128S24525260

Dust Devil Tracks

Dust devils that leave dark- or light-toned tracks are common on Mars and they can also be found on the Earth’s surface. Dust devil tracks (hereinafter DDTs) are ephemeral surface features with mostly sub-annual lifetimes. Regarding their size, DDT widths can range between ∼1 m and ∼1 km, depending on the diameter of dust devil that created the track, and DDT lengths range from a few tens of meters to several kilometers, limited by the duration and horizontal ground speed of dust devils. DDTs can be classified into three main types based on their morphology and albedo in contrast to their surroundings; all are found on both planets: (a) dark continuous DDTs, (b) dark cycloidal DDTs, and (c) bright DDTs. Dark continuous DDTs are the most common type on Mars. They are characterized by their relatively homogenous and continuous low albedo surface tracks. Based on terrestrial and martian in situ studies, these DDTs most likely form when surficial dust layers are removed to expose larger-grained substrate material (coarse sands of ≥500 μm in diameter). The exposure of larger-grained materials changes the photometric properties of the surface; hence leading to lower albedo tracks because grain size is photometrically inversely proportional to the surface reflectance. However, although not observed so far, compositional differences (i.e., color differences) might also lead to albedo contrasts when dust is removed to expose substrate materials with mineralogical differences. For dark continuous DDTs, albedo drop measurements are around 2.5 % in the wavelength range of 550–850 nm on Mars and around 0.5 % in the wavelength range from 300–1100 nm on Earth. The removal of an equivalent layer thickness around 1 μm is sufficient for the formation of visible dark continuous DDTs on Mars and Earth. The next type of DDTs, dark cycloidal DDTs, are characterized by their low albedo pattern of overlapping scallops. Terrestrial in situ studies imply that they are formed when sand-sized material that is eroded from the outer vortex area of a dust devil is redeposited in annular patterns in the central vortex region. This type of DDT can also be found in on Mars in orbital image data, and although in situ studies are lacking, terrestrial analog studies, laboratory work, and numerical modeling suggest they have the same formation mechanism as those on Earth. Finally, bright DDTs are characterized by their continuous track pattern and high albedo compared to their undisturbed surroundings. They are found on both planets, but to date they have only been analyzed in situ on Earth. Here, the destruction of aggregates of dust, silt and sand by dust devils leads to smooth surfaces in contrast to the undisturbed rough surfaces surrounding the track. The resulting change in photometric properties occurs because the smoother surfaces have a higher reflectance compared to the surrounding rough surface, leading to bright DDTs. On Mars, the destruction of surficial dust-aggregates may also lead to bright DDTs. However, higher reflective surfaces may be produced by other formation mechanisms, such as dust compaction by passing dust devils, as this may also cause changes in photometric properties. On Mars, DDTs in general are found at all elevations and on a global scale, except on the permanent polar caps. DDT maximum areal densities occur during spring and summer in both hemispheres produced by an increase in dust devil activity caused by maximum insolation. Regionally, dust devil densities vary spatially likely controlled by changes in dust cover thicknesses and substrate materials. This variability makes it difficult to infer dust devil activity from DDT frequencies. Furthermore, only a fraction of dust devils leave tracks. However, DDTs can be used as proxies for dust devil lifetimes and wind directions and speeds, and they can also be used to predict lander or rover solar panel clearing events. Overall, the high DDT frequency in many areas on Mars leads to drastic albedo changes that affect large-scale weather patterns

Analysis of bovine blastocysts indicates ovarian stimulation does not induce chromosome errors, nor discordance between inner-cell mass and trophectoderm lineages

Contemporary systems for oocyte retrieval and culture of both cattle and human embryos are suboptimal with respect to pregnancy outcomes following transfer. In humans, chromosome abnormalities are the leading cause of early pregnancy loss in assisted reproduction. Consequently, pre-implantation genetic testing for aneuploidy (PGT-A) is widespread and there is considerable interest in its application to identify suitable cattle IVP embryos for transfer. Here we report on the nature and extent of chromosomal abnormalities following transvaginal follicular aspiration (OPU) and IVP in cattle. Nine sexually mature Holstein heifers underwent nine sequential cycles of OPU-IVP (six non-stimulated and three stimulated cycles), generating 459 blastocysts from 783 oocytes. We adopted a SNP-array approach normally employed in genomic evaluations but reanalysed (Turner et al., 2019; Theriogenology 125: 249) to detect levels of meiotic aneuploidy. Specifically, we asked whether ovarian stimulation increased the level of aneuploidy in either trophectoderm (TE) or inner-cell mass (ICM) lineages of blastocysts generated from OPU-IVP cycles. The proportion of Day 8 blastocysts of inseminated was greater (P < 0.001) for stimulated than non-stimulated cycles (0.712 ± 0.0288 vs. 0.466 ± 0.0360), but the overall proportion aneuploidy was similar for both groups (0.241 ± 0.0231). Most abnormalities consisted of meiotic trisomies. Twenty in vivo derived blastocysts recovered from the same donors were all euploid, thus indicating that 24 h of maturation is primarily responsible for aneuploidy induction. Chromosomal errors in OPU-IVP blastocysts decreased (P < 0.001) proportionately as stage/grade improved (from 0.373 for expanded Grade 2 to 0.128 for hatching Grade 1 blastocysts). Importantly, there was a high degree of concordance in the incidence of aneuploidy between TE and ICM lineages. Proportionately, 0.94 were “perfectly concordant” (i.e. identical result in both); 0.01 were imperfectly concordant (differing abnormalities detected); 0.05 were discordant; of which 0.03 detected a potentially lethal TE abnormality (false positives), leaving only 0.02 false negatives. These data support the use of TE biopsies for PGT-A in embryos undergoing genomic evaluation in cattle breeding. Finally, we report chromosome-specific errors and a high degree of variability in the incidence of aneuploidy between donors, suggesting a genetic contribution that merits further investigation

Fatty acid metabolism in marine fish: Low activity of fatty acyl Δ5 desaturation in gilthead sea bream ( Sparus aurata ) cells

Marine fish are known to have an absolute dietary requirement for C20 and C22 highly unsaturated fatty acids. Previous studies using cultured cell lines indicated that underlying this requirement in marine fish was either a deficiency in fatty acyl Δ5 desaturase or C18-20 elongase activity. Recently, Ghioni et al. (Biochim. Biophys. Acta, 1437, 170-181, 1999) presented evidence that in turbot cells there was low activity of C18-20 elongase whereas Δ5 desaturase had high activity. In the present study, the fatty acid desaturase/elongase pathway was investigated in a cell line (SAF-1) from another carnivorous marine fish, sea bream. The metabolic conversions of a range of radiolabelled polyunsaturated fatty acids that comprised the direct substrates for Δ6 desaturase ([1-14C]18:2n-6 and [1-14C]18:3n-3), C18-20 elongase ([U-14C]18:4n-3), Δ5 desaturase ([1-14C]20:3n-6 and [U-14C]20:4n-3) and C20-22 elongase ([1-14C]20:4n-6 and [1-14C]20:5n-3) were utilized. The results showed that fatty acyl Δ6 desaturase in SAF-1 cells was highly active and there was substantial C18-20 elongase and C20-22 elongase activities. A deficiency in the desaturation/elongation pathway was clearly identified at the level of the fatty acyl Δ5 desaturase which was very low, particularly with 20:4n-3 as substrate. In comparison, the apparent activities of Δ6 desaturase, C18-20 elongase and C20-22 elongase were approximately 94-fold, 27-fold and 16-fold greater than that for Δ5 desaturase towards their respective n-3 polyunsaturated fatty acid substrates. The evidence obtained in the SAF-1 cell line is consistent with the dietary requirement for C20 and C22 highly unsaturated fatty acids in the marine fish, the sea bream, being primarily due to a deficiency in fatty acid Δ5 desaturase activity

Colossal dielectric constants in transition-metal oxides

Many transition-metal oxides show very large ("colossal") magnitudes of the dielectric constant and thus have immense potential for applications in modern microelectronics and for the development of new capacitance-based energy-storage devices. In the present work, we thoroughly discuss the mechanisms that can lead to colossal values of the dielectric constant, especially emphasising effects generated by external and internal interfaces, including electronic phase separation. In addition, we provide a detailed overview and discussion of the dielectric properties of CaCu3Ti4O12 and related systems, which is today's most investigated material with colossal dielectric constant. Also a variety of further transition-metal oxides with large dielectric constants are treated in detail, among them the system La2-xSrxNiO4 where electronic phase separation may play a role in the generation of a colossal dielectric constant.Comment: 31 pages, 18 figures, submitted to Eur. Phys. J. for publication in the Special Topics volume "Cooperative Phenomena in Solids: Metal-Insulator Transitions and Ordering of Microscopic Degrees of Freedom