Insulin analogues have been engineered to enhance desired molecular properties without altering immunogenicity. The majority of insulin pharmacology studies are conducted in healthy volunteers and ...patients with type 1 diabetes. At present, there are more patients with type 2 than type 1 diabetes receiving insulin treatment. As the responsibility for initiating insulin therapy in these patients continues to shift to primary care, it will be important for general practitioners to understand the different pharmacological properties of insulin preparations in patients with type 2 diabetes, so that treatment can be adapted to meet patients' physiological and lifestyle requirements. The purpose of this review is to summarize pharmacological studies of insulin analogues in patients with type 2 diabetes. Faster onset of action of rapid acting insulin analogues has improved postprandial glycaemic control. Biphasic insulin analogues are associated with a lower incidence of nocturnal hypoglycaemia compared with human biphasic preparations and allow for intensification from once to twice or thrice daily dosing. More predictable glycaemic‐lowering profiles of the insulin analogues have also led to reductions in nocturnal hypoglycaemia, particularly comparing long‐acting insulin analogues with protaminated human insulin. Enhancing insulin self‐association and reversible binding with albumin has led to further reductions in variability. However, improvements can still be made. Effective once daily clinical dosing of long‐acting insulin analogues is not possible in all patients. In addition, the protaminated component of biphasic insulin analogues do not provide the duration of action or profile for physiological basal insulin replacement and neither insulin glargine nor insulin detemir are suitable for mixing with other insulin analogues as this would substantially alter their pharmacokinetic properties. Enhancing the pharmacological predictability and extending the duration of action could simplify insulin titration and further reduce the incidence of hypoglycaemia.
X‐ray free‐electron lasers (XFELs) deliver pulses of coherent X‐rays on the femtosecond time scale, with potentially high repetition rates. While XFELs provide high peak intensities, both the ...intensity and the centroid of the beam fluctuate strongly on a pulse‐to‐pulse basis, motivating high‐rate beam diagnostics that operate over a large dynamic range. The fast drift velocity, low X‐ray absorption and high radiation tolerance properties of chemical vapour deposition diamonds make these crystals a promising candidate material for developing a fast (multi‐GHz) pass‐through diagnostic for the next generation of XFELs. A new approach to the design of a diamond sensor signal path is presented, along with associated characterization studies performed in the XPP endstation of the LINAC Coherent Light Source (LCLS) at SLAC. Qualitative charge collection profiles (collected charge versus time) are presented and compared with those from a commercially available detector. Quantitative results on the charge collection efficiency and signal collection times are presented over a range of approximately four orders of magnitude in the generated electron–hole plasma density.
Two approaches to the design of a diamond sensor signal path were explored using high‐intensity X‐ray pulses from the LINAC Coherent Light Source at SLAC. Results on the charge‐collection efficiency and signal collection time are presented over a range of approximately four orders of magnitude in the generated electron–hole plasma density.
Low Gain Avalanche Diodes (LGADs) are thin (20-50
μm
) silicon diode sensors with modest internal gain (typically 5 to 50) and exceptional time resolution (17
ps
to 50
ps
). However, the granularity ...of such devices is limited to the millimeter scale due to the need to include protection structures at the boundaries of the readout pads to avoid premature breakdown due to large local electric fields. Here, we present a new approach – the Deep-Junction LGAD (DJ-LGAD) – that decouples the high-field gain region from the readout plane. This approach is expected to improve the achievable LGAD granularity to the tens-of-micron scale while maintaining direct charge collection on the segmented electrodes.
Development of diamond-based diagnostics for next-generation XFELs Padilla, R.; Gonzalez, E.; Kachiguine, S. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2023, Volume:
1057
Journal Article
Peer reviewed
Open access
The composition and performance of three different diamond sensor based pass-through diagnostics are presented. A position-sensitive quadrant sensor was designed and characterized using the XPP beam ...at the SLAC LCLS, demonstrating a generated-charge resolution of 0.025 pC and a position sensitivity of 2 μm, measurable pulse-by-pulse at a repetition rate of up to 50 MHz. A compact signal path capable of repetition rates up to 1 GHz was used to characterize the charge collection properties of diamond sensors as a function of the density of electron-hole pairs created within the sensor, finding a limit of approximately 1016 electron-hole pairs per cm3 beyond which the collection efficiency and time began to degrade. Finally, a proposed scheme for measuring ionizing radiation at multi-GHz rates is presented, along with results preliminarily demonstrating signal transport capability in excess of 5 GHz.
The recent development of silicon diode Low Gain Avalanche Detectors (LGADs) has opened the possibility of enhanced response and faster frame rates for the detection of X-rays produced by ...next-generation light sources. Preliminary results are presented on the exposure of an LGAD to a series of 500 MHz streams of X-rays with energies between 6 and 16 keV from the SLAC SSRL. X-ray absorption pulses from neighboring beam pulses, separated by 2 nsec, are well resolved. Additional results from a novel, AC-coupled LGAD, excited by a narrow infrared laser beam, indicate a point-spread function with a full width of approximately 400μm. Further optimization of the AC-LGAD design should allow the extent of the point-spread function to be further reduced, and a granularity of 100×100μm2 or finer to be reached.
Objectives This paper describes the rationale behind the National Social Life, Health, and Aging Project’s (NSHAP) social networks module, data collection procedures, and the measurement of several ...egocentric network properties. This includes a discussion of network size, composition, volume of contact with network members, density, and bridging potential. Data on the extent to which older adults involve network members in personal health matters are also discussed. Methods Descriptive statistics are presented for key network measures. Sociodemographic distributions of these measures are presented. Older adults’ likelihood of discussing health with network members is also broken down by network member characteristics. Results Older adults tended to have large, kin-centered, dense networks, with some bridging potential. Network characteristics were related to age, gender, race/ethnicity, education, and health. Older adults tended to be very likely to involve network members (especially close ties) in health discussions and medical decision making. Discussion The data reiterate the relevance of social networks to older adults’ health. We close by discussing how the NSHAP measures might be employed in future analyses of health.
Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. ...Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci ( NOD2, MHC , and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78 ), even after exclusion of NOD2, MHC , and 3p21 (p=9·23 × 10−18 ). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4 ). Interpretation Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Funding International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
The inferred cost of work-related stress call for prevention strategies that aim at detecting early warning signs at the workplace. This paper goes one step towards the goal of developing a personal ...health system for detecting stress. We analyze the discriminative power of electrodermal activity (EDA) in distinguishing stress from cognitive load in an office environment. A collective of 33 subjects underwent a laboratory intervention that included mild cognitive load and two stress factors, which are relevant at the workplace: mental stress induced by solving arithmetic problems under time pressure and psychosocial stress induced by social-evaluative threat. During the experiments, a wearable device was used to monitor the EDA as a measure of the individual stress reaction. Analysis of the data showed that the distributions of the EDA peak height and the instantaneous peak rate carry information about the stress level of a person. Six classifiers were investigated regarding their ability to discriminate cognitive load from stress. A maximum accuracy of 82.8% was achieved for discriminating stress from cognitive load. This would allow keeping track of stressful phases during a working day by using a wearable EDA device.
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