The Dynamic Insulin Sensitivity and Secretion Test (DISST) - a novel measure of insulin sensitivity

Objective: To validate the methodology for the Dynamic Insulin Sensitivity and Secretion Test (DISST) and to demonstrate its potential in clinical and research settings. Methods: 123 men and women had routine clinical and biochemical measurements, an oral glucose tolerance test and a DISST. For the DISST, participants were cannulated for blood sampling and bolus administration. Blood samples were drawn at t=0, 10, 15, 25 and 35 minutes for measurement of glucose, insulin and C-peptide. A 10g bolus of intravenous glucose at t=5 minutes and 1U of intravenous insulin immediately after the t=15 minute sample were given. Fifty participants also had a hyperinsulinaemic euglycaemic clamp. Relationships between DISST insulin sensitivity (SI) and the clamp, and both DISST SI and secretion and other metabolic variables were measured. Results: A Bland-Altman plot showed little bias in the comparison of DISST with the clamp; with DISST underestimating the glucose clamp by 0.1·10-2·mg·l·kg-1·min-1·pmol-1 (90%CI -0.2 to 0). The correlation between SI as measured by DISST and the clamp was 0.82, the c unit for the ROC analysis for the two tests was 0.96. Metabolic variables showed significant correlations with DISST IS, and the second phase of insulin release. DISST also appears able to distinguish different insulin secretion patterns in individuals with identical SI values. Conclusions: DISST is a simple, dynamic test that compares favourably with the clamp in assessing SI and allows simultaneous assessment of insulin secretion. DISST has the potential to provide even more information about the pathophysiology of diabetes than more complicated tests

First dose ChAdOx1 and BNT162b2 COVID-19 vaccinations and cerebral venous sinus thrombosis : a pooled self-controlled case series study of 11.6 million individuals in England, Scotland, and Wales

Funding: This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20029, AS). EAVE II is funded by the Medical Research Council (https://mrc.ukri.org/) (UKRI MC_PC 19075, AS) with the support of BREATHE, The Health Data Research Hub for Respiratory Health (MC_PC_19004, AS), which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. This work was supported by the Con-COV team funded by the Medical Research Council (grant number: MR/V028367/1, RL). This work was supported by Health Data Research UK, which receives its funding from HDR UK Ltd (HDR-9006, RL) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation (BHF) and the Wellcome Trust. This work was supported by the ADR Wales programme of work (https://www.adruk.org/). ADR Wales is part of the Economic and Social Research Council (part of UK Research and Innovation) funded ADR UK (grant ES/S007393/1, RL). SVK acknowledges funding from NHS Research Scotland Senior Clinical Fellowship (SCAF/15/02, SVK), the MRC (MC_UU_00022/2, SVK), and the Scottish Government Chief Scientist Office (SPHSU17, SVK).Background : Several countries restricted the administration of ChAdOx1 to older age groups in 2021 over safety concerns following case reports and observed versus expected analyses suggesting a possible association with cerebral venous sinus thrombosis (CVST). Large datasets are required to precisely estimate the association between Coronavirus Disease 2019 (COVID-19) vaccination and CVST due to the extreme rarity of this event. We aimed to accomplish this by combining national data from England, Scotland, and Wales. Methods and findings : We created data platforms consisting of linked primary care, secondary care, mortality, and virological testing data in each of England, Scotland, and Wales, with a combined cohort of 11,637,157 people and 6,808,293 person years of follow-up. The cohort start date was December 8, 2020, and the end date was June 30, 2021. The outcome measure we examined was incident CVST events recorded in either primary or secondary care records. We carried out a self-controlled case series (SCCS) analysis of this outcome following first dose vaccination with ChAdOx1 and BNT162b2. The observation period consisted of an initial 90-day reference period, followed by a 2-week prerisk period directly prior to vaccination, and a 4-week risk period following vaccination. Counts of CVST cases from each country were tallied, then expanded into a full dataset with 1 row for each individual and observation time period. There was a combined total of 201 incident CVST events in the cohorts (29.5 per million person years). There were 81 CVST events in the observation period among those who a received first dose of ChAdOx1 (approximately 16.34 per million doses) and 40 for those who received a first dose of BNT162b2 (approximately 12.60 per million doses). We fitted conditional Poisson models to estimate incidence rate ratios (IRRs). Vaccination with ChAdOx1 was associated with an elevated risk of incident CVST events in the 28 days following vaccination, IRR = 1.93 (95% confidence interval (CI) 1.20 to 3.11). We did not find an association between BNT162b2 and CVST in the 28 days following vaccination, IRR = 0.78 (95% CI 0.34 to 1.77). Our study had some limitations. The SCCS study design implicitly controls for variables that are constant over the observation period, but also assumes that outcome events are independent of exposure. This assumption may not be satisfied in the case of CVST, firstly because it is a serious adverse event, and secondly because the vaccination programme in the United Kingdom prioritised the clinically extremely vulnerable and those with underlying health conditions, which may have caused a selection effect for individuals more prone to CVST. Although we pooled data from several large datasets, there was still a low number of events, which may have caused imprecision in our estimates. Conclusions : In this study, we observed a small elevated risk of CVST events following vaccination with ChAdOx1, but not BNT162b2. Our analysis pooled information from large datasets from England, Scotland, and Wales. This evidence may be useful in risk–benefit analyses of vaccine policies and in providing quantification of risks associated with vaccination to the general public.Peer reviewe

GW250114: Testing Hawking’s area law and the Kerr nature of black holes

The gravitational-wave signal GW250114 was observed by the two LIGO detectors with a network matched-filter signal-to-noise ratio of 80. The signal was emitted by the coalescence of two black holes with near-equal masses m1 ¼ 33.6þ1.2 −0.8M⊙ and m2 ¼ 32.2þ0.8 −1.3M⊙, and small spins χ1;2 ≤ 0.26 (90% credibility) and negligible eccentricity e ≤ 0.03. Postmerger data excluding the peak region are consistent with the dominant quadrupolar ðl ¼ jmj ¼ 2Þ mode of a Kerr black hole and its first overtone. We constrain the modes’ frequencies to 30% of the Kerr spectrum, providing a test of the remnant’s Kerr nature. We also examine Hawking’s area law, also known as the second law of black hole mechanics, which states that the total area of the black hole event horizons cannot decrease with time. A range of analyses that exclude up to five of the strongest merger cycles confirm that the remnant area is larger than the sum of the initial areas to high credibility

GW241011 and GW241110: exploring binary formation and fundamental physics with asymmetric, high-spin black hole coalescences

We report the observation of gravitational waves from two binary black hole coalescences during the fourth observing run of the LIGO–Virgo–KAGRA detector network, GW241011 and GW241110. The sources of these two signals are characterized by rapid and precisely measured primary spins, nonnegligible spin–orbit misalignment, and unequal mass ratios between their constituent black holes. These properties are characteristic of binaries in which the more massive object was itself formed from a previous binary black hole merger and suggest that the sources of GW241011 and GW241110 may have formed in dense stellar environments in which repeated mergers can take place. As the third-loudest gravitational-wave event published to date, with a median network signal-to-noise ratio of 36.0, GW241011 furthermore yields stringent constraints on the Kerr nature of black holes, the multipolar structure of gravitational-wave generation, and the existence of ultralight bosons within the mass range 10−13–10−12 eV

GW231123: a binary black hole merger with total mass 190–265 M⊙

On 2023 November 23, the two LIGO observatories both detected GW231123, a gravitational-wave signal consistent with the merger of two black holes with masses 137+23-18 M⊙ and 101+22-50 M⊙ (90% credible intervals), at a luminosity distance of 0.7–4.1 Gpc, a redshift of 0.40+0.27-0.25, and with a network signal-to-noise ratio of ∼20.7. Both black holes exhibit high spins— 0.90+0.10-0.19 and 0.80+0.20-0.52, respectively. A massive black hole remnant is supported by an independent ringdown analysis. Some properties of GW231123 are subject to large systematic uncertainties, as indicated by differences in the inferred parameters between signal models. The primary black hole lies within or above the theorized mass gap where black holes between 60–130 M⊙ should be rare, due to pair-instability mechanisms, while the secondary spans the gap. The observation of GW231123 therefore suggests the formation of black holes from channels beyond standard stellar collapse and that intermediate-mass black holes of mass ∼200 M⊙ form through gravitational-wave-driven mergers

The Dynamic Insulin Sensitivity and Secretion Test (DISST) - a novel measure of insulin sensitivity

Objective: To validate the methodology for the Dynamic Insulin Sensitivity and Secretion Test (DISST) and to demonstrate its potential in clinical and research settings. Methods: 123 men and women had routine clinical and biochemical measurements, an oral glucose tolerance test and a DISST. For the DISST, participants were cannulated for blood sampling and bolus administration. Blood samples were drawn at t=0, 10, 15, 25 and 35 minutes for measurement of glucose, insulin and C-peptide. A 10g bolus of intravenous glucose at t=5 minutes and 1U of intravenous insulin immediately after the t=15 minute sample were given. Fifty participants also had a hyperinsulinaemic euglycaemic clamp. Relationships between DISST insulin sensitivity (SI) and the clamp, and both DISST SI and secretion and other metabolic variables were measured. Results: A Bland-Altman plot showed little bias in the comparison of DISST with the clamp; with DISST underestimating the glucose clamp by 0.1·10-2·mg·l·kg-1·min-1·pmol-1 (90%CI -0.2 to 0). The correlation between SI as measured by DISST and the clamp was 0.82, the c unit for the ROC analysis for the two tests was 0.96. Metabolic variables showed significant correlations with DISST IS, and the second phase of insulin release. DISST also appears able to distinguish different insulin secretion patterns in individuals with identical SI values. Conclusions: DISST is a simple, dynamic test that compares favourably with the clamp in assessing SI and allows simultaneous assessment of insulin secretion. DISST has the potential to provide even more information about the pathophysiology of diabetes than more complicated tests

Design and clinical pilot testing of the model-based Dynamic Insulin Sensitivity and Secretion Test (DISST)

Background: Insulin resistance is a significant risk factor in the pathogenesis of type 2 diabetes. This article presents pilot study results of the dynamic insulin sensitivity and secretion test (DISST), a high-resolution, low-intensity test to diagnose insulin sensitivity (IS) and characterize pancreatic insulin secretion in response to a (small) glucose challenge. This pilot study examines the effect of glucose and insulin dose on the DISST, and tests its repeatability. Methods: DISST tests were performed on 16 subjects randomly allocated to low (5 g glucose, 0.5 U insulin), medium (10 g glucose, 1 U insulin) and high dose (20 g glucose, 2 U insulin) protocols. Two or three tests were performed on each subject a few days apart. Results: Average variability in IS between low and medium dose was 10.3% (p = .50) and between medium and high dose 6.0% (p = .87). Geometric mean variability between tests was 6.0% (multiplicative standard deviation (MSD) 4.9%). Geometric mean variability in first phase endogenous insulin response was 6.8% (MSD 2.2%). Results were most consistent in subjects with low IS. Conclusions: These findings suggest that DISST may be an easily performed dynamic test to quantify IS with high resolution, especially among those with reduced IS

Capillary electrophoresis of human follicular fluid

Some of the major serum proteins that are also found in follicular fluid, including transferrin, α-macroglobulin and albumin, are thought to play a role in oocyte maturation. This study set out to identify proteins in human follicular fluid by capillary zone electrophoresis and to investigate their relationship to follicular/oocyte maturity and fertility outcome. 176 individual follicular fluid samples, from 30 women undertaking in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI), were run using an optimized capillary zone electrophoresis method that gave a good separation of sixteen peaks in most samples. Nine of the peaks were identified and quantified but seven remain unknown and require further proteomic identification. Of the identified protein peaks, levels of each were corrected for follicular volume and total content calculated. No significant difference in protein levels was found with regard to oocyte recovery and fertilization. Protein concentrations tended to decrease as the follicular sphere increased whilst total content in follicular fluid increased in proportion to size. This is consistent with simple transudation across a sphere surface area which does not increase in proportion to the follicular fluid. This is not true of the concentration and content pattern of other proteins/biomolecules which are produced by follicular cells locally. In conclusion, neither concentration nor absolute levels of nine major proteins identified in follicular fluids correlated with oocyte presence and fertility outcome. Future work to remove more concentrated proteins (e.g. albumin) would enhance separation of smaller peaks and identification of the unknown molecules