The use of metformin in patients with renal impairment

Metformin, a biguanide, is widely accepted to be the preferred first-line oral antihyperglycaemic agent to manage type 2 diabetes. There is considerable concern that patients receiving metformin therapy may be at an increased risk of developing lactic acidosis. The risk has traditionally been assumed to be increased in patients with chronic renal impairment, resulting in many patients being denied access to an effective first-line treatment agent. The overarching aims of this thesis were to explore the safe use of metformin and to create a renal dosing guideline that will mitigate the risk of lactic acidosis. The safe use of metformin was explored by formally evaluating the association between metformin therapy and lactic acidosis in published case reports of metformin associated lactic acidosis (MALA) using two causality assessments. Metformin was found to play only a possible role in the development of lactic acidosis based on the results from the causality assessments. Almost all cases presented with other risk factors that could on their own have caused lactic acidosis. A subgroup analysis was performed in MALA cases with a history of chronic renal impairment to explore the relationship between metformin dose, plasma concentration and lactic acidosis. Most cases presented with acute renal failure, confounding the relationship between metformin dose and plasma concentrations. The prescribed metformin dose exceeded the dosing recommendations in over 60% of cases with an estimated glomerular filtration rate of <60 mL/min by a median of 1000 mg/day. Despite this, based on simulations, the pre-admission plasma metformin concentrations measured pre-dose did not exceed the proposed upper limit of the therapeutic range of 5 mg/L. A quantitative analysis was performed to explore the relationship between plasma metformin and lactate concentrations. Plasma metformin concentrations greater than 4.5 mg/L were found to be associated with severe hyperlactatemia. These findings suggest that metformin doses should be adjusted to maintain plasma concentrations below 4.5 mg/L to mitigate the risk of lactic acidosis. A noncompartmental pharmacokinetic analysis was performed to explore the pharmacokinetics of metformin in renal impairment, from which an empirical renal dosing guideline for metformin was developed. Patients with poorer renal function were found to have lower apparent and renal clearance for metformin. These findings support the notion that metformin can be used safely for the treatment of type 2 diabetes mellitus in patients with chronic renal impairment provided plasma metformin concentrations are maintained within a safe therapeutic range. A population pharmacokinetic model for metformin was developed and evaluated. A covariate analysis found that renal function and total body weight could describe patient variability in the apparent clearance and central compartment volume for metformin, respectively. The developed population pharmacokinetic model was used to assess the safety of the empirical renal dosing guidelines and the current published renal dosing guidelines in the New Zealand Formulary. Based on the simulations, plasma metformin concentrations are not expected to exceed the upper limit of safety of 4.5 mg/L under either of the dosing guidelines. The influence of flip-flop pharmacokinetics in population pharmacokinetic models was explored using metformin as a motivating example. Approaches to address problems arising due to flip-flop in population pharmacokinetic models are presented in this thesis. In conclusion, the findings in this thesis support the notion that metformin can be used safely for the treatment of type 2 diabetes mellitus provided plasma metformin concentrations are maintained within a safe range. In addition, an empirical renal dosing equation for metformin was developed and assessed for safety

Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology: Vascular impairments in HD

ObjectiveAlthough the underlying cause of Huntington's disease (HD) is well established, the actual pathophysiological processes involved remain to be fully elucidated. In other proteinopathies such as Alzheimer's and Parkinson's diseases, there is evidence for impairments of the cerebral vasculature as well as the blood–brain barrier (BBB), which have been suggested to contribute to their pathophysiology. We investigated whether similar changes are also present in HD.MethodsWe used 3‐ and 7‐Tesla magnetic resonance imaging as well as postmortem tissue analyses to assess blood vessel impairments in HD patients. Our findings were further investigated in the R6/2 mouse model using in situ cerebral perfusion, histological analysis, Western blotting, as well as transmission and scanning electron microscopy.ResultsWe found mutant huntingtin protein (mHtt) aggregates to be present in all major components of the neurovascular unit of both R6/2 mice and HD patients. This was accompanied by an increase in blood vessel density, a reduction in blood vessel diameter, as well as BBB leakage in the striatum of R6/2 mice, which correlated with a reduced expression of tight junction‐associated proteins and increased numbers of transcytotic vesicles, which occasionally contained mHtt aggregates. We confirmed the existence of similar vascular and BBB changes in HD patients.InterpretationTaken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications. Ann Neurol 2015;78:160–17

A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers

BackgroundThe benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T½), limited tumor microenvironment targeting, and substantial systemic toxicity. We developed a strategy to extend the rIL-12 T½ that depends on binding albumin in vivo to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (FHAB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted.MethodsSB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101.ResultsParticipants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T½ of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines.ConclusionSON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572

ALMA Survey of Orion Planck Galactic Cold Clumps (ALMASOP) : Density Structure of Centrally Concentrated Prestellar Cores from Multiscale Observations

Starless cores represent the initial stage of evolution toward (proto)star formation, and a subset of them, known as prestellar cores, with high density (similar to 10(6) cm(-3) or higher) and being centrally concentrated are expected to be embryos of (proto)stars. Determining the density profile of prestellar cores therefore provides an important opportunity to gauge the initial conditions of star formation. In this work, we perform rigorous modeling to estimate the density profiles of three nearly spherical prestellar cores among a sample of five highly dense cores detected by our recent observations. We employed multiscale observational data of the (sub)millimeter dust continuum emission, including those obtained by SCUBA-2 on the James Clerk Maxwell Telescope with a resolution of similar to 5600 au and by multiple Atacama Large Millimeter/submillimeter Array observations with a resolution as high as similar to 480 au. We are able to consistently reproduce the observed multiscale dust continuum images of the cores with a simple prescribed density profile, which bears an inner region of flat density and an r (-2) profile toward the outer region. By utilizing the peak density and the size of the inner flat region as a proxy for the dynamical stage of the cores, we find that the three modeled cores are most likely unstable and prone to collapse. The sizes of the inner flat regions, as compact as similar to 500 au, signify them as being the highly evolved prestellar cores rarely found to date.Peer reviewe

ALMA Survey of Orion Planck Galactic Cold Clumps (ALMASOP) : Detection of Extremely High-density Compact Structure of Prestellar Cores and Multiple Substructures Within

Prestellar cores are self-gravitating dense and cold structures within molecular clouds where future stars are born. They are expected, at the stage of transitioning to the protostellar phase, to harbor centrally concentrated dense (sub)structures that will seed the formation of a new star or the binary/multiple stellar systems. Characterizing this critical stage of evolution is key to our understanding of star formation. In this work, we report the detection of high-density (sub)structures on the thousand-astronomical-unit (au) scale in a sample of dense prestellar cores. Through our recent ALMA observations toward the Orion Planck Galactic Cold Clumps, we have found five extremely dense prestellar cores, which have centrally concentrated regions of similar to 2000 au in size, and several 10(7) cm(-3) in average density. Masses of these centrally dense regions are in the range of 0.30 to 6.89 M. For the first time, our higher resolution observations (0.8 '' similar to 320 au) further reveal that one of the cores shows clear signatures of fragmentation; such individual substructures/fragments have sizes of 800-1700 au, masses of 0.08 to 0.84 M, densities of 2 - 8 x 10(7) cm(-3), and separations of similar to 1200 au. The substructures are massive enough (greater than or similar to 0.1 M) to form young stellar objects and are likely examples of the earliest stage of stellar embryos that can lead to widely (similar to 1200 au) separated multiple systems.Peer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The use of metformin in patients with renal impairment

Metformin, a biguanide, is widely accepted to be the preferred first-line oral antihyperglycaemic agent to manage type 2 diabetes. There is considerable concern that patients receiving metformin therapy may be at an increased risk of developing lactic acidosis. The risk has traditionally been assumed to be increased in patients with chronic renal impairment, resulting in many patients being denied access to an effective first-line treatment agent. The overarching aims of this thesis were to explore the safe use of metformin and to create a renal dosing guideline that will mitigate the risk of lactic acidosis. The safe use of metformin was explored by formally evaluating the association between metformin therapy and lactic acidosis in published case reports of metformin associated lactic acidosis (MALA) using two causality assessments. Metformin was found to play only a possible role in the development of lactic acidosis based on the results from the causality assessments. Almost all cases presented with other risk factors that could on their own have caused lactic acidosis. A subgroup analysis was performed in MALA cases with a history of chronic renal impairment to explore the relationship between metformin dose, plasma concentration and lactic acidosis. Most cases presented with acute renal failure, confounding the relationship between metformin dose and plasma concentrations. The prescribed metformin dose exceeded the dosing recommendations in over 60% of cases with an estimated glomerular filtration rate of <60 mL/min by a median of 1000 mg/day. Despite this, based on simulations, the pre-admission plasma metformin concentrations measured pre-dose did not exceed the proposed upper limit of the therapeutic range of 5 mg/L. A quantitative analysis was performed to explore the relationship between plasma metformin and lactate concentrations. Plasma metformin concentrations greater than 4.5 mg/L were found to be associated with severe hyperlactatemia. These findings suggest that metformin doses should be adjusted to maintain plasma concentrations below 4.5 mg/L to mitigate the risk of lactic acidosis. A noncompartmental pharmacokinetic analysis was performed to explore the pharmacokinetics of metformin in renal impairment, from which an empirical renal dosing guideline for metformin was developed. Patients with poorer renal function were found to have lower apparent and renal clearance for metformin. These findings support the notion that metformin can be used safely for the treatment of type 2 diabetes mellitus in patients with chronic renal impairment provided plasma metformin concentrations are maintained within a safe therapeutic range. A population pharmacokinetic model for metformin was developed and evaluated. A covariate analysis found that renal function and total body weight could describe patient variability in the apparent clearance and central compartment volume for metformin, respectively. The developed population pharmacokinetic model was used to assess the safety of the empirical renal dosing guidelines and the current published renal dosing guidelines in the New Zealand Formulary. Based on the simulations, plasma metformin concentrations are not expected to exceed the upper limit of safety of 4.5 mg/L under either of the dosing guidelines. The influence of flip-flop pharmacokinetics in population pharmacokinetic models was explored using metformin as a motivating example. Approaches to address problems arising due to flip-flop in population pharmacokinetic models are presented in this thesis. In conclusion, the findings in this thesis support the notion that metformin can be used safely for the treatment of type 2 diabetes mellitus provided plasma metformin concentrations are maintained within a safe range. In addition, an empirical renal dosing equation for metformin was developed and assessed for safety