The Correlation Between Body Mass Index and Health-Related Quality of Life: Data from Two Weight Loss Intervention Studies.

INTRODUCTION: The correlation between body mass index (BMI) and utility in participants with obesity was assessed using health-related quality-of-life data collected in two weight loss intervention studies, SCALE and STEP 1. METHODS: Short Form Health Survey 36-Item (SF-36) scores from SCALE and STEP 1 were mapped to EuroQoL-5 dimensions-3 levels (EQ-5D-3L) using an established algorithm to derive utilities for the UK. SF-36 scores from STEP 1 were converted into Short Form 6 dimension (SF-6D) utilities for Portugal using the tool developed by the University of Sheffield. The correlation between baseline BMI and utility was assessed by multiple linear regression analyses, controlling for demographic and clinical parameters. RESULTS: A higher baseline BMI correlated with lower EQ-5D-3L and SF-6D utilities, although the trend was non-significant. Assuming linearity between BMI ranges 30-40 kg/m2, an additional unit of BMI correlated with 0.0041 and 0.0031 lower EQ-5D-3L scores in SCALE and 0.0039 and 0.0047 lower EQ-5D-3L and 0.0027 and 0.0020 lower SF-6D scores in STEP 1 for men and women, respectively. CONCLUSION: In individuals with comparable demographic characteristics and weight-related comorbidities, a 1 unit change in BMI leads to a difference of up to 0.005 in utility indices. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: SCALE (NCT01272219) and STEP 1 (NCT03548935).

Cost-effectiveness analyses compare health benefits and costs between treatments to inform decisions on healthcare resource allocation. Health benefits are typically quantified as quality-adjusted life-years (QALYs) gained. The calculation of QALYs relies on health-related quality-of-life (HRQoL) data, which are collected from participants. However, to allow comparisons across multiple interventions and diseases, HRQoL needs to be converted into a standardized, generic measure, i.e., a utility index ranging from 0 (equivalent to death) to 1 (perfect health). In this study, HRQoL data from the SCALE and STEP 1 clinical trials were converted into utility indexes and analyzed against participants' weight at study start, expressed as body mass index (BMI, kg/m²). Our study indicates that there is a negative correlation between BMI and health utility at a population level whereby an additional unit of BMI, within the range of 30­40 kg/m², was consistently correlated with an up to 0.005 worsening in the utility index across men and women. The estimated effect size was small, indicating that BMI alone may not explain the differences in participants' HRQoL and general population evaluation of these.

Breast Cancer Stem Cells Upregulate IRF6 in Stromal Fibroblasts to Induce Stromagenesis.

The microenvironment of a cancer stem cell (CSC) niche is often found in coexistence with cancer-associated fibroblasts (CAFs). Here, we show the first in-depth analysis of the interaction between primary triple-negative breast cancer stem cells (BCSCs) with fibroblasts. Using 2D co-culture models with specific seeding ratios, we identified stromal fibroblast aggregation at the BCSC cluster periphery, and, on closer observation, the aggregated fibroblasts was found to encircle BCSC clusters in nematic organization. In addition, collagen type I and fibronectin accumulation were also found at the BCSC-stromal periphery. MACE-Seq analysis of BCSC-encapsulating fibroblasts displayed the transformation of stromal fibroblasts to CAFs and the upregulation of fibrosis regulating genes of which the Interferon Regulatory Factor 6 (IRF6) gene was identified. Loss of function experiments with the IRF6 gene decreased fibroblast encapsulation around BCSC clusters in 2D co-cultures. In BCSC xenografts, fibroblast IRF6 expression led to an increase in the stromal area and fibroblast density in tumors, in addition to a reduction in necrotic growth. Based on our findings, we propose that fibroblast IRF6 function is an important factor in the development of the stromal microenvironment and in sustaining the BCSC tumor niche.

Cost of illness and labour market disaffiliation among patients with migraine discontinuing triptan treatment: A Danish nationwide register study from 1995 to 2021.

BACKGROUND: Migraine presents significant health and economic challenges. Despite the widespread use of triptans, some patients discontinue them because of insufficient relief or adverse effects. Using national registers, the present study investigates the excess costs and labour market disaffiliation of Danish patients discontinuing triptan treatment. METHODS: The study included all individuals ≥18 years ("patients") who discontinued redemption of triptan prescriptions between 1998 and 2019. They were categorized by number of distinct triptans redeemed before discontinuation: one, two or three or more. A control group was established from the general population without triptan redemptions, three per patient, matched by year of birth, sex and region of residence. We estimated excess direct and indirect costs from 5 years prior ("year -5") to 10 years post ("year 10") the first triptan redemption. RESULTS: We identified 211,026 patients who discontinued triptan redemption, 82% after one, 14% after two and 4% after three or more distinct triptans. Over the period from year -5 to year 10, average excess healthcare costs per patient in these cohorts were EUR 9,554, EUR 10,942 and EUR 12,812 respectively. Over the same period, these patients earned EUR 27,964, EUR 35,920 and EUR 50,076 less than their respective controls, and received higher public transfer payments of EUR 20,181, EUR 23,264 and EUR 26,459. CONCLUSIONS: Triptan discontinuers, who appear to have exhausted all current treatment avenues, face high direct and very high indirect excess costs attributable to migraine, and experience substantial increased labour market disaffiliation.

Tipping-point transition from transient to persistent inflammation in pancreatic islets.

Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1ß. While transient exposure to low IL-1ß concentrations improves insulin secretion and ß-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective ß-cell death. IL-1 is secreted locally by islet-resident macrophages and ß-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1ß with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway-IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1ß amplifying cells are more prone to transit into persistent IL-1ß mode. Our results are likely not limited to IL-1ß but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications.

Metabolic Dysfunction in New-Onset Idiopathic Intracranial Hypertension: Identification of Novel Biomarkers.

OBJECTIVE: Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity. METHODS: This is a prospective case-control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry. RESULTS: Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate-severe versus mild papilledema (p = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (p = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (p = 0.01, r = -0.35). Higher baseline serum S1P (p = 0.018) and lower CSF LysoPC-16 (p = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH. INTERPRETATION: We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595-607.

Identification of candidate SNPs associated with embryo mortality and fertility traits in lactating Holstein cows.

Introduction: Targeted single nucleotide polymorphisms (SNPs) have been used in genomic prediction methodologies to enhance the accuracy of associated genetic transmitting abilities in Holstein cows. The objective of this study was to identify and validate SNPs associated with fertility traits impacting early embryo mortality. Methods: The mRNA sequencing data from day 16 normal (n = 9) and embryo mortality (n = 6) conceptuses from lactating multiparous Holstein cows were used to detect SNPs. The selection of specific genes with SNPs as preliminary candidates was based on associations with reproductive and fertility traits. Validation of candidate SNPs and genotype-to-phenotype analyses were conducted in a separate cohort of lactating primiparous Holstein cows (n = 500). After genotyping, candidate SNPs were filtered using a quality control pipeline via PLINK software. Continuous numeric and binary models from reproductive traits were evaluated using the mixed procedure for a generalized linear model-one way ANOVA or logistic regression, respectively. Results: Sixty-nine candidate SNPs were initially identified, but only 23 passed quality control procedures. Ultimately, the study incorporated 466 observations for statistical analysis after excluding animals with missing genotypes or phenotypes. Significant (p <0.05) associations with fertility traits were identified in seven of the 23 SNPs: DSC2 (cows with the A allele were older at first calving); SREBF1 and UBD (cows with the T or G alleles took longer to conceive); DECR1 and FASN (cows with the C allele were less likely to become pregnant at first artificial insemination); SREBF1 and BOLA-DMB (cows with the T allele were less likely to be pregnant at 150 days in milk). It was also determined that two candidate SNPs within the DSC2 gene were tag SNPs. Only DSC2 SNPs had an important allele substitution effect in cows with the G allele, which had a decreased age at first calving by 10 days. Discussion: Candidate SNPs found in this study could be used to develop genetic selection tools to improve fertility traits in dairy production systems.

Oxygen-defective electrostrictors for soft electromechanics.

Electromechanical metal oxides, such as piezoceramics, are often incompatible with soft polymers due to their crystallinity requirements, leading to high processing temperatures. This study explores the potential of ceria-based thin films as electromechanical actuators for flexible electronics. Oxygen-deficient fluorites, like cerium oxide, are centrosymmetric nonpiezoelectric crystalline metal oxides that demonstrate giant electrostriction. These films, deposited at low temperatures, integrate seamlessly with various soft substrates like polyimide and PET. Ceria thin films exhibit remarkable electrostriction (M33 > 10-16 m2 V-2) and inverse pseudo-piezo coefficients (e33 > 500 pmV-1), enabling large displacements in soft electromechanical systems. Our study explores resonant and off-resonant configurations in the low-frequency regime (<1 kHz), demonstrating versatility for three-dimensional and transparent electronics. This work advances the understanding of oxygen-defective metal oxide electromechanical properties and paves the way for developing versatile and efficient electromechanical systems for applications in biomedical devices, optical devices, and beyond.

Uncovering the heritable components of multimorbidities and disease trajectories using a nationwide cohort.

Quantifying the contribution of genetics and environmental effects on disease initiation and progression, as well as the shared genetics of different diseases, is vital for the understanding of the disease etiology of multimorbidities. In this study, we leverage nationwide Danish registries to provide a granular atlas of the genetic origin of disease phenotypes for a cohort of all Danes 1978-2018 with partially known pedigree (n = 6.3 million). We estimate the heritability and genetic correlation between thousands of disease phenotypes using a novel approach that can be scaled to nationwide data. Our findings confirm the importance of genetics for a number of known associations and increase the resolution of heritability by adding numerous associations, some of which point to shared biologically origin of different phenotypes. We also establish the heritability of disease trajectories and the importance of sex-specific genetic contributions. Results can be accessed at https://h2.cpr.ku.dk/ .

Longitudinal metabolite and protein trajectories prior to diabetes mellitus diagnosis in Danish blood donors: a nested case-control study.

AIMS/HYPOTHESIS: Metabolic risk factors and plasma biomarkers for diabetes have previously been shown to change prior to a clinical diabetes diagnosis. However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their temporal association with incident diabetes. METHODS: We performed a targeted analysis of 54 proteins and 171 metabolites and lipoprotein particles measured in three sequential samples spanning up to 11 years of follow-up in 324 individuals with incident diabetes and 359 individuals without diabetes in the Danish Blood Donor Study (DBDS) matched for sex and birth year distribution. We used linear mixed-effects models to identify temporal changes before a diabetes diagnosis, either for any incident diabetes diagnosis or for type 1 and type 2 diabetes mellitus diagnoses specifically. We further performed linear and non-linear feature selection, adding 28 polygenic risk scores to the biomarker pool. We tested the time-to-event prediction gain of the biomarkers with the highest variable importance, compared with selected clinical covariates and plasma glucose. RESULTS: We identified two proteins and 16 metabolites and lipoprotein particles whose levels changed temporally before diabetes diagnosis and for which the estimated marginal means were significant after FDR adjustment. Sixteen of these have not previously been described. Additionally, 75 biomarkers were consistently higher or lower in the years before a diabetes diagnosis. We identified a single temporal biomarker for type 1 diabetes, IL-17A/F, a cytokine that is associated with multiple other autoimmune diseases. Inclusion of 12 biomarkers improved the 10-year prediction of a diabetes diagnosis (i.e. the area under the receiver operating curve increased from 0.79 to 0.84), compared with clinical information and plasma glucose alone. CONCLUSIONS/INTERPRETATION: Systemic molecular changes manifest in plasma several years before a diabetes diagnosis. A particular subset of biomarkers shows distinct, time-dependent patterns, offering potential as predictive markers for diabetes onset. Notably, these biomarkers show shared and distinct patterns between type 1 diabetes and type 2 diabetes. After independent replication, our findings may be used to develop new clinical prediction models.

Tackling social disconnection: an umbrella review of RCT-based interventions targeting social isolation and loneliness.

BACKGROUND: Social isolation and loneliness are urgent public health concerns associated with negative physical and mental health outcomes. Understanding effective remedies is crucial in addressing these problems. This umbrella review aimed to synthesize and critically appraise scientific evidence on the effectiveness of social isolation and loneliness interventions overall and across subgroups. We focused on systematic reviews (SRs) of randomized controlled trials (RCTs). METHODS: We searched seven databases (June 2022 and updated June 2023) and supplemented the search with grey literature and reference screening to identify SRs published since 2017. Screening, data extraction, and quality assessment using the AMSTAR2 tool were conducted independently by author pairs, with disagreements resolved through discussion. RESULTS: We included 29 SRs, 16 with meta-analysis and 13 with narrative synthesis. All SRs focused on loneliness, with 12 additionally examining social isolation. Four SRs focused on young people, 11 on all ages, and 14 on older adults. The most frequently examined intervention types were social (social contact, social support), psychological (therapy, psychoeducation, social skills training), and digital (e.g., computer use and online support). Meta-analyses indicated small-to-moderate beneficial effects, while narrative synthesis demonstrated mixed or no effect. Social interventions for social isolation and psychological interventions for loneliness were the most promising. However, caution is warranted due to the effects' small magnitude, significant heterogeneity, and the variable quality of SRs. Digital and other interventions showed mixed or no effect; however, caution is advised in interpreting these results due to the highly diverse nature of the interventions studied. CONCLUSIONS: This overview of SRs shows small to moderate effectiveness of social interventions in reducing social isolation and psychological ones in tackling loneliness. Further rigorously conducted RCTs and SRs are needed to guide policy decisions regarding the implementation of efficacious and scalable interventions. Evaluation should focus on both preventive structural interventions and tailored mitigating strategies that address specific types and causes of loneliness.

Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage.

Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. Functional annotation analysis indicated candidate genes HAND2, TBX3 and RAP2C/FRMD7 at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.

Responses at various levels of ecological hierarchy indicate acclimation to sequential sublethal heatwaves in a temperate benthic ecosystem.

Marine heatwaves have caused massive mortality in coastal benthic ecosystems, altering community composition. Here, we aim to understand the effects of single and sequential sublethal heatwaves in a temperate benthic ecosystem, investigating their disturbance on various levels of ecological hierarchy, i.e. individual physiology, trophic groups' biomass and ecosystem carbon fluxes. To do so, we performed a near-natural experiment using outdoor benthic mesocosms along spring/summer, where communities were exposed to different thermal regimes: without heatwaves (0HW), with one heatwave (1HW) and with three heatwaves (3HWs). Gastropods were negatively impacted by one single heatwave treatment, but the exposure to three sequential heatwaves caused no response, indicating ecological stress memory. The magnitude of ecosystem carbon fluxes mostly decreased after 1HW, with a marked negative impact on mesograzers' feeding, while the overall intensity of carbon fluxes increased after 3HWs. Consumers' acclimation after the exposure to sequential heatwaves increased grazing activity, representing a threat for the macroalgae biomass. The evaluation of physiological responses and ecological interactions is crucial to interpret variations in community composition and to detect early signs of stress. Our results reveal the spread of heatwave effects along the ecological hierarchical levels, helping to predict the trajectories of ecosystem development.This article is part of the theme issue 'Connected interactions: enriching food web research by spatial and social interactions'.

On the importance of scale in evolutionary quantitative genetics.

The informed use of scales and units in evolutionary quantitative genetics is often neglected, and naïve standardizations can cause misinterpretations of empirical results. A potentially influential example of such neglect can be found in the recent book by Arnold (2023. Evolutionary quantitative genetics. Oxford University Press). There, Arnold championed the use of heritability over mean-scaled genetic variance as a measure of evolutionary potential arguing that mean-scaled genetic variances are correlated with trait means while heritabilities are not. Here, we show that Arnold's empirical result is an artifact of ignoring the units in which traits are measured. More importantly, Arnold's argument mistakenly assumes that the goal of mean scaling is to remove the relationship between mean and variance. In our view, the purpose of mean scaling is to put traits with different units on a common scale that makes evolutionary changes, or their potential, readily interpretable and comparable in terms of proportions of the mean.

Three modes of evolution?Remarks on rates of evolution and time scaling.

Rates of evolution get smaller when they are measured over longer time intervals. As first shown by Gingerich, rates of morphological change measured from fossil time series show a robust minus-one scaling with time span, implying that evolutionary changes are just as large when measured over a hundred years as when measured over a hundred-thousand years. On even longer time scales, however, the scaling shifts toward a minus-half exponent consistent with evolution behaving as Brownian motion, as commonly observed in phylogenetic comparative studies. Here, I discuss how such scaling patterns arise, and I derive the patterns expected from standard stochastic models of evolution. I argue that observed shifts cannot be easily explained by simple univariate models, but require shifts in mode of evolution as time scale is changing. To illustrate this idea, I present a hypothesis about three distinct, but connected, modes of evolution. I analyze the scaling patterns predicted from this, and use the results to discuss how rates of evolution should be measured and interpreted. I argue that distinct modes of evolution at different time scales act to decouple micro- and macroevolution, and criticize various attempts at extrapolating from one to the other.

Interferon-tau infusion into the ovine corpus luteum delays luteolysis†.

Conceptus-derived interferon-tau (IFNT) initiates maternal recognition of pregnancy in ewes by paracrine actions on the endometrium and endocrine action on the corpus luteum (CL). To examine the effect of IFNT on the CL without inducing IFN-stimulated genes (ISGs) in the endometrium, recombinant ovine IFNT (roIFNT) or bovine serum albumin was delivered directly into CLs via osmotic pumps at a rate of 10, 50, or 100 ng/h from days 9 to 12 of the estrous cycle. Endometrial and CL samples were collected on day 12. 50 ng/h of roIFNT induced ISG15 in the CL on day 12 without affecting endometrial ISG15 concentrations. In a second experiment, roIFNT (50 ng/h) was infused into the CL from days 10 to 17 of the estrous cycle and serum samples were collected daily. Serum progesterone concentrations were significantly higher from days 15 to 17 in roIFNT-infused ewes compared to controls. Levels of LHCGR, STAR, CYP11A1, HSL, OPA1, and protein kinase A mRNA and proteins were higher in the roIFNT-infused CLs compared to the controls. Levels of ISG15 and MX1 mRNA increased in the CLs of roIFNT-infused ewes but not in the endometrium. Endometrial ESR1 mRNA and protein concentrations were higher in the controls compared to roIFNT-infused ewes. In conclusion, intra-luteal delivery of roIFNT induced ISGs, stabilized steroidogenesis in the CL, and delayed luteolysis without inducing endometrial IFN-stimulated genes. Inhibition of ESR1 in the endometrium of roIFNT-infused ewes was observed suggesting that direct delivery of IFNT to the CL has an additional anti-luteolytic effect on the endometrium.

In vitro reminiscence: uterine programming in vivo affects respective luminal epithelial cells function in vitro†.

In cattle, the endometrium during diestrus and early pregnancy displays cellular responses that are consequences of prior, transient stimuli. Goal was to establish a model to study cellular memory in the endometrium. The hypothesis is that stimuli given to endometrium in vivo are retained as a cellular memory that remains after bovine uterine epithelial cells (BUECs) are isolated, cultured, and further stimulated in vitro. Objectives were to measure BUEC proliferation/migration and responsiveness to recombinant bovine Interferon-tau (rbIFNT) in vitro: among cows that showed estrus (experiment 1 [Exp1]), cows that became or not pregnant to artificial insemination (Exp2), cows that received or not supplemental progesterone (P4; Exp3) and cows that received or not a COX-1/2 inhibitor (Exp4). Only cows that displayed estrus were included in studies. For all experiments endometrial cytology was collected 4 days after estrus, BUECs were cultured, propagated, and submitted to rbIFNT treatment and an in vitro scratch assay. In Exp1, different cows spontaneously grouped according to proliferative/migratory capacity and responsiveness to rbIFNT of their respective BUECs. In Exp2, BUECs from pregnant cows showed greater rbIFNT responsiveness and cellular proliferation. In Exp3, BUECs from cows supplemented with P4 presented inhibited proliferation and increased expression of RSAD2. In Exp4, Flunixin Meglumine modified rbIFNT responsiveness of BUECs in an IFN-signaling pathway-specific manner. In conclusion, physiological and pharmacological stimuli received by the endometrium in vivo were retained as cellular memory in BUECs, persisted in culture, and changed BUEC proliferation/migration and responsiveness to rbIFNT, which are characteristics associated with fertility in cattle.

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.

Stable measurement of chemistry, immunochemistry, and hematology analytes in a heparin-based anticoagulant with iloprost additive: A promising candidate for the polyvalent blood collection tube.

INTRODUCTION: A polyvalent blood collection tube could potentially reduce the number and volume of blood samples drawn from patients and reduce the risk of tube mix-ups in a point-of-care setting in the emergency department and the intensive care unit. METHODS: Four different concentrations of our experimental heparin anticoagulant with iloprost additive (HEP-ILOP 50 nM, 150 nM, 1000 nM, and 10 µM, respectively) were tested for significant differences and bias performance specifications against EDTA for 29 hematology analytes, and the highest concentration (HEP-ILOP 10 µM) against lithium heparin for 14 chemistry and immunochemistry analytes. Samples were drawn from 79 consenting subjects from the Oncology Department (n = 38) and the Intensive and Intermediary Care Unit (n = 41). RESULTS: For hematology analytes, the HEP-ILOP formulation generally provided stable measurement within optimal requirements within 5 h after sampling (mean 104 ± 56 min), with very little difference between the four HEP-ILOP concentrations. Because of differences in platelet and red blood cell swelling between EDTA and HEP-ILOP, all size-dependent analytes required proportional factorization to produce similar results. Platelet count by impedance similarly required factorization, whereas the fluorescent method provided results identical with EDTA. Chemistry and immunochemistry analytes were within optimal requirements except for potassium, lactate dehydrogenase, and glucose, indicating a cytoprotective effect of iloprost reducing cell metabolism and rupture, thereby producing results closer to in vivo conditions. CONCLUSIONS: Our novel dry-sprayed anticoagulant formulation, HEP-ILOP, is a promising candidate for a polyvalent blood collection tube, enabling the analysis of hematology, chemistry, and immunochemistry analytes in the same tube.

Genome-wide association study reveals a locus in ADARB2 for complete freedom from headache in Danish Blood Donors.

Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association study of individuals who have never experienced a headache. We included 63,992 individuals (2,998 individuals with complete freedom from headache and 60,994 controls) from the Danish Blood Donor Study Genomic Cohort. Participants were included in two rounds, from 2015 to 2018 and in 2020. We discovered a genome-wide significant association, with the lead variant rs7904615[G] in ADARB2 (EAF = 27%, OR = 1.20 [1.13-1.27], p = 3.92 × 10-9). The genomic locus was replicated in a non-overlapping cohort of 13,032 individuals (539 individuals with complete freedom from headache and 12,493 controls) from the Danish Blood Donor Study Genomic Cohort (p < 0.05, two-sided). Participants for the replication were included from 2015 to 2020. In conclusion, we show that complete freedom from headache has a genetic component, and we suggest that ADARB2 is involved in complete freedom from headache. The genomic locus was specific for complete freedom from headache and was not associated with any primary headache disorders.