Explore the vast range of titles available.

ESK‐001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune‐mediated diseases. In 2 phase I studies, a first‐in‐human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple‐dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK‐001 in healthy participants using a randomized, double‐blind, placebo‐controlled study design. ESK‐001 was rapidly absorbed with systemic exposures generally increasing dose‐proportionally across all cohorts. The mean terminal half‐life ranged from 8 to 13 h with no to minimal accumulation of ESK‐001 following q.d. doses and ~2‐fold accumulation following Q12 doses. Less than 1% of unchanged ESK‐001 was eliminated in urine. ESK‐001 inhibited the downstream TYK2 pathway as shown by inhibition of pSTAT1 expression. Transcriptomic analysis of unstimulated whole blood samples confirmed dose‐dependent inhibition of Type I IFN‐induced genes and SIGLEC1, a novel TYK2‐responsive biomarker. By correlating PK exposure data with PD readouts, a strong PK/PD relationship was demonstrated. There were no deaths, serious treatment‐emergent adverse events (TEAEs), nor severe TEAEs, and most TEAEs were mild in severity. In conclusion, ESK‐001 was generally safe and well‐tolerated in healthy participants, showed linear dose‐dependent PK characteristics, and maximally inhibited TYK2‐dependent pathways with a predictable concentration‐dependent PK/PD relationship. These findings were used to select the dose range of ESK‐001 for the STRIDE phase II trial in plaque psoriasis and to support further clinical development of ESK‐001 in other TYK2‐mediated diseases.

Botulinum toxin type A (BoNTA) products are widely used for therapeutic and aesthetic indications, but there is a need for longer-lasting treatments that maintain symptom relief between injections and reduce the frequency of re-treatment. DaxibotulinumtoxinA for Injection (DAXI) is a novel BoNTA product containing highly purified 150-kDa core neurotoxin and is the first to be formulated with a proprietary stabilizing excipient peptide (RTP004) instead of human serum albumin. The positively charged RTP004 has been shown to enhance binding of the neurotoxin to neuronal surfaces, which may enhance the likelihood of neurotoxin internalization. DAXI produces robust, extended efficacy across both aesthetic and therapeutic indications. In an extensive glabellar lines clinical program, DAXI showed a high degree of efficacy, a consistent median time to loss of none or mild glabellar line severity of 24 weeks, and median time until return to baseline of up to 28 weeks. In adults with cervical dystonia, DAXI at 125 U and 250 U significantly improved Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores, with a median duration of efficacy of 24 and 20 weeks, respectively, which compares favorably with the 12–14 weeks’ duration reported for approved BoNTA products. Overall, DAXI was well tolerated, and the consistent extended duration of effect suggests that DAXI has the potential to improve the management of both aesthetic and therapeutic conditions. Plain Language Summary Botulinum toxin is used to block the nerve signals that cause muscles to contract. Products containing botulinum toxin are commonly given by injection to treat muscle spasms (such as cervical dystonia, a painful condition where the neck muscles contract involuntarily) and for cosmetic treatment of frown lines. However, the effects of the currently approved botulinum toxin products typically wear off about 3–4 months after injection and so the injections must be repeated regularly. A new product called DAXI (DaxibotulinumtoxinA for Injection) has been developed. In this product, the botulinum toxin is formulated with a unique protein (called RTP004) that has been designed to help deliver the botulinum toxin to the nerve cells. Research suggests that the RTP004 protein in DAXI adheres the botulinum toxin to the nerves close to the injection site, potentially making its effect last longer. To date, DAXI has been studied in over 3800 patients. The studies have shown that DAXI is effective for treating neck spasms (cervical dystonia) and for reducing the appearance of frown lines. Importantly, the effects of DAXI lasted up to 6 months, which is longer than seen with other botulinum toxin products. The side effects seen with DAXI are consistent in nature and frequency with those seen with other botulinum toxin products. These findings suggest that DAXI can improve both medical and cosmetic treatments due to its longer-lasting effect.

The Event Horizon Telescope (EHT) Collaboration recently published the first images of the supermassive black holes in the cores of the Messier 87 and Milky Way galaxies. These observations have provided a new means to study supermassive black holes and probe physical processes occurring in the strong-field regime. We review the prospects of future observations and theoretical studies of supermassive black hole systems. Current ground-based very-long-baseline interferometry (VLBI) arrays like the EHT and proposed future extensions like the next-generation Event Horizon Telescope will greatly enhance the capabilities of black-hole imaging interferometry. These enhancements will open up several previously inaccessible avenues of investigation, thereby providing important new insights into the properties of supermassive black holes and their environments. This review describes the current state of knowledge for five key science cases, summarising the unique challenges and opportunities for fundamental physics investigations that future mm/sub-mm VLBI developments will enable.

The Event Horizon Telescope (EHT) Collaboration recently published the first images of the supermassive black holes in the cores of the Messier 87 and Milky Way galaxies. These observations have provided a new means to study supermassive black holes and probe physical processes occurring in the strong-field regime. We review the prospects of future observations and theoretical studies of supermassive black hole systems with the next-generation Event Horizon Telescope (ngEHT) project, which will greatly enhance the capabilities of the existing EHT array. These enhancements will open up several previously inaccessible avenues of investigation, thereby providing important new insights into the properties of supermassive black holes and their environments. This review describes the current state of knowledge for five key science cases, summarising the unique challenges and opportunities for fundamental physics investigations that the ngEHT will enable.

The use of tissue adhesives has been proposed as an anastomosis reinforcement; however, their efficacy has not been evaluated in a contaminated environment. The objective of this study was to determine if the use of sutures reinforced with ethyl-2-cyanoacrylate for colonic anastomoses in the presence of fecal peritonitis, in a murine animal model, decreases the frequency of dehiscence. Wistar rats were used. Fecal peritonitis was established until reaching 18 hours of evolution. Then, resection and anastomosis of the colon were performed with only polydioxanone (PDS) sutures in the control group and reinforcement with ethyl-2-cyanoacrylate in the experimental group. The dehiscence frequency and burst pressure were evaluated six days after the anastomosis was performed. We included 30 Wistar rats, all males, with a median age of five months and an average weight of 350.43 g. Anastomotic dehiscence was observed in 53.33% of the control group, in contrast with 13.33% of the experimental group (p = 0.020). There was no significant difference in burst pressure between the two groups. The use of ethyl-2-cyanoacrylate, in an experimental murine animal model, as reinforcement in colonic anastomoses in the presence of fecal peritonitis decreases the frequency of anastomotic dehiscence, although it does not increase resistance to burst pressure.

ObjectiveThe common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date.MethodsSamples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their association in a meta-analysis to increase the consistency of the results, including 10 European ancestry cohorts comprising 2363 patients with SSc-ILD, 3526 SSc patients without ILD and 15 076 controls.ResultsMeta-analysis showed no significant association between rs35705950 and SSc-ILD, either comparing patients with SSc with and without ILD (p value: 0.588, OR: 1.05, 95% CI: 0.87 to 1.27) nor patients with SSc-ILD with controls (p value: 0.061, OR: 1.16, 95% CI: 0.99 to 1.36). Moreover, none of the additional 903 variants tested in the genomic region reached statistical significance.ConclusionDespite analysing the largest and most statistically powered SSc-ILD cohort to date, we found no evidence of association between the MUC5B promoter variant rs35705950 and its surrounding SNPs with SSc-ILD. These results suggest that the pathogenic mechanisms underlying SSc-ILD may only partially overlap with those of other similar ILDs, such as IPF or RA-ILD. This highlights the need for further studies regarding their genetic architecture.

BackgroundRheumatoid Arthritis (RA) is an autoimmune disease that can cause systemic manifestations such as interstitial lung disease (ILD). In these patients serum autoantibodies may appear, such as Rheumatoid Factor (RF) and Anti-Citrullinated Peptide antibody (anti-CCP), important for its relationship with structural damage and extra-articular manifestations.ObjectivesTo determine the presence of anti-CCP and RF, clinical-radiological characteristics and evaluate the degree of association between the titles of anti-CCP and RF and the time course of disease in patients with RA and diagnosis of ILD.MethodsWe performed a descriptive study, including 45 patients, treated at a specialized consultation Interstitial lung diseases, during the first half of 2015. Patients were subdivided into groups based on RF level: <24 U/ml Negative, 24–72 U/ml Low Titer and >72 U/ml High Titer. Anti-CCP level: 0–10 U/ml Negative, 10–150 U/ml Low Titer, 151–299 U/ml Moderate Titer and>300 U/ml High Titer.Furthermore, ILD has been divided into different subtypes (the diagnostic includes a clinical exam, pulmonary function tests and high resolution CT): Usual Interstitial Pneumonia (UIP), nonspecific Interstitial Pneumonia (NSIP), Lymphocytic Interstitial Pneumonia (LIN), bronchiolitis obliterans (BO).Evolution time (ET) of the disease was defined as the difference in months between the date of diagnosis of RA and the date of diagnosis of pulmonary involvement. The association between ET and Anti-CCP level and RF level was studied by two analyzes of variance of a ranking factor.The association between the categories of titer and subtype ILD was studied by two tests Chi-square.ResultsBaseline characteristics were: 32 women and 13 men with a mean age of 66±9.6 years (mean ± SD), 36 RA and 9 with secondary Sjogren's syndrome. The most common extraarticular manifestation was ocular 37%. Erosive disease was present in 80% patients.82% were RF positive (High Titer 78% and Low Titer 22%) and 8% seronegative.Anti-CCP were tested in 32 (71%) and present in 29 (27% High Titer, 42% Moderate Titer and 31% Low Titer).The mean time from RA diagnosis to ILD diagnosis was 6.87 years, with a standard deviation of 6.90 years.The time course of the disease is not significantly (p<0.05) affected by the titer of anti-CCP or the RF. On the one hand, the enormous variability in the time course of the disease and on the other the lack of information about the time of the determination of autoantibody titers, could explain the lack of statistical association found.Among the different subtypes nor have we found: NSIP 42%, 35% UIP, LIN 7%, 15% BO. No significant association (p<0.05) between the titer of RF and anti-CCP with radiological clinical pattern in our series did not appreciate.ConclusionsIn our study, the high titers of RF and anti-CCP were not associated with prematurity on lung involvement in patients with RA, considering the enormous variability in the time evolution has been observed in the sample. Moreover RF levels and anti-CCP also not associated with subtype ILD.Further prospective studies are needed to fully assess the implications of a positive RF and anti-CCP in patients with RA and ILD.Disclosure of InterestNone declared

The Event Horizon Telescope (EHT) Collaboration recently published the first images of the supermassive black holes in the cores of the Messier 87 and Milky Way galaxies. These observations have provided a new means to study supermassive black holes and probe physical processes occurring in the strong-field regime. We review the prospects of future observations and theoretical studies of supermassive black hole systems with the next-generation Event Horizon Telescope (ngEHT) project, which will greatly enhance the capabilities of the existing EHT array. These enhancements will open up several previously inaccessible avenues of investigation, thereby providing important new insights into the properties of supermassive black holes and their environments. This review describes the current state of knowledge for five key science cases, summarising the unique challenges and opportunities for fundamental physics investigations that the ngEHT will enable.