The sphingosine‐1‐phosphate 1 receptor (S1P1R) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte ...egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune‐mediated, inflammatory diseases. This first‐in‐human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose‐escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose‐limiting toxicities. The most common ozanimod‐related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady‐state volume of distribution (73–101 L/kg), moderate oral clearance (204–227 L/h), and an elimination half‐life of approximately 17 to 21 hours. Ozanimod produced a robust dose‐dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose‐dependent negative chronotropic effect was observed following the first dose, with the dose‐escalation regimen attenuating the first‐dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once‐daily regimens under clinical investigation.
Left‐leaning molecules: As shown by X‐ray crystallography, NMR spectroscopy, and DFT calculations, N‐(2‐fluoroethyl)pyridinium (see picture; C gray, H white, N blue, F green) and related cations ...prefer a gauche conformation. In these systems, the gauche effect is attributed to an electrostatic interaction that does not involve hydrogen bonding.
Current success in organ transplantation is dependent upon the use of calcineurin‐inhibitor‐based immunosuppressive regimens. Unfortunately, current immunotherapy targets molecules with ubiquitous ...expression resulting in devastating non‐immune side effects. T‐cell costimulation has been identified as a new potential immunosuppressive target. The best characterized pathway includes CD28, its homologue CTLA4 and their ligands CD80 and CD86. While an immunoglobulin fusion protein construct of CTLA4 suppressed rejection in rodents, it lacked efficacy in primate transplant models. In an attempt to increase the biologic potency of the parent molecule a novel, modified version of CTLA4‐Ig, LEA29Y (belatacept), was constructed. Two amino acid substitutions (L104E and A29Y) gave rise to slower dissociation rates for both CD86 and CD80. The increased avidity resulted in a 10‐fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre‐clinical primate model. The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants.
Septic arthritis is a serious condition with significant morbidity and mortality, routinely diagnosed using culture. The FDA has recently approved the rapid molecular BioFire® Joint Infection Panel ...(BJIP) for synovial fluid. We aimed to evaluate the BJIP compared to culture and its potential use in patient management. A multicentre retrospective evaluation of BJIP was conducted in the UK and Ireland. Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated between the BJIP and routine culture. A multidisciplinary team (MDT) discussion addressing the optimal or potential case use of the assay practice was facilitated. Three hundred ninety-nine surplus synovial fluid samples (~ 70% from native joints) from eight centres were processed using BJIP in addition to routine culture. An increased yield of positive results was detected using BJIP compared to routine culture (98 vs 83), giving an overall PPA of 91.6% and overall NPA of 93% for the BJIP compared to culture results. The BJIP detected resistant markers and additional organisms that could influence antibiotic choices including
Neisseria gonorrhoeae
and
Kingella kingae
. The MDT agreed that the assay could be used, in addition to standard methods, in adult and children patients with specialist advice use based on local needs. Rapid results from BJIP were assessed as having potential clinical impact on patient management. Organisms not included in the panel may be clinically significant and may limit the value of this test for PJI.
Arterial pathologies in athletes Peach, George; Sinha, Sidhartha; Hinchliffe, Robert J
Journal of cardiovascular surgery,
04/2017, Letnik:
58, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Identification and treatment of arterial pathologies in athletes can present a significant challenge because symptoms may be nonspecific and standard examination is often unremarkable. Sportspeople ...frequently experience long delays to diagnosis, during which time their ability to exercise and their quality of life may be severely impacted. Though the conditions that affect this young patient group may not be widely seen in the general population, knowledge of their existence and recognition of the need for specialist referral can aid early identification and appropriate management. Due to the relatively low number of reported cases, there is a paucity of robust evidence regarding optimal management of these conditions and treatment recommendations are therefore based largely upon expert consensus. It is hoped that wider use of international registries will help to address this deficit and inform future guidelines.
Ozanimod is a novel, selective, oral sphingosine‐1‐phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double‐blind, ...placebo‐controlled, positive‐controlled, parallel‐group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time‐matched, placebo‐corrected, baseline‐adjusted mean QTcF (ΔΔQTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2‐sided 90% confidence intervals for ΔΔQTcF for both ozanimod 1 and 2 mg were below the 10‐millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ΔΔQTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimod's evolving favorable cardiac safety profile.
Background
To evaluate the psychometric properties of three new condition-specific questionnaires designed to assess outcomes amongst patients under pre-operative surveillance for a small abdominal ...aortic aneurysm (AAA) or who have undergone aneurysm repair. These tools are the Aneurysm-Dependent Quality of Life measure (AneurysmDQoL), the Aneurysm Symptom Rating Questionnaire (AneurysmSRQ) and the Aneurysm Treatment Satisfaction Questionnaire (AneurysmTSQ).
Results
The questionnaires were sent to 297 patients with abdominal aortic aneurysm (AAA) or who had undergone AAA repair (using open or endovascular technique) sampled from five UK NHS Trusts. Exploratory Factor Analysis was used to examine factor structure together with reliability analysis. A subset of 65 patients completed the questionnaires a second time four months later. One hundred and ninety-seven patients (178 men; 18 women) provided data for analysis (69% response rate): mean age was 75 years (range 60–95). Nineteen were under pre-operative surveillance for AAA and 178 had undergone AAA repair (70 open repair; 104 endovascular repair; 4 uncertain). Exploratory Factor Analysis of the AneurysmDQoL and the AneurysmTSQ each demonstrated a one-factor structure. The AneurysmSRQ demonstrated a six-factor structure (emotional, weight loss, lower limb, cognitive, general malaise and gastrointestinal symptoms) and a one-factor composite symptom scale. All scales have clean factor structures: item loadings above 0.40, no cross-loadings, and no factors with fewer than three items. Internal consistency reliability was excellent (α = 0.869–0.959) and test-retest reliability good (Intraclass correlation coefficient = 0.70–0.88).
Conclusions
The three new questionnaires have a clear structure and strong reliability and are now ready for use in clinical trials and routine practice, which will allow evaluation of responsiveness to change.
Iliac artery endofibrosis is an uncommon condition, which should be considered in young athletes with exertional lower limb symptoms. Imaging often appears normal at rest, and the diagnosis can be ...missed if clinical assessment is inadequate. We report a successful case of entirely minimally invasive surgical treatment for iliac artery endofibrosis in a 41-year-old cyclist. This novel technique offers superior potential for intraoperative assessment and aids enhancement in recovery after surgery. It is likely to be particularly appealing to elite athletes.
We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological ...abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities.
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