Evaluation of NTP42, a novel thromboxane receptor antagonist, in a first-in-human phase I clinical trial.

Background: The thromboxane receptor (TP) antagonist NTP42 is in clinical development for treatment of cardiopulmonary diseases, such as pulmonary arterial hypertension. In this randomized, placebo-controlled Phase I clinical trial, NTP42, administered as the oral formulation NTP42:KVA4, was evaluated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy males. Methods: The first-in-human trial had three Parts: A, single ascending dose (SAD) study with seven groups given 0.25-243 mg NTP42:KVA4 or placebo; B, food effect study where one SAD group (9 mg) was also given NTP42:KVA4 or placebo after a high-fat breakfast; C, multiple ascending dose study with three groups given 15-135 mg NTP42:KVA4 or placebo once-daily for 7 days. Results: Seventy-nine volunteers participated. No serious adverse events occurred, where any drug- or placebo-related adverse events were mild to moderate, with no correlation to NTP42:KVA4 dose. NTP42 was rapidly absorbed, yielding dose proportional increases in exposure after single and repeat dosing. PK confirmed that, with a clearance (T1/2) of 18.7 h, NTP42:KVA4 is suited to once-daily dosing, can be taken with or without food, and does not accumulate on repeat dosing. At doses ≥1 mg, NTP42 led to complete and sustained inhibition of thromboxane-, but not ADP-, induced platelet aggregation ex vivo, with direct correlation between NTP42 exposure and duration of PD effects. Conclusion: Orally administered NTP42:KVA4 was well tolerated, with favorable PK/PD profiles and evidence of specific TP target engagement. These findings support continued clinical development of NTP42:KVA4 for cardiopulmonary or other relevant diseases with unmet needs. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04919863.

The effect of surgical complications on ENT trainees.

BACKGROUND: The 'second victim phenomenon' is a term attributed to the traumatic effect a medical error can have on healthcare professionals. Patient safety incidents have been shown to occur in as many as one in seven patients in hospital. These incidents cause significant, potentially devastating, trauma to patients and their relatives, and can have deep and long-lasting effects on the health professionals involved. These incidents can have a negative impact on doctors' emotional wellbeing; their professional practice in relation to this impact has not been extensively investigated in surgical trainees. METHOD: A survey of UK otolaryngology trainees was conducted to investigate the effects of complications and medical errors on trainees, and examine how these are discussed within departments. RESULTS AND CONCLUSION: The findings suggest that further training is required and would be warmly received by otolaryngology trainees as part of higher surgical training.

Influence of temperature on prevalence of health and welfare conditions in pigs: time-series analysis of pig abattoir inspection data in England and Wales.

The prevalence of many diseases in pigs displays seasonal distributions. Despite growing concerns about the impacts of climate change, we do not yet have a good understanding of the role that weather factors play in explaining such seasonal patterns. In this study, national and county-level aggregated abattoir inspection data were assessed for England and Wales during 2010-2015. Seasonally-adjusted relationships were characterised between weekly ambient maximum temperature and the prevalence of both respiratory conditions and tail biting detected at slaughter. The prevalence of respiratory conditions showed cyclical annual patterns with peaks in the summer months and troughs in the winter months each year. However, there were no obvious associations with either high or low temperatures. The prevalence of tail biting generally increased as temperatures decreased, but associations were not supported by statistical evidence: across all counties there was a relative risk of 1.028 (95% CI 0.776-1.363) for every 1 °C fall in temperature. Whilst the seasonal patterns observed in this study are similar to those reported in previous studies, the lack of statistical evidence for an explicit association with ambient temperature may possibly be explained by the lack of information on date of disease onset. There is also the possibility that other time-varying factors not investigated here may be driving some of the seasonal patterns.

Implementing a guideline for acute tonsillitis using an ambulatory medical unit.

OBJECTIVE: Acute tonsillitis represents a significant proportion of admissions to ENT departments nationally. Given current hospital pressures, it is vital to look for safe alternatives to admission. This study explores the safe management of patients in an ambulatory medical unit, without the need for admission. METHODS: A retrospective review of 48 patients' notes was carried out. Following the development and implementation of a guideline for acute tonsillitis, a prospective re-audit of 41 patients was carried out, measuring length of stay, overnight admissions and re-admissions. RESULTS: The rate of overnight admission following implementation of the guideline fell from 0.75 to 0.29, and average length of stay dropped from 19.2 to 9.5 hours. There were two re-admissions in each cycle of the audit, which represents a non-significant increase. CONCLUSION: The tonsillitis guideline has significantly reduced admissions and length of stay. Re-admissions remain low, demonstrating that this is a safe and cost-effective intervention.

Enhanced bioscience content is urgently needed in UK pre-registration nursing curricula.

Achieving adequate bioscience learning and assessment in pre registration nursing programs has been problematic for many decades. This has been discussed extensively in national and international health care literature. Despite this, the quantity and quality of bioscience content appears currently in many UK registered nursing programs, to be in a period of decline. Sub optimal bioscience knowledge of registered nurses has been consistently correlated with avoidable morbidity and mortality. An increasing evidence base indicates that a higher level of educated registered nurse, leads to improved health outcomes. It is therefore clear that continuing to fail to address the bioscience problem in nursing education has the potential to incur considerable adverse impact on the UK populations' health. The recent publication of new Nursing and Midwifery Council (NMC) standards of proficiency for registered nurses, and standards for pre-registration nursing programs require nurse education providers across the UK, to write new curriculum. The purpose of this discussion paper is to present the case for enhanced bioscience content within these.

Olecranon fractures in children and adolescents: outcomes based on fracture fixation.

PURPOSE: Open reduction and internal fixation with a tension band construct is the standard treatment for displaced transverse intra-articular olecranon fractures. The purpose of this study is to describe the outcomes of tension band fixation of olecranon fractures in children, specifically assessing the need for revision fixation and hardware removal. METHODS: Patients less than 18 years of age diagnosed with a displaced transverse intra-articular olecranon fracture and treated with tension band fixation between 2008 and 2017 were retrospectively enrolled. Operative treatment was with tension band wire (TBW) or tension band suture (TBS) constructs. RESULTS: A total of 46 patients, 36 male and ten female with a mean age of 12.3 years (6 to 17), were included. Surgical fixation was with TBW in 17 patients and TBS in 29 patients. Revision fixation due to failure and fracture displacement was required in 6% of the TBW group and 14% of the TBS group (p = 0.19). The patients who required revision fixation in the TBS group were older (14.7 years versus 11.6 years, p = 0.05) and heavier (70.5 kg versus 48.5 kg, p = 0.05) than those in the same group who did not require revision fixation. CONCLUSION: Paediatric olecranon fractures treated with TBW or TBS fixation unite in the majority of patients with similar need for hardware removal due to prominence and/or pain between fixation techniques. In a select group of older patients weighing greater than 50 kg, TBS constructs demonstrate increased failure rates, requiring revision fixation, and should be avoided in this population group. LEVEL OF EVIDENCE: IV.

Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial.

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

The experience of the Santé Diabète NGO in the fight against diabetes in Africa.

Several years ago, infectious diseases such as tuberculosis, HIV/AIDS, and malaria were the principal health menace on an international scale. But, today, noncommunicable diseases (NCD), such as diabetes and cardiovascular diseases, are a health emergency in both high- and low-income countries. The NGO Santé Diabète (Diabetes Health) has now been developing actions for diabetes prevention and management in Africa for 15 years. The strategies they have developed combine advocacy, support for the Ministry of Health for the implementation of plans to fight NCDs, staff training, and the establishment of a structure for prevention and management. In Mali, these activities, begun a decade ago, now manage 15,000 patients with diabetes.

Measuring mortality and the burden of adult disease associated with adverse childhood experiences in England: a national survey.

BACKGROUND: ACE (adverse childhood experience) studies typically examine the links between childhood stressors and adult health harming behaviours. Using an enhanced ACE survey methodology, we examine impacts of ACEs on non-communicable diseases and incorporate a proxy measure of premature mortality in England. METHODS: A nationally representative survey was undertaken (n = 3885, aged 18-69, April-July 2013). Socio-demographically controlled proportional hazards analyses examined the associations between the number of ACE categories (<18 years; e.g. child abuse and family dysfunction such as domestic violence) and cancer, diabetes, stroke, respiratory, liver/digestive and cardiovascular disease. Sibling (n = 6983) mortality was similarly analysed as a measure of premature mortality. RESULTS: Of the total, 46.4% of respondents reported ≥1 and 8.3% ≥4 ACEs. Disease development was strongly associated with increased ACEs (e.g. hazard ratios, HR, 0 versus ≥4 ACEs; cancer, 2.38 (1.48-3.83); diabetes, 2.99 (1.90-4.72); stroke, 5.79 (2.43-13.80, all P < 0.001). Individuals with ≥4 ACEs (versus no ACEs) had a 2.76 times higher rate of developing any disease before age 70 years. Adjusted HR for mortality was strongly linked to ACEs (≥4 versus 0 ACEs; HR, 1.97 (1.39-2.79), P < 0.001). CONCLUSIONS: Radically different life-course trajectories are associated with exposure to increased ACEs. Interventions to prevent ACEs are available but rarely implemented at scale. Treating the resulting health costs across the life course is unsustainable.

Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin.

AIMS: To show that albiglutide, a glucagon-like peptide-1 receptor agonist, is an effective and generally safe treatment to improve glycaemic control in patients with type 2 diabetes mellitus whose hyperglycaemia is inadequately controlled with pioglitazone (with or without metformin). METHODS: In this 3-year, randomized, double-blind, placebo-controlled study, 310 adult patients on a regimen of pioglitazone (with or without metformin) were randomly assigned to receive additional treatment with albiglutide [30 mg subcutaneous (s.c.) once weekly, n = 155] or matching placebo (n = 155). The primary efficacy endpoint was change from baseline to week 52 (intention-to-treat) in glycated haemoglobin (HbA1c). RESULTS: The model-adjusted change from baseline in HbA1c at week 52 was significantly better with albiglutide than with placebo (-0.8%, 95% confidence interval -1.0, -0.6; p < 0.0001). Change from baseline fasting plasma glucose was -1.3 mmol/l in the albiglutide group and +0.4 mmol/l in the placebo group (p < 0.0001); a significantly higher percentage of patients reached the HbA1c goals with albiglutide (p < 0.0001), and the rate of hyperglycaemia rescue up to week 52 for albiglutide was 24.4 versus 47.7% for placebo (p < 0.0001). Albiglutide plus pioglitazone had no impact on weight, and severe hypoglycaemia was observed rarely (n = 2). With few exceptions, the results of safety assessments were similar between the groups, and most adverse events (AEs) were mild or moderate. The 52-week incidence rates for gastrointestinal AEs for albiglutide and placebo were: 31.3 and 29.8%, respectively (diarrhoea: 11.3 and 8.6%; nausea: 10.7 and 11.3%; vomiting: 4.0 and 4.0%). CONCLUSIONS: Albiglutide 30 mg administered once weekly as an add-on to pioglitazone (with or without metformin) provided effective and durable glucose lowering and was generally well tolerated.

Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459.

BACKGROUND: The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. A study was conducted to determine the effect of lower once daily doses of OC000459 and to define the phenotype of subjects most responsive to treatment. METHODS: Adult subjects (percentage of predicted forced expiratory volume in 1 s (FEV1 ) 60-85%) were randomized to OC000459 at three dose levels (25 mg once daily, 200 mg once daily or 100 mg twice daily) or placebo for 12 weeks (n = 117-125 per group, full analysis set). The primary endpoint was the change from baseline in prebronchodilator FEV1 , and secondary endpoints included Asthma Control Questionnaire (ACQ) and Standardised Asthma Quality of Life Questionnaire [AQLQ(S)], and incidence of exacerbations and respiratory tract infections. RESULTS: OC459 caused a significant improvement in FEV1 compared with placebo at a dose of 25 mg once daily (P = 0.028). A similar increase was observed in the other dose groups, and the mean change in FEV1 in the pooled dose groups at endpoint was 95 ml greater than placebo (P = 0.024). In a post hoc analysis of atopic eosinophilic subjects with uncontrolled asthma, a mean increase in FEV1 of 220 ml was observed compared with placebo (P = 0.005). The mean increase in FEV1 was more marked in younger subjects in this group: for subjects aged ≤40 years, there was a mean increase of 355 ml compared with placebo (P = 0.007). Improvements in ACQ and AQLQ(S) were observed in both the full analysis set and the atopic eosinophilic subgroup. There was a lower incidence of exacerbations and respiratory infections in subjects treated with OC000459. There were no drug-related serious adverse events. CONCLUSIONS: OC000459 is a safe and effective oral anti-inflammatory agent, which achieved clinically meaningful improvements in lung function and asthma control in allergic asthmatics with an eosinophil-dominant form of the disease. A dose of 25 mg given once daily was as effective as the higher doses studied.

Shape selectivity by guest-driven restructuring of a porous material.

A flexible metal-organic framework selectively sorbs para- (pX) over meta-xylene (mX) by synergic restructuring around pX coupled with generation of unused void space upon mX loading. The nature of the structural change suggests more generally that flexible structures which are initially mismatched in terms of fit and capacity to the preferred guest are strong candidates for effective molecular separations.

Vein visualization: patient characteristic factors and efficacy of a new infrared vein finder technology.

BACKGROUND: We investigated the patient characteristic factors that correlate with identification of i.v. cannulation sites with normal eyesight. We evaluated a new infrared vein finding (VF) technology device in identifying i.v. cannulation sites. METHODS: Each subject underwent two observations: one using the conventional method (CM) of normal, unassisted eyesight and the other with the infrared VF device, VueTek's Veinsite™ (VF). A power analysis for moderate effect size (ß=0.95) required 54 samples for within-subject differences. RESULTS: Patient characteristic profiles were obtained from 384 subjects (768 observations). Our sample population exhibited an overall average of 5.8 [95% confidence interval (CI) 5.4-6.2] veins using CM. As a whole, CM vein visualization were less effective among obese [4.5 (95% CI 3.8-5.3)], African-American [4.6 (95% CI 3.6-5.5 veins)], and Asian [5.1 (95% CI 4.1-6.0)] subjects. Next, the VF technology identified an average of 9.1 (95% CI 8.6-9.5) possible cannulation sites compared with CM [average of 5.8 (95% CI 5.4-6.2)]. Seventy-six obese subjects had an average of 4.5 (95% CI 3.8-5.3) and 8.2 (95% CI 7.4-9.1) veins viewable by CM and VF, respectively. In dark skin subjects, 9.1 (95% CI 8.3-9.9) veins were visible by VF compared with 5.4 (95% CI 4.8-6.0) with CM. CONCLUSIONS: African-American or Asian ethnicity, and obesity were associated with decreased vein visibility. The visibility of veins eligible for cannulation increased for all subgroups using a new infrared device.

The CRTH2 antagonist OC000459 reduces nasal and ocular symptoms in allergic subjects exposed to grass pollen, a randomised, placebo-controlled, double-blind trial.

BACKGROUND: CRTH2 mediates activation of Th2 cells, eosinophils and basophils in response to prostaglandin D(2). The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. The objective of the present study was to determine the involvement of CRTH2 in promoting nasal and ocular symptoms in allergic subjects exposed to grass pollen. METHODS: A single centre, randomised, double-blind, placebo-controlled, two-way crossover study was conducted in 35 male subjects allergic to grass pollen comparing OC000459 200 mg bid with placebo for 8 days. Subjects were exposed to grass pollen (≥ 1400 grains/m(3)) for 6 h on the 2nd and 8th days of treatment and assessed for nasal symptoms, ocular symptoms, other symptoms, nasal secretion weight and rhinomanometry over the 6-h period. After a washout period of 3 weeks, subjects were switched to the alternative treatment for a further 8 days. The trial was registered on the clinical trials.gov database (Identifier NCT01448902). RESULTS: During the first treatment period, treatment with OC000459 significantly reduced both nasal and ocular symptoms in allergic subjects compared with placebo after challenge with grass pollen. A significant effect was observed on the 2nd day of dosing which was increased on the 8th day of dosing. The therapeutic effects of OC000459 persisted into the second treatment period despite a 3-week washout phase. The safety profile of OC000459 was similar to that of placebo. CONCLUSION: Treatment with OC000459 was well tolerated and led to a significant and persistent reduction in the symptoms of rhinoconjunctivitis.

A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma.

BACKGROUND: CRTH2 is a G-protein-coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D(2) and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma. OBJECTIVE: To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double-blind, parallel group trial in steroid-free subjects with moderate persistent asthma. METHODS: Adult subjects were randomized to oral OC000459 200 mg twice daily (N=65) or a placebo (N=67) for 28 days. The primary end-point was the change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV(1) ); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials.gov database (Identifier NCT01057927). RESULTS: Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded non-compliant subjects. In the FA population, the mean change in FEV(1) was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P=0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P=0.0113 and 0.37, P=0.0022, respectively]. OC000459 also improved the night-time symptom scores (mean reduction of 0.36 vs. 0.11, P=0.008, FA population; 0.37 vs. 0.12, P=0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P=0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P=0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment. CONCLUSION AND CLINICAL RELEVANCE: This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.

Scaling behavior of electronic excitations in assemblies of molecules with degenerate ground states.

The behavior of long space-time excitations in many-electron systems with ground state degeneracy is explored via multiscale analysis. The analysis starts with an ansatz for the wave function's dual dependence on the N-electron configuration (i.e., both by direct means and by indirect means via a set of order parameters). It is shown that a Dirac-like equation form of the wave equation emerges in the limit where the ratio epsilon (of the average nearest-neighbor distance to the characteristic length of the long-scale phenomenon of interest) is small. Examples of the long scale are the size of a quantum dot, nanotube, or wavelength of a density disturbance. The velocities in the Dirac-like equation are the transition moments of the single-particle momentum operator connecting degenerate ground states. While detailed band structure and the independent quasi-particle picture could underlie the behavior of some systems (as commonly suggested for graphene), the present scaling law results show it is not necessarily the only explanation. Rather, it can follow from the scaling properties of low-lying, long spatial scale excitations and ground state degeneracy, even in strongly interacting systems. The generality of our findings suggests graphene may be just one of many examples of Dirac-like equation behavior. A preliminary validation of our quantum scaling law for molecular arrays is presented. As our scaling law constitutes a coarse-grained wave equation, path integral or other methods derived from it hold great promise for calibration-free, long-time simulation of many-particle quantum systems.

Plasma cell cheilitis.

Plasma cell cheilitis is a rare, idiopathic mucosal condition, which has previously been given scant attention among oral and maxillofacial publications. We present a case of plasma cell cheilitis, with the differential diagnosis and options for treatment.

Poststroke cerebral peduncular atrophy correlates with a measure of corticospinal tract injury in the cerebral hemisphere.

BACKGROUND AND PURPOSE: Methods have not been well developed and tested to predict the extent of remote degeneration in the central nervous system that follows cerebral infarction. We hypothesized that the extent of infarction overlap with the cerebral hemispheric course of the corticospinal tract (CST) on structural MR imaging predicts the extent of ipsilateral cerebral peduncular atrophy in patients with chronic stroke. MATERIALS AND METHODS: Hemiparetic patients (n = 34) with supratentorial unilateral infarctions who were at least 1 year poststroke onset and enrolled in research protocols of Constraint-Induced Movement therapy underwent volumetric T1 MR imaging of the brain. The following measures were calculated for each patient: 1) the maximal proportion of the CST in the cerebral hemisphere on axial section that was overlapped by infarction, 2) total infarction volume, and 3) the ratio of the cross-sectional area of the ipsilateral cerebral peduncle to the area of the contralateral cerebral peduncle (peduncular asymmetry ratio). Correlation analyses evaluated the predictive value of CST injury or infarction volume for the peduncular asymmetry ratio. RESULTS: CST injury correlated significantly with the peduncular asymmetry ratio (r = -0.65; P < .001), whereas infarction volume did not (r = -0.31; P = .09). CONCLUSIONS: The extent of postinfarction CST injury in the cerebral hemisphere predicts the extent of ipsilateral cerebral peduncular atrophy. More generally, the findings suggest that the extent of remote wallerian degeneration of a fiber tract is strongly related to its extent of injury directly at the site of infarction.

Randomised controlled cross-over comparison of continuous positive airway pressure through the Hamilton Galileo ventilator with a Dräger CF 800 device.

In this controlled, randomised cross-over trial on 26 intensive care patients, we compared the effects on haemodynamic and respiratory profiles of continuous positive airway pressure delivered through the Hamilton Galileo ventilator or a Drager CF 800 device. We also compared the nursing time saved using the two approaches when weaning patients from mechanical ventilation. We did not find significant differences in haemodynamics, respiratory rate, physiological dead space, oxygen saturation and carbon dioxide production between the continuous positive airway pressure generated by the Galileo and Drager machines. However, there was a 10-fold reduction in nursing time using the Galileo ventilator compared with the Drager generator. We conclude that continuous positive airway pressure delivered through the Galileo ventilator is as efficient as a Drager device but consumes less nursing time.