The perceived waning of biologics in severe asthma.

BACKGROUND: Biologics are highly effective in severe asthma and used at fixed dosing intervals. However, in clinical practice, dosing intervals are sometimes shortened if patients perceive a decreased biologic effect before the next administration. The occurrence and clinical relevance of this perceived waning of biological effect is unknown. OBJECTIVE: To explore (1) the frequency, severity and conditions, (2) associated symptoms and (3) relationship with clinical characteristics of the patient-perceived waning effect of biologics before the next administration. METHODS: Severe asthma patients receiving biological treatment ≥4 months were included. Based on 17 semi-structured patient interviews, we developed a questionnaire focusing on the waning effect of biologics before the next administration, which was distributed among 129 patients. Clinical characteristics, including asthma control (ACQ) and quality of life (AQLQ) scores, were collected from patient files. RESULTS: 65/101 patients who completed the questionnaire reported a waning of biological effect, graded as severe (median (IQR) 6.5 (5-7.5) on a 0-10 BORG-scale). Waning manifested in a broad spectrum of symptoms. Patients reporting waning had higher ACQ and lower AQLQ scores versus those without (p < 0.05) and higher BORG-scores were associated with higher exacerbation rate (ρ = 0.309, p = 0.013). A third of all patients were in favor of extending or shortening their dosing interval. CONCLUSION: Two-thirds of severe asthma patients report waning of biologic effect at the end of the dosing interval, which is associated with poorer asthma control and quality of life. The diversity in observed waning of effect opens the way for research into more individualized dosing of biologics.

High prevalence of peripheral neuropathy in multiple myeloma patients and the impact of vitamin D levels, a cross-sectional study.

PURPOSE: Peripheral neuropathy (PN) is common in patients with multiple myeloma (MM). We hypothesized that the relationship between hypovitaminosis D and PN described in diabetes mellitus patients may also be present in MM patients. METHODS: To study this potential association, we assessed the incidence of hypovitaminosis D (vitamin D < 75 nmol/L [= 30 ng/mL]) in smouldering and active MM patients in two Dutch hospitals. Furthermore, a validated questionnaire was used to distinguish different PN grades. RESULTS: Of the 120 patients included between January 2017 and August 2018, 84% had an inadequate vitamin D level (median vitamin D level 49.5 nmol/L [IQR 34-65 nmol/L]; mean age: 68 years [SD ± 7.7]; males: 58%). PN was reported by 69% of patients (n = 83); however, of these 83 patients, PN was not documented in the medical records of 52%. An association was found between lower vitamin D levels and higher incidence of PN in the total population (P = 0.035), and in the active MM patients (P = 0.016). CONCLUSION: This multi-centre cohort study showed that PN and hypovitaminosis D are common in MM patients, and addressing low vitamin D levels in the treatment of MM patients might be beneficial in reducing the risk of PN. More attention for PN is warranted, as PN is underreported by clinicians. Further research is needed to fully understand the implications of vitamin D in the development of PN in patients with MM. CLINICAL TRIAL REGISTRATION: Netherland Trial Register NL5835, date of registration July 28, 2016.

The use of a direct bronchial challenge test in primary care to diagnose asthma.

Many asthmatics in primary care have mild symptoms and lack airflow obstruction. If variable expiratory airflow limitation cannot be determined by spirometry or peak expiratory flow, despite a history of respiratory symptoms, a positive bronchial challenge test (BCT) can confirm the diagnosis of asthma. However, BCT is traditionally performed in secondary care. In this observational real-life study, we retrospectively analyze 5-year data of a primary care diagnostic center carrying out BCT by histamine provocation. In total, 998 primary care patients aged ≥16 years underwent BCT, without any adverse events reported. To explore diagnostic accuracy, we examine 584 patients with a high pretest probability of asthma. Fifty-seven percent of these patients have a positive BCT result and can be accurately diagnosed with asthma. Our real-life data show BCT is safe and feasible in a suitably equipped primary care diagnostic center. Furthermore, it could potentially reduce diagnostic referrals to secondary care.

Prediction of response to biological treatment with monoclonal antibodies in severe asthma.

In recent years, major developments have occurred in severe asthma management. Different asthma phenotypes and subgroups have been identified and new treatment options have become available. A total of five monoclonal antibodies are currently approved in severe asthma treatment: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. These drugs have been shown to reduce exacerbations and to have an oral corticosteroid-sparing effect in many severe asthma patients. However, biological treatment is not successful in all patients and should be discontinued in non-responsive patients. Treating the right patient with the right biologic, and therefore biologic response prediction, has become a major point of interest in severe asthma management. A variety of response outcomes is utilized in the different clinical trials, as well as a huge range of potential predicting factors. Also, regarding the timing of the response evaluation, there are considerable differences between studies. This review summarizes the results from studies on predicting responses and responders to biological treatment in severe asthma, taking into account clinical, functional and inflammatory parameters assessed prior to the start of treatment as well as following a few months of therapy. In addition, future perspectives are discussed, highlighting the need for more research to improve patient identification and treatment responses in the field of biological treatment in severe asthma.

Correction: Energetics, barriers and vibrational spectra of partially and fully hydrogenated hexagonal boron nitride.

Correction for 'Energetics, barriers and vibrational spectra of partially and fully hydrogenated hexagonal boron nitride' by J. M. H. Kroes et al., Phys. Chem. Chem. Phys., 2016, 18, 19359-19367.

Density functional based simulations of proton permeation of graphene and hexagonal boron nitride.

Using density functional theory, we study proton permeation through graphene and hexagonal boron nitride. We consider several factors influencing the barriers for permeation, including structural optimization, the role of the solvent, surface curvature and proton transport through hydrogenated samples. Furthermore, we discuss the ground state charge transfer from the membrane to the proton and the strong tendency for bond formation. If the process is assumed to be slow we find that none of these effects lead to a satisfactory answer to the observed discrepancies between theory and experiment.

Energetics, barriers and vibrational spectra of partially and fully hydrogenated hexagonal boron nitride.

We study hydrogen chemisorption at full coverage and low concentrations on hexagonal boron nitride (h-BN). Chemisorption trends reveal the complex nature of hydrogenation. Barriers for diffusion are found to be significantly altered by the presence of additional H atoms. Moreover, the presence of a Stone-Wales defect may dramatically enhance the bond strength of H to the h-BN surface. These findings provide new insights to understand and characterize hydrogenated boron nitride.

Propagation of uncertainties in soil and pesticide properties to pesticide leaching.

In the new Dutch decision tree for the evaluation of pesticide leaching to groundwater, spatially distributed soil data are used by the GeoPEARL model to calculate the 90th percentile of the spatial cumulative distribution function of the leaching concentration in the area of potential usage (SP90). Until now it was not known to what extent uncertainties in soil and pesticide properties propagate to spatially aggregated parameters like the SP90. A study was performed to quantify the uncertainties in soil and pesticide properties and to analyze their contribution to the uncertainty in SP90. First, uncertainties in the soil and pesticide properties were quantified. Next, a regular grid sample of points covering the whole of the agricultural area in the Netherlands was randomly selected. At the grid nodes, realizations from the probability distributions of the uncertain inputs were generated and used as input to a Monte Carlo uncertainty propagation analysis. The analysis showed that the uncertainty concerning the SP90 is 10 times smaller than the uncertainty about the leaching concentration at individual point locations. The parameters that contribute most to the uncertainty about the SP90 are, however, the same as the parameters that contribute most to uncertainty about the leaching concentration at individual point locations (e.g., the transformation half-life in soil and the coefficient of sorption on organic matter). Taking uncertainties in soil and pesticide properties into account further leads to a systematic increase of the predicted SP90. The important implication for pesticide regulation is that the leaching concentration is systematically underestimated when these uncertainties are ignored.

A single copy of apolipoprotein B-48 is present on the human chylomicron remnant.

Individuals homozygous for the e2 allele encoding apolipoprotein E exhibit a remnant removal defect and accumulate substantial levels of intestinally derived particles containing apolipoprotein B-48 (apoB-48). Such lipoproteins were isolated from the plasma of E2/E2 individuals, and further purified by affinity chromatography using a polyclonal antibody specific for selective binding and removal of apoB-100-containing lipoproteins. The unbound lipoproteins, termed chylomicron remnants, were particles with average hydrated diameters of 31.2 nm as determined by dynamic light scattering. They contained apoB-48 and ApoE as their only protein components. The number of apoB-48 molecules on each lipoprotein was assessed by counting the number of antibody molecules bound to the surface of the chylomicron remnants, using either a monoclonal antibody specific for a single epitope on apoB-48 or a mixture of two such monoclonal antibodies specific for widely separated epitopes. The results of this analysis seem unambiguous: no more than one apoB-48 resides on the chylomicron remnant. Because apoB appears to be unable to transfer among lipoprotein particles, it may be inferred that nascent chylomicrons also contain a single copy of apoB-48.

The time course of metabolic changes induced by dietary cholesterol in guinea pigs.

The time course of the effects of dietary cholesterol on the lipid composition of liver, plasma and red cells of guinea pigs, of the pathological changes of tissues and of hematological parameters was studied. The purpose was to identify the primary injury and so to contribute to the eludication of the mechanism(s) for the development of the hemolytic anemia observed in this species after long-term cholesterol supplementation. The results showed that the initial effects observed within 1 week occur in the liver lipids and histology accompanied by changes in plasma and RBC lipids. These events were followed by further, slower increases of tissue lipids without major qualitative changes. The earliest signs of an anemia were observed between weeks 5 and 7. We conclude that the primary insult of cholesterol is liver damage leading to the production of abnormal plasma lipoproteins which in turn cause a net increase of RBC-cholesterol that is accompanied by their morphological abnormalities. The hemolytic anemia does not seem to be caused directly by either the altered composition of RBC nor their altered morphology.