Transcutaneous ultrasound level check for selective dorsal rhizotomy.

AIM: Single-level selective dorsal rhizotomy (SDR) surgery requires an intra-operative level check to identify the L1 vertebral level or the conus medullaris. Typically, this requires a pre-operative or intra-operative x-ray. We present our experience using initial transcutaneous ultrasound as an alternative to x-ray level check. METHODS: A prospective SDR database was used to identify patients. The operation notes were reviewed to identify the level check method and any complications or wrong-level surgery. RESULTS: Data are reported for the first 160 SDR surgeries performed within our centre, mean age 6.47 years (range 2.5-19 years). The first 11 patients had combined x-ray and transcutaneous ultrasound for pre-incision level check. This allowed the neurosurgeon to assess the accuracy and feasibility of using transcutaneous ultrasound instead of x-ray. The subsequent 149 patients had ultrasound alone for transcutaneous pre-incision level check. An intra-operative ultrasound level check was performed for all patients following skin incision and dissection down to the spinal lamina. In this way, the conus level was confirmed before dural opening. For all patients at all ages, the combination of initial transcutaneous ultrasound followed by intra-operative ultrasound allowed accurate identification of the conus. There were no instances of wrong-level surgery. Learning points are presented within this paper. CONCLUSION: Combined use of transcutaneous ultrasound followed by intra-operative ultrasound can allow accurate identification of the conus, saving radiation exposure and potentially improving theatre efficiency. Appropriate training and experience are required for any neurosurgeon using these techniques.

Understanding Organisms Using Ecological Observatory Networks.

Human activities are rapidly changing ecosystems around the world. These changes have widespread implications for the preservation of biodiversity, agricultural productivity, prevalence of zoonotic diseases, and sociopolitical conflict. To understand and improve the predictive capacity for these and other biological phenomena, some scientists are now relying on observatory networks, which are often composed of systems of sensors, teams of field researchers, and databases of abiotic and biotic measurements across multiple temporal and spatial scales. One well-known example is NEON, the US-based National Ecological Observatory Network. Although NEON and similar networks have informed studies of population, community, and ecosystem ecology for years, they have been minimally used by organismal biologists. NEON provides organismal biologists, in particular those interested in NEON's focal taxa, with an unprecedented opportunity to study phenomena such as range expansions, disease epidemics, invasive species colonization, macrophysiology, and other biological processes that fundamentally involve organismal variation. Here, we use NEON as an exemplar of the promise of observatory networks for understanding the causes and consequences of morphological, behavioral, molecular, and physiological variation among individual organisms.

Repeated conditionally automated driving on the road: How do drivers leave the loop over time?

The goal of this on the road driving study was to investigate how drivers adapt their behavior when driving with conditional vehicle automation (SAE L3) on different occasions. Specifically, we focused on changes in how fast drivers took over control from automation and how their gaze off the road changed over time. On each of three consecutive days, 21 participants drove for 50 min, in a conditionally automated vehicle (Wizard of Oz methodology), on a typical German commuting highway. Over these rides the take-over behavior and gaze behavior were analyzed. The data show that drivers' reactions to non-critical, system initiated, take-overs took about 5.62 s and did not change within individual rides, but on average became 0.72 s faster over the three rides. After these self-paced take-over requests a final urgent take-over request was issued at the end of the third ride. In this scenario participants took over rapidly with an average of 5.28 s. This urgent take-over time was not found to be different from the self-paced take-over requests in the same ride. Regarding gaze behavior, participants' overall longest glance off the road and the percentage of time looked off the road increased within each ride, but stayed stable over the three rides. Taken together, our results suggest that drivers regularly leave the loop by gazing off the road, but multiple exposures to take-over situations in automated driving allow drivers to come back into loop faster.

Secondary metabolite biosynthetic diversity in the fungal family Hypoxylaceae and Xylaria hypoxylon.

To date little is known about the genetic background that drives the production and diversification of secondary metabolites in the Hypoxylaceae. With the recent availability of high-quality genome sequences for 13 representative species and one relative (Xylaria hypoxylon) we attempted to survey the diversity of biosynthetic pathways in these organisms to investigate their true potential as secondary metabolite producers. Manual search strategies based on the accumulated knowledge on biosynthesis in fungi enabled us to identify 783 biosynthetic pathways across 14 studied species, the majority of which were arranged in biosynthetic gene clusters (BGC). The similarity of BGCs was analysed with the BiG-SCAPE engine which organised the BGCs into 375 gene cluster families (GCF). Only ten GCFs were conserved across all of these fungi indicating that speciation is accompanied by changes in secondary metabolism. From the known compounds produced by the family members some can be directly correlated with identified BGCs which is highlighted herein by the azaphilone, dihydroxynaphthalene, tropolone, cytochalasan, terrequinone, terphenyl and brasilane pathways giving insights into the evolution and diversification of those compound classes. Vice versa, products of various BGCs can be predicted through homology analysis with known pathways from other fungi as shown for the identified ergot alkaloid, trigazaphilone, curvupallide, viridicatumtoxin and swainsonine BGCs. However, the majority of BGCs had no obvious links to known products from the Hypoxylaceae or other well-studied biosynthetic pathways from fungi. These findings highlight that the number of known compounds strongly underrepresents the biosynthetic potential in these fungi and that a tremendous number of unidentified secondary metabolites is still hidden. Moreover, with increasing numbers of genomes for further Hypoxylaceae species becoming available, the likelihood of revealing new biosynthetic pathways that encode new, potentially useful compounds will significantly improve. Reaching a better understanding of the biology of these producers, and further development of genetic methods for their manipulation, will be crucial to access their treasures.

Effects of increasing dietary inclusion of camelina cake on growth performance of growing-finishing pigs.

The objective of this experiment was to determine the dietary inclusion rate of camelina cake (CC) that would support the growth performance of growing-finishing pigs similar to that of a corn-soybean meal-based diet. Pigs (n = 192; BW = 35.2 kg; Duroc x (Yorkshire x Landrace)), balanced for sex and initial weight, were assigned to pens (8 pigs/pen) and pens were assigned randomly to one of four dietary treatments (6 pens/treatment). Treatments consisted of a non GMO corn-soybean meal control diet (CON), or CON containing 5% (5CC), 10% (10CC), or 15% (15CC) camelina cake. Feed disappearance on a pen basis and individual body weights of pigs were recorded every other week to calculate average daily gain (ADG), average daily feed intake (ADFI), and gain to feed ratio (G:F) on a pen basis. Prior to harvest, real-time ultrasonic measurements of back fat depth and loin eye area were collected on all live pigs. Pigs were harvested as a single group at about 23 weeks of age at a commercial abattoir. Data were analyzed using Proc Glimmix with dietary treatment as a fixed effect and pen serving as the experimental unit. Growth performance data collected over time were analyzed using repeated measures within the Proc Glimmix procedure. Overall, pigs fed CON exhibited similar ADG to those consuming 5CC and higher ADG than pigs consuming 10CC and 15CC diets (1.10 kg vs. 1.05 kg for 10CC and 1.02 kg for 15CC; P < 0.05 for both mean comparisons). Pigs fed CON consumed more feed than pigs fed any of the CC diets (ADFI = 2.66 kg for CON vs. 2.46 kg for 5CC, 2.46 kg for 10CC and 2.47 kg for 15CC; P < 0.05 for all). These differences resulted in heavier (P < 0.05) CON-fed pigs at marketing than 10CC or 15CC-fed pigs. There were no differences in any carcass traits analyzed. From these data, we conclude that feeding up to 5% CC in corn-soybean meal-based diets did not negatively influence growth performance, or carcass traits of growing-finishing pigs.

Keeping the driver in the loop through semi-automated or manual lane changes in conditionally automated driving.

In the current study we investigated if drivers of conditionally automated vehicles can be kept in the loop through lane change maneuvers. More specifically, we examined whether involving drivers in lane-changes during a conditionally automated ride can influence critical take-over behavior and keep drivers' gaze on the road. In a repeated measures driving simulator study (n = 85), drivers drove the same route three times, each trial containing four lane changes that were all either (1) automated, (2) semi-automated or (3) manual. Each ride ended with a critical take-over situation that could be solved by braking and/or steering. Critical take-over reactions were analyzed with a linear mixed model and parametric accelerated failure time survival analysis. As expected, semi-automated and manual lane changes throughout the ride led to 13.5% and 17.0% faster maximum deceleration compared to automated lane changes. Additionally, semi-automated and manual lane changes improved the quality of the take-over by significantly decreasing standard deviation of the steering wheel angle. Unexpectedly, drivers in the semi-automated condition were slowest to start the braking maneuver. This may have been caused by the drivers' confusion as to how the semi-automated system would react. Additionally, the percentage gaze off-the-road was significantly decreased by the semi-automated (6.0%) and manual (6.6%) lane changes. Taken together, the results suggest that semi-automated and manual transitions may be an alarm-free instrument which developers could use to help maintain drivers' perception-action loop and improve automated driving safety.

Unique Genetic and Histological Signatures of Mouse Pericardial Adipose Tissue.

Obesity is a major risk factor for a plethora of metabolic disturbances including diabetes and cardiovascular disease. Accumulating evidence is showing that there is an adipose tissue depot-dependent relationship with obesity-induced metabolic dysfunction. While some adipose depots, such as subcutaneous fat, are generally metabolically innocuous, others such as visceral fat, are directly deleterious. A lesser known visceral adipose depot is the pericardial adipose tissue depot. We therefore set out to examine its transcriptional and morphological signature under chow and high-fat fed conditions, in comparison with other adipose depots, using a mouse model. Our results revealed that under chow conditions pericardial adipose tissue has uncoupling-protein 1 gene expression levels which are significantly higher than classical subcutaneous and visceral adipose depots. We also observed that under high-fat diet conditions, the pericardial adipose depot exhibits greatly upregulated transcript levels of inflammatory cytokines. Our results collectively indicate, for the first time, that the pericardial adipose tissue possesses a unique transcriptional and histological signature which has features of both a beige (brown fat-like) but also pro-inflammatory depot, such as visceral fat. This unique profile may be involved in metabolic dysfunction associated with obesity.

Adverse respiratory outcomes following conventional long-course radiotherapy for non-small-cell lung cancer in patients with pre-existing pulmonary fibrosis: A comparative retrospective study.

INTRODUCTION: There is some evidence to suggest that patients with underlying pulmonary fibrosis (PF) have increased risk of adverse respiratory and survival outcomes, when treated with conventional, long-course radiotherapy (RT) for non-small-cell lung cancer (NSCLC). We performed a retrospective analysis to determine the size of these risks. METHODS: Data from 21 patients with PF (cases) were retrospectively analysed for respiratory toxicity and mortality outcomes, and compared with 84 patients without PF (non-cases). Age and mean lung dose were included as covariates in regression analyses. The additional predictive value of other patient, disease and treatment characteristics on radiation pneumonitis (RP) risk and severity was explored. RESULTS: There was a numerical (though not statistically significant) increase in grade ≥ 2 RP among PF cases (OR 2.74, P = 0.074). Cases were significantly more likely to discontinue radical treatment early (OR 6.10, P = 0.015). There was a significant association between increased RP severity and underlying PF (P = 0.039), with RP strongly implicated in the death in 3 of 21 cases (14.3%) compared to 1 non-case (1.2%). Cases experienced increased grade ≥ 2 respiratory toxicity otherwise (OR 4.35, P = 0.020) and poorer median overall survival (0.6 versus 1.7 years, P < 0.001). Two cases, and no non-cases, died during the proposed RT period. None of the analysed patient, disease or treatment factors, was a significant additional predictor of RP risk/severity. CONCLUSION: Patients with PF are at increased risk of treatment discontinuation, respiratory morbidity and mortality, and poor survival following conventional RT for NSCLC. Caution should be exercised when offering high-dose RT to these patients.

Early Induction of Cross-Reactive CD8+ T-Cell Responses in Tonsils After Live-Attenuated Influenza Vaccination in Children.

BACKGROUND: Live-attenuated influenza vaccine (LAIV) was licensed for prophylaxis of children 2-17 years old in Europe in 2012 and is administered as a nasal spray. Live-attenuated influenza vaccine induces both mucosal and systemic antibodies and systemic T-cell responses. Tonsils are the lymph nodes serving the upper respiratory tract, acting as both induction and effector site for mucosal immunity. METHODS: Here, we have studied the early tonsillar T-cell responses induced in children after LAIV. Thirty-nine children were immunized with trivalent LAIV (containing A/H1N1, A/H3N2, and B viruses) at days 3, 7, and 14 before tonsillectomy. Nonvaccinated controls were included for comparison. Tonsils and peripheral blood (pre- and postvaccination) were collected to study T-cell responses. RESULTS: Tonsillar and systemic T-cell responses differed between influenza strains, and both were found against H3N2 and B viruses, whereas only systemic responses were observed against A/H1N1. A significant increase in cross-reactive tonsillar CD8+ T cells recognizing conserved epitopes from a broad range of seasonal and pandemic viruses occurred at day 14. Tonsillar T cells showed significant cytokine responses (Th1, Th2, and granulocyte-macrophage colony-stimulating factor). CONCLUSIONS: Our findings support the use of LAIV in children to elicit broadly cross-reactive T cells, which are not induced by traditional inactivated influenza vaccines and may provide protection to novel virus strains.

Clueless forms dynamic, insulin-responsive bliss particles sensitive to stress.

Drosophila Clueless (Clu) is a ribonucleoprotein that directly affects mitochondrial function. Loss of clu causes mitochondrial damage, and Clu associates with proteins on the mitochondrial outer membrane. Clu's subcellular pattern is diffuse throughout the cytoplasm, but Clu also forms large mitochondria-associated particles. Clu particles are reminiscent of ribonucleoprotein particles such as stress granules and processing bodies. Ribonucleoprotein particles play critical roles in the cell by regulating mRNAs spatially and temporally. Here, we show that Clu particles are unique, highly dynamic and rapidly disperse in response to stress in contrast to processing bodies and autophagosomes. In addition, Clu particle formation is dependent on diet as ovaries from starved females no longer contain Clu particles, and insulin signaling is necessary and sufficient for Clu particle formation. Oxidative stress also disperses particles. Since Clu particles are only present under optimal conditions, we have termed them "bliss particles". We also demonstrate that many aspects of Clu function are conserved in the yeast homolog Clu1p. These observations identify Clu particles as stress-sensitive cytoplasmic particles whose absence corresponds with altered cell stress and mitochondrial localization.

Reduction of fibrillar strain-rate sensitivity in steroid-induced osteoporosis linked to changes in mineralized fibrillar nanostructure.

As bone is used in a dynamic mechanical environment, understanding the structural origins of its time-dependent mechanical behaviour - and the alterations in metabolic bone disease - is of interest. However, at the scale of the mineralized fibrillar matrix (nanometre-level), the nature of the strain-rate dependent mechanics is incompletely understood. Here, we investigate the fibrillar- and mineral-deformation behaviour in a murine model of Cushing's syndrome, used to understand steroid induced osteoporosis, using synchrotron small- and wide-angle scattering/diffraction combined with in situ tensile testing at three strain rates ranging from 10-4 to 10-1 s-1. We find that the effective fibril- and mineral-modulus and fibrillar-reorientation show no significant increase with strain-rate in osteoporotic bone, but increase significantly in normal (wild-type) bone. By applying a fibril-lamellar two-level structural model of bone matrix deformation to fit the results, we obtain indications that altered collagen-mineral interactions at the nanoscale - along with altered fibrillar orientation distributions - may be the underlying reason for this altered strain-rate sensitivity. Our results suggest that an altered strain-rate sensitivity of the bone matrix in osteoporosis may be one of the contributing factors to reduced mechanical competence in such metabolic bone disorders, and that increasing this sensitivity may improve biomechanical performance.

Disparities in the management of paediatric splenic injury.

BACKGROUND: The non-operative management of splenic injury in children is recommended widely, and is possible in over 95 per cent of episodes. Practice appears to vary between centres. METHODS: The Trauma Audit and Research Network (TARN) database was interrogated to determine the management of isolated paediatric splenic injuries in hospitals in England and Wales. Rates of non-operative management, duration of hospital stay, readmission and mortality were recorded. Management in paediatric surgical hospitals was compared with that in adult hospitals. RESULTS: Between January 2000 and December 2015 there were 574 episodes. Children treated in a paediatric surgical hospital had a 95·7 per cent rate of non-operative management, compared with 75·5 per cent in an adult hospital (P < 0·001). Splenectomy was done in 2·3 per cent of children in hospitals with a paediatric surgeon and in 17·2 per cent of those treated in an adult hospital (P < 0·001). There was a significant difference in the rate of non-operative management in children of all ages. There was some improvement in non-operative management in adult hospitals in the later part of the study, but significant ongoing differences remained. CONCLUSION: The management of children with isolated splenic injury is different depending on where they are treated. The rate of non-operative management is lower in hospitals without a paediatric surgeon present.

Zoledronic acid in the management of mesothelioma - a feasibility study (Zol-A Trial): study protocol for a randomised controlled trial.

BACKGROUND: Nitrogen containing bisphosphonates such as zoledronic acid (ZA) are known to contain certain anti-cancer properties. These have been investigated in the past in various cancers such as breast, prostate and colon. ZA in particular has shown promising results in pre-clinical studies. We propose a multicentre double-blind randomised controlled feasibility study to assess the recruitment and acceptability of ZA/placebo alongside chemotherapy in malignant pleural mesothelioma (MPM). METHODS: Patients will be recruited for a 13-month period from October 2016 to November 2017. Eligible patients will be identified via the regional mesothelioma multidisciplinary team meeting. Those who receive chemotherapy will be randomised to receive either ZA or placebo alongside their chemotherapy. Those who decline chemotherapy will be offered to join the trial on the non-randomised open-labelled arm of the trial. Patients will receive a maximum of six cycles of ZA/placebo, at three-weekly cycles. All patients will be followed up for six months from randomisation. Semi-structured interviews to gather data on acceptability of trial procedures, tolerability of ZA and other relevant information will take place after the participants have completed their six cycles of treatment. For a better understanding about non-participation in mesothelioma trials we also aim to interview those who decline to take part in the trial. DISCUSSION: The qualitative and quantitative data gathered in this feasibility trial will hopefully pave the way to designing a robust full phase III trial to investigate the potential synergistic effect of ZA and current standard treatment for MPM, cisplatin-pemetrexed combination chemotherapy. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN45536692 . Registered on 9 August 2016. EudraCT no. 2015-004433-26.

Bone matrix development in steroid-induced osteoporosis is associated with a consistently reduced fibrillar stiffness linked to altered bone mineral quality.

Glucocorticoid-induced osteoporosis (GIOP) is a major secondary form of osteoporosis, with the fracture risk significantly elevated - at similar levels of bone mineral density - in patients taking glucocorticoids compared with non-users. The adverse bone structural changes at multiple hierarchical levels in GIOP, and their mechanistic consequences leading to reduced load-bearing capacity, are not clearly understood. Here we combine experimental X-ray nanoscale mechanical imaging with analytical modelling of the bone matrix mechanics to determine mechanisms causing bone material quality deterioration during development of GIOP. In situ synchrotron small-angle X-ray diffraction combined with tensile testing was used to measure nanoscale deformation mechanisms in a murine model of GIOP, due to a corticotrophin-releasing hormone promoter mutation, at multiple ages (8-, 12-, 24- and 36 weeks), complemented by quantitative micro-computed tomography and backscattered electron imaging to determine mineral concentrations. We develop a two-level hierarchical model of the bone matrix (mineralized fibril and lamella) to predict fibrillar mechanical response as a function of architectural parameters of the mineralized matrix. The fibrillar elastic modulus of GIOP-bone is lower than healthy bone throughout development, and nearly constant in time, in contrast to the progressively increasing stiffness in healthy bone. The lower mineral platelet aspect ratio value for GIOP compared to healthy bone in the multiscale model can explain the fibrillar deformation. Consistent with this result, independent measurement of mineral platelet lengths from wide-angle X-ray diffraction finds a shorter mineral platelet length in GIOP. Our results show how lowered mineralization combined with altered mineral nanostructure in GIOP leads to lowered mechanical competence. SIGNIFICANCE STATEMENT: Increased fragility in musculoskeletal disorders like osteoporosis are believed to arise due to alterations in bone structure at multiple length-scales from the organ down to the supramolecular-level, where collagen molecules and elongated mineral nanoparticles form stiff fibrils. However, the nature of these molecular-level alterations are not known. Here we used X-ray scattering to determine both how bone fibrils deform in secondary osteoporosis, as well as how the fibril orientation and mineral nanoparticle structure changes. We found that osteoporotic fibrils become less stiff both because the mineral nanoparticles became shorter and less efficient at transferring load from collagen, and because the fibrils are more randomly oriented. These results will help in the design of new composite musculoskeletal implants for bone repair.

Impact of erythrocyte species on assays for influenza serology.

The influenza viruses have the ability to agglutinate erythrocytes by binding to sialic acid receptors on the host cell. Human influenza viruses preferentially bind to sialic acid linked to galactose by α 2.6 linkage, while avian influenza viruses preferentially bind to sialic acid linked to Gal by α 2.3 linkage. There is a close correlation between the ability of influenza A viruses to agglutinate erythrocytes from different animal species and their receptor specificity. The haemagglutination and haemagglutination inhibition assays are influenced by the species of erythrocytes. To provide an overview of the expression of sialic acid receptors on different erythrocytes, avian (turkey, chicken, pigeon) and mammalian (sheep, horse, human) species have been analysed by flow cytometry. Chicken, turkey and human erythrocytes display both types of linkages. Horse and sheep erythrocytes show almost exclusively α 2.3 Gal linkages, while pigeon erythrocytes express almost exclusively α 2.6 Gal linkages. The erythrocytes from the same avian and mammalian species have been evaluated by haemagglutination and haemagglutination inhibition assays with seasonal and avian strains. Chicken and turkey erythrocytes seem to be the most appropriate for both assays with seasonal influenza strains, in addition to pigeon erythrocytes, particularly for the B strains. In the case of the avian strain, chicken erythrocytes are suitable for haemagglutination assay and horse erythrocytes for haemagglutination inhibition assay. The choice of erythrocytes has a significant impact on the titres measured by both assays.

Effectiveness of different corn dried distillers grains with solubles feeding strategies and increasing the time intervals between the second Improvest dose and slaughter of immunologically castrated pigs on belly and pork fat quality.

Effects of dried distillers grains with solubles (DDGS) feeding strategies (a corn-soybean meal (CS) fed continously; CS+40% DDGS fed continously; CS+40, 30, 20, or 10% DDGS in 4 phases, respectively; or CS+40% DDGS in phases 1 to 3 and CS in phase 4 before slaughter) on belly and pork fat quality of immunologically castrated (n=192) pigs were evaluated. All pigs received the first Improvest dose at 11week of age, and the second dose at 9, 7, or 5week before slaughter at 24week of age. Increasing the time interval of the second Improvest dose before slaughter reduced IV in all fat depots and increased belly thickness. Gradually decreasing dietary DDGS and DDGS withdrawal feeding strategies reduced IV in all fat depots. Calculated IV were greater using the Meadus et al. (2010) equation compared with using the AOCS (1998) equation because it includes more long-chain unsaturated fatty acids.

NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice.

Nicotinamide nucleotide transhydrogenase, NNT, is a ubiquitous protein of the inner mitochondrial membrane with a key role in mitochondrial redox balance. NNT produces high concentrations of NADPH for detoxification of reactive oxygen species by glutathione and thioredoxin pathways. In humans, NNT dysfunction leads to an adrenal-specific disorder, glucocorticoid deficiency. Certain substrains of C57BL/6 mice contain a spontaneously occurring inactivating Nnt mutation and display glucocorticoid deficiency along with glucose intolerance and reduced insulin secretion. To understand the underlying mechanism(s) behind the glucocorticoid deficiency, we performed comprehensive RNA-seq on adrenals from wild-type (C57BL/6N), mutant (C57BL/6J) and BAC transgenic mice overexpressing Nnt (C57BL/6JBAC). The following results were obtained. Our data suggest that Nnt deletion (or overexpression) reduces adrenal steroidogenic output by decreasing the expression of crucial, mitochondrial antioxidant (Prdx3 and Txnrd2) and steroidogenic (Cyp11a1) enzymes. Pathway analysis also revealed upregulation of heat shock protein machinery and haemoglobins possibly in response to the oxidative stress initiated by NNT ablation. In conclusion, using transcriptomic profiling in adrenals from three mouse models, we showed that disturbances in adrenal redox homeostasis are mediated not only by under expression of NNT but also by its overexpression. Further, we demonstrated that both under expression or overexpression of NNT reduced corticosterone output implying a central role for it in the control of steroidogenesis. This is likely due to a reduction in the expression of a key steroidogenic enzyme, Cyp11a1, which mirrored the reduction in corticosterone output.

Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy.

BACKGROUND AND PURPOSE: We have previously shown that patients with multiple sclerosis receiving immunomodulatory treatment have reduced seroprotection rates after influenza immunization. The aim of this study was to further investigate the influence of immunomodulatory therapies on the antibody response and seroprotection rates in patients immunized with seasonal influenza vaccine in 2012/2013 compared with healthy controls. METHODS: Ninety patients receiving fingolimod, glatiramer acetate, interferon beta-1a/1b, natalizumab or no therapy were compared with 62 healthy controls. All subjects received the inactivated split virus vaccine in 2012 and serum samples were collected pre-vaccination and 3, 6 and 12 months post-vaccination. The vaccine responses were evaluated by the hemagglutination inhibition assay and adjusted for age and gender. RESULTS: No significant differences in rates of protection against H1N1 for interferon beta-1a/1b and glatiramer acetate were observed as compared with controls at 3, 6 and 12 months. Fingolimod provided reduced protection at all time points post-vaccination, whereas natalizumab displayed reduced protection at 3 and 6 months. Patients without immunomodulation did not display protection rates that were significantly different from the controls at 3 and 12 months. CONCLUSION: These findings suggest that patients with multiple sclerosis receiving fingolimod or natalizumab should be considered for a second dose of the vaccine in cases of insufficient protection. Our results further indicate that new immunomodulatory treatment regimens should be systematically evaluated for their influence on influenza-specific vaccine responses.