Observing the primary steps of ion solvation in helium droplets.

Solvation is a ubiquitous phenomenon in the natural sciences. At the macroscopic level, it is well understood through thermodynamics and chemical reaction kinetics1,2. At the atomic level, the primary steps of solvation are the attraction and binding of individual molecules or atoms of a solvent to molecules or ions of a solute1. These steps have, however, never been observed in real time. Here we instantly create a single sodium ion at the surface of a liquid helium nanodroplet3,4, and measure the number of solvent atoms that successively attach to the ion as a function of time. We found that the binding dynamics of the first five helium atoms is well described by a Poissonian process with a binding rate of 2.0 atoms per picosecond. This rate is consistent with time-dependent density-functional-theory simulations of the solvation process. Furthermore, our measurements enable an estimate of the energy removed from the region around the sodium ion as a function of time, revealing that half of the total solvation energy is dissipated after four picoseconds. Our experimental method opens possibilities for benchmarking theoretical models of ion solvation and for time-resolved measurements of cation-molecule complex formation.

Effects of anti-CD20 therapy on circulating and intrathecal follicular helper T cell subsets in multiple sclerosis.

Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25- Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25- Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25- Tfh cells, and the frequency of CSF CD25- Tfh cells. The study suggests that CD25- Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.

Neoehrlichiosis associated with ocrelizumab in a patient with multiple sclerosis: A case report.

OBJECTIVE: To describe a case of neoehrlichiosis, an emerging opportunistic tick-borne infection, in a patient with multiple sclerosis (MS) treated with ocrelizumab. METHODS: This is a case study. RESULTS: Our patient developed clinical infection over several months while on ocrelizumab and was ultimately diagnosed with neoehrlichiosis, caused by the bacteria Neoehrlichia mikurensis. Resolution of symptoms began within a few days after the initiation of antibiotic treatment. CONCLUSION: We describe the first probable case of ocrelizumab-associated neoehrlichiosis in a patient with MS. Clinicians should be aware of this potentially debilitating and life-threatening infection in patients receiving CD20-depleting therapy.

Extended interval dosing with ocrelizumab in multiple sclerosis.

BACKGROUND: This study investigates clinical and biomarker differences between standard interval dosing (SID) and extended interval dosing (EID) of ocrelizumab therapy in multiple sclerosis (MS). METHODS: This is a prospective, double-arm, open-label, multi-center study in Denmark. Participants diagnosed with MS on ocrelizumab therapy >12 months were included (n = 184). Clinical, radiological, and blood-based biomarker outcomes were evaluated. MRI disease activity, relapses, worsening of neurostatus, and No Evidence of Disease Activity-3 (NEDA-3) were used as a combined endpoint. RESULTS: Out of 184 participants, 107 participants received EID (58.2%), whereas 77 participants received SID (41.8%). The average extension was 9 weeks with a maximum of 78 weeks. When comparing EID to SID, we found higher levels of B-cells, lower serum concentrations of ocrelizumab, and similar levels of age-adjusted NFL and GFAP in the two groups. No difference in NEDA-3 between EID and SID was demonstrated (hazard ratio: 1.174, p = 0.69). Higher levels of NFL were identified in participants with disease activity. Body mass index correlated with levels of ocrelizumab and B-cells. CONCLUSION: Extending one treatment interval of ocrelizumab on average 9 weeks and up to 78 weeks did not result in clinical, radiological, or biomarker evidence of worsening compared with SID.

Predicting Individual Hearing-Aid Preference From Self-Reported Listening Experiences in Daily Life.

OBJECTIVES: The study compared the utility of two approaches for collecting real-world listening experiences to predict hearing-aid preference: a retrospective questionnaire (Speech, Spatial, and Qualities of Hearing Scale [SSQ]) and in-situ Ecological Momentary Assessment (EMA). The rationale being that each approach likely provides different and yet complementary information. In addition, it was examined how self-reported listening activity and hearing-aid data-logging can augment EMAs for individualized and contextualized hearing outcome assessments. DESIGN: Experienced hearing-aid users (N = 40) with mild-to-moderate symmetrical sensorineural hearing loss completed the SSQ questionnaire and gave repeated EMAs for two wear periods of 2-weeks each with two different hearing-aid models that differed mainly in their noise reduction technology. The EMAs were linked to a self-reported listening activity and sound environment parameters (from hearing-aid data-logging) recorded at the time of EMA completion. Wear order was randomized by hearing-aid model. Linear mixed-effects models and Random Forest models with five-fold cross-validation were used to assess the statistical associations between listening experiences and end-of-trial preferences, and to evaluate how accurately EMAs predicted preference within individuals. RESULTS: Only 6 of the 49 SSQ items significantly discriminated between responses made for the end-of-trial preferred versus nonpreferred hearing-aid model. For the EMAs, questions related to perception of the sound from the hearing aids were all significantly associated with preference, and these associations were strongest in EMAs completed in sound environments with predominantly low SNR and listening activities related to television, people talking, nonspecific listening, and music listening. Mean differences in listening experiences from SSQ and EMA correctly predicted preference in 71.8% and 72.5% of included participants, respectively. However, a prognostic classification of single EMAs into end-of-trial preference with a Random Forest model achieved a 93.8% accuracy when contextual information was included. CONCLUSIONS: SSQ and EMA predicted preference equally well when considering mean differences, however, EMAs had a high prognostic classifications accuracy due to the repeated-measures nature, which make them ideal for individualized hearing outcome investigations, especially when responses are combined with contextual information about the sound environment.

Neoehrlichia mikurensis-An emerging opportunistic tick-borne infection in immunosuppressed patients.

BACKGROUND: Neoehrlichia mikurensis (N. mikurensis) is a newly discovered tick-borne pathogen that can inflict life-threatening illness in immunocompromised patients. N. mikurensis infection is only detectable by polymerase chain reaction (PCR)-based methodologies. We describe three distinct clinical manifestations of N. mikurensis infection (neoehrlichiosis) in Danish patients receiving B-lymphocyte-depleting therapy, rituximab, for underlying hematological, rheumatological, or neurological disorders. All three patients went through a protracted pre-diagnostic period. METHODS: N. mikurensis DNA was detected and confirmed using two methods. Blood was tested by specific real-time PCR targeting the groEL gene and by 16S and 18S profiling followed by sequencing. Bone marrow was analyzed by 16S and 18S profiling. RESULTS: N. mikurensis was detected in blood samples in all three cases and in bone marrow from one of the three. The severity of the symptoms ranged from prolonged fever lasting more than 6 months to life-threatening hyperinflammation in the form of hemophagocytic lymphohistiocytosis (HLH). Interestingly, all patients presented with splenomegaly and two with hepatomegaly. After starting doxycycline therapy, symptoms were relieved within a few days, and biochemistry and organomegaly quickly normalized. CONCLUSION: We present three Danish patients recognized by the same clinician over a period of 6 months, strongly suggesting that many cases are going unrecognized. Second, we describe the first case of N. mikurensis-induced HLH and emphasize the potential severity of undetected neoehrlichiosis.

Implementation of a coagulation component into a phosphate kinetics model in haemodialysis therapy: A tool for detection of clotting problems?

A coagulation component should be considered in phosphate kinetics modelling because intradialytic coagulation of the extracorporeal circuit and dialyser might reduce phosphate removal in haemodialysis. Thus, the objective of this study was to add and evaluate coagulation as an individual linear clearance reduction component to a promising three-compartment model assuming progressive intradialytic clotting. The model was modified and validated on intradialytic plasma and dialysate phosphate samples from 12 haemodialysis patients collected during two treatments (HD1 and HD2) at a Danish hospital ward. The most suitable clearance reduction in each treatment was identified by minimizing the root mean square error (RMSE). The model simulations with and without clearance reduction were compared based on RMSE and coefficient of determination (R2 ) values. Improvements were found for 17 of the 24 model simulations when clearance reduction was added to the model. The slopes of the clearance reduction were in the range of 0.011-0.632/h. Three improvements were found to be statistically significant (|observed z value| > 1.96). A very significant correlation (R2  = 0.708) between the slopes for HD1 and HD2 was found. Adding the clearance reduction component to the model seems promising in phosphate kinetics modelling and might be explained, at least in part, by intradialytic coagulation. In future studies, the model might be developed further to serve as a potentially useful tool for the quantitative detection of clotting problems in haemodialysis. NEW FINDINGS: What is the central question of this study? The aim was to add an intradialytic coagulation component to a modified version of a promising three-compartment phosphate kinetics model. The hypothesis was that circuit and dialyser clotting can be modelled by an individual linear phosphate clearance reduction component during haemodialysis treatment. What is the main finding and its importance? Improvements were found for 17 of 24 model simulations when clearance reduction was added to the model. Thus, the kinetics model seems promising and could be a useful tool for the quantitative detection of clotting problems in haemodialysis patients.

Linking lesions in sensorimotor cortex to contralateral hand function in multiple sclerosis: a 7†T MRI study.

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially.

Modeling pulse wave velocity trajectories-challenges, opportunities, and pitfalls.

In this commentary, we discuss the analysis of trajectories of pulse wave velocity in a longitudinal cohort study of children with chronic kidney disease (the Cardiovascular Comorbidity in Children with Chronic Kidney Disease - Transplantation study). We revisit the analysis made by the study authors and unravel some additional limitations. We also reevaluate the implicit assumptions that were made in the chosen analysis and suggest extensions of the basic linear mixed model to obtain more differentiated answers to research questions in nephrology.

Osteoprotegerin predicts cardiovascular events in patients treated with haemodialysis.

BACKGROUND: Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers and the association with inflammatory cytokines and cardiovascular (CV) outcomes. METHODS: This prospective study enrolled haemodialysis patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1, fibroblast growth factor 23, leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest (RF) algorithm. The association between bone-associated proteins with all-cause death, CV death and CVEs was analysed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data and dialysis duration. RESULTS: We enrolled 331 patients [63.7% men; mean age, 65 years (standard deviation 14.6)] in a prospective cohort study with 5 years of follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death and four biomarkers were associated with CVEs. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins and only OPG remained associated with CVEs in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVEs in integrated discrimination improvement and net reclassification improvement analyses. CONCLUSIONS: OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD and CTSL1) was affected by cytokine inflammation activity.

Are fatty acids associated with disease activity and biomarkers in patients with psoriatic arthritis? Data from a multicenter clinical trial.

The pathogenesis of psoriatic arthritis (PsA) involves inflammation and bone and soft tissue turnover. Dietary fatty acids have previously been associated with pro-inflammatory effects induced by saturated fatty acids (SFA) and anti-inflammatory effects achieved by at least some polyunsaturated fatty acids (PUFA). The aim of the study was to investigate the correlations between the content of fatty acids in granulocytes and clinical and biochemical markers of PsA. A total of 140 patients with PsA were included. Skin and joint disease activity were assessed. Fatty acid composition in granulocytes was determined by gas chromatography. Competitive enzyme-linked immunosorbent assays were used to assess bone and soft tissue turnover. The content of SFA, n-6 PUFA or n-3 PUFA in granulocytes was not associated with disease activity. Marine n-3 PUFA was significantly positively correlated with collagen degradation. In contrast, n-6 PUFA was significantly positively correlated with collagen formation and negatively correlated with collagen degradation. However, the correlations were all weak. No association was found between the content of fatty acids in granulocytes and disease activity in this population of patients with PsA. The correlation between fatty acids and biomarkers of bone and soft tissue turnover needs further investigation.

Investigating the Provision and Context of Use of Hearing Aid Listening Programs From Real-world Data: Observational Study.

BACKGROUND: Listening programs enable hearing aid (HA) users to change device settings for specific listening situations and thereby personalize their listening experience. However, investigations into real-world use of such listening programs to support clinical decisions and evaluate the success of HA treatment are lacking. OBJECTIVE: We aimed to investigate the provision of listening programs among a large group of in-market HA users and the context in which the programs are typically used. METHODS: First, we analyzed how many and which programs were provided to 32,336 in-market HA users. Second, we explored 332,271 program selections from 1312 selected users to investigate the sound environments in which specific programs were used and whether such environments reflect the listening intent conveyed by the name of the used program. Our analysis was based on real-world longitudinal data logged by smartphone-connected HAs. RESULTS: In our sample, 57.71% (18,663/32,336) of the HA users had programs for specific listening situations, which is a higher proportion than previously reported, most likely because of the inclusion criteria. On the basis of association rule mining, we identified a primary additional listening program, Speech in Noise, which is frequent among users and often provided when other additional programs are also provided. We also identified 2 secondary additional programs (Comfort and Music), which are frequent among users who get ≥3 programs and usually provided in combination with Speech in Noise. In addition, 2 programs (TV and Remote Mic) were related to the use of external accessories and not found to be associated with other programs. On average, users selected Speech in Noise, Comfort, and Music in louder, noisier, and less-modulated (all P<.01) environments compared with the environment in which they selected the default program, General. The difference from the sound environment in which they selected General was significantly larger in the minutes following program selection than in the minutes preceding it. CONCLUSIONS: This study provides a deeper insight into the provision of listening programs on a large scale and demonstrates that additional listening programs are used as intended and according to the sound environment conveyed by the program name.

Acute posterior multifocal placoid pigment epitheliopathy resembling multiple sclerosis.

A 23-year-old man presented with right eye blurred vision; he was diagnosed with acute posterior multifocal placoid pigment epitheliopathy (APMPPE), and his symptoms resolved with prednisolone. Two months later, he developed a right arm weakness that resolved after 3 weeks. MR scan of brain identified changes suggesting multiple sclerosis, with four hyperintense FLAIR lesions; there was contrast enhancement of two lesions and no diffusion restriction. Cerebrospinal fluid showed mononuclear pleocytosis. We eventually diagnosed these as APMPPE-associated CNS lesions. APMPPE is a rare inflammatory chorioretinopathy that rarely can resemble multiple sclerosis clinically and radiologically.

Exploring the effects of oily fish consumption on measures of acute and long-term stress in healthy 8-9-year-old children: the FiSK Junior randomised trial.

Long-chain n-3 PUFA (n-3 LCPUFA) are known to reduce blood pressure (BP), heart rate and vagal tone, but potential stress-mitigating effects of n-3 LCPUFA are not well investigated. We explored the effects of oily fish consumption on long-term stress and the stress response in schoolchildren. Healthy 8-9-year-old children were randomised to receive about 300 g/week of oily fish or poultry for 12 weeks (199 randomised, 197 completing). At baseline and endpoint, we measured erythrocyte n-3 LCPUFA, hair cortisol and the response to a 1-min cold pressor test (CPT) on saliva cortisol, BP and continuous electrocardiogram recordings. Post-intervention hair cortisol did not differ between the groups, but sex-specificity was indicated (Psex × group = 0·074, boys: -0·9 (95 % CI -2·9, 1·0) ng/g, girls: 0·7 (95 % CI -0·2, 1·6) ng/g). Children in the fish group tended to be less prone to terminate CPT prematurely (OR 0·20 (95 % CI 0·02, 1·04)). Mean heart beat interval during CPT was 18·2 (95 % CI 0·3, 36·6) ms longer and high frequency power increased (159 (95 % CI 29, 289) ms2) in the fish v. poultry group. The cardiac autonomic response in the 10 min following CPT was characterised by a sympathetic peak followed by a parasympathetic peak, which was most pronounced in the fish group. This exploratory study does not support a strong effect of oily fish consumption on stress but indicates that oily fish consumption may increase vagal cardiac tone during the physiological response to CPT. These results warrant further investigation.

Effect of n-3 PUFA on extracellular matrix protein turnover in patients with psoriatic arthritis: a randomized, double-blind, placebo-controlled trial.

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by involvement of skin, axial and peripheral skeleton. An altered balance between extracellular matrix (ECM) formation and breakdown is a key event in PsA, and changes in ECM protein metabolites may provide insight to tissue changes. Dietary fish oils (n-3 PUFA) might affect the inflammation driven tissue turnover. The aim was to evaluate ECM metabolites in patients with PsA compared to healthy individuals and investigate the effects of n-3 PUFA. The 24-week randomized, double-blind, placebo-controlled trial of PUFA included 142 patients with PsA. Fifty-seven healthy individuals were included for comparison. This study is a sub-study investigating biomarkers of tissue remodelling as secondary outcomes. Serum samples at baseline and 24 weeks and healthy individuals were obtained, while a panel of ECM metabolites reflecting bone and soft tissue turnover were measured by ELISAs: PRO-C1, PRO-C3, PRO-C4, C1M, C3M, C4M, CTX-I and Osteocalcin (OC). C1M, PRO-C3, PRO-C4 and C4M was found to be elevated in PsA patients compared to the healthy individuals (from 56 to 792%, all p < 0.0001), where no differences were found for OC, CTX-I, PRO-C1 and C3M. PRO-C3 was increased by 7% in patients receiving n-3 PUFA after 24 weeks compared to baseline levels (p = 0.002). None of the other biomarkers was changed with n-3 PUFA treatment. This indicates that tissue turnover is increased in PsA patients compared to healthy individuals, while n-3 PUFA treatment for 24 weeks did not have an effect on tissue turnover. Trial registration NCT01818804. Registered 27 March 2013-Completed 18 February 2016. https://clinicaltrials.gov/ct2/show/NCT01818804?term=NCT01818804&rank=1.

Arrhythmias in Patients on Maintenance Dialysis: A Cross-sectional Study.

RATIONALE & OBJECTIVE: Patients with kidney failure treated with maintenance dialysis experience a high rate of mortality, in part due to sudden cardiac death caused by arrhythmias. The prevalence of arrhythmias, including the subset that are clinically significant, is not well known. This study sought to estimate the prevalence of arrhythmias, characterize the pattern of arrhythmic events in relation to dialysis treatments, and identify associated clinical characteristics. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 152 patients with kidney failure treated with maintenance dialysis in Denmark. EXPOSURES: Dialysis treatment; clinical characteristics; cardiac output and preload defined using echocardiography. OUTCOMES: Prevalence and pattern of arrhythmias on 48-hour Holter monitoring; odds ratios for arrhythmias. ANALYTICAL APPROACH: Descriptive analysis of the prevalence of arrhythmias. Pattern of arrhythmias described using a repeated-measures negative binomial regression model. Associations between clinical characteristics and echocardiographic findings with arrhythmias were assessed using logistic regression. RESULTS: Among the 152 patients studied, 83.6% were treated with in-center dialysis; 10.5%, with home hemodialysis; and 5.9%, with peritoneal dialysis. Premature atrial and ventricular complexes were seen in nearly all patients and 41% had paroxysmal supraventricular tachycardia. Clinically significant arrhythmias included persistent atrial fibrillation observed among 8.6% of patients, paroxysmal atrial fibrillation among 3.9%, nonsustained ventricular tachycardia among 19.7%, bradycardia among 4.6%, advanced second-degree atrioventricular block among 1.3%, and third-degree atrioventricular block among 2.6%. Premature ventricular complexes were more common on dialysis days, while tachyarrhythmias were more often observed during dialysis and in the immediate postdialytic period. Older age (OR per 10 years older, 1.53; 95% CI, 1.15-2.03; P=0.003), elevated preload (OR, 4.02; 95% CI, 1.05-15.35; P=0.04), and lower cardiac output (OR per 1L/min greater, 0.66; 95% CI, 0.44-1.00; P=0.05) were independently associated with clinically significant arrhythmias. LIMITATIONS: Arrhythmia monitoring limited to 48 hours; small sample size; heterogeneous nature of the population, risk for residual confounding. CONCLUSIONS: Arrhythmias, including clinically significant abnormal rhythms, were common. Tachyarrhythmias were more frequent during dialysis and the immediate postdialytic period. The relevance of these findings to clinical outcomes requires additional study.

Application of Big Data to Support Evidence-Based Public Health Policy Decision-Making for Hearing.

Ideally, public health policies are formulated from scientific data; however, policy-specific data are often unavailable. Big data can generate ecologically-valid, high-quality scientific evidence, and therefore has the potential to change how public health policies are formulated. Here, we discuss the use of big data for developing evidence-based hearing health policies, using data collected and analyzed with a research prototype of a data repository known as EVOTION (EVidence-based management of hearing impairments: public health pOlicy-making based on fusing big data analytics and simulaTION), to illustrate our points. Data in the repository consist of audiometric clinical data, prospective real-world data collected from hearing aids and an app, and responses to questionnaires collected for research purposes. To date, we have used the platform and a synthetic dataset to model the estimated risk of noise-induced hearing loss and have shown novel evidence of ways in which external factors influence hearing aid usage patterns. We contend that this research prototype data repository illustrates the value of using big data for policy-making by providing high-quality evidence that could be used to formulate and evaluate the impact of hearing health care policies.

GPR15+ T cells are Th17 like, increased in smokers and associated with multiple sclerosis.

Smoking is a risk factor for the development and progression of multiple sclerosis (MS); however, the pathogenic effects of smoking are poorly understood. We studied the smoking-associated chemokine receptor-like molecule GPR15 in relation to relapsing-remitting MS (RRMS). Using microarray analyses and qPCR we found elevated GPR15 in blood cells from smokers, and increased GPR15 expression in RRMS. By flow cytometry we detected increased frequencies of GPR15 expressing T and B cells in smokers, but no difference between patients with RRMS and healthy controls. However, after cell culture with the autoantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein, frequencies of MBP-reactive and non-proliferating GPR15+CD4+ T cells were increased in patients with RRMS compared with healthy controls. GPR15+CD4+ T cells produced IL-17 and were enriched in the cerebrospinal fluid (CSF). Furthermore, in the CSF of patients with RRMS, GPR15+ T cells were associated with CCR6+CXCR3+/CCR6-CXCR3+ phenotypes and correlated positively with concentrations of the newly identified GPR15-ligand (GPR15L), myelin degradation and disability. In conclusion, we have identified a proinflammatory cell type linking smoking with pathogenic immune cell functions in RRMS.

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

BACKGROUND: Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. OBJECTIVE: To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. METHODS: CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). RESULTS: In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. CONCLUSION: These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Treatment of iron deficiency in patients with chronic kidney disease: A prospective observational study of iron isomaltoside (NIMO Scandinavia)
.

AIMS: Iron deficiency is common in patients with chronic kidney disease (CKD). Appropriate iron substitution is critical and intravenous iron is an established therapy for these patients. The objective of this study was to assess treatment routine, -effectiveness, and safety of iron isomaltoside (Monofer®, Pharma-cosmos A/S, Holbaek, Denmark) in CKD patients in clinical practice. MATERIALS AND METHODS: This was a prospective observational study conducted in predialysis CKD patients treated with iron isomaltoside according to the product label and to routine clinical care. RESULTS: The study included 108 patients with predialysis CKD: 22 were in stage 2 - 3, 41 in stage 4, and 45 in stage 5. The mean (standard deviation) age was 67 (15) years, and 55% of patients were male. The majority of patients (65%) received one iron isomaltoside treatment. In patients with a baseline Hb < 10 g/dL, the mean dose of iron isomaltoside in the study was lower than the estimated total iron requirement (567 mg versus 921 mg). A treatment response of Hb ≥ 1 g/dL was achieved in 16/28 (57%) of patients, and the mean post-treatment Hb level was 10.5 g/dL. The probability of retreatment did not correlate with dose, but no dose administered was > 1,000 mg. There were no serious adverse drug reactions. One non-serious adverse drug reaction - injection site discoloration - was reported, and the patient had an uneventful recovery. CONCLUSION: Iron isomaltoside shows a good effectiveness and safety profile in predialysis CKD patients. However, some patients did not receive adequate iron doses to allow for optimal correction of their iron deficiency anemia.