The fusion protein of wild-type canine distemper virus is a major determinant of persistent infection.

The wild-type A75/17 canine distemper virus (CDV) strain induces a persistent infection in the central nervous system but infects cell lines very inefficiently. In contrast, the genetically more distant Onderstepoort CDV vaccine strain (OP-CDV) induces extensive syncytia formation. Here, we investigated the roles of wild-type fusion (F(WT)) and attachment (H(WT)) proteins in Vero cells expressing, or not, the canine SLAM receptor by transfection experiments and by studying recombinants viruses expressing different combinations of wild-type and OP-CDV glycoproteins. We show that low fusogenicity is not due to a defect of the envelope proteins to reach the cell surface and that H(WT) determines persistent infection in a receptor-dependent manner, emphasizing the role of SLAM as a potent enhancer of fusogenicity. However, importantly, F(WT) reduced cell-to-cell fusion independently of the cell surface receptor, thus demonstrating that the fusion protein of the neurovirulent A75/17-CDV strain plays a key role in determining persistent infection.

Synergistic action of image-guided radiotherapy and androgen deprivation therapy.

The combined use of androgen deprivation therapy (ADT) and image-guided radiotherapy (IGRT) can improve overall survival in aggressive, localized prostate cancer. However, owing to the adverse effects of prolonged ADT, it is imperative to identify the patients who would benefit from this combined-modality therapy relative to the use of IGRT alone. Opportunities exist for more personalized approaches in treating aggressive, locally advanced prostate cancer. Biomarkers--such as disseminated tumour cells, circulating tumour cells, genomic signatures and molecular imaging techniques--could identify the patients who are at greatest risk for systemic metastases and who would benefit from the addition of systemic ADT. By contrast, when biomarkers of systemic disease are not present, treatment could proceed using local IGRT alone. The choice of drug, treatment duration and timing of ADT relative to IGRT could be predicated on these personalized approaches to prostate cancer medicine. These novel treatment intensification and reduction strategies could result in improved prostate-cancer-specific survival and overall survival, without incurring the added expense of metabolic syndrome and other adverse effects of ADT in all patients.

Use of antiarrhythmic drugs during ablation of persistent atrial fibrillation: observations from a large single-centre cohort

Catheter ablation of complex fractionated atrial electrograms (CFAE), also known as defragmentation ablation, may be considered for the treatment of persistent atrial fibrillation (AF) beyond pulmonary vein isolation (PVI). Concomitant antiarrhythmic drug (AAD) therapy is common, but the relevance of AAD administration and its optimal timing during ablation remain unclear. Therefore, we investigated the use and timing of AADs during defragmentation ablation and their possible implications for AF termination and ablation success in a large cohort of patients. Retrospectively, we included 200 consecutive patients (age: 61 ± 12 years, LA diameter: 47 ± 8 mm) with persistent AF (episode duration 47 ± 72 weeks) who underwent de novo ablation including CFAE ablation. In all patients, PVI was performed prior to CFAE ablation. The use and timing of AADs were registered. The follow-ups consisted of Holter ECGs and clinical visits. Termination of AF was achieved in 132 patients (66 %). Intraprocedural AADs were administered in 168/200 patients (84 %) 45 ± 27 min after completion of PVI. Amiodarone was used in the majority of the patients (160/168). The timing of AAD administration was predicted by the atrial fibrillation cycle length (AFCL). At follow-up, 88 patients (46 %) were free from atrial arrhythmia. Multivariate logistic regression analysis revealed that administration of AAD early after PVI, LA size, duration of AF history, sex and AFCL were predictors of AF termination. The administration of AAD and its timing were not predictive of outcome, and age was the sole independent predictor of AF recurrence. The administration of AAD during ablation was common in this large cohort of persistent AF patients. The choice to administer AAD therapy and the timing of the administration during ablation were influenced by AFCL, and these factors did not significantly influence the moderate single procedure success rate in this retrospective analysis.

Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success

BACKGROUND In the meantime, catheter ablation is widely used for the treatment of persistent atrial fibrillation (AF). There is a paucity of data about long-term outcomes. This study evaluates (1) 5-year single and multiple procedure success and (2) prognostic factors for arrhythmia recurrences after catheter ablation of persistent AF using the stepwise approach aiming at AF termination. METHODS AND RESULTS A total of 549 patients with persistent AF underwent de novo catheter ablation using the stepwise approach (2007-2009). A total of 493 patients were included (Holter ECGs ≥ every 6 months). Mean follow-up was 59 ± 16 months with 2.1 ± 1.1 procedures per patient. Single and multiple procedure success rates were 20.1% and 55.9%, respectively (80% off antiarrhythmic drug). Antiarrhythmic drug-free multiple procedure success was 46%. Long-term recurrences (n=171) were paroxysmal AF in 48 patients (28%) and persistent AF/atrial tachycardia in 123 patients (72%). Multivariable recurrent event analysis revealed the following factors favoring arrhythmia recurrence: failure to terminate AF during index procedure (hazard ratio [HR], 1.279; 95% confidence interval [CI], 1.093-1.497; P = 0.002), number of procedures (HR, 1.154; 95% CI, 1.051-1.267; P = 0.003), female sex (HR, 1.263; 95% CI, 1.027-1.553; P = 0.027), and the presence of structural heart disease (HR, 1.236; 95% CI, 1.003-1.524; P = 0.047). AF termination was correlated with a higher rate of consecutive procedures because of atrial tachycardia recurrences (P = 0.003; HR, 1.71; 95% CI, 1.20-2.43). CONCLUSIONS Catheter ablation of persistent AF using the stepwise approach provides limited long-term freedom of arrhythmias often requiring multiple procedures. AF termination, the number of procedures, sex, and the presence of structural heart disease correlate with outcome success. AF termination is associated with consecutive atrial tachycardia procedures.

Independent at heart: persistent association of altitude with ischaemic heart disease mortality after consideration of climate, topography and built environment.

BACKGROUND Living at higher altitude was dose-dependently associated with lower risk of ischaemic heart disease (IHD). Higher altitudes have different climatic, topographic and built environment properties than lowland regions. It is unclear whether these environmental factors mediate/confound the association between altitude and IHD. We examined how much of the altitude-IHD association is explained by variations in exposure at place of residence to sunshine, temperature, precipitation, aspect, slope and distance to main road. METHODS We included 4.2 million individuals aged 40-84 at baseline living in Switzerland at altitudes 195-2971 m above sea level (ie, full range of residence), providing 77 127 IHD deaths. Mortality data 2000-2008, sociodemographic/economic information and coordinates of residence were obtained from the Swiss National Cohort, a longitudinal, census-based record linkage study. Environment information was modelled to residence level using Weibull regression models. RESULTS In the model not adjusted for other environmental factors, IHD mortality linearly decreased with increasing altitude resulting in a lower risk (HR, 95% CI 0.67, 0.60 to 0.74) for those living >1500 m (vs<600 m). This association remained after adjustment for all other environmental factors 0.74 (0.66 to 0.82). CONCLUSIONS The benefit of living at higher altitude was only partially confounded by variations in climate, topography and built environment. Rather, physical environment factors appear to have an independent effect and may impact on cardiovascular health in a cumulative way. Inclusion of additional modifiable factors as well as individual information on traditional IHD risk factors in our combined environmental model could help to identify strategies for the reduction of inequalities in IHD mortality.

Length of the Mitral Isthmus But Not Anatomical Location of Ablation Line Predicts Bidirectional Mitral Isthmus Block in Patients Undergoing Catheter Ablation of Persistent Atrial Fibrillation: A Randomized Controlled Trial

INTRODUCTION Mitral isthmus (MI) ablation is an effective option in patients undergoing ablation for persistent atrial fibrillation (AF). Achieving bidirectional conduction block across the MI is challenging, and predictors of MI ablation success remain incompletely understood. We sought to determine the impact of anatomical location of the ablation line on the efficacy of MI ablation. METHODS AND RESULTS A total of 40 consecutive patients (87% male; 54 ± 10 years) undergoing stepwise AF ablation were included. MI ablation was performed in sinus rhythm. MI ablation was performed from the left inferior PV to either the posterior (group 1) or the anterolateral (group 2) mitral annulus depending on randomization. The length of the MI line (measured with the 3D mapping system) and the amplitude of the EGMs at 3 positions on the MI were measured in each patient. MI block was achieved in 14/19 (74%) patients in group 1 and 15/21 (71%) patients in group 2 (P = NS). Total MI radiofrequency time (18 ± 7 min vs. 17 ± 8 min; P = NS) was similar between groups. Patients with incomplete MI block had a longer MI length (34 ± 6 mm vs. 24 ± 5 mm; P < 0.001), a higher bipolar voltage along the MI (1.75 ± 0.74 mV vs. 1.05 ± 0.69 mV; P < 0.01), and a longer history of continuous AF (19 ± 17 months vs. 10 ± 10 months; P < 0.05). In multivariate analysis, decreased length of the MI was an independent predictor of successful MI block (OR 1.5; 95% CI 1.1-2.1; P < 0.05). CONCLUSIONS Increased length but not anatomical location of the MI predicts failure to achieve bidirectional MI block during ablation of persistent AF.

Postnatal persistent infection with classical Swine Fever virus and its immunological implications.

It is well established that trans-placental transmission of classical swine fever virus (CSFV) during mid-gestation can lead to persistently infected offspring. The aim of the present study was to evaluate the ability of CSFV to induce viral persistence upon early postnatal infection. Two litters of 10 piglets each were infected intranasally on the day of birth with low and moderate virulence CSFV isolates, respectively. During six weeks after postnatal infection, most of the piglets remained clinically healthy, despite persistent high virus titres in the serum. Importantly, these animals were unable to mount any detectable humoral and cellular immune response. At necropsy, the most prominent gross pathological lesion was a severe thymus atrophy. Four weeks after infection, PBMCs from the persistently infected seronegative piglets were unresponsive to both, specific CSFV and non-specific PHA stimulation in terms of IFN-γ-producing cells. These results suggested the development of a state of immunosuppression in these postnatally persistently infected pigs. However, IL-10 was undetectable in the sera of the persistently infected animals. Interestingly, CSFV-stimulated PBMCs from the persistently infected piglets produced IL-10. Nevertheless, despite the addition of the anti-IL-10 antibody in the PBMC culture from persistently infected piglets, the response of the IFN-γ producing cells was not restored. Therefore, other factors than IL-10 may be involved in the general suppression of the T-cell responses upon CSFV and mitogen activation. Interestingly, bone marrow immature granulocytes were increased and targeted by the virus in persistently infected piglets. Taken together, we provided the first data demonstrating the feasibility of CSFV in generating a postnatal persistent disease, which has not been shown for other members of the Pestivirus genus yet. Since serological methods are routinely used in CSFV surveillance, persistently infected pigs might go unnoticed. In addition to the epidemiological and economic significance of persistent CSFV infection, this model could be useful for understanding the mechanisms of viral persistence.

The spectrum of the non-rapid eye movement sleep electroencephalogram following total sleep deprivation is trait-like

The sleep electroencephalogram (EEG) spectrum is unique to an individual and stable across multiple baseline recordings. The aim of this study was to examine whether the sleep EEG spectrum exhibits the same stable characteristics after acute total sleep deprivation. Polysomnography (PSG) was recorded in 20 healthy adults across consecutive sleep periods. Three nights of baseline sleep [12 h time in bed (TIB)] following 12 h of wakefulness were interleaved with three nights of recovery sleep (12 h TIB) following 36 h of sustained wakefulness. Spectral analysis of the non-rapid eye movement (NREM) sleep EEG (C3LM derivation) was used to calculate power in 0.25 Hz frequency bins between 0.75 and 16.0 Hz. Intraclass correlation coefficients (ICCs) were calculated to assess stable individual differences for baseline and recovery night spectra separately and combined. ICCs were high across all frequencies for baseline and recovery and for baseline and recovery combined. These results show that the spectrum of the NREM sleep EEG is substantially different among individuals, highly stable within individuals and robust to an experimental challenge (i.e. sleep deprivation) known to have considerable impact on the NREM sleep EEG. These findings indicate that the NREM sleep EEG represents a trait.

A growth factor-induced, spatially organizing cytoskeletal module enables rapid and persistent fibroblast migration

Directional migration requires robust front/back polarity. We find that fibroblasts treated with platelet-derived growth factor (PDGF) and prepolarized by plating on a fibronectin line substrate exhibit persistent migration for hours. This does not occur in the absence of PDGF or on uniformly coated fibronectin substrates. Persistent migration arises from establishment of two functional modules at cell front and back. At the front, formation of a zone containing podosome-like structures (PLS) dynamically correlates with low RhoA and myosin activity and absence of a contractile lamella. At the back, myosin contractility specifically controls tail retraction with minimal crosstalk to the front module. The PLS zone is maintained in a dynamic steady state that preserves size and position relative to the cell front, allowing for long-term coordination of front and back modules. We propose that front/back uncoupling achieved by the PLS zone is crucial for persistent migration in the absence of directional cues.

Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis.

INTRODUCTION Despite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of treatments or their combinations are not well understood. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP) is the only psychotherapy that has been specifically designed for chronic depression and has been examined in an increasing number of trials against medications, alone or in combination. When several treatment alternatives are available for a certain condition, network meta-analysis (NMA) provides a powerful tool to examine their relative efficacy by combining all direct and indirect comparisons. Individual participant data (IPD) meta-analysis enables exploration of impacts of individual characteristics that lead to a differentiated approach matching treatments to specific subgroups of patients. METHODS AND ANALYSIS We will search for all randomised controlled trials that compared CBASP, pharmacotherapy or their combination, in the treatment of patients with persistent depressive disorder, in Cochrane CENTRAL, PUBMED, SCOPUS and PsycINFO, supplemented by personal contacts. Individual participant data will be sought from the principal investigators of all the identified trials. Our primary outcomes are depression severity as measured on a continuous observer-rated scale for depression, and dropouts for any reason as a proxy measure of overall treatment acceptability. We will conduct a one-step IPD-NMA to compare CBASP, medications and their combinations, and also carry out a meta-regression to identify their prognostic factors and effect moderators. The model will be fitted in OpenBUGS, using vague priors for all location parameters. For the heterogeneity we will use a half-normal prior on the SD. ETHICS AND DISSEMINATION This study requires no ethical approval. We will publish the findings in a peer-reviewed journal. The study results will contribute to more finely differentiated therapeutics for patients suffering from this chronically disabling disorder. TRIAL REGISTRATION NUMBER CRD42016035886.

The Effects of Heat Acclimation Followed by Sleep Deprivation on Perceived Exertion, Thirst, and Thermal Sensations in Exercising Males

Subjects were tested while walking on a tradmill for 11 days in a row at sub-maximal levels for 90 minutes the heat. After the 10th day, subjects were kept awake for 24 hours before being tested in a state of sleep deprivation on the 11th day. Subjects rated their perceived exertion, thirst levels, and thermal sensations at regular intervals before, during, and after exercise each day. The changes in RPE, thirst, and thermal sensations were examined to determine the progression of heat acclimation and to observe changes in the subjects' perceived workloads. While subjects were significantly less thirsty on day 10 than when beginning the study on day 1, no significant changes occured in regards to thermal sensations or RPE values. On the 11th day, these variables were again observed in order to examine the effects of sleep deprivation on the adaptations of heat acclimation. After 28 hours of sleep loss, subjects rated themselves as feeling significantly more thristy after exercise than they had on day 10, yet again there was no significant change in thermal sensations or RPE values. Throughout the study, RPE and thermal sensation ratings seemed to be closely linked while sensations of thirst fluctuated independently.