Nearest-neighbor directed random hyperbolic graphs.

Undirected hyperbolic graph models have been extensively used as models of scale-free small-world networks with high clustering coefficient. Here we presented a simple directed hyperbolic model where nodes randomly distributed on a hyperbolic disk are connected to a fixed number m of their nearest spatial neighbors. We introduce also a canonical version of this network (which we call "network with varied connection radius"), where maximal length of outgoing bond is space dependent and is determined by fixing the average out-degree to m. We study local bond length, in-degree, and reciprocity in these networks as a function of spacial coordinates of the nodes and show that the network has a distinct core-periphery structure. We show that for small densities of nodes the overall in-degree has a truncated power-law distribution. We demonstrate that reciprocity of the network can be regulated by adjusting an additional temperature-like parameter without changing other global properties of the network.

Telehealth mitigates COPD disease progression compared to standard of care: a randomized controlled crossover trial.

BACKGROUND: We showed excellent adherence and satisfaction with our telehealth care (TC) approach for COPD. Here, the results of a consecutive randomized controlled trial are presented. METHODS: Patients were randomly assigned to TC or standard care (SC). During TC, patients answered six daily questions online, and focused on the early recognition of exacerbations, in addition to SC. RESULTS: The mean increase in COPD assessment test (CAT) was 1.8 vs. 3.6 points/year in the TC and SC groups, respectively (P = 0.0015). Satisfaction with care (VAS) at baseline was 8.2; at the end of SC, 8.5 (P = 0.062); and after TC, 8.8 (P < 0.001). We detected significantly more moderate exacerbations during TC. CONCLUSION: Whilst receiving TC, the slope of the CAT increase - an indicator of the naturally progressive course of COPD - was reduced by 50%. Satisfaction with care increased with TC. The higher number of detected moderate exacerbations probably indicates a higher diagnostic sensitivity than without TC.

Many-body contacts in fractal polymer chains and fractional Brownian trajectories.

We calculate the probabilities that a trajectory of a fractional Brownian motion with arbitrary fractal dimension d_{f} visits the same spot n≥3 times, at given moments t_{1},...,t_{n}, and obtain a determinant expression for these probabilities in terms of a displacement-displacement covariance matrix. Except for the standard Brownian trajectories with d_{f}=2, the resulting many-body contact probabilities cannot be factorized into a product of single-loop contributions. Within a Gaussian network model of a self-interacting polymer chain, which we suggested recently [K. Polovnikov et al., Soft Matter 14, 6561 (2018)1744-683X10.1039/C8SM00785C], the probabilities we calculate here can be interpreted as probabilities of multibody contacts in a fractal polymer conformation with the same fractal dimension d_{f}. This Gaussian approach, which implies a mapping from fractional Brownian motion trajectories to polymer conformations, can be used as a semiquantitative model of polymer chains in topologically stabilized conformations, e.g., in melts of unconcatenated rings or in the chromatin fiber, which is the material medium containing genetic information. The model presented here can be used, therefore, as a benchmark for interpretation of the data of many-body contacts in genomes, which we expect to be available soon in, e.g., Hi-C experiments.

Effective Hamiltonian of topologically stabilized polymer states.

Topologically stabilized polymer conformations in melts of nonconcatenated polymer rings and crumpled globules are considered to be a good candidate for the description of the spatial structure of mitotic chromosomes. Despite significant efforts, the microscopic Hamiltonian capable of describing such systems still remains unknown. We describe a polymer conformation by a Gaussian network - a system with a Hamiltonian quadratic in all coordinates - and show that by tuning interaction constants, one can obtain equilibrium conformations with any fractal dimension between 2 (an ideal polymer chain) and 3 (a crumpled globule). Monomer-to-monomer distances in topologically stabilized states, according to available numerical data, fit very well the Gaussian distribution, giving an additional argument in support of the quadratic Hamiltonian model. Mathematically, the polymer conformations are mapped onto the trajectories of a subdiffusive fractal Brownian particle. Moreover, we explicitly show that the quadratic Hamiltonian with a hierarchical set of coupling constants provides the microscopic background for the description of the path integral of the fractional Brownian motion with an algebraically decaying kernel.

Fractal Folding and Medium Viscoelasticity Contribute Jointly to Chromosome Dynamics.

Chromosomes are key players of cell physiology, their dynamics provides valuable information about its physical organization. In both prokaryotes and eukaryotes, the short-time motion of chromosomal loci has been described with a Rouse model in a simple or viscoelastic medium. However, little emphasis has been put on the influence of the folded organization of chromosomes on the local dynamics. Clearly, stress propagation, and thus dynamics, must be affected by such organization, but a theory allowing us to extract such information from data, e.g., on two-point correlations, is lacking. Here, we describe a theoretical framework able to answer this general polymer dynamics question. We provide a scaling analysis of the stress-propagation time between two loci at a given arclength distance along the chromosomal coordinate. The results suggest a precise way to assess folding information from the dynamical coupling of chromosome segments. Additionally, we realize this framework in a specific model of a polymer whose long-range interactions are designed to make it fold in a fractal way and immersed in a medium characterized by subdiffusive fractional Langevin motion with a tunable scaling exponent. This allows us to derive explicit analytical expressions for the correlation functions.

Analgesia by telemedically supported paramedics compared with physician-administered analgesia: A prospective, interventional, multicentre trial.

BACKGROUND: In German emergency medical services (EMS), the analgesia is restricted to physicians. In this prospective, interventional, multicentre trial, complications with and quality of telemedically delegated analgesia were evaluated. METHODS: If prehospital analgesia was necessary, five telemedically equipped paramedic ambulances from four different districts could consult a telemedicine centre. Analgesics were delegated based on a predefined algorithm. Telemedically assisted cases were compared with local historical regular EMS missions using matched pairs. The primary outcome was the frequency of therapeutic complications (respiratory/circulatory insufficiency, allergic reactions). Secondary outcomes were quality of analgesia (11-point numerical rating scale, NRS) and the frequency of nausea/vomiting. RESULTS: Analgesia was necessary in 106 telemedically assisted missions. In 23 cases, the telemedical procedure was used until an EMS physician arrived. Of the remaining 83 cases, 80 could be matched to comparable controls. Complications did not occur in either the study group or the control group (0 vs. 0; p = N/A). Complete NRS documentation was noted in 65/80 (study group) and 32/80 (control group) cases (p < 0.0001). Adequate initial pain reduction (quality indicator: reduction of NRS ≥ 2 points or NRS < 5 at end of mission) occurred in 61/65 versus 31/32 cases (p = 1.0); NRS reduction during mission was 3.78 ± 2.0 versus 4.38 ± 2.2 points (p = 0.0159). Nausea and vomiting occurred with equal frequency in both groups. CONCLUSIONS: Telemedical delegation of analgesics to paramedics was safe and led to a pain reduction superior to the published minimum standard in both groups. The documentation quality was better in the telemedicine group. WHAT DOES THIS STUDY ADD?: Little is known about the safety and quality of prehospital analgesia carried out by emergency medical services (EMS). Beside potential quality problems, in some countries meaningful pain reduction is limited by legal regulations that allow only physicians to administer analgesics. This first multicentre prospective trial for telemedically delegated analgesia demonstrates that remote analgesia is possible and safe and retains equivalent analgesic quality compared with that administered by onsite EMS physicians.

Eigenvalue tunneling and decay of quenched random network.

We consider the canonical ensemble of N-vertex Erdos-Rényi (ER) random topological graphs with quenched vertex degree, and with fugacity µ for each closed triple of bonds. We claim complete defragmentation of large-N graphs into the collection of [p^{-1}] almost full subgraphs (cliques) above critical fugacity, µ_{c}, where p is the ER bond formation probability. Evolution of the spectral density, ρ(λ), of the adjacency matrix with increasing µ leads to the formation of a multizonal support for µ>µ_{c}. Eigenvalue tunneling from the central zone to the side one means formation of a new clique in the defragmentation process. The adjacency matrix of the network ground state has a block-diagonal form, where the number of vertices in blocks fluctuates around the mean value Np. The spectral density of the whole network in this regime has triangular shape. We interpret the phenomena from the viewpoint of the conventional random matrix model and speculate about possible physical applications.

[Evaluation of the German version of the caregiver reaction assessment questionnaire for informal caregivers of patients with neovascular age-related macular degeneration]. / Evaluierung der deutschen Version des Caregiver Reaction Assessment-Fragebogens bei betreuenden Angehörigen von Patienten mit neovaskulärer altersbedingter Makuladegeneration.

BACKGROUND: Informal caregivers of patients with loss of vision often have to give physical and emotional support because of the high level of dependence induced. Although it is known that these informal caregivers suffer a higher risk of being affected by burn-out syndrome or depression, the various dimensions of burden, especially of informal caregivers of patients with neovascular age-related macular degeneration (nv-AMD) have not yet been investigated. OBJECTIVE: The objective of this study was the evaluation of the German version of the caregiver reaction assessment (CRA) questionnaire in a collective of informal caregivers of patients with nv-AMD. In this context the positive and negative influences on the informal caregivers were assessed. MATERIAL AND METHODS: Between January 2013 and July 2014 a total of 150 informal caregivers of patients with nv-AMD filled out the CRA independently using a questionnaire survey which had been translated into German. Based on this collective, the psychometric characteristics of the translated questionnaire were evaluated. RESULTS: The informal caregivers of the current collective reported a lower burden in the five subgroups disrupted schedule, lack of family support, self-esteem, health problems and financial problems, compared to the previous CRA studies with caregivers of patients with other diseases. The informal caregivers saw the greatest burden as the disruption of their schedule. Through a principal component analysis the five subgroups could be identified as five factors. It was shown that 19 out of the 24 items could be assigned to the same factors as in the original English version. The internal consistency of the five subgroups was acceptable except for the subscale on self-esteem. CONCLUSION: In this study the CRA has been confirmed as a suitable instrument to assess both positive and negative reactions of informal caregivers related to caregiving of patients with nv-AMD. The results provide support for a five subscale structure of the CRA in the original English version but five items of the questionnaire could be assigned to another subscale.

Anomalous diffusion in fractal globules.

The fractal globule state is a popular model for describing chromatin packing in eukaryotic nuclei. Here we provide a scaling theory and dissipative particle dynamics computer simulation for the thermal motion of monomers in the fractal globule state. Simulations starting from different entanglement-free initial states show good convergence which provides evidence supporting the existence of a unique metastable fractal globule state. We show monomer motion in this state to be subdiffusive described by ⟨X(2)(t)⟩∼t(αF) with αF close to 0.4. This result is in good agreement with existing experimental data on the chromatin dynamics, which makes an additional argument in support of the fractal globule model of chromatin packing.

Chronological bias in randomized clinical trials arising from different types of unobserved time trends.

BACKGROUND: In clinical trials patients are commonly recruited sequentially over time incurring the risk of chronological bias due to (unobserved) time trends. To minimize the risk of chronological bias, a suitable randomization procedure should be chosen. OBJECTIVES: Considering different time trend scenarios, we aim at a detailed evaluation of the extent of chronological bias under permuted block randomization in order to provide recommendations regarding the choice of randomization at the design stage of a clinical trial and to assess the maximum extent of bias for a realized sequence in the analysis stage. METHODS: For the assessment of chronological bias we consider linear, logarithmic and stepwise trends illustrating typical changes during recruitment in clinical practice. Bias and variance of the treatment effect estimator as well as the empirical type I error rate when applying the t-test are investigated. Different sample sizes, block sizes and strengths of time trends are considered. RESULTS: Using large block sizes, a notable bias exists in the estimate of the treatment effect for specific sequences. This results in a heavily inflated type I error for realized worst-case sequences and an enlarged mean squared error of the treatment effect estimator. Decreasing the block size restricts these effects of time trends. Already applying permuted block randomization with two blocks instead of the random allocation rule achieves a good reduction of the mean squared error and of the inflated type I error. Averaged over all sequences, the type I error of the t-test is far below the nominal significance level due to an overestimated variance. CONCLUSIONS: Unobserved time trends can induce a strong bias in the treatment effect estimate and in the test decision. Therefore, already in the design stage of a clinical trial a suitable randomization procedure should be chosen. According to our results, small block sizes should be preferred, but also medium block sizes are sufficient to restrict chronological bias to an acceptable extent if other contrary aspects have to be considered (e.g. serious risk of selection bias). Regardless of the block size, a blocked ANOVA should be used because the t-test is far too conservative, even for weak time trends.

Islands of stability in motif distributions of random networks.

We consider random nondirected networks subject to dynamics conserving vertex degrees and study, analytically and numerically, equilibrium three-vertex motif distributions in the presence of an external field h coupled to one of the motifs. For small h, the numerics is well described by the "chemical kinetics" for the concentrations of motifs based on the law of mass action. For larger h, a transition into some trapped motif state occurs in Erdos-Rényi networks. We explain the existence of the transition by employing the notion of the entropy of the motif distribution and describe it in terms of a phenomenological Landau-type theory with a nonzero cubic term. A localization transition should always occur if the entropy function is nonconvex. We conjecture that this phenomenon is the origin of the motifs' pattern formation in real evolutionary networks.

Anatomic changes of target vessels after fenestrated and branched aortic aneurysm repair.

AIM: Objective of this study was to evaluate the anatomic changes of the stented target vessels after endovascular repair of complex aortic aneurysms. METHODS: Between July 2011 and December 2013, 53 aortic aneurysms were treated in our department with fenestrated and branched stent-graft devices. Forty-two of these patients were pre- and postoperatively scanned with a high resolution computer tomography (CT) (Cook Zenith® fenestrated or branched, Australia Pty. Ltd., Brisbane, Australia: N.=19; AnacondaTM fenestrated, Vascutek, Glasgow, Scotland, UK: N.=23). The other 11 out of the 53 patients did not receive a CT scan, because of a pre-existing renal failure. In the CT scans we retrospectively evaluated the anatomic vessel deviation at the origin of the target vessel and the vessel shift distal to the stent. For the first measurement the CT scans were loaded into OsiriX MD®, and the pre- and postoperative angles of the target vessels were measured and subtracted. For matching, the CT-scans were normalized at vertebral body lumbar 2. The second measured angle was the maximal measured angle distal to the target vessel stent-graft. RESULTS: Altogether, 113 target vessels were stented (celiac trunk [CT] 15, superior mesenteric arteries [SMA] 26, renal arteries [RA] 72), with 97 balloon-expandable PTFE stents: 90 Atrium V12 (Maquet Getinge group, Hudson, NH, USA), 7 BeGrafts (Bentley InnoMed, Hechingen, Germany) and 16 self-expandable fluency PTFE stents (Bard, Karlsruhe, Germany). The mean anatomic deviation at the target vessel origin was 28±17.3 and the mean vessel shift distal to the stent was 36.3±18.8. There were no significant differences between the main device and the target vessel stent types. CONCLUSION: Fenestrated and branched stent-graft solutions for aortic aneurysm repair induce changes of the target vessel anatomy. We did not observe significant differences between the several devices.

Overlap of two Brownian trajectories: exact results for scaling functions.

We consider two random walkers starting at the same time t=0 from different points in space separated by a given distance R. We compute the average volume of the space visited by both walkers up to time t as a function of R and t and dimensionality of space d. For d<4, this volume, after proper renormalization, is shown to be expressed through a scaling function of a single variable R/√t. We provide general integral formulas for scaling functions for arbitrary dimensionality d<4. In contrast, we show that no scaling function exists for higher dimensionalities d≥4.

Assessment of panobacumab as adjunctive immunotherapy for the treatment of nosocomial Pseudomonas aeruginosa pneumonia.

The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64-79] versus an average of 50 years old (IQR: 30-73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16-22) versus 15 (IQR: 10-19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan-Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0-11.5] versus 18.5 [IQR: 8-30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia.

New alphabet-dependent morphological transition in random RNA alignment.

We study the fraction f of nucleotides involved in the formation of a cactuslike secondary structure of random heteropolymer RNA-like molecules. In the low-temperature limit, we study this fraction as a function of the number c of different nucleotide species. We show, that with changing c, the secondary structures of random RNAs undergo a morphological transition: f(c)→1 for c≤c(cr) as the chain length n goes to infinity, signaling the formation of a virtually perfect gapless secondary structure; while f(c)<1 for c>c(cr), which means that a nonperfect structure with gaps is formed. The strict upper and lower bounds 2≤c(cr)≤4 are proven, and the numerical evidence for c(cr) is presented. The relevance of the transition from the evolutional point of view is discussed.

Human metapneumovirus infection after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The clinical characteristics of human metapneumovirus (hMPV)-associated lower respiratory tract infection (LRTI) after allogeneic hematopoietic stem cell transplantation (HSCT) is not well described. We describe the clinical course in eight HSCT recipients suffering from hMPV infection. METHODS: We prospectively included all patients with hMPV-associated LRTI after allogeneic HSCT during a period of 1 year. hMPV was diagnosed by multiplex polymerase chain reaction (PCR) from bronchoalveolar lavage (BAL). RESULTS: Eight patients with hMPV-associated LRTI were identified from 93 BAL samples. Three of the eight patients had co-infections with other pathogens. The median age of the patients was 45 years [interquartile range (IQR) 36.8-53.5], the median time posttransplant was 473 days (IQR 251-1,165), 5/8 patients had chronic graft-versus-host disease (cGvHD), and 6/8 patients received immunosuppression. Chest computed tomography (CT) scanning showed a ground-glass pattern in 7/8 patients. Seven of eight patients required hospitalization due to severe symptoms and hypoxemia. All were treated with intravenous immunoglobulin (IVIG), which was combined with oral ribavirin in six patients. The mortality rate was 12.5 % (1/8). CONCLUSIONS: hMPV-associated LRTI in allogeneic HSCT recipients are not uncommon and present with unspecific respiratory symptoms, ground-glass pattern in CT scanning, and co-infection.

[Occupational rhinitis and asthma]. / Berufliche Rhinitis und Asthma.

Allergic rhinoconjunctivits and asthma are frequent diseases. About one in ten asthma cases is caused by an occupational hazard, either by an allergic or a non-immunologic mechanism. Primary or secondary preventive measures should be able to prevent these cases. Often, occupational rhinitis precedes the development of occupational asthma. Important causative agents are flours, plant and enzyme powders, laboratory animals, latex, isocyanates and hardeners, epoxy resins, acrylates, formaldehyde and welding fumes. Early diagnosis and the installation of protective measures are decisive for the prognosis of occupational respiratory disease.