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Background/Objectives : Odontogenic sinusitis (ODS) is the most common cause of unilateral maxillary sinus opacification. Initial treatment consists of intranasal steroids and antimicrobial therapy. In case of persistence of the disease, endoscopic sinus surgery (ESS) is advised. It is still not clear what extension of ESS is required and whether frontal sinusotomy or ethmoidectomy is justified in ODS with frontal sinus involvement. Methods : Adult patients presented with uncomplicated recalcitrant bacterial ODS due to endodontic-related dental pathology were evaluated by an otolaryngologist and a dentist and scheduled for ESS. Sinus CT scan demonstrated opacification of maxillary sinus and partial or complete opacification of extramaxillary sinuses ipsilateral to the side of ODS. Patients were undergoing either maxillary antrostomy, antroethmoidectomy, or antroethmofrontostomy. Preoperative and postoperative evaluations were done with nasal endoscopy, dental examination, subjective and radiological symptoms. Results : The study group consisted of 30 patients. Statistically significant decreases in values after surgery were found for SNOT-22, OHIP-14, Lund-Mackay, Lund-Kennedy, and Zinreich scale. Tooth pain was present in 40% cases during the first visit and in 10% during the follow-up visit. Foul smell was initially reported by 73.3% and by one patient during follow-up visit (3.3%). Significantly longer total recovery time and more crusting was marked for antroethmofrontostomy when compared to maxillary antrostomy. Conclusions : ESS resolved ODS with ethmoid and frontal involvement in almost every case. Minimal surgery led to improved overall clinical success in the same way as antroethmofrontostomy without risking the frontal recess scarring and stenosis.

Background: One of the most common causes of bacterial odontogenic sinusitis (ODS) is endodontic disease with periapical lesions (PAL). Referrals between otolaryngologists and dental specialists are indispensable for proper diagnosis and treatment. If the disease does not resolve after medical and root-canal treatment (RCT), tooth extraction, endoscopic sinus surgery (ESS) or both are the ways of management.The aim was to clarify the predictive value of disease's radiological characteristics for the further surgical intervention., Methodology: 68 symptomatic patients evaluated by an otolaryngologist and dental specialist were included to this prospective observational cohort study. Patients who failed medical treatment of sinusitis (intranasal steroids, saline rinses and antibiotics) and RCT were treated either with ESS, tooth extraction or both at the same time., Results: 87% of patients required surgical intervention. 12% improved after tooth extraction alone, 47% after ESS and 31% required both procedures. The degree of maxillary sinus' (MS) opacification was not correlated with the need of invasive procedures implementation, as opposed to ostiomeatal complex' patency (p<0.001). Cortical bone destruction towards the MS and multiple tooth roots involvement suggested ODS resolution only after combined surgical approach (p=0.041)., Conclusions: Radiological characteristics of causative tooth and patency of ostiomeatal unit correlate with the evolution of ODS and need for either ESS and/or tooth extraction. Patients with multiple roots affected, shorter distance to the MS floor and PAL's with visible bone destruction may require tooth extraction and ESS to resolve ODS completely., Clinical Implications: Radiological data may help in earlier diagnosis and treatment of ODS with PALs for both otolaryngologists and dental specialists.

The differential diagnosis of unilateral sinus disease (USD) is broad, and while concerning etiologies like sinonasal neoplasia, invasive fungal sinusitis, and cerebrospinal fluid rhinorrhea should always be considered, most cases are due to noninvasive inflammatory or infectious conditions. To diagnose USD appropriately, clinicians must integrate the clinical history and examination, nasal endoscopy, computed tomography (CT), and possibly MRI. Odontogenic sinusitis (ODS) is the most common cause of unilateral maxillary sinus opacification on CT, with 45% to 75% of such cases being odontogenic in nature. This study provides USD diagnostic considerations and reinforces the diagnostic approach to ODS., Competing Interests: Disclosure J.R. Craig: Research consultant, Aerin Medical Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: The aim of this study was to evaluate the safety and efficacy of the piezoelectric knife as a new tool for frontal beak surgery in patients with chronic rhinosinusitis (CRS) both in terms of imaging and perception of symptoms' outcomes., Materials and Methods: The study involved 28 patients with CRS who underwent endoscopic sinus surgery (ESS) using a piezoelectric knife in the frontal recess region. Assessment of sinus imaging and patients' quality of life (QoL) was performed before and after surgery with the Lund-Kennedy and Lund-Mackay systems and the 22-item Sino-Nasal Outcomes Test (SNOT-22)., Results: Median scores on the Lund-Kennedy and Lund-Mackay systems decreased within 24 weeks after surgery with piezo knife assistance by 4 and 5 points, respectively. QoL improved with SNOT-22 scores decreasing by 35.5 points., Conclusions: ESS with the piezoelectric knife used for frontal beak reduction turned out to be a safe procedure. In the studied group of patients, the improvement was observed in terms of imaging, patients' perceptions of symptoms, and QoL outcomes. Therefore, the piezoelectric knife might be a valuable supporting tool in ESS in patients with CRS, although further observation is needed.

Background: Spinal muscular atrophy (SMA) is a rare, progressive, neuromuscular disorder. Recent advances in treatment require an updated assessment of burden to inform reimbursement decisions., Objectives: To quantify healthcare resource utilisation (HCRU) and cost of care for patients with SMA., Methods: Cohort study of patients with SMA identified in the Swedish National Patient Registry (2007-2018), matched to a reference cohort grouped into four SMA types (1, 2, 3, unspecified adult onset [UAO]). HCRU included inpatient admissions, outpatient visits, procedures, and dispensed medications. Direct medical costs were estimated by multiplying HCRU by respective unit costs. Average annual HCRU and medical costs were modelled for SMA versus reference cohorts to estimate differences attributable to the disease (i.e., average treatment effect estimand). The trajectory of direct costs over time were assessed using synthetic cohorts., Results: We identified 290 SMA patients. Annualised HCRU was higher in SMA patients compared with reference cohorts. Highest risk ratios were observed for inpatient overnight stays for type 1 (risk ratio [RR]: 29.2; 95% confidence interval [CI]: 16.0, 53.5) and type 2 (RR: 23.3; 95% CI: 16.4,33.1). Mean annual direct medical costs per patient for each year since first diagnosis were greatest for type 1 (€114,185 and SMA-attributable: €113,380), type 2 (€61,876 and SMA-attributable: €61,237), type 3 (€45,518 and SMA-attributable: €44,556), and UAO (€4046 and SMA-attributable: €2098). Costs were greatest in the 2-3 years after the first diagnosis for all types., Discussion and Conclusion: The economic burden attributable to SMA is significant. Further research is needed to understand the burden in other European countries and the impact of new treatments., (© 2024. The Author(s).)

The widespread popularity of Machine Learning (ML) models in healthcare solutions has increased the demand for their interpretability and accountability. In this paper, we propose the Physiologically-Informed Gaussian Process (PhGP) classification model, an interpretable machine learning model founded on the Bayesian nature of Gaussian Processes (GPs). Specifically, we inject problem-specific domain knowledge of inherent physiological mechanisms underlying the psycho-physiological states as a prior distribution over the GP latent space. Thus, to estimate the hyper-parameters in PhGP, we rely on the information from raw physiological signals as well as the designed prior function encoding the physiologically-inspired modelling assumptions. Alongside this new model, we present novel interpretability metrics that highlight the most informative input regions that contribute to the GP prediction. We evaluate the ability of PhGP to provide an accurate and interpretable classification on three different datasets, including electrodermal activity (EDA) signals collected during emotional, painful, and stressful tasks. Our results demonstrate that, for all three tasks, recognition performance is improved by using the PhGP model compared to competitive methods. Moreover, PhGP is able to provide physiological sound interpretations over its predictions.

Endodontic disease with formation of periapical lesions (PALs) is one of the most common causes of chronic odontogenic sinusitis (ODS). It requires close collaboration between otolaryngologists and dentists, but the best sequence of management is still unknown. The aim of the present study is to clarify how radiological characteristics of teeth with PALs and previous root-canal treatment (RCT) influence the clinical evolution of the disease and to define the predictive value of its radiological and endoscopic features in determining the need for further surgical intervention. A total of 68 symptomatic patients with ODS with PALs were included in the study. The evaluation was performed by an otolaryngologist and a dentist based on a medical interview, nasal endoscopy, cold pulp testing and tomography images. Patients were prospectively followed for at least 12 months, during which nasal steroids, saline irrigations and RCT were administered. The criteria of disease improvement were: decrease of symptoms, healed sinonasal mucosa in endoscopy and radiological resolution of periapical radiolucency and sinus inflammation. Results showed that 9 (13%) patients improved after conservative treatment and 59 (87%) required further surgical intervention. Patients who improved after medical treatment and RCT were younger ( p = 0.043) and had a greater distance from the top of the periapical lesion to the maxillary sinus' floor ( p = 0.003). When expansion of PALs and bone destruction toward the maxillary sinus was observed on radiological imaging ( p = 0.041), and when more than one tooth root was affected ( p = 0.004), patients were more likely to require surgical intervention. In conclusion, the more roots that are affected and the closer the top of the PAL is to the maxillary sinus' floor, the greater the possibility of medical treatment and RCT failure. When the bone destruction extends into the maxillary sinus, patients eventually require both tooth extraction and FESS in order to resolve ODS completely.

Introduction: Endodontic pathology is one of the most common causes of odontogenic sinusitis, and its evaluation is challenging. Omission of periapical lesions in diagnostic process leads to recurrent sinusitis after cessation of medical therapy., Methods: Sixty-one symptomatic patients presented with odontogenic sinusitis with periapical lesions of teeth adjacent to the maxillary sinus were included in the study. Symptoms evaluated with SNOT-22 and OHIP-14 questionnaires were compared to signs during endoscopic and radiological evaluation., Results: Coexistence of odontogenic sinusitis with nasal polyps significantly decreases the quality of life, especially concerning the emotional domain (p = 0.047). Patency of ostiomeatal corresponds well with the severity of sinonasal symptoms reported with SNOT-22 (p = 0.051). Extent of maxillary sinus opacifications scored with Zinreich scale correlates positively with the presence of discharge (p = 0.001) and edema (p = 0.072) in the endoscopic Lund-Kennedy scale. Among 67 teeth with periapical lesions, 73.1% had undergone previous root canal treatment, but in 47.8% of cases, it was defined as incomplete. Endodontic status did not affect the severity of patient's complaints., Conclusion: In case of odontogenic sinusitis of endodontic origin, endoscopic signs correlate better than radiological with the self-reported symptoms. In order to better evaluate the severity of the disease and possible need of surgical intervention, both otolaryngologists and dental specialists should focus on extent of inflammatory lesions in the maxillary sinus., (© 2022 S. Karger AG, Basel.)

Introduction: Although the symptoms and radiographic signs may mimic rhinogenic sinusitis, odontogenic sinusitis (OS) with periapical lesions (PALs) is fundamentally an endodontic infection. It is considered to be one of the main causes of OS, especially when presented unilaterally. Despite this routine dental examination is not performed and periapical infection frequently remains undiagnosed by otolaryngologists and radiologists., Material and Methods: This prospective observational study covered a group of 61 patients with symptomatic OS with PAL. Assessment of quality of life was done using the 22-item Sino-Nasal Outcome Test-22 (SNOT-22) and Oral Health-Impact Profile-14 (OHIP-14). Temporal and etiological relationship between the dental cause and sinonasal complication was established among the otolaryngologist and dental specialist based on the clinical symptoms, nasal endoscopy described according to the modified Lund-MacKay scale, computed tomography (CT) scans measured and scored in compliance with Lund- Kennedy, Zinreich and Estrela scales., Results: Out of 61 patients, 28 (46%) were women and 33 (54%) men. Group median age 49.1 years, ranged from 22.8 to 78.9 years. Total OHIP-14 score was 12.7 ± 11.3, with the highest value obtained in domains describing physical pain (mean 2.9 ± 2.4, median 3) in which the highest score was obtained in item 3 - painful aching in mouth and/or teeth - scored ≥2 by 52.5% of participants. Concerning dental symptoms 11.5% of patients were asymptomatic. Total SNOT-22 score was 40.7 ± 21.1, with the highest value in domains describing nasal symptoms. 23% of patients reported mild, 44.3% moderate and 32.7% severe symptoms. In the endoscopic evaluation 86.8% of cases presented discharge, 73.8% mucosal edema. In 11.5% of cases the polypoid tissues was observed in nasal cavities. The first molar tooth was the most frequently affected with an incidence of 42.6%, followed by the second molar (27.9%). In 33 (48.5%) of cases the inflammatory process caused the discontinuity of the sinus floor, which in 51.5% coexisted with total maxillary sinus opacification. 10 teeth (14.7%) had the periapical lesions with a diameter exceeding 8 mm. In case of the multi-rooted teeth, PALs were usually encountered at more than one root (57.4%). Maxillary and ethmoid sinus were affected in 54% of cases and additional frontal sinus involvement in 32.8%. In 69.6% patients, ostiomeatal complex was obstructed., Conclusions: Persistent sinonasal symptoms such as rhinorrhea, post-nasal drip and nose congestion along with dental pain may suggest endodontic nature of OS, especially after previous root-canal treatment. The bigger the PAL is in diameter and the closer to the maxillary sinus, the greater effect on its mucosal involvement and obstruction of ostiomeatal complex is observed. PALs around molar or premolar tooth apexes with coexistence of unilateral sinus opacifications should be noticed and mentioned by radiologists and evaluated by dental specialists in order to refer the patient to further treatment., (Copyright © 2021. Published by Elsevier Inc.)

<b> Introduction:</b> Usually the symptoms presented in odontogenic sinusitis do not differ from chronic sinusitis of other origin. However, odontogenic sinusitis is considered as an independent disease which requires specific diagnostic approach and treatment. </br></br> <b>Aim:</b> The aim of the study is to define the main symptoms of odontogenic rhinosinusitis with periapical lesions and its impact on the quality of life. </br></br> <b>Material and methods:</b> The SNOT-22 and OHIP-14 questionnaires were distributed among 26 symptomatic patients suffering from odontogenic sinusitis with periapical lesions in the teeth that remain in close contact with the maxillary sinus floor. Data was collected by means of an interview and standard examination performed by an otolaryngologist and a maxillofacial surgeon. The symptoms were also objectified using nasal endoscopy and radiological studies. The acquired data was statistically analyzed. </br></br> <b>Results:</b> The total OHIP-14 score was 14.7 ± 11.3, whereas the total SNOT-22 score was 44.6 ± 18.8. Women scored significantly higher in the total SNOT-22 score as well as domains concerning nasal symptoms, quality of sleep, and emotional symptoms. The answers given in similar items were comparable between both questionnaires. </br></br> <b>Conclusions:</b> Properly diagnosed odontogenic sinusitis (OS) with periapical lesions (PAL) will improve the quality of health-care and spare the patients inadequate procedures. Standard examination should include a unified and validated question-naire concerning both sinonasal and oral symptoms. Painful aching in the mouth and discomfort during eating might help to identify the OS with PAL during a medical interview and help both ENT (ear-nose-throat) specialists and dentists to establish proper patient-oriented diagnosis and treatment.

Glyphosate is used for cereal, vegetable and fruit crops for reducing or inhibiting the growth of weeds as well as a desiccant for various grain crops. That is why, glyphosate has been shown to be accumulated in humans and animals through ingestion of food of both plant and animal origin. The study aimed to assessed the effect of glyphosate, its metabolites: aminomethylphosphonic acid (AMPA), methylphosphonic acid and its impurities: PMIDA, N-methylglyphosate, hydroxymethylphosphonic acid and bis(phosphonomethyl)amine on apoptosis induction in human peripheral blood mononuclear cells (PBMCs). PBMCs were exposed to the compounds studied at the concentrations ranging from 0.01 to 5 mM for 4 h. We have observed an increase in reactive oxygen species (including hydroxyl radical) and cytosolic calcium ions levels as well as reduction of transmembrane mitochondrial potential (ΔΨm) in PBMCs exposed to the compounds examined. All substances studied changed PBMCs membrane permeability, activated caspase-8, -9, -3 and caused chromatin condensation, which showed that they were capable of inducing apoptosis both via extrinsic and particularly intrinsic pathway. Generally the study demonstrated that there were no differences between apoptotic changes induced by glyphosate, its metabolites or impurities, and observed changes were provoked by high concentrations of investigated compounds., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ecological momentary assessment (EMA) and ecological momentary intervention (EMI) are alternative approaches to retrospective self-reports and face-to-face treatments, and they make it possible to repeatedly assess patients in naturalistic settings and extend psychological support into real life. The increase in smartphone applications and the availability of low-cost wearable biosensors have further improved the potential of EMA and EMI, which, however, have not yet been applied in clinical practice. Here, we conducted a systematic review, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to explore the state of the art of technology-based EMA and EMI for major depressive disorder (MDD). A total of 33 articles were included (EMA = 26; EMI = 7). First, we provide a detailed analysis of the included studies from technical (sampling methods, duration, prompts), clinical (fields of application, adherence rates, dropouts, intervention effectiveness), and technological (adopted devices) perspectives. Then, we identify the advantages of using information and communications technologies (ICTs) to extend the potential of these approaches to the understanding, assessment, and intervention in depression. Furthermore, we point out the relevant issues that still need to be addressed within this field, and we discuss how EMA and EMI could benefit from the use of sensors and biosensors, along with recent advances in machine learning for affective modelling., Competing Interests: The authors declare that no competing interests exist.

Background: Ecological momentary assessments (EMAs) and ecological momentary interventions (EMIs) represent a novel approach for the assessment and delivery of psychological support to depressed patients in daily life. Beyond the classical paper-and-pencil daily diaries, the more recent progresses in Information and Communication Technologies (ICT) enabled researchers to bring all the needed processes together in only one device, i.e., response signaling, repeated symptom collection, information storage, secure data transfer, and psychological support delivery. Despite evidence showing the feasibility and acceptability of these techniques, EMAs are only beginning to be applied in real clinical practice, whether the development of EMIs for clinically depressed patients is still very limited. The objective of this systematic review is to provide the state of the art of technology-based EMAs and EMIs for major depressive disorder (MDD), with the aim of leading the way to possible future directions for the clinical practice., Methods: We will conduct a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Data sources will include two bibliographic databases, PubMed and Web of Science (Web of Knowledge), supplemented by searches for unpublished or ongoing studies. Eligible studies will report data for adult (≥ 18 years old) with a primary (both current and past) diagnosis of MDD, defined by a valid criterion standard. We will consider studies adopting technology-based EMAs and EMIs for the investigation and/or assessment of depression and for the delivery of a psychological intervention. We will exclude studies adopting paper-and-pencil tools., Discussion: The proposed systematic review will provide new insights on the advantages and benefits of adopting technology-based EMAs and EMIs for MDD in the traditional clinical practice, taking into consideration both clinical and technological issues. The potential of using sensors and biosensors along with machine learning for affective modeling will also be discussed.

Living systems are inherently stochastic and operate in a noisy environment, yet despite all these uncertainties, they perform their functions in a surprisingly reliable way. The biochemical mechanisms used by natural systems to tolerate and control noise are still not fully understood, and this issue also limits our capacity to engineer reliable, quantitative synthetic biological circuits. We study how representative models of biochemical systems propagate and attenuate noise, accounting for intrinsic as well as extrinsic noise. We investigate three molecular noise-filtering mechanisms, study their noise-reduction capabilities and limitations, and show that nonlinear dynamics such as complex formation are necessary for efficient noise reduction. We further suggest that the derived molecular filters are widespread in gene expression and regulation and, particularly, that microRNAs can serve as such noise filters. To our knowledge, our results provide new insight into how biochemical networks control noise and could be useful to build robust synthetic circuits., (Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Inspired by albatrosses that use thermal lifts to fly across oceans we develop a simple model of gliders that serves us to study theoretical limitations of unlimited exploration of the Earth. Our studies, grounded in physical theory of continuous percolation and biased random walks, allow us to identify a variety of percolation transitions, which are understood as providing potentially unlimited movement through a space in a specified direction. We discover an unexpected phenomenon of self-organization of gliders in clusters, which resembles the flock organization of birds. This self-organization is intriguing, as it occurs thanks to exchange of information only and without any particular rules that could favor the clustering of the gliders (in contrast to the causes well known in literature, like, for example, attractive forces used in the Vicsek-type models or fitness functions used in evolutionary computation).

PRISM-games is a tool for modelling, verification and strategy synthesis for stochastic multi-player games. These allow models to incorporate both probability, to represent uncertainty, unreliability or randomisation, and game-theoretic aspects, for systems where different entities have opposing objectives. Applications include autonomous transport, security protocols, energy management systems and many more. We provide a detailed overview of the PRISM-games tool, including its modelling and property specification formalisms, and its underlying architecture and implementation. In particular, we discuss some of its key features, which include multi-objective and compositional approaches to verification and strategy synthesis. We also discuss the scalability and efficiency of the tool and give an overview of some of the case studies to which it has been applied.

We explore the range of probabilistic behaviours that can be engineered with Chemical Reaction Networks (CRNs). We give methods to "program" CRNs so that their steady state is chosen from some desired target distribution that has finite support in [Formula: see text], with [Formula: see text]. Moreover, any distribution with countable infinite support can be approximated with arbitrarily small error under the [Formula: see text] norm. We also give optimized schemes for special distributions, including the uniform distribution. Finally, we formulate a calculus to compute on distributions that is complete for finite support distributions, and can be compiled to a restricted class of CRNs that at steady state realize those distributions.

Chemical reaction networks (CRNs) are a versatile language for describing the dynamical behaviour of chemical kinetics, capable of modelling a variety of digital and analogue processes. While CRN designs for synchronous sequential logic circuits have been proposed and their implementation in DNA demonstrated, a physical realisation of these devices is difficult because of their reliance on a clock. Asynchronous sequential logic, on the other hand, does not require a clock, and instead relies on handshaking protocols to ensure the temporal ordering of different phases of the computation. This paper provides novel CRN designs for the construction of asynchronous logic, arithmetic and control flow elements based on a bi-molecular reaction motif with catalytic reactions and uniform reaction rates. We model and validate the designs for the deterministic and stochastic semantics using Microsoft's GEC tool and the probabilistic model checker PRISM, demonstrating their ability to emulate the function of asynchronous components under low molecular count.

Glyphosate is a very important herbicide that is widely used in the agriculture, and thus the exposure of humans to this substance and its metabolites has been noted. The purpose of this study was to assess DNA damage (determination of single and double strand-breaks by the comet assay) as well as to evaluate DNA methylation (global DNA methylation and methylation of p16 (CDKN2A) and p53 (TP53) promoter regions) in human peripheral blood mononuclear cells (PBMCs) exposed to glyphosate. PBMCs were incubated with the compound studied at concentrations ranging from 0.1 to 10 mM for 24 h. The study has shown that glyphosate induced DNA lesions, which were effectively repaired. However, PBMCs were unable to repair completely DNA damage induced by glyphosate. We also observed a decrease in global DNA methylation level at 0.25 mM of glyphosate. Glyphosate at 0.25 mM and 0.5 mM increased p53 promoter methylation, while it did not induce statistically significant changes in methylation of p16 promoter. To sum up, we have shown for the first time that glyphosate (at high concentrations from 0.5 to 10 mM) may induce DNA damage in leucocytes such as PBMCs and cause DNA methylation in human cells., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Survival after radical cystectomy (RC) is affected by various factors. Significance of preoperative health status and its influence on treatment outcome is uncertain. The aim of the study was to prospectively evaluate overall survival, cause of death and the role of comorbidities in mortality during the first 12 months following RC., Material and Methods: All patients who underwent RC between January 2014 and May 2016 for T1-T4 bladder cancer in a single center were prospectively followed. Stage and comorbidities were explored as predictors of overall survival (OS). Patient status was assessed for at least 12 months., Results: Follow-up was available for 25 men and 19 women at the mean age 67. Median time of follow-up for survivors was 16 months. Six-month and 1-year OS was 84% and 77%. Out of 11 deaths, 8 were related to cancer progression and 3 patients died for other causes. All deaths apart from one occurred in the first year after surgery. One-year OS was affected mostly by tumor stage: 95% for pT1-2 vs. 62.5% for pT3-4; p = 0.01. Worse outcome was found in patients ≥72 years old, (44% vs. 86%; p = 0.02) and among women (63% vs. 88%; p = 0.07). When patients who died were compared to survivors the following distribution of comorbidities was found: diabetes mellitus - 30.0% vs. 11.8%, p = 0.3; history of stroke - 30.0% vs. 2.9%, p = 0.1; thyroid disease - 30.0% vs. 11.8%, p = 0.3., Conclusions: Majority of patients died because cystectomy was performed too late. History of stroke, diabetes mellitus, and thyroid diseases should be assessed as possible risk factors in larger studies.

Stochastic evolution of Chemical Reactions Networks (CRNs) over time is usually analyzed through solving the Chemical Master Equation (CME) or performing extensive simulations. Analysing stochasticity is often needed, particularly when some molecules occur in low numbers. Unfortunately, both approaches become infeasible if the system is complex and/or it cannot be ensured that initial populations are small. We develop a probabilistic logic for CRNs that enables stochastic analysis of the evolution of populations of molecular species. We present an approximate model checking algorithm based on the Linear Noise Approximation (LNA) of the CME, whose computational complexity is independent of the population size of each species and polynomial in the number of different species. The algorithm requires the solution of first order polynomial differential equations. We prove that our approach is valid for any CRN close enough to the thermodynamical limit. However, we show on four case studies that it can still provide good approximation even for low molecule counts. Our approach enables rigorous analysis of CRNs that are not analyzable by solving the CME, but are far from the deterministic limit. Moreover, it can be used for a fast approximate stochastic characterization of a CRN., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

The toxicity of herbicides to animals and human is an issue of worldwide concern. The present study has been undertaken to assess toxic effect of widely used pesticide-glyphosate, its metabolites: aminomethylphosphonic acid (AMPA) and methylphosphonic acid and its impurities: N-(phosphonomethyl)iminodiacetic acid (PMIDA), N-methylglyphosate, hydroxymethylphosphonic acid and bis-(phosphonomethyl)amine on human peripheral blood mononuclear cells (PBMCs). We have evaluated the effect of those compounds on viability, ATP level, size (FSC-A parameter) and granulation (SSC-A parameter) of the cells studied. Human peripheral blood mononuclear cells were exposed to different concentrations of glyphosate, its metabolites and impurities (0.01-10 mM) for 4 and 24 h. It was found that investigated compounds caused statistically significant decrease in viability and ATP level of PBMCs. The strongest changes in cell viability and ATP level were observed after 24 h incubation of PBMCs with bis-(phosphonomethyl)amine, and particularly PMIDA. Moreover, all studied compounds changed cell granularity, while PMIDA and bis-(phosphonomethyl)amine altered PBMCs size. It may be concluded that bis-(phosphonomethyl)amine, and PMIDA caused a slightly stronger damage to PBMCs than did glyphosate. Changes in the parameters studied in PBMCs were observed only at high concentrations of the compounds examined, which clearly shows that they may occur in this cell type only as a result of acute poisoning of human organism with these substances.

We present a modelling framework, and basic model parameterization, for the study of DNA origami folding at the level of DNA domains. Our approach is explicitly kinetic and does not assume a specific folding pathway. The binding of each staple is associated with a free-energy change that depends on staple sequence, the possibility of coaxial stacking with neighbouring domains, and the entropic cost of constraining the scaffold by inserting staple crossovers. A rigorous thermodynamic model is difficult to implement as a result of the complex, multiply connected geometry of the scaffold: we present a solution to this problem for planar origami. Coaxial stacking of helices and entropic terms, particularly when loop closure exponents are taken to be larger than those for ideal chains, introduce interactions between staples. These cooperative interactions lead to the prediction of sharp assembly transitions with notable hysteresis that are consistent with experimental observations. We show that the model reproduces the experimentally observed consequences of reducing staple concentration, accelerated cooling, and absent staples. We also present a simpler methodology that gives consistent results and can be used to study a wider range of systems including non-planar origami.

In this study, the effect of monochloroacetic acid (MCAA), dichloroacetic acid (DCAA), monobromoacetic acid (MBAA) and dibromoacetic acid (DBAA) on human peripheral blood mononuclear cells (PBMCs) was assessed. HAAs studied induced at millimolar concentrations necrotic alterations in PBMCs with the strongest effect noted for MBAA and DBAA. Chloro- and bromoacetic acids also provoked changes in PBMCs morphology because they caused a strong decrease in cell size (particularly DCAA and DBAA) and increase in cell granulation (mainly MBAA and DBAA). All HAAs studied, and DCAA and DBAA in particular (at lower concentrations than those, which caused necrosis) induced apoptotic changes, which was confirmed by analysis of alterations in cell membrane permeability and caspase 8, 9 and 3 activation. Moreover, HAAs examined (mainly dihalogenated acids) strongly increased transmembrane mitochondrial potential and enhanced ROS (mainly hydroxyl radical) formation, which was possibly associated with apoptotic changes provoked by those substances. The results showed that DBAA exhibited the strongest effects on PBMCs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

DNA origami is a robust assembly technique that folds a single-stranded DNA template into a target structure by annealing it with hundreds of short 'staple' strands. Its guiding design principle is that the target structure is the single most stable configuration. The folding transition is cooperative and, as in the case of proteins, is governed by information encoded in the polymer sequence. A typical origami folds primarily into the desired shape, but misfolded structures can kinetically trap the system and reduce the yield. Although adjusting assembly conditions or following empirical design rules can improve yield, well-folded origami often need to be separated from misfolded structures. The problem could in principle be avoided if assembly pathway and kinetics were fully understood and then rationally optimized. To this end, here we present a DNA origami system with the unusual property of being able to form a small set of distinguishable and well-folded shapes that represent discrete and approximately degenerate energy minima in a vast folding landscape, thus allowing us to probe the assembly process. The obtained high yield of well-folded origami structures confirms the existence of efficient folding pathways, while the shape distribution provides information about individual trajectories through the folding landscape. We find that, similarly to protein folding, the assembly of DNA origami is highly cooperative; that reversible bond formation is important in recovering from transient misfoldings; and that the early formation of long-range connections can very effectively enforce particular folds. We use these insights to inform the design of the system so as to steer assembly towards desired structures. Expanding the rational design process to include the assembly pathway should thus enable more reproducible synthesis, particularly when targeting more complex structures. We anticipate that this expansion will be essential if DNA origami is to continue its rapid development and become a reliable manufacturing technology.

Implantable cardiac pacemakers are medical devices that can monitor and correct abnormal heart rhythms. To provide the necessary safety assurance for pacemaker software, both testing and verification of the code, as well as testing the entire pacemaker hardware in the loop, is necessary. In this paper, we present a hardware testbed that enables detailed hardware-in-the-loop simulation and energy optimisation of pacemaker algorithms with respect to a heart model. Both the heart and the pacemaker models are encoded in Simulink/Stateflow™ and translated into executable code, with the pacemaker executed directly on the microcontroller. We evaluate the usefulness of the testbed by developing a parameter synthesis algorithm which optimises the timing parameters based on power measurements acquired in real-time. The experiments performed on real measurements successfully demonstrate that the testbed is capable of energy minimisation in real-time and obtains safe pacemaker timing parameters.

Glyphosate [N-(phosphonomethyl)glycine] is used all over the world to protect agricultural and horticultural crops. According to initial reports, glyphosate has been considered to be safe for humans and animals; nevertheless, recent investigations had proven its toxicity. Extensive use of glyphosate and the conviction of its low toxicity leads to a situation in which it is used in excessive amounts in agriculture. That is why, we have investigated the effect of the most commonly used pesticide: glyphosate, its metabolites and impurities on acetylcholinesterase (AChE) activity (in vitro) in human erythrocytes, which is biochemically similar to acetylcholinesterase present in neural synapses. The analysis of noxious effects of metabolites and impurities of pesticides seems to be very important to evaluate toxicological risk that is associated with the effect of pesticide formulations (requirement of the EU regulations 1107/200/EC). The erythrocytes were incubated with xenobiotics at concentrations range from 0.01 to 5 mM for 1 and 4 h. Statistically significant decrease in AChE activity (about 20%) was observed only at high concentrations of the compounds (0.25-5 mM), which enter body only as a result of acute poisoning. There were no statistically significant differences in the effect of the investigated compounds, while the changes caused by them were similar after 1 and 4 h incubation. The investigated metabolites and impurities did not cause stronger changes in AChE activity than glyphosate itself. It may be concluded that the compounds studied (used in the concentrations that are usually determined in the environment) do not disturb function of human erythrocyte acetylcholinesterase., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The toxicity of herbicides to animals and human is an issue of worldwide concern. The present study was undertaken to evaluate toxic potential of widely used pesticide - glyphosate, its metabolites: aminomethylphosphonic acid (AMPA); methylphosphonic acid and its impurities: N-(phosphonomethyl)iminodiacetic acid (PMIDA), N-methylglyphosate, hydroxymethylphosphonic acid and bis-(phosphonomethyl)amine. We evaluated the effect of those compounds on hemolysis, hemoglobin oxidation, reactive oxygen species (ROS) formation and changes in morphology of human erythrocytes. The erythrocytes were exposed to different concentrations of glyphosate and its metabolites and impurities (0.01-5mM) for 1, 4 and 24h. Glyphosate, its metabolites and impurities induced a little hemolysis and hemoglobin oxidation. All changes were very low, even after 24h incubation. Most of the investigated compounds induced reactive oxygen species formation from 0.25mM, except the N-methylglyphosate which caused an increase in ROS formation from 0.5mM. Moreover, the investigated xenobiotics did not change the size and shape (except bis-(phosphonomethyl)amine) of the human erythrocytes. Changes in human erythrocytes were observed only when high concentrations of the compounds were applied. Some investigated metabolites and impurities caused a slight stronger damage to human erythrocytes than a glyphosate. The results clearly show that the changes induced in the erythrocytes can occur only as a result of poisoning with these compounds., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Glyphosate (N-(phosphonomethyl)glycine) is an active ingredient of the most widely used herbicide formulations in protecting agricultural and horticultural crops. Numerous results (mostly published in the years 2010-2013) concerning the action of glyphosate and its formulations in the recent decade were analyzed. Initial reports about alleged biodegradability of glyphosate in the environment turned out to be wrong. It has been shown that glyphosate remains in the soil and can reach people by spreading along with groundwater. Recent publications have shown that glyphosate is detected at low concentrations in the human blood. Publications cited in this article, which indicate a possible induction of neoplastic changes by glyphosate formulation, have raised great concern and controversy in the scientific world. Presenting adverse effects of glyphosate and its formulations we focused on the role of glyphosate formulations in hormonal disorders by impeding the expression of steroidogenic acute regulatory protein and the inhibition of aromatase activity. The impact of glyphosate on oxygen reactive species formation, changes in redox system and the effect on necrosis and apoptosis in various types of cells was shown. We also revealed that glyphosate as a phosphonate herbicide does not inhibit directly the activity of acetylcholinesterase. Based on numerous studies it was noted that commercial formulations of glyphosate exhibit higher toxicity than that of the active substance itself. The discussed problems clearly show the need to evaluate the toxicity of glyphosate and its formulations and related potential threat to humans.

Designing correct, robust DNA devices is difficult because of the many possibilities for unwanted interference between molecules in the system. DNA strand displacement has been proposed as a design paradigm for DNA devices, and the DNA strand displacement (DSD) programming language has been developed as a means of formally programming and analysing these devices to check for unwanted interference. We demonstrate, for the first time, the use of probabilistic verification techniques to analyse the correctness, reliability and performance of DNA devices during the design phase. We use the probabilistic model checker prism, in combination with the DSD language, to design and debug DNA strand displacement components and to investigate their kinetics. We show how our techniques can be used to identify design flaws and to evaluate the merits of contrasting design decisions, even on devices comprising relatively few inputs. We then demonstrate the use of these components to construct a DNA strand displacement device for approximate majority voting. Finally, we discuss some of the challenges and possible directions for applying these methods to more complex designs.

Individuals confronted with a life-threatening illness often report posttraumatic growth (PTG) or finding benefits in disease. These positive evaluations of personal strength, perceptions of improved personal relations and new possibilities may represent a defensive response (cf Janus-face model). Three studies investigated the effects of mortality reminders on reports of PTG or benefit findings among people living with life-threatening illness or their caregivers. 80 people living with HIV (study 1), 164 breast cancer survivors (study 2) and 50 family caregivers for a patient with huntington disease (study 3) were randomly assigned to the experimental (mortality reminders) or control conditions. Across three studies, those exposed to mortality reminders reported lower PTG or benefit finding, compared to the controls. These effects were moderated by time elapsed since diagnosis: mortality reminders led to lower PTG/benefit finding among those who received the diagnosis more recently. The results provide an insight into the defensive character of PTG/finding benefits in illness and changes in the function of these beliefs over time elapsing since diagnosis.

Introduction: The paper concerns definition of the level of posttraumatic growth (PTG), the psychological adaptation mechanism occurring after extreme experiences in life, such as being informed of having HIV infection., Aim: The study is experimental, aiming to assess whether correlations between exposure to thoughts of stressful experiences and their psychological consequences are mediated by an efficient mechanism of buffering anxiety, Material/methods: Fifty-four men and 26 women infected with HIV who underwent manipulated exposure to mortality according to the hypotheses of the terror management theory (TMT) were included. Subjects were randomly assigned to the control group (dental anxiety) or the experimental group (fear of dying)., Results: The results confirmed the assumptions of the terror management theory. The subjects had an efficient mechanism of alleviating the fear of dying, the so-called "anxiety buffer." The analysis revealed a high level of posttraumatic growth and advantages derived from the disease. The paper additionally characterizes the specific group of HIV-positive people, their functioning in society and the family. It touches on such issues as professional work, relations with relatives and friends, social life, and adherence., Conclusions: The study has shown that the specific group of people infected with HIV managed very well to adapt to the circumstances. One may say that as a consequence of acquiring the infection, the subjects have experienced significant changes of personality, which have ultimately led to an improvement of their lives and offered new possibilities for personal and social development to them. All the recorded changes fit into the TMT paradigm., (® Postepy Hig Med Dosw)

Time and cost are the enemies of cell biology. The number of experiments required to rigorously dissect and comprehend a pathway of even modest complexity is daunting. Methods are needed to formulate biological pathways in a machine-analysable fashion, which would automate the process of considering all possible experiments in a complex pathway and identify those that command attention. In this Essay, we describe a method that is based on the exploitation of computational tools that were originally developed to analyse reactive communicating computer systems such as mobile phones and web browsers. In this approach, the biological process is articulated as an executable computer program that can be interrogated using methods that were developed to analyse complex software systems. Using case studies of the FGF, MAPK and Delta/Notch pathways, we show that the application of this technology can yield interesting insights into the behaviour of signalling pathways, which have subsequently been corroborated by experimental data.

It was found that infection of Escherichia coli by bacteriophage lambda is inhibited in the presence of certain bile salts and carbohydrates when cells are in the "OFF" state for production of the phase-variable cell surface protein antigen 43 (Ag43). The inhibition of phage growth was found to be due to a significant impairment in the process of phage adsorption. Expression of the gene encoding Ag43 (agn43) from a plasmid or inactivation of the oxyR gene (encoding an activator of genes important for defence against oxidative stress) suppressed this inhibition. A mutation, rpoA341, in the gene encoding the alpha subunit of RNA polymerase also facilitated phage adsorption in the presence of bile salts and carbohydrates. The rpoA341 mutation promoted efficient production of Ag43 in a genetic background that would otherwise be in the "OFF" phase for expression of the agn43 gene. Analysis of a reporter gene fusion demonstrated that the promoter for the agn43 gene was more active in the rpoA341 mutant than in the otherwise isogenic rpoA(+) strain. The combined inhibitory action of bile salts and carbohydrates on phage adsorption and the abolition of this inhibition by production of Ag43 was not restricted to lambda, as a similar phenomenon was observed for the coliphages P1 and T4.