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Objective: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. Design, Patients and Measurements: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. Results: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p <.001), had larger tumours (2.9 vs. 1.8 cm, p <.001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p <.001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p =.003), hypertension (50.0% vs. 31.7%, p =.041) and catecholamine‐related symptoms (37.9% vs. 17.5%, p =.012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p =.013), micturition spells (OR = 6.79, p =.007), hypertension (OR = 3.98, p =.011), and sweating (OR = 41.72, p =.013) increased the probability of initiating presurgical biochemical testing. Conclusions: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis. [ABSTRACT FROM AUTHOR]

In this article, we extend a previously developed globally optimal enumeration methodology for the synthesis of heat exchanger networks (HENs) to include the basic design of heat exchangers (HEXs). The method addresses together all trade‐offs between network structure, energy usage, and the basic design of the HEXs. Without loss of generality, we focus on shell‐and‐tube HEXs. Unlike previous approaches, such as Pinch Analysis, Metaheuristic methods, or Mathematical Programming, our procedure guarantees global optimality. The procedure is not iterative and does not present any convergence challenges. We enumerate HEN structures using a mixed‐integer linear programming method and we use Set Trimming followed by sorting for the HEX design. In addition, because some network structures are incompatible with single shell exchangers, we use multiple shell exchangers in series. The comparison of the results of the proposed approach with solutions obtained using two alternative methods extracted from the literature indicates that considerable cost reductions may be obtained. [ABSTRACT FROM AUTHOR]

An astonishing range of morphologies and life strategies has arisen across the vast diversity of protists, allowing them to thrive in most environments. In model protists, like Tetrahymena, Dictyostelium, or Trypanosoma, life cycles involving multiple life stages with different morphologies have been well characterized. In contrast, knowledge of the life cycles of free‐living protists, which primarily consist of uncultivated environmental lineages, remains largely fragmentary. Various life stages and lineage‐specific cellular innovations have been observed in the field for uncultivated protists, but such innovations generally lack functional characterization and have unknown physiological and ecological roles. In the actual state of knowledge, evidence of sexual processes is confirmed for 20% of free‐living protist lineages. Nevertheless, at the onset of eukaryotic diversification, common molecular trends emerged to promote genetic recombination, establishing sex as an inherent feature of protists. Here, we review protist life cycles from the viewpoint of life cycle transitions and genetics across major eukaryotic lineages. We focus on the scarcely observed sexual cycle of free‐living protists, summarizing evidence for its existence and describing key genes governing its progression, as well as, current methods for studying the genetics of sexual cycles in both cultivable and uncultivated protist groups. [ABSTRACT FROM AUTHOR]

Blooms of the coccolithophore Gephyrocapsa huxleyi (formerly Emiliania huxleyi) are routinely infected by a specific lytic virus (EhV) that kills host cells and drives bloom termination. However, the impact of EhV on nutrient retention and stoichiometric ratios of particulate organic matter remains unknown, limiting our current understanding of the biogeochemical significance of the G. huxleyi–EhV interaction. To tackle this knowledge gap, we surveyed both nitrate, phosphate, and alkalinity consumption by the cells, as well as the elemental composition (C : N : P) of particulate organic matter during infections in culture. We found that within 24 h of infection, alkalinity concentration in the solution stabilized, and nutrient uptake declined to low levels. In parallel, the molar ratio of carbon to nitrogen in particulate organic matter increased by 10–17% and the nitrogen to phosphorus ratio declined by 5–12% relative to the noninfected algal cultures. These variations likely resulted from intracellular lipid accumulation as part of viral infection as well as the differential retention of phosphorus‐rich macromolecular pools in decaying cells, respectively. After infection, as most host cells lysed, we detected a progressive enrichment in phosphorus and nitrogen relative to carbon in the remaining particulate organic matter, which could be attributed to the accumulation of colonizing heterotrophic bacteria with a distinct elemental composition. This study indicate that marine viruses influence the elemental stoichiometry and fate of phytoplankton‐born organic materials in the oceans. [ABSTRACT FROM AUTHOR]

Coccolithophores have global ecological and biogeochemical significance as the most important calcifying marine phytoplankton group. The structure and selection of prokaryotic communities associated with the most abundant coccolithophore and bloom‐forming species, Emiliania huxleyi, are still poorly known. In this study, we assessed the diversity of bacterial communities associated with an E. huxleyi bloom in the Celtic Sea (Eastern North Atlantic), exposed axenic E. huxleyi cultures to prokaryotic communities derived from bloom and non‐bloom conditions, and followed the dynamics of their microbiome composition over one year. Bloom‐associated prokaryotic communities were dominated by SAR11, Marine group II Euryarchaeota and Rhodobacterales and contained substantial proportions of known indicators of phytoplankton bloom demises such as Flavobacteriaceae and Pseudoalteromonadaceae. The taxonomic richness of bacteria derived from natural communities associated with axenic E. huxleyi rapidly shifted and then stabilized over time. The succession of microorganisms recruited from the environment was consistently dependent on the composition of the initial bacterioplankton community. Phycosphere‐associated communities derived from the E. huxleyi bloom were highly similar to one another, suggesting deterministic processes, whereas cultures from non‐bloom conditions show an effect of stochasticity. Overall, this work sheds new light on the importance of the initial inoculum composition in microbiome recruitment and elucidates the temporal dynamics of its composition and long‐term stability. [ABSTRACT FROM AUTHOR]

To evaluate molecular assays for Mpox diagnosis available in various clinical microbiology services in Spain through a quality control (QC) approach. A total of 14 centers from across Spain participated in the study. The Reference Laboratory dispatched eight serum samples and eight nucleic acid extracts to each participating center. Some samples were spiked with Mpox or Vaccinia virus to mimic positive samples for Mpox or other orthopox viruses. Participating centers provided information on the results obtained, as well as the laboratory methods used. Among the 14 participating centers seven different commercial assays were employed, with the most commonly used kit being LightMix Modular Orthopox/Monkeypox (Mpox) Virus (Roche®). Of the 12 centers conducting Mpox determinations, concordance ranged from 62.5% (n = 1) to 100% (n = 11) for eluates and from 75.0% (n = 1) to 100% (n = 10) for serum. Among the 10 centers performing Orthopoxvirus determinations, a 100% concordance was observed for eluates, while for serum, concordance ranged from 87.5% (n = 6) to 100% (n = 4). Repeatedly, 6 different centers reported a false negative in serum samples for Orthopoxvirus diagnosis, particularly in a sample with borderline Ct = 39. Conversely, one center, using the TaqMan™ Mpox Virus Microbe Detection Assay (Thermo Fisher), reported false positives in Mpox diagnosis for samples spiked with vaccinia virus due to cross‐reactions. We observed a positive correlation of various diagnostic assays for Mpox used by the participating centers with the reference values. Our results highlight the significance of standardization, validation, and ongoing QC in the microbiological diagnosis of infectious diseases, which might be particularly relevant for emerging viruses. [ABSTRACT FROM AUTHOR]

This study presents the first detailed description of the upper sedimentary succession of the late Pleistocene and Holocene deposits in the Gulf of San Jorge (Patagonia) based on several hundred kilometers of high‐resolution seismic (sparker) profiles and numerous sediment cores. High‐resolution seismic stratigraphy confirms the existence of a paleo‐fluvial network formed during sea‐level lowstands and buried by central basin estuarine deposits during the last marine transgression. Analyses of lithostratigraphy and radiocarbon ages indicate the onset of subtidal sedimentation at ~14 cal ka bp. Before the onset of subtidal conditions, the first steps of marine incursion seem to have led to the development of lagoonal/wind–tidal flat environments, advocating for a sea‐level stillstand. An abrupt increase in the log(Ti/Ca) ratio in a distinct multi‐centimeter‐thick layer and the identification of a wave‐ravinement surface suggest rapid sea‐level rise in the gulf prior to ~14 cal ka bp, consistent with Meltwater Pulse 1A. Overall, this study highlights the significant impact of sea‐level rise on sedimentation in the gulf from the onset of marine incursions to the mid‐Holocene, as well as the reduced contribution, as currently observed, of riverine inputs due to the progressive diminution and withdrawal of glacial drainage starting before the Holocene. [ABSTRACT FROM AUTHOR]

In this article, we use Set Trimming to obtain the globally optimal design of distillation column trays, that is, the column diameter and the geometrical design of the trays (weir, downcomer, etc.) that minimize mass or cost. We assume that the operating conditions (vapor and liquid flow rates, compositions, temperatures) are given. The design task is, to this day, presented in textbooks as a trial and verification procedure. We show that Set Trimming guarantees global optimality and is amenable to exploring alternative global optima. Compared with the employment of a mixed‐integer nonlinear programming (MINLP) approach using commercial global optimizers, we show that Set Trimming is a more robust option with competitive computational times for individual design problems. It also exhibits a significant reduction in computational effort when alternative optimal solutions are sought. [ABSTRACT FROM AUTHOR]

The process synthesis problem referred to as work and heat exchange networks (WHENs) asks to determine the optimal heat exchanger network intertwined with compressors, expanders, and valves, all integrated into one single network, such that streams with certain initial temperature and pressure attain their temperature and pressure targets at minimum cost. This article presents a procedure that obtains the globally optimal solution of Minimal WHEN systems using an enumeration scheme, using only a few subproblems, each one solved using mathematical programming to global optimality. Minimal structures feature one compression/decompression task and one heat exchange task per stream. In addition, we depart from the ideal gas assumption and use a cubic equation of state for stream properties. Finally, the approach allows for the use of turboexpanders. Four examples are presented to show the effectiveness and accuracy of the proposed method. [ABSTRACT FROM AUTHOR]

Background: The Agility multileaf collimator (MLC) mounted in Elekta linear accelerators features some unique design characteristics, such as large leaf thickness, eccentric curvature at the leaf tip, and defocused leaf sides ('tilting'). These characteristics offer several advantages but modeling them in treatment planning systems (TPSs) is challenging. Purpose: The goals of this study were to investigate the challenges faced when modeling the Agility in two commercial TPSs (Monaco and RayStation) and to explore how the implemented MLC models could be improved in the future. Methods: Four linear accelerators equipped with the Agility, located at different centers, were used for the study. Three centers use the RayStation TPS and the other one uses Monaco. For comparison purposes, data from four Varian linear accelerators with the Millennium 120 MLC were also included. Average doses measured with asynchronous sweeping gap tests were used to characterize and compare the characteristics of the Millennium and the Agility MLCs and to assess the MLC model in the TPSs. The FOURL test included in the ExpressQA package, provided by Elekta, was also used to evaluate the tongue‐and‐groove with radiochromic films. Finally, raytracing was used to investigate the impact of the MLC geometry and to understand the results obtained for each MLC. Results: The geometry of the Agility produces dosimetric effects associated with the rounded leaf end up to a distance 20 mm away from the leaf tip end measured at the isocenter plane. This affects the tongue‐and‐groove shadowing, which progressively increases along the distance to the tip end. The RayStation and Monaco TPSs did not account for this effect, which made trade‐offs in the MLC parameters necessary and greatly varied the final MLC parameters used by different centers. Raytracing showed that these challenging leaf tip effects were directly related to the MLC geometry and that the characteristics mainly responsible for the large leaf tip effects of the Agility were its tilting design and its small source‐to‐collimator distance. Conclusions: The MLC models implemented in RayStation and Monaco could not accurately reproduce the leaf tip effects for the Agility. Therefore, trade‐offs are needed and the optimal MLC parameters are dependent on the specific characteristics of treatment plans. Refining the MLC models for the Agility to better approximate the measured leaf tip and tongue‐and‐groove effects would extend the validity of the MLC model, reduce the variability in the MLC parameters used by the community, and facilitate the standardization of the MLC configuration process. [ABSTRACT FROM AUTHOR]

Competitive game‐based learning within Second Life enables effective teaching of basic radiological anatomy and radiological signs to medical students, with good acceptance and results when students participate voluntarily, but unknown in a compulsory context. The objectives of this study were to reproduce a competitive online game based on self‐guided presentations and multiple‐choice tests in a mandatory format, to evaluate its development and student perceptions compared to a voluntary edition in 2015 (N = 90). In 2016 and 2017, respectively, 191 and 182 third‐year medical students participated in the game as a mandatory course activity. The mean (±SD) score of the game was 74.7% (±19.5%) in 2015, 71.2% (±21.5%) in 2016, and 67.5% (±21.5%) in 2017 (P < 0.01). Participants valued positively the organization and educational contents but found the virtual world less attractive and the game less interesting than in the voluntary edition. The experience globally was rated with 8.2 (±1.5), 7.8 (±1.5), and 7.1 (±1.7) mean points (±SD) in a ten‐point scale, in the 2015, 2016, and 2017 editions, respectively (P < 0.05). Competitive learning games within virtual worlds like Second Life have great learning potential in radiology, but the mean score in the game decreased, acceptance of virtual world technology was lower, and opinion about the game was worse with a compulsory participation, and even worse when dropouts were not allowed. Under the conditions in which this study was conducted, learning games in three‐dimensional virtual environments should be voluntary to maintain adequate motivation and engagement of medical students. [ABSTRACT FROM AUTHOR]

We extend a formulation of the heat exchanger design optimization with fouling modeling to consider the effect of fouling on hydraulics. A shell‐side fouling model was added so the optimization can consider cases with fouling in the tube and shell sides. The focus is the design of heat exchangers with fouling behavior associated with a threshold model, like in crude preheat trains. We solve the optimization problem by using a newly proposed Set Trimming technique. We compare our results with the traditional approach of using fixed fouling factors and the previous approach of not considering the hydraulic impact of fouling. We conclude that considering the deposit thickness leads to more realistic results that are different than the ones obtained using the previous approaches. Moreover, we show that previous approaches can render designs with larger pressure drops than the maximum imposed by the constraints, as well as exchangers with higher areas. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to assess the tolerability and safety of galcanezumab in patients with chronic cluster headache (CH) with up to 15 months of treatment. Background: Chronic CH is a highly debilitating disease with a substantial and unmet medical need. Methods: Patients were randomized to receive placebo or galcanezumab (300 mg) monthly for 12 weeks, followed by an optional 52‐week open‐label extension and 16‐week posttreatment follow‐up (washout). This is a secondary analysis and long‐term follow‐up of a previously conducted clinical trial. The safety analysis included patients who received galcanezumab at any time during the study. Outcomes included adverse events (AEs), discontinuations, laboratory values, vital signs, electrocardiograms (ECGs), and suicidality ratings. Results: A total of 233 patients received at least one galcanezumab dose. The mean exposure was 341 days. Galcanezumab‐treated patients were mostly male (n = 169/233; 72.5%) with a mean age of 44.9 (±10.9) years. Treatment‐emergent adverse events (TEAEs) were reported by 185 patients (n = 185/233; 79.4%), 23 patients (n = 23/233; 9.9%) reported serious adverse events (SAEs), and 18 patients (n = 18/233; 7.7%) discontinued due to AEs. The SAE CH was reported by three patients. The most common TEAEs (>10%) were nasopharyngitis (n = 41/233; 17.6%) and injection site pain (n = 33/233; 14.2%). 27.5% of patients (n = 64/233) had TEAEs related to injection sites. Likely hypersensitivity events, including injection site rash, injection site urticaria, and injection site hypersensitivity were reported (n = 14/233; 6.0%). There were past histories of suicidal ideation (n = 55/237; 23.2%) and suicidal behavior (n = 9/236; 3.8%). During the study, 15 patients (n = 15/230; 6.5%), seven with previous history, reported suicidal ideation. One patient had a nonfatal suicide attempt during the open‐label extension and an aborted attempt during the washout. There were no new safety findings compared with the placebo‐controlled treatment period in laboratory values, vital signs, or ECGs. Conclusions: Galcanezumab 300 mg monthly had a favorable tolerability and safety profile in patients with chronic CH with up to 15 months of treatment. [ABSTRACT FROM AUTHOR]

In this work, the enumeration algorithms presented in Parts I and II for the globally optimal synthesis of minimal and non‐minimal heat exchanger networks are extended to consider non‐isothermal mixing. New mathematical models, including non‐isothermal mixing constraints, are proposed to target the bounds of energy consumption and the binding exchanger minimum approximation temperature. These models are solved using the algorithms, which involve solving systems of equations instead of mathematical programming. Three global optimization strategies are proposed to optimize each enumerated structure, involving the use of a global solver directly, or the use of a Golden Search based on energy consumption and a flowrate optimization model considering non‐isothermal mixing. The flowrate optimization model is reformulated as a convex problem, which is solved by using nonlinear programming or a mathematical programming‐free methodology, that is, solving Karush–Kuhn–Tucker equations. A new Global Optimum Search Algorithm is developed and examples are tested comparing different optimization strategies. [ABSTRACT FROM AUTHOR]

Aims/Purpose: To assess the influence of cataract formation on the lens thickness (LT), anterior (ACS) and posterior (PCS) cortex space and nuclear thickness (NT). Methods: A prospective cross‐sectional study including patients seeking for cataract surgery was performed. The standardized Lens Opacification Classification System (LOCS)‐III was used to classify lens opacities. A control group composed of non‐cataractous patients was also created. In addition, cataract patients were also classified according to the cataract location (presence or absence of cortical, nuclear or posterior subcapsular cataract). Optical biometry was performed to measure LT, ACS, NT and PCS. Propensity score was used to match cataract and non‐cataract patients one‐to‐one for sex, age and axial length. Groups were compared using the Student's t‐test or Yuen's test. Results: A sample of 603 volunteers (403 females, 200 males) aged 59.1 ± 18.8 years was recruited. Before matching, the lens cataract and the non‐cataract group was composed of 361 cataractous and 242 non‐cataractous volunteers. Also, all participants were classified into cortical and non‐cortical cataract groups (226 vs. 377), nuclear and non‐nuclear cataract groups (313 vs. 209) and into subcapsular and non‐subcapsular cataract groups (242 vs. 361). Before matching, cataract groups showed significant (p ≤ 0.003) higher LT (4.52 ± 0.39 vs. 3.94 ± 0.46 mm), ACS (0.75 ± 0.20 vs. 0.58 ± 0.23 mm), NT (3.34 ± 0.23 vs. 3.18 ± 0.25 mm) and PCS (0.42 ± 0.19 vs. 0.37 ± 0.19 mm). After matching, the lens, cortical, nuclear and subcapsular cataract samples were composed of 146, 258, 182 and 226 participants, respectively. Then, no significant (p ≥ 0.08) differences were found for LT, ACS, NT and PCS. Conclusions: Thickness of the lens and/or its main components is not changed due to cataract formation. The progressive lens growth associated to aging might be the main confounding factor misleading the outcomes of previous studies that reported differences in LT between cataractous and non‐cataractous patients. [ABSTRACT FROM AUTHOR]

Introduction: Chronic asthma is a heterogeneous disease, and increased eosinophils have been shown to predict increased asthma exacerbations, especially in adults. Recent recommendations suggest the need for supplemental PPV‐23 vaccination in older children with chronic asthma. Methods: To investigate differences in preschool asthma, our case‐cohort study comprised of 127 children, mean age 47 months (32‐65), with a history of asthma exacerbations requiring more than three courses of systemic steroid bursts and more than six antibiotics courses in the previous year. Results: At baseline, mean antibody titer response to Streptococcus pneumoniae was decreased at 2.6 ± 2 out of 14 serotypes, despite prior complete pneumococcal conjugate vaccine (PCV) vaccinations. All children were readministered pneumococcal vaccinations with PCV‐13 booster and/or PPSV‐23. Mean postvaccination pneumococcal vaccine (PV) titer response was 16 ± 5 out of 23 serotypes. After contacting 91 parents/caretakers, 75 responded with less frequency of corticosteroids and antibiotic use for asthma exacerbations after PV. This group had baseline eosinophil counts of 211 ± 36/µL, while those without improvement were significantly higher at 371 ± 123/µL,*P <.05. There were no significant differences (P >.05) between the two groups from other baseline measures including demography or atopic status. Conclusions: This subset of children with exacerbation‐prone asthma had poor antibody titer response to Streptococcus pneumoniae, even with prior complete PCV‐13 immunization. Identification of low antibody responses to PV serotypes may provide a targeted therapeutic approach to reduce wheezing exacerbations in a precise asthma phenotype in children. [ABSTRACT FROM AUTHOR]

Legius syndrome is characterized by numerous café‐au‐lait macules and intertriginous freckling, but typically lacks the distinctive tumor manifestations of neurofibromatosis type 1. We report two siblings with Legius syndrome and Lisch nodules illustrating the importance of eye surveillance in these patients. [ABSTRACT FROM AUTHOR]

Game‐based learning can have a positive impact on medical education, and virtual worlds have great potential for supporting immersive online games. It is necessary to reinforce current medical students' knowledge about radiological anatomy and radiological signs. To meet this need, the objectives of this study were: to design a competition‐based game in the virtual world, Second Life and to analyze the students' perceptions of Second Life and the game, as well as to analyze the medium‐term retention of knowledge and the potential impact on the final grades. Ninety out of 197 (45.6%) third‐year medical students voluntarily participated in an online game based on self‐guided presentations and multiple‐choice tests over six 6‐day stages. Participants and non‐participants were invited to perform an evaluation questionnaire about the experience and a post‐exposure knowledge test. Participants rated the experience with mean scores equal to or higher than 8.1 on a 10‐point scale, highlighting the professor (9.5 ± 1.1; mean ± SD) and the virtual environment (8.9 ± 1.1). Participants had better results in the post‐exposure test than non‐participants (59.0 ± 13.5 versus 45.3 ± 11.5; P < 0.001) and a lower percentage of answers left blank (6.7 ± 8.4 versus 13.1 ± 12.9; P = 0.014). Competitive game‐based learning within Second Life is an effective and well‐accepted means of teaching core radiological anatomy and radiological signs content to medical students. The higher medium‐term outcomes obtained by participants may indicate effective learning with the game. Additionally, valuable positive perceptions about the game, the educational contents, and the potential benefit for their education were discovered among non‐participants. [ABSTRACT FROM AUTHOR]

Mixotrophic algae that combine photoautotrophy with phagotrophy in a single cell are prevalent in marine ecosystems. Here, we assessed the ability of food ingestion in coccolithophores, an important group of calcifying haptophytes inhabiting the oceans. We tested four species from different coccolithophore lineages (Emiliania huxleyi, Calcidiscus leptoporus, Coccolithus braarudii, and Calyptrosphaera sphaeroidea). For both E. huxleyi and C. leptoporus we included different life phases (haploid and diploid). For C. braarudii we only tested diploid heterococcolithophore cells, while for C. sphaeroidea we only tested haploid holococcolithophore cells. Phagotrophy was assessed using fluorescently labeled bacteria (FLB) as model prey item, under nutrient‐replete and phosphate‐limited conditions. We detected by microscopy ingestion of FLB by all species, except the diploid C. braarudii strain. However, a previous study detected ingestion by haploid cells of C. braarudii. These overall results indicate that mixotrophy and the ability to ingest prey is widespread in coccolithophores. Yet, in all tested species the ingestion of FLB was low (<1% of the population contained prey at all time points over 2 days), namely for E. huxleyi and the diploid cells from C. leptoporus where detection of ingestion was sporadic. Moreover, no clear differences were detected between life phases in E. huxleyi and C. leptoporus under equal circumstances, or between replete and limited growth conditions. [ABSTRACT FROM AUTHOR]

In Part I of this work, the synthesis of minimal heat exchanger networks using the isothermal mixing stage‐wise superstructure was presented. In this Part II, an extension of the algorithm presented in Part I is made to consider networks that allow multiple solutions regarding heat allocation, that is, they have energy loops where heat loads can be rearranged without changing the overall energy consumption. We extend the strategy of our Part I to use a set of nested loops to enumerate the number of units, the structure of matches, the energy consumption, different values of exchanger minimum approximation temperature (EMAT), and different locations where EMAT is active. All the models used are linear and are aided by capital cost evaluations. As in Part I, we claim global optimality based on our conjectures. Literature examples are solved to show the effectiveness of the algorithm. [ABSTRACT FROM AUTHOR]

This article introduces the concept of minimal structure (MSTR) and presents an enumeration algorithm for the synthesis of heat exchanger networks based on MSTR. Minimal Structures refer to a class of heat exchanger networks featuring acyclic heat transfer networks without energy loops. The enumerations used are either exhaustive or smart with a stopping criterion. Without loss of generality we use the isothermal mixing Synheat model, that is, the method applies identically to other superstructures, with likely variations in the optimization models associated to each step. A conjecture is used to state that the algorithm renders solutions that are globally optimal. Literature examples are used to demonstrate the capabilities of the enumeration algorithm. Most of our solutions compare favorably with the best reported ones in literature, with exceptions where the reported solution is not minimal. [ABSTRACT FROM AUTHOR]

Background: The International Classification of Headache Disorders lists different subtypes of medication overuse headache (MOH), according to the medication overused. The aim of this study is to evaluate whether the different subtypes correspond to clinically distinguishable phenotypes in a large population. Method: This descriptive cross‐sectional observational study included 660 patients with MOH referred to headache centers in Europe and Latin America as a part of the COMOESTAS project. Information about clinical features was collected with structured patient interviews and with self‐administered questionnaires for measuring disability, anxiety, and depression. Results: Female/male ratio, body mass index, marital status, and level of education were similar among in subjects enrolled in the 5 centers. The mean age was higher among subjects overusing triptans (T‐MOH) with respect to subjects overusing simple analgesic (A‐MOH). Duration of headache before chronification was longer in T‐MOH (19.2 ± 11.9 years) and in subjects overusing ergotamines (E‐MOH, 17.8 ± 11.7 years) with respect to the A‐MOH group (13.1 ± 10.9; P < .001 and P = .017, respectively) and in T‐MOH with respect multiple drug classes (M‐MOH, 14.9 ± 11.7; P = .030). Migraine Disability Assessment (MIDAS) score was significantly lower in E‐MOH group (33.6 ± 41.6), while T‐MOH group (56.8 ± 40.6) had a significant lower MIDAS score with respect to M‐MOH (67.2 ± 62.5; P = .016 and P = .037, respectively). Prevalence of depression and anxiety was lower in patients overusing T with respect to other groups of patients (χ2  = 10.953, P = .027 and χ2 = 25.725, P < .001, respectively). Conclusion: In this study on a large and very well characterized population of MOH, we describe the distinctive clinical characteristics of MOH subtypes. These findings contribute to more clearly define the clinical picture of a poorly delineated headache disorder. They also provide some insights in the possible trajectories leading to this highly disabling chronic headache, that is classified as a secondary form, but whose occurrence is entirely dependent on an underlying primary headache. [ABSTRACT FROM AUTHOR]

Importance Rare transforming growth factor beta‐induced (TGFBI) gene variants are involved in autosomal dominant corneal dystrophies (CDs) with heterogeneous clinical features. Background: The purpose of this study was to analyse TGFBI gene variants and genotype‐phenotype correlations in a cohort affected by atypical stromal CD. Design Retrospective cohort study (from May 2014 to September 2017). Participants: Thirty‐five individuals from 10 unrelated South European families presenting atypical lattice CD (LCD) were included. Methods: Corneal phenotypes were assessed by slit‐lamp examination and optical coherence tomography (OCT). Contrast sensitivity was measured under mesopic conditions. Genomic DNA was obtained from blood samples, and all 17 TGFBI exons were screened for variants by Sanger sequencing. Main Outcome Measures: p.(L558P) variant of TGFBI gene. Results: The p.(L558P) variant was identified in 22 members of the 10 families diagnosed with atypical LCD, characterized by late‐onset and absence of recurrent erosion syndrome. OCT revealed punctiform deposits in the deep‐mid stroma and normal anterior stroma. This variant was demonstrated to be transmitted with the disease according to autosomal dominant inheritance in most families. Conclusions and Relevance: To the best of our knowledge, we describe a detailed clinical characterization of the largest CD cohort carrying the TGFBI p.(L558P) variant. We propose that the atypical phenotype of this recently reported alteration can be classified as a form of LCD type IV. The results show that OCT and anterior‐posterior analysis of the stromal location of the opacities, along with a genetic analysis of TGFBI, are required to ensure accurate diagnosis and management of CDs. [ABSTRACT FROM AUTHOR]

This article presents a method for the mathematical optimization of the design of heat exchangers including fouling rate modeling for the tube‐side. The description of the fouling rate in crude preheat trains of petroleum distillation units is commonly based on threshold models (Ebert‐Panchal model and its variants). Our formulation of the design problem employs a mixed‐integer linear programing approach; therefore the solution is the global optimum and common nonconvergence drawbacks of mixed‐integer nonlinear programming models are totally avoided. Three different examples are employed to compare the proposed approach with an optimization procedure using fixed fouling resistances. The results indicate that in two problems was possible to obtain design solutions associated to smaller heat exchangers. Additionally, three case studies are also explored to discuss how fouling is related to crude types, pressure drop manipulation, and energy integration. © 2018 American Institute of Chemical Engineers AIChE J, 64: 2089–2102, 2018 [ABSTRACT FROM AUTHOR]

In a recent article, Gonçalves et al., introduced a linear and rigorous methodology for equipment design, in particular shell‐and‐tube heat exchanger. Here, we explore its application to air coolers, a problem that we solve globally for the first time. Because the approach is linear, results are globally optimal. The objective function is the total annualized cost. The constraints include the thermal and hydraulic modeling of the process stream flow in the tube bundle and the air flow through the finned surface. In addition, we worked on reducing computing time, through an analysis of different alternatives for the description of the original discrete variables organized in sets of binary variables. The performance of the proposed approach is illustrated through its comparison with an air cooler described in the literature. © 2017 American Institute of Chemical Engineers AIChE J, 64: 886–903, 2018 [ABSTRACT FROM AUTHOR]

Lacosamide is a new‐generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT. We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration (CVVH) and several AEDs. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high‐performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5–12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half‐life was 21 hours, and the sieving coefficient was 0.8 (± 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH. [ABSTRACT FROM AUTHOR]

The design of heat exchangers, especially shell and tube heat exchangers was originally proposed as a trial and error procedure where guesses of the heat transfer coefficient were made and then verified after the design was finished. This traditional approach is highly dependent of the experience of a skilled engineer and it usually results in oversizing. Later, optimization techniques were proposed for the automatic generation of the best design alternative. Among these methods, there are heuristic and stochastic approaches as well as mathematical programming. In all cases, the models are mixed integer non-linear and non-convex. In the case of mathematical programming solution procedures, all the solution approaches were likely to be trapped in a local optimum solution, unless global optimization is used. In addition, it is very well-known that local solvers need good initial values or sometimes they do not even find a feasible solution. In this article, we propose to use a robust mixed integer global optimization procedure to obtain the optimal design. Our model is linear thanks to the use of standardized and discrete geometric values of the heat exchanger main mechanical components and a reformulation of integer nonlinear expressions without losing any rigor. © 2016 American Institute of Chemical Engineers AIChE J, 63: 1907-1922, 2017 [ABSTRACT FROM AUTHOR]

The minimum interfacial tension to be reached in enhanced oil recovery by surfactant flooding implies the attainment of a so-called optimum formulation. Part 1 of the present review showed that this formulation may be described as a numerical correlation between the involved variables defining the oil, the water, the surfactant and the temperature. Since it is unlikely to find a single surfactant matching the crude/brine/T/P system characteristic of a reservoir, a mixture of at least two surfactant species is always used. The scan technique method to test the mixing requires about ten interfacial tension or phase behavior experiments and results in a single data. Hence, the scan experiments have to be repeated many times to find a minimum tension which is low enough, e.g. 0.001 mN/m, for the given crude oil-brine system. Part 2 of this review has shown that there are many formulation variables and thus too many possibilities to easily choose experimental conditions. Since there is no simple method to select two or more surfactant species, the choice is made from partial experience or intuition, and sometimes at random. The laboratory time and cost to reach an appropriate optimum formulation is often excessive. Part 3 of this review shows that by cleverly using a three-surfactant mixture, the experimental work to attain a very low interfacial tension for a given reservoir case can be considerably reduced. It is a matter of using the available information along a proper sequential step by step path toward the optimum. [ABSTRACT FROM AUTHOR]

Purpose Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. Methods Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. Results Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. Conclusion We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Current methods for assessing children's dietary intake, such as interviewer-administered 24-h dietary recall (24-h DR), are time consuming and resource intensive. Self-administered instruments offer a low-cost diet assessment method for use with children. The present study assessed the validity of the Portuguese self-administered, computerised, 24-h DR ( PAC24) against the observation of school lunch. Methods Forty-one, 7-10-year-old children from two elementary schools, in Lisbon, were observed during school lunch followed by completion of the PAC24 the next day. Accuracy for reporting items was measured in terms of matches, intrusions and omissions; accuracy for reporting amounts was measured in terms of arithmetic and absolute differences for matches and amounts for omissions and intrusions; and accuracy for reporting items and amounts combined was measured in terms of total inaccuracy. The ratio of the estimated weight of food consumed with the actual weight consumed was calculated along with the limits of agreement using the method of Bland and Altman. Results Comparison of PAC24 against observations at the food level resulted in values of 67.0% for matches, 11.5% for intrusions and 21.5% for omissions. The mean for total inaccuracy was 3.44 servings. For amounts, accuracy was high for matches (−0.17 and 0.23 servings for arithmetic and absolute differences, respectively) and lower for omissions (0.61 servings) and intrusions (0.55 servings). PAC24 was found to under-estimate the weight of food on average by 32% of actual intake. Conclusions PAC24 is a lower-burden procedure for both respondents and researchers and, with slight modification, comprises a promising method for assessing diet among children. [ABSTRACT FROM AUTHOR]

Infection with the helminth Schistosoma mansoni results in hepatointestinal granulomatous inflammation mediated by CD4 T cells directed against parasite eggs. The severity of disease varies greatly in humans and mice; however, the genetic basis of such a heterogenous immune response remains poorly understood. Here we show that, despite their close genetic relationship, C57BL/10SnJ (B10) mice developed significantly more pronounced immunopathology and higher T helper 17 cell responses than C57BL/6J (B6) mice. Similarly, live egg-stimulated B10-derived dendritic cells (DCs) produced significantly more IL-1β and IL-23, resulting in higher IL-17 production by CD4 T cells. Gene expression analysis disclosed a heightened proinflammatory cytokine profile together with a strikingly lower expression of Ym1 in B10 versus B6 mice, consistent with failure of B10 DCs to attain alternative activation. To genetically dissect the differential response, we developed and analyzed congenic mouse strains that capture major regions of allelic variation, and found that the level of inflammation was controlled by a relatively small number of genes in a locus mapping to chromosome 4 117-143 MB. Our study has thus identified novel genomic regions that regulate the severity of the schistosome infection by way of controlling the mode of DC activation and consequent CD4 T-cell subset development. [ABSTRACT FROM AUTHOR]

Background & Aims Liver regeneration is a multistage process that unfolds gradually, with different mediators acting at different stages of regeneration. Calcium (Ca2+) signalling is essential for liver regeneration. In hepatocytes, Ca2+ signalling results from the activation of inositol 1,4,5-trisphosphate receptors (InsP3R) of which two of the three known isoforms are expressed (InsP3R-I and InsP3R- II). Here, we investigated the role of the InsP3R-I-dependent Ca2+ signals in hepatic proliferation during liver regeneration. Methods Partial hepatectomy ( HX) in combination with knockdown of InsP3R-I (Adsi RNA-I) was used to evaluate the role of InsP3R-I on liver regeneration and hepatocyte proliferation, as assessed by liver to body mass ratio, PCNA expression, immunoblots and measurements of intracellular Ca2+ signalling. Results Adsi RNA-I efficiently infected the liver as demonstrated by the expression of β-galactosidase throughout the liver lobules. Moreover, this construct selectively and efficiently reduced the expression of InsP3R-I, as evaluated by immunoblots. Expression of Adsi RNA-I in liver decreased peak Ca2+ amplitude induced by vasopressin in isolated hepatocytes 2 days after HX. Reduced InsP3R-I expression prior to HX also delayed liver regeneration, as measured by liver to body weight ratio, and reduced hepatocyte proliferation, as evaluated by PCNA staining, at the same time point. At later stages of regeneration, control hepatocytes showed a decreased expression of InsP3R, as well as reduced InsP3R-mediated Ca2+ signalling, events that did not affect liver growth. Conclusion Together, these results show that InsP3R-I-dependent Ca2+ signalling is an early triggering pathway required for liver regeneration. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose The purpose of this study is to estimate the risk of nonfatal acute myocardial infarction (AMI) associated with traditional NSAIDs (tNSAIDs), non-narcotic analgesics (paracetamol and metamizole), and symptomatic slow-acting drugs in osteoarthritis (SYSADOAs) overall and in different subgroups of patients. Methods We performed a nested case-control study using a Primary Care Database (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria), over the study period, 2001-2007. We included patients aged 40-90 years, with nonfatal AMI and randomly selected controls matched for age, sex and calendar year. Exposure to drugs was assessed within a 30-day window before the index date. Results We did not find an association with nonfatal AMI in patients at low-intermediate background cardiovascular risk (odds ratio = 0.92; 95% confidence interval: 0.76-1.12), whereas there was a moderate significant association among those at high risk (1.28; 1.06-1.54) or when tNSAIDs were used for longer than 365 days (1.43; 1.12-1.82). The greatest risk occurred when these two conditions were combined (1.80; 1.26-2.58). The risk varied across individual tNSAIDs, with ibuprofen (0.95; 0.78-1.16) in the lower and aceclofenac (1.59; 1.15-2.19) in the upper part of the range. Low-dose aspirin did not modify the risk profile showed by any of the individual tNSAIDs examined. Paracetamol (0.84; 0.74-0.95), metamizole (1.06; 0.87-1.29) and SYSADOAs (0.68; 0.47-0.99) were not associated with an increased risk overall or in any subgroup of patients. Conclusions The risk of nonfatal AMI varied with individual tNSAIDs, duration of treatment and background cardiovascular risk. Paracetamol, metamizole and SYSADOAs did not increase the risk in any of the conditions examined. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: Monotherapy with protease‐inhibitors (MPI) may be an alternative to cART for HIV treatment. We assessed the impact of this strategy on immune activation, bacterial translocation and inflammation. Methods: We performed a cross‐sectional study comparing patients on successful MPI (n=40) with patients on cART (n=20). Activation, senescence, exhaustion and differentiation stage in CD4+ and CD8+ T lymphocyte subsets, markers of monocyte activation, microbial translocation, inflammation, coagulation and low‐level viremia were assessed. Results: CD4+ or CD8+ T lymphocyte subset parameters were not significantly different between both groups. Conversely, as compared with triple cART, MPI patients showed a higher proportion of activated monocytes (CD14+ CD16−CD163+ cells, p=0.031), soluble markers of monocyte activation (sCD14 p=0.004, sCD163 p=0.002), microbial translocation (lipopolysaccharide (LPS)‐binding protein; LBP p=0.07), inflammation (IL‐6 p=0.04) and low‐level viremia (p=0.035). In a multivariate model, a higher level of CD14+ CD16−CD163+ cells and sCD14, and presence of very low‐level viremia were independently associated with MPI. Monocyte activation was independently associated with markers of inflammation (IL‐6, p=0.006), microbial translocation (LBP, p=0.01) and low‐level viremia (p=0.01). Conclusions: Patients on MPI showed a higher level of monocyte activation than patients on standard therapy. Microbial translocation and low‐level viremia were associated with the high level of monocyte activation observed in patients on MPI. The long‐term clinical consequences of these findings should be assessed. [ABSTRACT FROM AUTHOR]

Many ultrasonic sensors intended for non‐destructive testing include a plastic or metal element, known as buffer rod, between the ultrasonic transducer and the material under analysis. Buffer rods are often terminated in the form of a conical tip for ultrasonic inspection of liquid‐like substances. The conical tip is carefully shaped in a 45° angle to favour the in phase reception of all the components of the ultrasonic wave reflected at the buffer tip, obtaining thus a maximum amplitude measurement signal. The effect of the buffer rod cone angle on measurement signals is studied in this work. A straightforward approximate formula for the effect of the error angle on measurement signal amplitude is used. Simulations are performed using a two‐dimensional finite differences tool. Measurements are conducted with the same operating conditions and buffer rod materials and dimensions as those defined for both approximate formula evaluation and simulations. Thus, a comparison of the approximate formula, simulation and measurement results are established. Furthermore, the significance of some parameters such as ultrasonic transducer operating frequency and diameter, and buffer rod material are also analysed. The obtained results show that significant loss of the measurement signal amplitude is found only for cone error angles beyond the range of usual machining errors. [ABSTRACT FROM AUTHOR]

Obtaining information on the way human activities impact protected wildlife is not an easy task. Here, we analyze the news published by knowledgeable naturalists in Spain's most prestigious and oldest magazine devoted to the study and conservation of nature, during a 28-year period (1982-2009). We studied the logarithm of the ratio of news published annually on direct (poaching, trapping and poisoning) versus indirect impacts (road casualties, electrocutions and collisions with infrastructure), and it turned out to be negative, strong (5% annual decrease) and statistically significant, suggesting an exponential decrease of the ratio. The decreasing trend was stronger ( λ = 9%) when considering only direct impacts excluding cases of poisoning that showed an increasing trend over time, showing a more realistic idea of the decreasing impact by hunters. Our modelling clearly showed that the decreasing trend in the ratio was explained by the decreasing number of hunting licences active on a yearly basis, controlled by the increase in indirect impacts. In order to validate our results, we compared our analysis with the trend shown by vertebrate admissions to a major rescue centre in eastern Spain from 1994 to 2011. The results of this second analysis showed a trend with a similar inversion of causes of impact but of a stronger magnitude ( λ = 15%). We discuss our findings within the context of a rapidly changing economy, evolving from a rural structure to an industrialized one, and provide some applied conservation recommendations. Indirect impacts caused by infrastructure should be approached, correcting technical problems, particularly black spots where mortality cases concentrate. Direct impacts, notably the rise in the rate of poisoning cases, need to be handled, managing the causes of increase of generalist predators, such as habitat structure, promoting the return of top predators and removing sources of subsidy, better than only fighting poaching by force. [ABSTRACT FROM AUTHOR]