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The availability of fixed nitrogen limits overall agricultural crop production worldwide. The so-called modern "green revolution" catalyzed by the widespread application of nitrogenous fertilizer has propelled global population growth. It has led to imbalances in global biogeochemical nitrogen cycling, resulting in a "nitrogen problem" that is growing at a similar trajectory to the "carbon problem". As a result of the increasing imbalances in nitrogen cycling and additional environmental problems such as soil acidification, there is renewed and increasing interest in increasing the contributions of biological nitrogen fixation to reduce the inputs of nitrogenous fertilizers in agriculture. Interestingly, biological nitrogen fixation, or life's ability to convert atmospheric dinitrogen to ammonia, is restricted to microbial life and not associated with any known eukaryotes. It is not clear why plants never evolved the ability to fix nitrogen and rather form associations with nitrogen-fixing microorganisms. Perhaps it is because of the large energy demand of the process, the oxygen sensitivity of the enzymatic apparatus, or simply failure to encounter the appropriate selective pressure. Whatever the reason, it is clear that this ability of crop plants, especially cereals, would transform modern agriculture once again. Successfully engineering plants will require creating an oxygen-free niche that can supply ample energy in a tightly regulated manner to minimize energy waste and ensure the ammonia produced is assimilated. Nitrogen-fixing aerobic bacteria can perhaps provide a blueprint for engineering nitrogen-fixing plants. This short review discusses the key features of robust nitrogen fixation in the model nitrogen-fixing aerobe, gamma proteobacteria Azotobacter vinelandii, in the context of the basic requirements for engineering nitrogen-fixing plants. [ABSTRACT FROM AUTHOR]

Gram-negative bacteria use the T6SS to eject effectors into prey cells, aided by delivery domains. Recently uncovered by Carobbi et al. , a new delivery domain, PIX, allowed the identification of hundreds of new effectors. They are order- and function-specific and exclusively orphan effectors, raising novel questions in the field. [ABSTRACT FROM AUTHOR]

The availability of fixed nitrogen limits overall agricultural crop production worldwide. The so-called modern “green revolution” catalyzed by the widespread application of nitrogenous fertilizer has propelled global population growth. It has led to imbalances in global biogeochemical nitrogen cycling, resulting in a “nitrogen problem” that is growing at a similar trajectory to the “carbon problem”. As a result of the increasing imbalances in nitrogen cycling and additional environmental problems such as soil acidification, there is renewed and increasing interest in increasing the contributions of biological nitrogen fixation to reduce the inputs of nitrogenous fertilizers in agriculture. Interestingly, biological nitrogen fixation, or life’s ability to convert atmospheric dinitrogen to ammonia, is restricted to microbial life and not associated with any known eukaryotes. It is not clear why plants never evolved the ability to fix nitrogen and rather form associations with nitrogen-fixing microorganisms. Perhaps it is because of the large energy demand of the process, the oxygen sensitivity of the enzymatic apparatus, or simply failure to encounter the appropriate selective pressure. Whatever the reason, it is clear that this ability of crop plants, especially cereals, would transform modern agriculture once again. Successfully engineering plants will require creating an oxygen-free niche that can supply ample energy in a tightly regulated manner to minimize energy waste and ensure the ammonia produced is assimilated. Nitrogen-fixing aerobic bacteria can perhaps provide a blueprint for engineering nitrogen-fixing plants. This short review discusses the key features of robust nitrogen fixation in the model nitrogen-fixing aerobe, gamma proteobacteria Azotobacter vinelandii, in the context of the basic requirements for engineering nitrogen-fixing plants.

Key Clinical Message: In hemophilia patients undergoing cardiac surgery, ROTEM® and Quantra® viscoelastic tests are useful to monitor perioperative hemostatic status and a single dose of rIX‐FP is safe and avoids any hemorrhagic or thrombotic complication. Cardiac surgery poses a high hemostatic risk in patients with hemophilia. We present the first case of an adult patient with hemophilia B on treatment with albutrepenonacog alfa (rIX‐FP) who underwent surgery for acute coronary syndrome. Treatment with rIX‐FP made it possible to perform the surgery safely. [ABSTRACT FROM AUTHOR]

Key Clinical Message In hemophilia patients undergoing cardiac surgery, ROTEM® and Quantra® viscoelastic tests are useful to monitor perioperative hemostatic status and a single dose of rIX‐FP is safe and avoids any hemorrhagic or thrombotic complication. Abstract Cardiac surgery poses a high hemostatic risk in patients with hemophilia. We present the first case of an adult patient with hemophilia B on treatment with albutrepenonacog alfa (rIX‐FP) who underwent surgery for acute coronary syndrome. Treatment with rIX‐FP made it possible to perform the surgery safely.

A multiband (MB) echo‐planar imaging (EPI) sequence is compared to a multiband multiecho (MBME) EPI protocol to investigate differences in sensitivity for task functional magnetic resonance imaging (fMRI) at 3 T. Multiecho sampling improves sensitivity in areas where single‐echo‐EPI suffers from dropouts. However, It requires in‐plane acceleration to reduce the echo train length, limiting the slice acceleration factor and the temporal and spatial resolution Data were acquired for both protocols in two sessions 24 h apart using an adapted color‐word interference Stroop task. Besides protocol comparison statistically, we performed test–retest reliability across sessions for different protocols and denoising methods. We evaluated the sensitivity of two different echo‐combination strategies for MBME‐EPI. We examined the performance of three different data denoising approaches: "Standard," "AROMA," and "FIX" for MB and MBME, and assessed whether a specific method is preferable. We consider using an appropriate autoregressive model order within the general linear model framework to correct TR differences between the protocols. The comparison between protocols and denoising methods showed at group level significantly higher mean z‐scores and the number of active voxels for MBME in the motor, subcortical and medial frontal cortices. When comparing different echo combinations, our results suggest that a contrast‐to‐noise ratio weighted echo combination improves sensitivity in MBME compared to simple echo‐summation. This study indicates that MBME can be a preferred protocol in task fMRI at spatial resolution (≥2 mm), primarily in medial prefrontal and subcortical areas. [ABSTRACT FROM AUTHOR]

As it is presently employed, grounding permits grounding many things from one ground. In this paper, I show why this is a mistake by pushing for a uniqueness principle on grounding. After arguing in favor of this principle, I say something about it and kinds of grounding, discuss a similar principle, and consider its import on a formal feature of grounding, ontology, and ontological simplicity. [ABSTRACT FROM AUTHOR]

Background: Mild haemophilia (MH) is mainly characterized by haemorrhages secondary to surgery/invasive procedures or trauma. Haemostatic treatment in MH ranges from on demand to short prophylaxis according to the type of bleeding events and the basal clotting factor level. Oral surgery and dental extractions can represent a frequent haemostatic challenge in MH requiring appropriate treatment. However, only few studies on limited numbers of patients are available in the literature regarding the implications of dental management in patients with MH. Objectives: The purpose of the study was to evaluate the impact of dental care on the burden of haemostatic treatment in patients affected by MH. Methods: We conducted a retrospective multicentre study evaluating adult patients with MH regularly examined at the Haemophilia Treatment Centres (HTCs) of the Saint‐Luc University Hospital, Brussels (Belgium) and of Paolo Giaccone Hospital, Palermo (Italy). The population consisted of 107 male patients with MH, with a mean age of 39 years (range 18–81 years). Results: The majority of patients (86/107, 79%) needed at least one treatment within the study period, and 44% (38/86) of them received haemostatic therapy for dental care. Haemostatic therapy in our study varied from antifibrinolytic therapy alone and perioperative factor replacement to the absence of treatment at all. The great majority of oral interventions (27/42, 64%) were managed with clotting factor concentrate. Conclusion: This study demonstrates that dental care currently represents a major reason for haemostatic treatments in patients with MH. Maintaining good oral health appears as a priority to minimize avoidable replacement therapy and optimize resources. [ABSTRACT FROM AUTHOR]

Introduction: The B‐Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). Aim: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. Methods: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1–5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5–< 40 IU/dL), age 12.1 years, disease. Twenty‐nine participants had inhibitors or a history of inhibitors. Three versions of the EQ‐5D instrument were used as a measure of QoL: proxy (ages 4–7), youth (ages 8–15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range‐of‐motion (ROM) for elbows, knees and ankles was assessed using a four‐point scale, from which a composite score was calculated. Results: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ‐5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. Conclusion: The B‐Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB. [ABSTRACT FROM AUTHOR]

Blood coagulation is a vital physiological mechanism to stop blood loss following an injury to a blood vessel. This process starts immediately upon damage to the endothelium lining a blood vessel, and results in the formation of a platelet plug that closes the site of injury. In this repair operation, an essential component is the coagulation factor IX (FIX), a serine protease encoded by the F9 gene and whose deficiency causes hemophilia B. If not treated by prophylaxis or gene therapy, patients with this condition are at risk of life-threatening bleeding episodes. In this sense, a deep understanding of the FIX protein and its activated form (FIXa) is essential to develop efficient therapeutics. In this study, we used well-studied structural analysis techniques to create a residue interaction network of the FIXa protein. Here, the nodes are the amino acids of FIXa, and two nodes are connected by an edge if the two residues are in close proximity in the FIXa 3D structure. This representation accurately captured fundamental properties of each amino acid of the FIXa structure, as we found by validating our findings against hundreds of clinical reports about the severity of HB. Finally, we established a machine learning framework named HemB-Class to predict the effect of mutations of all FIXa residues to all other amino acids and used it to disambiguate several conflicting medical reports. Together, these methods provide a comprehensive map of the FIXa protein architecture and establish a robust platform for the rational design of FIX therapeutics.

It is well established that head motion and physiological processes (e.g. cardiac and breathing activity) should be taken into consideration when analyzing and interpreting results in fMRI studies. However, even though recent studies aimed to evaluate the performance of different preprocessing pipelines there is still no consensus on the optimal strategy. This is partly due to the fact that the quality control (QC) metrics used to evaluate differences in performance across pipelines have often yielded contradictory results. Furthermore, preprocessing techniques based on physiological recordings or data decomposition techniques (e.g. aCompCor) have not been comprehensively examined. Here, to address the aforementioned issues, we propose a framework that summarizes the scores from eight previously proposed and novel QC metrics to a reduced set of two QC metrics that reflect the signal-to-noise ratio and the reduction in motion artifacts and biases in the preprocessed fMRI data. Using this framework, we evaluate the performance of three commonly used practices on the quality of data: 1) Removal of nuisance regressors from fMRI data, 2) discarding motion-contaminated volumes (i.e., scrubbing) before regression, and 3) low-pass filtering the data and the nuisance regressors before their removal. Using resting-state fMRI data from the Human Connectome Project, we show that the scores of the examined QC metrics improve the most when the global signal (GS) and about 17% of principal components from white matter (WM) are removed from the data. Finally, we observe a small further improvement with low-pass filtering at 0.20 Hz and milder variants of WM denoising, but not with scrubbing. [ABSTRACT FROM AUTHOR]

PurposeTo systematically evaluate the benefits of reducing and fixing displaced lesser trochanter (LT) of trochanteric fractures and when this procedure is worth the effect.MethodsFrom database establishment through March 2021, four online databases (PubMed, Cochrane, Embase, and Web of Science) were searched for relevant literature that investigated reduction and fixation for displaced LT of trochanteric fractures. The papers were then screened by two reviewers independently and in duplicate according to prior inclusion and exclusion criteria. Demographic data as well as data on fracture types, surgical protocols, and surgical outcomes were recorded, analyzed, and interpreted.ResultsTotal 10 clinical studies with 928 patients were included, in which 48 cases had intact LT and 880 cases involved the displaced LT, of which 196 (22.27%) cases underwent reduction and fixation for LT while the rest of 684 (77.73%) cases not. In these studies, complications were evaluated as a more applicable predictive parameter for operation than postoperative hip function.ConclusionIt was beneficial to reduce and fix the displaced LT when one of the conditions below occurred: displacement distance of LT ≥2 cm, quantity of comminuted LT fragments ≥2, and range of LT fragments in medial wall ≥75%; the fracture line of LT fragments reaching or exceeding the midline of the posterior wall.

Aims: Hemophilia B (HB) is a rare congenital disorder characterized by bleeding-related complications which are managed by prophylactic or post-bleeding event ("on-demand") replacement of clotting factor IX (FIX). The standard of care for severe HB is life-long prophylaxis with standard half-life (SHL) or extended half-life (EHL) products given every 2-3 or 7-14 days, respectively. FIX treatment costs in the US have been investigated, but the lifetime costs of HB treatment have not been well characterized, particularly related to the impact of joint health deterioration and associated health resource utilization. We developed a decision-analytic model to explore outcomes, costs and underlying cost drivers associated with FIX treatment options over the lifetime of an adult with severe or moderately severe HB. Materials and methods: With participation from clinicians, health technology assessment specialists and patient advocates, a Markov model was constructed to estimate bleeding events and costs associated with health states including "bleed into joint", "bleed not into joint", "no bleed" and "death". Sub-models of joint health were based on 0, 1, or ≥2 areas of chronic joint damage. US third-party payer and societal perspectives were considered with a lifetime horizon; sensitivity analyses tested the robustness of primary findings. Results: Total adult lifetime costs per patient with severe and moderately severe HB were $21,086,607 for SHL FIX prophylaxis, $22,987,483 for EHL FIX prophylaxis, and $20,971,826 for on-demand FIX treatment. For FIX prophylaxis, the cost of FIX treatment accounts for >90% of the total HB treatment costs. Conclusions: This decision analytic model demonstrated significant economic burden associated with the current HB treatment paradigm. [ABSTRACT FROM AUTHOR]

This article examines the technology of futures supply, which includes three directions in its structure: trading, clearing (clearing organization, position calculations), supply process (non-deliverable contracts, deliveries of goods at a specific elevator, electronic warehouse document management, electronic digital signature system). The schemes of application of futures instruments at grain elevators have been singled out. It was found out that the domestic system of grain accounting at grain elevators loses much in comparison with the system of custodial (depositary) accounting, in centralization, in the presence of unified rules, as well as in other parameters. It is proposed to use market makers to provide a continuous flow of exchange liquidity (that is, to provide liquidity to both buyers and sellers at the same time). Methodology. The scientific research is based on the developments of domestic and foreign economists, as well as own observations and conclusions. Results. It turned out that, in theory, every trader can become a market maker by placing a pending limit order in the trading blotter. Specific examples are given, with figures, of how exactly the same product can be traded on a low-liquid and a high-liquid exchange. Three scenarios are proposed and it is concluded that the probability of the third scenario is quite high. Practical implications. It is proved that the Last Look system is one of the methods for solving the problem of market maker risk. It is shown that the main data transfer protocols between the exchange and its institutional participants can be Fix and Fast Data Protocols. The advantages and disadvantages of Fix and Fast data protocols are highlighted. It was found that the Fast protocol is actively implemented on trading floors, but it is still inferior in prevalence to the "classic" protocol Fix. Value/originality. Ensure the use of futures instruments in elevators. It is proposed to use market makers to provide a continuous flow of exchange liquidity.

Since the cloning and characterization of the factor VIII (FVIII) and factor IX genes in the mid- 1980s, gene therapy has been perceived as having significant potential for the treatment of severe hemophilia. Now, some 35 years later, these proposals are close to being realized through the licensing of the first clinical gene therapy product. Adeno- associated viral vector- mediated gene therapy for hemophilia A and B has been extensively investigated in preclinical models over the past 20 years, and since 2011, there has been increasing evidence in early phase clinical trials that this thera- peutic strategy can provide safe and effective rescue of the hemostatic phenotype in severe hemophilia. As the uptake of hemophilia gene therapy progresses, it is clear that many aspects of the gene therapy process require crucial laboratory support to ensure safe and effective outcomes from his new therapeutic paradigm. These labo- ratory contributions extend from evaluations of the gene therapy vehicle, assess- ments of the patient immune status for the vector, and ultimately the performance of assays to determine the hemostatic benefit of the gene therapy and potentially of its long- term safety on the host genome. As with many aspects of past hemophilia care, the safe and effective delivery of gene therapy will require an informed and coordi- nated contribution from laboratory science. [ABSTRACT FROM AUTHOR]

Hemophilia B (HB) is a rare congenital disorder characterized by bleeding-related complications which are managed by prophylactic or post-bleeding event ("on-demand") replacement of clotting factor IX (FIX). The standard of care for severe HB is life-long prophylaxis with standard half-life (SHL) or extended half-life (EHL) products given every 2–3 or 7–14 days, respectively. FIX treatment costs in the US have been investigated, but the lifetime costs of HB treatment have not been well characterized, particularly related to the impact of joint health deterioration and associated health resource utilization. We developed a decision-analytic model to explore outcomes, costs and underlying cost drivers associated with FIX treatment options over the lifetime of an adult with severe or moderately severe HB. With participation from clinicians, health technology assessment specialists and patient advocates, a Markov model was constructed to estimate bleeding events and costs associated with health states including "bleed into joint", "bleed not into joint", "no bleed" and "death". Sub-models of joint health were based on 0, 1, or ≥2 areas of chronic joint damage. US third-party payer and societal perspectives were considered with a lifetime horizon; sensitivity analyses tested the robustness of primary findings. Total adult lifetime costs per patient with severe and moderately severe HB were $21,086,607 for SHL FIX prophylaxis, $22,987,483 for EHL FIX prophylaxis, and $20,971,826 for on-demand FIX treatment. For FIX prophylaxis, the cost of FIX treatment accounts for >90% of the total HB treatment costs. This decision analytic model demonstrated significant economic burden associated with the current HB treatment paradigm. [ABSTRACT FROM AUTHOR]

Objectives: In hemophilia A the presence of non-neutralizing antibodies (NNAs) against Factor VIII (FVIII) may predict the development of neutralizing antibodies (inhibitors) and accelerate the clearance of administrated FVIII concentrates. This systematic review aimed to assess: (1) the prevalence and incidence of NNAs in patients with congenital hemophilia without inhibitors and (2) the association between NNAs and patient and treatment characteristics.Methods: We conducted a search in MEDLINE, Embase, Web of Science and the Cochrane database. We included cross-sectional and longitudinal studies reporting on NNAs in patients with hemophilia A and B, who were inhibitor-negative at the start of the observation period. Data were extracted on: hemophilia type and severity, patient and treatment characteristics, NNA prevalence and incidence, NNA assays and inhibitor development. Two independent reviewers performed study selection, data extraction and risk of bias assessment, using adapted criteria of the Joanna Briggs Institute. Studies were classified as high-quality when ≥5/9 criteria were met. NNA assays were classified as high-quality when both quality criteria were met: (1) use of positive controls and (2) competition with FVIII to establish FVIII-specificity. We reported NNA prevalence and incidence for each study. The pooled NNA prevalence was assessed for well-designed studies in previously treated patients, employing high-quality NNA assays.Results: We included data from 2,723 inhibitor-negative patients with hemophilia A, derived from 28 studies. Most studies were cross-sectional (19/28) and none reported on NNAs in hemophilia B. Study design was of high quality in 16/28 studies and the NNA assay quality was high in 9/28 studies. Various NNA assays were used, predominantly ELISA (18/28) with different cut-off values. We found a large variety in NNA prevalence (Range, 0–100%). The pooled NNA prevalence in high-quality studies was 25% (95% CI, 16–38%). The incidence of new NNA development was reported in one study (0.01 NNA per person-exposure day).Conclusion: This systematic review identified studies that were heterogeneous in study design, patient population and NNA assay type, with NNA prevalence ranging from 0 to 100% in inhibitor-negative patients with hemophilia A. The pooled NNA prevalence was 25% in high-quality studies including only previously treated patients and performing high-quality NNA assays.

The Fix for precious metals is a global pricing benchmark that provides pricing and liquidity provision for market participants. We exploit the gradual change in the century old auction process to quantify the efficiencies related to more transparent pricing. Our focus is in the market impact of this change on exchange listed products. We find that reforms to the Fix have reduced quoted and effective bid‐ask spreads and improved overall market depth. The results imply a positive spillover effect stemming from timelier and more accurate pricing information. The conditions under which we observe the benefits from transparency are related to product liquidity and the degree of market segmentation. [ABSTRACT FROM AUTHOR]

Objectives: In hemophilia A the presence of non-neutralizing antibodies (NNAs) against Factor VIII (FVIII) may predict the development of neutralizing antibodies (inhibitors) and accelerate the clearance of administrated FVIII concentrates. This systematic review aimed to assess: (1) the prevalence and incidence of NNAs in patients with congenital hemophilia without inhibitors and (2) the association between NNAs and patient and treatment characteristics. Methods: We conducted a search in MEDLINE, Embase, Web of Science and the Cochrane database. We included cross-sectional and longitudinal studies reporting on NNAs in patients with hemophilia A and B, who were inhibitor-negative at the start of the observation period. Data were extracted on: hemophilia type and severity, patient and treatment characteristics, NNA prevalence and incidence, NNA assays and inhibitor development. Two independent reviewers performed study selection, data extraction and risk of bias assessment, using adapted criteria of the Joanna Briggs Institute. Studies were classified as high-quality when ≥5/9 criteria were met. NNA assays were classified as high-quality when both quality criteria were met: (1) use of positive controls and (2) competition with FVIII to establish FVIII-specificity. We reported NNA prevalence and incidence for each study. The pooled NNA prevalence was assessed for well-designed studies in previously treated patients, employing high-quality NNA assays. Results: We included data from 2,723 inhibitor-negative patients with hemophilia A, derived from 28 studies. Most studies were cross-sectional (19/28) and none reported on NNAs in hemophilia B. Study design was of high quality in 16/28 studies and the NNA assay quality was high in 9/28 studies. Various NNA assays were used, predominantly ELISA (18/28) with different cut-off values. We found a large variety in NNA prevalence (Range, 0–100%). The pooled NNA prevalence in high-quality studies was 25% (95% CI, 16–38%). The incidence of new NNA development was reported in one study (0.01 NNA per person-exposure day). Conclusion: This systematic review identified studies that were heterogeneous in study design, patient population and NNA assay type, with NNA prevalence ranging from 0 to 100% in inhibitor-negative patients with hemophilia A. The pooled NNA prevalence was 25% in high-quality studies including only previously treated patients and performing high-quality NNA assays. [ABSTRACT FROM AUTHOR]

Introduction: Certain haemophilia carriers demonstrate an increased bleeding tendency, mainly related to clotting factor deficiency. No study has so far formally compared the bleeding phenotype of women and girls with mild FVIII or FIX deficiency and associated management with that of male patients affected by mild haemophilia A and B. Material and methods: We retrospectively evaluated 44 women and girls with mild FVIII or FIX deficiency (FVIII or FIX 0.05‐0.5 IU/mL) and 77 male patients with mild haemophilia A or B and compared them with respect to clotting factor level, age at and trigger for diagnosis, as well as treatment modalities. Results: After excluding gender‐related haemorrhagic symptoms, haemophilia carriers with plasma factor levels in the mild haemophilia range and male patients affected by mild haemophilia present a comparable haemorrhagic profile, mainly characterized by mucocutaneous and postinjury bleeding. Haemophilia carriers with clotting factor deficiency, however, distinguish themselves in terms of later age at diagnosis, higher mean factor levels and trigger for diagnosis. Conclusions: Women and girls with mild FVIII or FIX deficiency should be considered as mild haemophilia patients and have access to care and management inspired from male haemophilia patients while integrating differences and specificities. Larger international studies comparing the clinical presentation and treatment modalities of mild clotting FVIII and FIX deficiencies in both haemophilia males and females should be encouraged. [ABSTRACT FROM AUTHOR]

This paper traces the transformative travels of the metaphor of the 'fix' across the unbounded terrain of geographical political economy. It argues for taking the fix seriously as a root metaphor of the field, a signifier of its history and theory-cultures. Critically excavating the entwined genealogies of the metaphor and the field, it illuminates several historically successive and thematic moments of 'fix thinking', including: the spatial fix (1980s); institutional and spatio-temporal fixes of regulationist-theoretical approaches (1990s); and the scalar fix of state rescaling theory (2000s). It reviews these stages and their broader intellectual and political implications for critical geographical scholarship. [ABSTRACT FROM AUTHOR]

Purpose: Colon mucinous carcinomas (MUCs) have two morphological patterns: (i) glands lined by mucinous epithelium with direct contact to the stroma (FIX) and (ii) carcinoma cells floating in mucin (FLO). In this study, we evaluated the prognostic value of these patterns. Methods: Digital images were captured from the 38 MUC's tissue sections. A grid with 140 points was laid over the computer screen. Totally, 100 points, falling on tumor cells floating in mucin (FLO patterned cells) or on cells contacting stroma (FIX patterned cells), were counted. Tumors were grouped according to the median value of the FIX patterned cells. Cases with more than this value were grouped as FIX and less were grouped as FLO cases. The prognostic value of FIX and FLO pattern was evaluated. Results: The median for FIX patterned cells was 66%, and the cases with lower values than this were grouped as FLO (N = 18; 47.37%), while the rest were grouped as FIX cases. There was no significant difference between FIX and FLO cases for overall survival cases (p = 0.167). For FIX cases, 62.7 and 51.3% of the patients were alive at second and third years, while this was 78.9 and 72.4% for the FLO group, respectively. Conclusions: This is the first study using a quantitative methodology depending on count pointing to evaluate FIX/FLO feature of MUCs to the best of our knowledge, although we could not observed any prognostic and clinicopathologic relationship statistically. This distinctive feature should be studied in larger cohorts with prognostic information, with a quantitative method, like the one that was applied in this study, in order to achieve strict conclusions. [ABSTRACT FROM AUTHOR]

In securities trading, low latency helps investors take the leading position in the market. Conventionally, market data is decoded with software running on general computers. However, the serial structure of software and complex operating system scheduling cause high latency. This paper designs an accelerator for decoding market data based on field-programmable gate array (FPGA). We propose a pipeline in the accelerator, where every part works independently and parallelly. Furthermore, we present a mechanism for encoding templates, which avoids reconstructing the accelerator and decreases the cost when the template is renewed. We evaluate this accelerator with real Financial Information eXchange (FIX) messages and FIX Adapting for Streaming (FAST) templates, attaining an average latency of 447 ns. [ABSTRACT FROM AUTHOR]

National critical infrastructure networks, such as banks and industrial control systems (ICSs), can be serious damaged in the event of a security incident. Therefore, in all these major infrastructures, closed networks are constructed to cut off the attack path. However, owing to the emergence of cloud, Internet of Things (IoT), and artificial intelligence (AI) services, network interconnection is rapidly increasing; thus, many major infrastructure networks can no longer be called closed networks. The ICS, which was previously a strictly closed network, is now usually called Industrial Internet of Things (IIoT) and exhibits many changes, such as smart factories and remote control. Many payment modules use the financial network through IoT or AI-assisted services. In this massive connected environment, the existing closed network defense system may cause difficulties in providing the service. Therefore, there is a need for technology that can continuously monitor the possibility of advanced attacks. In this paper, we define the normal-behavior-based rules from the perspective of network forensics and conduct visualization studies to detect all possible attacks against the control protocol DNP3 (Distributed Network Protocol) and the financial protocol called FIX (Finance Information Exchange). Thus, we detected suspicious network packets on the ICS network and the financial network and identified abnormal behavior that could be the basis of serious attacks. [ABSTRACT FROM AUTHOR]

This case report presents two cases (boys) of severe haemophilia A. After repeated doses of deficient coagulation factor (FVIII) inhibitors (antibody) have been detected. The presence of inhibitors significantly impairs treatment of haemophilia since it causes decreased treatment efficacy and increased probability of severe bleeding. A possible solution might be the immune tolerance treatment (ITT) with often high success rate. To improve patients' comfort during ITI treatment with frequent intravenous applications, it is almost necessary to place a venous port catheter which also helps to decrease potential risk of infectious complications. First boy has been successfully treated with ITI, whereas parents of the second boy have been refusing venous port implantation as well as ITT treatment itself. [ABSTRACT FROM AUTHOR]

Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently themost serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication. [ABSTRACT FROM AUTHOR]

One of the most common and unwanted side effects during oral anticoagulant therapy (OAT) is bleeding complications. In rare cases, vitamin K antagonist (VKA)-related bleeding events are associated with mutations affecting the F9 propeptide at amino acid position 37 due to a substitution of alanine to either valine or threonine. Based on our actual cohort of 18 patients, we update the knowledge on this rare phenotype and its origin. A founder mutation for both variants was reconfirmed by haplotype analysis of intronic and extragenic short tandem repeat (STR) polymorphisms with a higher prevalence in Switzerland than in other regions of Europe. Screening of healthy individuals for the presence of these F9 gene mutations did not identify any of these variants, thus proving the rare occurrence of this genotype. Furthermore, both variants were expressed in vitro and warfarin dose responses were studied. Our warfarin dose response analysis confirmed higher sensitivity of both variants to warfarin with the effect being more apparent for Ala37Thr. Thus, although F9 propeptide mutation-associated hypersensitivity to VKA is a rare phenomenon, awareness towards this bleeding phenotype is important to identify patients at risk. [ABSTRACT FROM AUTHOR]

Plasma-derived proteins are a subset of relevant biotherapeutics also known as “well-characterized biologicals”. They are enriched from plasma through several steps of physical and biochemical methodologies, reaching the regulatory accepted standards of safety, levels of impurities, activity and lot-to-lot consistency. Final products accepted for commercialization are submitted to tight analytical, functional and safety controls by a number of different approaches that fulfill the requirements of sensitivity and reliability. We report here the use of a multianalytical approach for the comparative evaluation of different lots of Factor IX isolated from plasma preparations and submitted or not to a step of nanofiltration. The approach include, among the other, proteomic techniques based on both MALDI-TOF and LC-MS Orbitrap mass spectrometry, circular dichroism for structural characterization, chromatographic and electrophoretic techniques, ELISA and functional assays based on clotting activity and binding to known anticoagulants. Comparative data obtained on two sets of nanofiltered and non-nanofiltered lots with different final activity show that the products have substantially overlapping profiles in terms of activity, contaminants, structural properties and protein content, suggesting that the proposed multianalytical approach is robust enough to be used for the routine validation of clinical lots. [ABSTRACT FROM AUTHOR]

Low-wage labour migration from lower- to higher-income economies has become a precondition for capital accumulation. As a part of this, neoliberal actors (businesses and states) strive to actively produce migrants with a strong work ethic. They do this in numerous ways. In this paper, we draw upon labour process theory to argue that a ‘mobility–immobility dynamic’ is a major way capital now controls precarious workers. The mobility–immobility dynamic relates to low-wage workers’ need to move (and often circulate) internationally but, once they have moved, a desire by businesses and states to keep them in place. The fixing of migrants both across space (through transnational mobility) and in place (through immobility) underlines the importance of a multi-scalar approach to understanding the control of the transnational working-class. We draw on evidence from European horticulture – 36 in-depth interviews with migrant workers, employers and community stakeholders in Norway and the United Kingdom – to highlight the mobility–immobility dynamic in practice. [ABSTRACT FROM AUTHOR]

The impact of agricultural land use on the composition of dissolved organic matter (DOM) and its effects on the aquatic carbon cycle are still largely unknown. A sensor for dissolved DOM in stream ecosystems based on fluorescence measurement was developed. It’s an easy to use handheld optical system for online monitoring of DOM under field-conditions. For the determination of DOM two indices are used, namely the freshness index (BIX) and the fluorescence index (FIX).

This review summarizes the evidence that collagen IV binding is physiologically important, and that the extravascular compartment of FIX is composed of type IV collagen. As we have previously demonstrated, 7 days post-infusion, FIXWT (BeneFIX) is able to control bleeding as well as the same dosage of Alprolix in hemophilia B mice, tested using the saphenous vein bleeding model (Alprolix is a chimeric FIX molecule joined at its C terminus to a Fc domain). Furthermore, we have shown that in hemophilia B mice, doses of BeneFIX or Alprolix (up to a dose of 150 IU/kg) have increased bleeding-control effectiveness in proportion to the dose up to a certain limit: higher doses are no more effective than the 150 IU/kg dose. These studies suggest that in hemophilia B mice, tested using the saphenous vein bleeding model, three things are true: first, extravascular FIX is at least as important for coagulation as is circulating FIX; second, measuring circulating levels of FIX may not be the best criterion for designing new "longer lasting" FIX molecules; and third, trough levels are less diagnostic for FIX therapy than they are for FVIII therapy. [ABSTRACT FROM AUTHOR]

Background The paradigm™2 and 4 phase 3 clinical trials investigated the safety and efficacy of nonacog beta pegol, a recombinant glyco PEGylated factor IX ( FIX) with extended half-life, in previously treated haemophilia B patients. Aim These post hoc analyses investigated the bleeding patterns in target joints. Methods Patients randomized to 40 or 10 IU kg−1 once weekly prophylaxis who had at least one target joint were included. Baseline demographics and disease-specific data were collected. Bleeding patterns were assessed, and an International Society on Thrombosis and Haemostasis ( ISTH) definition of target joints was used. Results A total of 67% and 8% of patients in the 40 and 10 IU kg−1 arm, respectively, did not experience target joint bleeds during the paradigm™2 trial. Twenty-four target joints were recorded in each prophylaxis arm at baseline. During the paradigm™2 trial, no bleeds were reported in 17 (71%) and 7 (29%) target joints in the 40 and 10 IU kg−1 arms respectively. All target joint bleeds in the 40 IU kg−1 once weekly prophylaxis arm were controlled with a single injection of 40 IU kg−1 nonacog beta pegol. By the latest ISTH definition, 90% and 58% of target joints in the 40 and 10 IU kg−1 arms, respectively, were no longer considered target joints at the end of the paradigm™2 trial. At the end of the paradigm™4 extension trial, all target joints in the 40 IU kg−1 arm were no longer considered target joints. Conclusion Routine prophylaxis with 40 IU kg−1 once weekly nonacog beta pegol has the potential for effective management of target joint bleeds in haemophilia B patients. [ABSTRACT FROM AUTHOR]