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In the microfabrication processes, it is necessary to examine the quality of the structures to ensure the whole process runs smoothly. However, the examination process of pattern defects is interrupted during the fabrication of high-aspect-ratio microstructures. The inevitable pattern defects arise from capillary forces which occur during the liquid drying process. In this paper, a new method that enables us to fix the microstructures with gel to restrict deformations before the rinsed liquid drying process has been proposed. It is effective to avoid the capillary forces by preventing the formation of the liquid level. The process parameters, types of gel, gel time and observation time were discussed and the flatness and thickness of the gel layer could be controlled. A series of high-aspect-ratio microstructures were fixed in good condition by gel. [ABSTRACT FROM AUTHOR]

• Anti-drug antibodies (ADA) complicate protein replacement therapy for monogenic disorders. • Antigen based oral tolerance induction can prevent the formation of ADAs. • Oral tolerance to antigen depends on the induction of regulatory T cells. • Plant-based antigen expression for oral tolerance has been tested in hemophilia and Pompe models. Protein based therapeutics have successfully improved the quality of life for patients of monogenic disorders like hemophilia, Pompe and Fabry disease. However, a significant proportion of patients develop immune responses towards intravenously infused therapeutic protein, which can complicate or neutralize treatment and compromise patient safety. Strategies aimed at circumventing immune responses following therapeutic protein infusion can greatly improve therapeutic efficacy. In recent years, antigen-based oral tolerance induction has shown promising results in the prevention and treatment of autoimmune diseases, food allergies and can prevent anti-drug antibody formation to protein replacement therapies. Oral tolerance exploits regulatory mechanisms that are initiated in the gut associated lymphoid tissue (GALT) to promote active suppression of orally ingested antigen. In this review, we outline general perceptions and current knowledge about the mechanisms of oral tolerance, including tissue specific sites of tolerance induction and the cells involved, with emphasis on antigen presenting cells and regulatory T cells. We define several factors, such as cytokines and metabolites that impact the stability and expansion potential of these immune modulatory cells. We highlight preclinical studies that have been performed to induce oral tolerance to therapeutic proteins or enzymes for single gene disorders, such as hemophilia or Pompe disease. These studies mainly utilize a transgenic plant-based system for oral delivery of antigen in conjugation with fusion protein technology that favors the prevention of antigen degradation in the stomach while enhancing uptake in the small intestine by antigen presenting cells and regulatory T cell induction, thereby promoting antigen specific systemic tolerance. [ABSTRACT FROM AUTHOR]

A "state of the Art" lecture titled "Hemostatic Defects in Congenital Disorders of Glycosylation" was presented at the ISTH 2022 congress. Congenital disorders of glycosylation (CDGs) are rare, inherited, metabolic diseases. The diagnosis of CDG is often challenging due to the broad variety of disorders, the variable level of severity, and phenotypic heterogeneity. Most CDGs are multisystem disorders, and neurologic involvement is frequent. Patients with CDG often present coagulation abnormalities characterized by low levels of procoagulant or anticoagulant factors. Antithrombin deficiency is frequently associated with factor XI deficiency and less frequently with a protein C, protein S, or factor IX deficiency. This coagulation profile differs from those observed in liver failure, disseminated intravascular coagulation, and vitamin K deficiency, and so, should prompt the physician to consider a diagnosis of CDG. Coagulopathy can lead to thrombotic and/or hemorrhagic complications. In patients with phosphomannomutase 2 deficiency (the most common CDG), thrombotic events are more frequent than hemorrhagic events. In other types of CDGs, both hemorrhagic and thrombotic events have been described. Overall, the hemostatic balance in these patients is precarious and necessitates close monitoring in a setting of acute illness with greater metabolic needs. Here, we review the most relevant hemostatic defects observed in CDG and their clinical implications. Finally, we summarize relevant new data on this topic presented at the ISTH 2022 congress., (© 2023 The Authors.)

Many have argued that the burning of fossil fuels is an essential component of the socionatural metabolism of capitalism as we know it, and that the anthropogenic climate change it is causing may finally bring about capitalism’s end. In this paper, I explore the potential for, instead, a societal shift towards renewable energy sources as the dominant components of global energy supplies to provide a socioecological ‘fix’ to current forms of crisis. In so doing, I develop a notion of an integrated socioecological fix that combines the central elements of Harvey’s ‘spatial fix’ and of neoliberal environmental ‘fixes’ that maintain accumulation by enrolling new elements of nonhuman nature into circuits of capital. I argue, first, that the capital intensiveness and spatial extensiveness of any such transition could provide a global-scale, if temporary, socioecological fix to capitalist crisis tendencies; and, second, that the creation of global scale geographies of renewable energy production, distribution, and consumption would necessarily involve powerful new rounds of investment in, and claims on, rural areas. These impacts would likely fall disproportionately on rural areas, where land values are lowest and existing users often have less power and fewer formal land rights. [ABSTRACT FROM AUTHOR]

ReRAM’s low voltage and low current programmability are attractive features to solve the scaling issues of conventional floating gate Flash. However, read instability in ReRAM is a critical issue, due to random telegraph noise (RTN), sensitivity to disturb and retention. In this work, the array-level characteristics of read stability in 50 nm Al x O y ReRAM are investigated and a circuit technique to improve stability is proposed and evaluated. First, in order to quantitatively assess memory cell stability, a method of stability characterization is defined. Next, based on this methodology, a proposal to improve read stability, called “stability check loop” is evaluated. The stability check loop is a stability verification procedure, by which, instability improvement of 7×, and read error rate improvement of 40% are obtained. [ABSTRACT FROM AUTHOR]

A multiband multi-echo (MBME) sequence is implemented and compared to a matched standard multi-echo (ME) protocol to investigate the potential improvement in sensitivity and spatial specificity at 7 T for resting state and task fMRI. ME acquisition is attractive because BOLD sensitivity is less affected by variation in T2*, and because of the potential for separating BOLD and non-BOLD signal components. MBME further reduces TR thus increasing the potential reduction in physiological noise. In this study we used FSL-FIX to clean ME and MBME resting state and task fMRI data (both 3.5 mm isotropic). After noise correction, the detection of resting state networks improves with more non-artifactual independent components being observed. Additional activation clusters for task data are discovered for MBME data (increased sensitivity) whereas existing clusters become more localized for resting state (improved spatial specificity). The results obtained indicate that MBME is superior to ME at high field strengths. [ABSTRACT FROM AUTHOR]

Introduction Prophylaxis is effective in reducing the number of bleeding episodes in patients with severe or moderately severe haemophilia A and B, including those with inhibitors. However, data, predominantly from observational studies, suggest more equivocal effects on health-related quality of life ( HRQoL). Aim To examine the impact of prophylaxis on HRQoL from prospective clinical trials. Methods We performed a systematic literature review of clinical trials evaluating the efficacy of prophylaxis with factor VIII, FIX or bypassing agents. Trials assessing HRQoL via validated instruments were selected and summarized. Results Thirteen trials (haemophilia A [ n = 8]; haemophilia B [ n = 2]; inhibitors [ n = 3]) met all inclusion criteria. HRQoL instruments included the EQ-5D, SF-36, Haem-QoL-A, Haem-A-QoL, Haemo-QoL and CHO- KLAT. Improvements in HRQoL following prophylaxis were observed with the EQ- VAS, SF-36 and haemophilia-specific instruments in adult patients and were associated with reduced pain, fewer restrictions in physical activities and better general health. Prophylaxis led to statistically significant or clinically meaningful HRQoL improvement in six trials and non-significant improvement in four trials; two trials found no improvement and one reported no data. Despite study differences, consistent trends suggested that patients previously treated solely on-demand and those who experienced marked reductions in the frequency of bleeding with prophylaxis had a greater improvement in HRQoL. Conclusion Contrary to findings of observational studies, the results from the majority of prospective trials using validated instruments showed positive trends for improved HRQoL with prophylaxis in adults. [ABSTRACT FROM AUTHOR]

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In [1], for an element of a finite full transformation semigroup of index m and period r, the authors obtained a unique factorisation α = θγ such that Shift(θ) ∩ Shift(γ) = Ø, where θ is a permutation of order r and γ is an m-potent element. The main aim of this article is to examine whether the condition Shift(θ) ∩ Shift(γ) = Ø in Theorem 4 [1] can be removed or not in the case n = m + r. [ABSTRACT FROM AUTHOR]

The success of cell microencapsulation technology in tissue engineering and protein delivery applications depends on the viability and functionality of the encapsulated cells, which in turn are dependent upon cell/matrix interactions. In this work, we compared the viability of cord blood-derived mesenchymal stromal cells (CB MSCs), engineered to secrete factor IX (FIX) for hemophilia treatment, and encapsulated in arginine-glycine-aspartate (RGD)-alginate versus fibrinogen-alginate microcapsules. We evaluated the effect of the biomimetic matrix on cell attachment, proliferation, and secretion of FIX. Compared with nonsupplemented alginate matrix, RGD-alginate significantly enhanced the viability of the encapsulated MSCs. Further, cells in RGD-alginate displayed distinct attachment morphology, thus suggesting that RGD-alginate can potentially be used for the encapsulation of MSCs in tissue engineering applications that require enhanced cell attachment and viability. However, our data also showed that RGD-alginate microcapsules, in contrast to fibrinogen-alginate microcapsules, did not significantly improve cell proliferation of or FIX secretion by encapsulated MSCs. Our findings suggest that evidence of cell attachment alone may not accurately predict the functionality of cells in biomimetic microcapsules. [ABSTRACT FROM AUTHOR]

CRISPR/Cas9-mediated site-specific insertion of exogenous genes holds potential for clinical applications. However, it is still infeasible because homologous recombination (HR) is inefficient, especially for non-dividing cells. To overcome the challenge, we report that a homology-independent targeted integration (HITI) strategy is used for permanent integration of high-specificity-activity Factor IX variant (F9 Padua, R338L) at the albumin (Alb) locus in a novel hemophilia B (HB) rat model. The knock-in efficiency reaches 3.66%, as determined by droplet digital PCR (ddPCR). The clotting time is reduced to a normal level four weeks after treatment, and the circulating factor IX (FIX) level is gradually increased up to 52% of the normal level over nine months even after partial hepatectomy, demonstrating the amelioration of hemophilia. Through primer-extension-mediated sequencing (PEM-seq), no significant off-target effect is detected. This study not only provides a novel model for HB but also identifies a promising therapeutic approach for rare inherited diseases., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Abstract: We conducted an experiment examining the influence of guarantee compensation and other service recovery tactics on customers’ justice perceptions across hotel failures of varying severity. Our study was driven by a noted lack of research into the benefits of service guarantees as a recovery tool and past findings suggesting that hotel management may be relying too heavily on guarantee compensation to recover failures. Findings suggest that compensation, fix and failure severity jointly influence customers’ perceptions of distributive justice. Perceived employee effort has a large influence on guests’ perceptions of interactional justice, however, it does not interact with failure severity to influence justice. [Copyright &y& Elsevier]

. Long-term, continuous prophylaxis for haemophilia began at a modest scale during the 1950s and 1960s in Sweden and The Netherlands. In the face of high cost and impediments to the performance of longitudinal, well-designed studies, it was decades before prophylaxis was considered to be the best practice in countries that could afford the cost. In 2007 and 2011, the only prospective randomized studies ever performed confirmed what large cohort studies in Europe had long since shown. Today, focus is on when to start prophylaxis, dosing and when/if to stop. Retrospective comparisons of the Swedish and Dutch cohorts, where different strategies have been used, indicate that a costly, high-dose regimen improves outcome, but not dramatically. A prospective comparison is now underway. Treatment, clinical outcome, clotting factor consumption and socioeconomic parameters will be compared between the two strategies. Results are expected to provide greater insight into the long-term consequences of the different prophylactic treatment strategies. The economic justification for prophylaxis has been addressed in several studies with varying results. While the majority (implicitly) suggest that prophylaxis is not cost effective at conventional willingness to pay for additional units in health thresholds, their results vary markedly. Closer inspection suggests that the primary reasons results differ include different definitions of prophylaxis, clotting factor price, discount rates, choice of outcome measures and time horizon. [ABSTRACT FROM AUTHOR]

Abstract: This paper introduces the evolution of the STEP protocol: the first Chinese securities information exchange standard, which is of full compatibility to the world de-facto FIX protocol and is officially issued in 2004. The challenges of applying STEP to the China''s stock market are also described. We propose a practical solution to address these challenges. Some trading businesses on the Chinese market based on the solutions are also described. Finally, the future of the STEP and the prospects of its application are presented. [Copyright &y& Elsevier]

Abstract: Over the past forty years the availability of coagulation factor replacement therapy has greatly contributed to the improved care of people with hemophilia. Following the blood-borne viral infections in the late 1970s and early 1980, caused by coagulation factor concentrates manufactured using non-virally inactivated pooled plasma, the need for safer treatment became crucial to the hemophilia community. The introduction of virus inactivated plasma-derived coagulation factors and then of recombinant products has revolutionized the care of these people. These therapeutic weapons have improved their quality of life and that of their families and permitted home treatment, i.e., factor replacement therapy at regular intervals in order to prevent both bleeding and the resultant joint damage (i.e. primary prophylaxis). Accordingly, a near normal lifestyle and life-expectancy have been achieved. The main current problem in hemophilia is the onset of alloantibodies inactivating the infused coagulation factor, even though immune tolerance regimens based on long-term daily injections of large dosages of coagulation factors are able to eradicate inhibitors in approximately two-thirds of affected patients. In addition availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of this complication. The major challenges of current treatment regimens, such the short half life of hemophilia therapeutics with need for frequent intravenous injections, encourage the current efforts to produce coagulation factors with more prolonged bioavailability. Finally, intensive research is devoted to gene transfer therapy, the only way to ultimately obtain cure in hemophilia [ABSTRACT FROM AUTHOR]

The piecewise exponential (PEXP) model for the reliability of multiple repairable systems is considered, and classic (maximum likelihood) and Bayesian inference are discussed under different model assumptions. In particular, inference using empirical and hierarchical Bayesian approaches are discussed. The PEXP model assumes that the times between failure are independent and exponentially distributed, but the mean is allowed to either increase or decrease with each failure. It can be an appropriate model for repairable systems in the context of reliability growth, specifically, test, analyze, and fix (TAAF), where the failure intensity remains constant as long as the system is working and can take discrete jumps at the time of a failure. It can also be applied when failures cause damage to the system, while system reliability remains constant during operation. By contrast, the nonhomogeneous Poisson process assumes that the reliability changes continuously and is unaffected by a failure. The application of this model to a real data set is presented under the hierarchical Bayesian approach and the classic and parametric empirical Bayes approach. [ABSTRACT FROM AUTHOR]

The sensitivity of APTT reagents to deficiencies of factors VIII, IX, XI and XII varies because of their composition. The APTT is used as a screening test for these factors, and a deficiency should manifest with a prolongation to the APTT, which may trigger the need for specific factor assays to be performed. The suitability of APTT reagents to detect mild deficiencies can be assessed by the analysis of the APTT of plasma, which has an increasing concentration of the factor in question. The APTT responsiveness can be determined from the intersection of the curve and the upper limit of the APTT normal reference range for that APTT reagent. We assessed the APTT responsiveness (in U/dl) to factors VIII, IX and XI of four APTT reagents; Actin FS (Siemens), Synthasil (IL), STA-PTTA (Stago) and Dapttin (Technoclone). Actin FS was the most sensitive reagent to mild reductions of factors VIII, IX and XI [Correction added on 26 October 2010, after first online publication: Synthasil was corrected to Actin FS]. STA-PTTA showed less sensitivity than Synthasil and Actin FS; Dapttin was insensitive to mild deficiencies of factors IX and XI and should not be used as a screening test. Both Synthasil and Actin FS are acceptable reagents to screen for reduced factors VIII, IX and XI, and the number of mildly reduced factors not diagnosed will be limited. [ABSTRACT FROM AUTHOR]

In limited feedback Transmit Beamforming for MISO systems, the most goals is to respect the constraints of the resources of the feedback channel (bandwidth and power). In the prior work systems, each user quantizes her channel state information (CSI) and fed back the corresponding number of bits to the base station every channel coherence time. Then, for a large number of users and a fixed number of feedback bits per user, the total number of feedback bits is large and the goal is not respected. In this paper, we show that the preference is to fix the total number of feedback bits. Accordingly, the number of users and the number of the feedback per user will be variable. And the number of active users is selected arbitrary from a large number of users. To analyze and validate the performance of this proposed idea, we are applying it to some techniques of transmitting Beamforming such as "the opportunistic Beamformnig (OBF)" and "the switched Sub Codebook (SSC)". Moreover, we study these two techniques with introducing the Schmidt algorithm (SA) to control the generated weights. [ABSTRACT FROM AUTHOR]

Haemophilia B is one of the most common inherited bleeding disorders and has a well understood pathophysiology. Our understanding of the molecular genetics of the disease has allowed the development of comprehensive carrier and prenatal diagnosis for this single gene disorder. Continuing technological developments improve our ability to provide genetic analysis in a rapid and cost-effective manner. This guideline aims to provide advice on current best laboratory practice when approaching genetic diagnosis of haemophilia B. [ABSTRACT FROM AUTHOR]

Recombinant human FIX (rFIX) was evaluated in 28 subjects, including 26 with mild, moderate, or severe haemophilia B and two haemophilia B carriers undergoing 36 surgical procedures. Preoperative rFIX dose was highly correlated with postinfusion FIX activity, r =0.61, P =0.0158. Peri- and post-operative estimated blood loss was similar to that expected in non-haemophilic individuals, and haemostasis was rated as excellent or good in 34 of 35 (97.1%) of the operative procedures. Transfusions were required in five of 36 (13.9%) procedures, including one liver transplantation, and three knee and one hip arthroplasties. Adverse events occurred in 15 of 28 (53.6%) subjects, but there were no perioperative haemorrhages, thromboembolic events, coagulation activation, viral transmission, or inhibitor formation. A transient low-responding FIX inhibitor developed in one subject preoperatively, but required no change in treatment and resolved 15 months later. Thus, rFIX was found to be safe and effective in achieving haemostasis in subjects with FIX deficiency undergoing surgery. [ABSTRACT FROM AUTHOR]

Haemophilia is an ideal condition for gene therapy because of its monogenetic character and the fact that it requires only a small amount of the expressed protein to achieve palliation. To date, research in the field of gene therapy for haemophilia has largely relied on retroviruses, adenoviruses and adeno-associated viruses as transfer vectors and the major aims will be to achieve stable longlasting in vivo expression of factors VIII or IX (FVIII or FIX) at therapeutic levels. Two clinical trials have been approved by the US Food and Drug Administration (FDA), using miniadenovirus FVIII and the intrahepatic and intramuscular delivery of adeno-associated virus FIX. In the third millennium, haemophilia treatment should encompass more ambitious goals through gene replacement, to result in permanent and safe haemophilia ‘eradication’, making haemophilia a part of the history of medicine. [ABSTRACT FROM AUTHOR]

Carrier detection and prenatal testing for haemophilia B in Oriental populations have been hampered by the lack of informative markers within the factor IX (FIX) gene. We detected a T/C nucleotide variation at nucleotide 32770 in the poly-A region of the FIX gene in the mother of a haemophilia B child. Analysis of 139 unrelated alleles revealed a heterozygosity rate of 0·193, thus offering an additional marker for linkage analysis. Together with two other polymorphic sites (5′ MseI and 3′ HhaI) found in Chinese and Thai populations, these polymorphisms were useful in 66% of the families studied. [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., Competing Interests: TL received consulting fees from Pola Chemical Industries, Japan, and speaker honoraria from Sanofi Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lopes, Nogueira and Rios.)

Introduction: Hemophilia A (HA) or B (HB) is an X-linked recessive disorder caused by a defect in the factor VIII (FVIII) or factor IX (FIX) gene which leads to the dysfunction of blood coagulation. Protein replacement therapy (PRT) uses recombinant proteins and plasma-derived products, which incurs high cost and inconvenience requiring routine intravenous infusions and life-time treatment. Understanding of detailed molecular mechanisms on FVIII gene function could provide innovative solutions to amend this disorder. In recent decades, gene therapeutics have advanced rapidly and a one-time cure solution has been proposed., Areas Covered: This review summarizes current understanding of molecular pathways involved in blood coagulation, with emphasis on FVIII's functional role. The existing knowledge and challenges on FVIII gene expression, from transcription, translation, post-translational modification including glycosylation to protein processing and secretion, and co-factor interactions are deciphered and potential molecular interventions discussed., Expert Opinion: This article reviews the potential treatment targets for HA and HB, including antibodies, small molecules and gene therapeutics, based on molecular mechanisms of FVIII biosynthesis, and further, assessing the pros and cons of these various treatment strategies. Understanding detailed FVIII protein synthesis and secretory pathways could provide exciting opportunities in identifying novel therapeutics to ameliorate hemophilia state.