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Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate). In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin. Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated. These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs. Clinicaltrials.gov NCT04231435 on January 18, 2020.

Fedratinib is an oral and selective Janus kinase 2 inhibitor that is indicated for treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Fedratinib is metabolized by cytochrome P450s (CYPs), primarily CYP3A4. The objective of this study was to determine the effects of the strong CYP3A4 inducer rifampin and moderate CYP3A4 inducer efavirenz on the pharmacokinetics of single doses of fedratinib. This Phase 1, open-label, two-part study (Part 1 for rifampin and Part 2 for efavirenz) was conducted in healthy adult men and women. A single dose of fedratinib (500 mg) was administered on Day 1. Participants received rifampin 600 mg daily or efavirenz 600 mg daily on Days 9–18. On Day 17, a single dose of fedratinib (500 mg) was coadministered with rifampin or efavirenz. Plasma fedratinib concentrations were measured using validated liquid chromatography–tandem mass spectrometry. Maximum observed plasma fedratinib concentrations were lowered by approximately 70% and 30% during coadministration with rifampin or efavirenz, respectively, compared with fedratinib alone. Geometric means of fedratinib area under the plasma concentration–time curve from 0 to infinity were decreased by 81% (90% confidence interval [CI], 77–83%) and 47% (90% CI, 40–53%) during coadministration with rifampin or efavirenz, respectively. Fedratinib was generally well tolerated when administered alone or in combination with rifampin or efavirenz. Significant reductions in fedratinib exposure were observed in the presence of strong or moderate CYP3A4 inducers. These results suggest that agents that are strong or moderate inducers of CYP3A4 should be avoided when coadministered with fedratinib. NCT03983239 (Registration date: June 12, 2019).

The miniaturization of microchips is always driving force for revolution and innovation in the electronic industry. When the pitch of bumps is getting smaller and smaller the ball size has to be gradually reduced. However the reliability of smaller ball size is getting weaker and weaker, so some traditional methods such as capillary underfilling, corner bonding and edge bonding process have been being implemented in board level assembly process to enhance drop and thermal cycling performance. These traditional processes have been increasingly considered to be bottleneck for further miniaturization because the completion of these processes demands more space. So the interest of eliminating these processes has been increased. To meet this demand, YINCAE has developed solder joint encapsulant adhesives for ball bumping applications to enhance solder joint strength resulting in improving drop and thermal cycling performance to eliminate underfilling, edge bonding or corner bonding process in the board level assembly process. In this paper we will discuss the ball bumping process, the reliability such as strength of solder joints, drop test performance and thermal cycling performance.

Hemiparesis is progressive muscle weakness in one half of the body, commonly observed in traumatic brain injury or stroke patients. Usually, physiotherapists design in-person assistive exercises to restore muscle strength and range of motion for affected side of the patient. Alternatively, functional electrical stimulation (FES) devices have also been used, though the equipment is expensive, non-portable, and provides limited configurability for personalized rehabilitation. This paper presents a low-cost, open architecture framework that enables: a) Remote programming of muscle stimulation routine by therapist; b) Delivery of FES sequence to patient wirelessly, and c) Provide quantitative feedback (through Electromyogram (EMG)) on dynamics of exercised muscle with progressive rehabilitation of the patient. The extensible framework overcomes the major drawback of expensive, closed commercial systems, thereby allowing integration of multiple sensors to monitor muscle function. Rehabilitation efficacy feedback will allow an opportunity to personalize rehabilitation and increase patient compliance.

Power system state estimation is heavily subjected to measurement error, which comes from the noise of measuring instruments, communication noise, and some unclear randomness. Traditional weighted least square (WLS), as the most universal state estimation method, attempts to minimize the residual between measurements and the estimation of measured variables, but it is unable to handle the measurement error. To solve this problem, based on random matrix theory, this paper proposes a data-driven approach to clean measurement error in matrix-level. Our method significantly reduces the negative effect of measurement error, and conducts a two-stage state estimation scheme combined with WLS. In this method, a Hermitian matrix is constructed to establish an invertible relationship between the eigenvalues of measurements and their covariance matrix. Random matrix tools, combined with an optimization scheme, are used to clean measurement error by shrinking the eigenvalues of the covariance matrix. With great robustness and generality, our approach is particularly suitable for large interconnected power grids. Our method has been numerically evaluated using different testing systems, multiple models of measured noise and matrix size ratios., Comment: has been accepted by IEEE trans on Power Systems

Objective: To report 2 cases of nonoperable intracranial bleeding associated with apixaban managed by 3-factor prothrombin complex concentrate (PCC3). Case Summaries: Case 1 presented with a 1.3-cm left parieto-occipital hemorrhage and a thin subdural hematoma (SDH) on the left tentorium of the brain about 6 hours after his last dose of apixaban. Case 2 presented with a 4-mm left parafalcine SDH with time of most recent apixaban dose unknown. The patients received 24.9 to 25.5 U/kg of PCC3 with none to 1 U fresh frozen plasma (FFP) and demonstrated minimal or no progression in lesions measured by repeat computed tomography (CT) after treatment. One patient was discharged to a skilled nursing facility after 8 days; the other patient was discharged to home after 18 days. Discussion: Apixaban has no specific antidote. Current bleeding management strategies are based on expert opinion. The risks and benefits for differing strategies are unclear, and little clinical experience for managing apixaban-associated intracranial bleeding has been reported to date. These cases describe the clinical use of PCC3 to manage parieto-occipital and subdural hemorrhage associated with apixaban in events not requiring surgical intervention. Conclusion: In these 2 cases, 25 U/kg PCC3, with none to one unit FFP, ceased apixaban-associated intracranial bleeding without apparent thrombogenic complications.

Solder joint encapsulant adhesives have been successfully used to enhance the strength of solder joints and improve thermal cycling as well as drop performance in finished products. The use of solder joint encapsulant adhesives can eliminate the need for underfill materials and the underfill process altogether, thus simplifying rework, which results in a lower cost of ownership. Solder joint encapsulant adhesives include: low temperature and high temperature solder joint encapsulant adhesives, and their derivatives. Each solder joint encapsulant adhesive has: unfilled and filled solder joint encapsulant adhesives, and solder joint encapsulant paste. Each solder joint encapsulant product has been designed for different applications. In this paper, we are going to discuss the details and future of solder joint encapsulant adhesives.

3D packaging has recently become very attractive because it can provide more flexibility in device design and supply chain, reduce the gap between silicon die and organic substrate, help miniaturize devices and meet the demand of high speed, provide more memory, more function and low cost. With the advancement of 3D packaging, the bump height is now down from 80μ to 10μ. When the bump diameter is 20–40μ and height 10μ, the process and reliability are obvious issues. It is well known that underfill can enhance the reliability for regular flip chip, however underfill won't help assembly process. In order to resolve some difficulties that 3D packaging faces, YINCAE Advanced Materials, LLC has developed solderable anisotropic conductive adhesives for 3D package applications. In this paper we will discuss the assembly process and reliability in detail.

The Biopharmaceutical Classification System (BCS), which is a scientific approach to categorize active drug ingredient based on its solubility and intestinal permeability into one of the four classes, has been used to set the pharmaceutical quality standards for drug products in western society. However, it has received little attention in the area of Chinese herbal medicine (CHM). This is likely, in part, due to the presence of multiple active components as well as lack of standardization of CHM. In this report, we apply BCS classification to CHMs provisionally as a basis for establishing improved in vitro quality standards. Based on a top-200 drugs selling list in China, a total of 31 CHM products comprising 50 official active marker compounds (AMCs) were provisionally classified according to BCS. Information on AMC content and doses of these CHM products were retrieved from the Chinese Pharmacopoeia. BCS parameters including solubility and permeability of the AMCs were predicted in silico (ACD/Laboratories). A BCS classification of CHMs according to biopharmaceutical properties of their AMCs is demonstrated to be feasible in the current study and can be used to provide a minimum set of quality standards. Our provisional results showed that 44% of the included AMCs were classified as Class III (high solubility, low permeability), followed by Class II (26%), Class I (18%), and Class IV (12%). A similar trend was observed when CHMs were classified in accordance with the BCS class of AMCs. Most (45%) of the included CHMs were classified as Class III, followed by Class II (16%), Class I (10%), and Class IV (6%); whereas 23% of the CHMs were of mixed class due to the presence of multiple individual AMCs with different BCS classifications. Moreover, about 60% of the AMCs were classified as high-solubility compounds (Class I and Class III), suggesting an important role for an in vitro dissolution test in setting quality control standards ensuring consistent biopharmaceutical quality for the commercially available CHM products. That is, provisionally, more than half of the AMCs of the top-selling CHMs included in this study would be candidates for a bioequivalence (BE) biowaiver, based on WHO recommendations and EMEA guidelines. Thus a dissolution requirement on these AMCs would represent a significant advance in the pharmaceutical quality of CHM today.

Silicon dioxide is normally used as filler in underfill. The thermal conductivity of underfill is less than 1 w/mk, which is not able to meet the current flip chip application requirements such as 3D stacked multi-chips packaging. No matter which direction the heat will be dissipated through PCB or chip, the heat has to pass through the underfill in 3D stacked chips. Therefore the increase of thermal conductivity of underfill can significantly enhance the reliability of electronic devices, particularly in 3D package devices. YINCAE Advanced Materials, LLC has developed a novel high thermal conductive underfill for flip chip applications. Diamond powder is selected as filler in our product system due to its excellent thermal stability and high thermal conductivity. Three different diamond powders have been used as filler in underfill, the thermal conductivity has been increased many times (up to 6w/mk), which can greatly reduce the thermal stress for solder joint. The flowability, pressure cooking test and other properties of underfill have been characterized and investigated. All details will be discussed in this paper.

More and more Land Grid Array (LGA) components are being used in electronic devices such as smartphones, tablets and computers. In order to enhance LGA mechanical strength and reliability, capillary flow underfill is used to improve reliability. However, due to the small gap, it is difficult for capillary underfill to flow into the LGA at SMT level. Due to cost considerations, there are usually no pre-heating underfill or cleaning flux residue processes at the SMT assembly line. YINCAE solder joint encapsulant SMT 256 has been successfully used with solder paste for LGA assembly. Solder joint encapsulant is used in in-line LGA soldering process with enhanced reliability. It eliminates the underfilling process and provides excellent reworkability. The shear strength of solder joint is stronger than that of underfilled components. The thermal cycling performance using solder joint encapsulant is much better than that using underfill. Bottom IC of POP has been studied for further understanding of LGA assembly process parameters. All details such as assembly process, drop test and thermal cycling test will be discussed in the full paper.

With the increasing demand of device miniaturization, high speed, more memory, more function, low cost, and more flexibility in device design and manufacturing chain, YINCAE has published a white paper on a first individual solder joint encapsulant which can eliminate underfilling process with at least five times solder joint increase and provide more flexibility for fine pitch and high density application. In order to meet the demand of manufacturing of high speed and low cost, YINCAE has invented a room temperature stable and jettable solder joint encapsulant adhesive – SMT 266. The invention of SMT 266 has allowed our customers to have more flexibility in their high-speed production line such as worry free on the work life of adhesive and workable jetting process. After being used in the customer field for a few years, the implementation of SMT266 has been approved improving the process yield, eliminating voids and cracks in solder joint, eliminating head-in-pillow issue for large component during lead free reflow process. The results from thermal cycling test indicated that the first failure cycles using SMT266 is high up to 6000 cycles, at least 4000 – 5000 cycles higher than other processes. The pull strength is 1.5 times higher than using solder paste plus underfilling process. All reliability data implied encapsulating each individual solder joint is the right direction to move toward. The enforcement mechanism will be discussed in our paper.

3D package has recently become very attractive because it can provide more flexibility in device design and supply chain, reduce the gap between silicon die and organic substrate, help miniaturize device and meet the demand of high speed, more memory, more function and low cost. With the advancement of 3D package, the bump height is now down from 80μ to 10 μ. When the bump diameter is 20–40μ and height 10μ, the process and reliability are obvious issues. It is well known that underfill can enhance the reliability for regular flip chip, however it is very difficult for traditional flip chip underfill or board level underfill flow into 10μ multi-layer of 3D package without process and reliability issues. A unique flip chip underfill series has been successfully developed, which not only function as traditional underfill such as flip chip but also work very well for 10μ bump height 3D package application. YINCAE underfill series allow fast flow into 3D package and fast cure. After underfilling and cure, there are no voids observed in underfill. In this paper, a total of four different underfills have been studied. Compared to the other flip chip underfill, YINCAE underfill has demonstrated both excellent workability and outstanding reliability. In terms of workability and reliability, the four different flip chip underfills can be ranked in the following order from best to worst: A underfill > B underfill > C underfill > D underfill.

In order to meet the demand of fine pitch and 3D package, and eliminate complex underfilling process, a first solder joint encapsulant has been invented. Solder joint encapsulant adhesive is to encapsulate each individual solder joint using polymer to enhance solder joint, and leave empty space in-between solder joints to avoid thermal stress applied onto solder joints. Now two kinds of solder joint encapsulants are SMT256 and SMT266, which have been used in the customer field. Using solder joint encapsulants – SMT256 and SMT266, the pull strength of solder joint has been increased by about five times, resulting in significant increase in the reliability. In this paper more details have been investigated.

A 14-year-old boy presented with a 6-year history of intermittent right submandibular swelling. It arose with no specific trigger but was associated with pain on swallowing. It usually lasted several hours before spontaneously subsiding. There was no pyrexia, sore throat, tuberculosis contact or foreign travel. On examination the lump measured 3×3 cm, was non-tender, firm, mobile, non-fluctuant, with normal …