Durect (United States)

In 2025, the Nobel Prize in Economic Sciences highlighted innovation-driven growth—one half awarded to Joel Mokyr for the prerequisites of sustained growth and the other half jointly to Philippe Aghion and Peter Howitt for the theory of sustained growth via creative destruction [1]. This provides a timely anchor for modern edutainment and AI adoption. We study the Astarly (ex - Mediastar) ecosystem to articulate how gamified learning and AI personalization jointly accelerate innovation cycles and global scaling in digital education.

Listing and transplanting patients with acute liver failure (ALF) is challenging, requiring rapid assessment of the likelihood of recovery. The availability of a large number of ALF liver explants, along with their clinical data, afforded an opportunity to retrospectively evaluate liver transplantation (LT) decision-making. We hypothesized that, with the benefit of hindsight, a small number of patients might have recovered without LT. Three hundred liver explants from ALF patients of varying etiologies who had undergone LT over 22 years in the Acute Liver Failure Study Group registry were reviewed for histopathological features and degree of necrosis by a committee of 8 hepatopathologists. A second committee of 8 experienced transplant hepatologists independently reviewed clinical data on these same 300 patients and retrospectively scored the likelihood that each patient required transplantation. Only 3 (1%) of those reviewed by the Clinical Committee were considered to "Definitely" not require liver grafting, while an additional 10 (3.3%) were deemed to "Possibly" not require transplantation (Not Likely Group, N=13). There was no difference in the degree of necrosis in explants in these groups, when compared to the remaining Likely Group, N=287 (95.6%), except in acetaminophen (APAP)-associated ALF, where the degree of necrosis was more uniformly graded as severe, correlating with the need for transplantation. Virtually every patient undergoing LT for ALF retrospectively appeared to need their transplant, based on expert clinical consensus review. Overall, there was poor correlation between clinical severity and apparent degree of necrosis seen in the 300 liver explants, except perhaps for APAP subjects.

Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis. Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication. With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role. Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases.

Most patients with alcohol-associated liver disease (ALD) engage in heavy drinking defined as 4 or more drinks per day (56 g) or 8 (112 g) or more drinks per week for women and 5 or more drinks per day (70 g) or15 (210 g) or more drinks per week for men. Although abstinence from alcohol after diagnosis of ALD improves life expectancy and reduces the risk of decompensation of liver disease, few studies have evaluated whether treatment of alcohol use disorders will reduce progression of liver disease and improve liver-related outcomes. In November 2021, the National Institute of Alcohol Abuse and Alcoholism commissioned a task force that included hepatologists, addiction medicine specialists, statisticians, clinical trialists and members of regulatory agencies to develop recommendations for the design and conduct of clinical trials to evaluate the effect of alcohol use, particularly treatment to reduce or eliminate alcohol use in patients with ALD. The task force conducted extensive reviews of relevant literature on alcohol use disorders and ALD. Findings were presented at one in-person meeting and discussed over the next 16 months to develop the final recommendations. As few clinical trials directly address this topic, the 28 recommendations approved by all members of the task force represent a consensus of expert opinions.

Shoulder arthroscopy can result in substantial postoperative pain. Sucrose acetate isobutyrate extended-release bupivacaine (SABER-Bupivacaine; trade name Posimir) is a novel depot formulation of bupivacaine designed to provide analgesia at the surgical site for up to 72 hours. The objective of this study was to evaluate the effect of SABER-Bupivacaine on pain and opioid consumption after arthroscopic subacromial decompression and to assess short-term and long-term safety. In this double-blind, placebo-controlled trial, 78 subjects were randomized in a 2:1 ratio to SABER-Bupivacaine 5 mL or SABER-placebo 5 mL injected into the subacromial space just before skin closure. Twenty-nine additional subjects were randomized on an exploratory basis to bupivacaine hydrochloride 20 mL, also injected subacromially. Subjects rated pain intensity on a 0 to 10 scale over the first 3 postoperative days and received intravenous or oral morphine for breakthrough pain. The coprimary efficacy end points were pain intensity on 90° shoulder flexion and cumulative morphine intake from 0 to 72 hours after surgery. The time to first use of opioid rescue analgesia was a secondary end point. The mean (SD) pain intensity was 5.16 (1.94) for SABER-Bupivacaine and 6.43 (1.77) for placebo (P = 0.012). The median consumption of intravenous morphine equivalents was 4.0 mg for SABER-Bupivacaine and 12.0 mg for placebo (P = 0.010). The median time to first use of morphine rescue was 12.4 hours for SABER-Bupivacaine and 1.2 hours for placebo (P = 0.014). The corresponding values for bupivacaine hydrochloride were 5.16 (2.38), 8.0 mg, and 1.4 hours. The incidence and severity of treatment-emergent adverse events were similar for all treatment groups, and no functional or radiographic differences were noted at the 6-month follow-up. Compared with placebo, SABER-Bupivacaine reduced pain and opioid analgesic consumption over 72 hours after arthroscopic subacromial decompression and prolonged the time to first use of opioid rescue analgesia. No safety signals were noted during the immediate postoperative period or at 6-month follow-up.

Implantable, osmotically driven drug delivery systems are applicable to the delivery of small molecules, peptides, proteins, and other biomolecules, and continue to be used at the forefront of development of new clinical therapies. Sustained, zero-order drug delivery from osmotic implants has been shown to achieve consistent pharmacokinetics in multiple models and therapies. The continuous infusion features of these systems can provide improved economics, convenience, and therapeutic benefit versus bolus dosing. In animal research, ALZET osmotic implantable pumps have demonstrated the benefits of continuous infusion versus bolus dosing in various therapeutic applications, including chemotherapy, angiogenesis, and obesity. Osmotic implantable pumps have been selected for site-specific delivery to enable continuous local site infusion and avoidance of systemic effects. Applications include delivery to the spine (analgesia), tumors (oncology), cochlea (gene expression), and the brain (neurodegenerative applications). Human use applications using DUROS osmotic implantable pumps have provided delivery of agents from 1 month to over 1 year for treatment of pain, cancer, diabetes, and hepatitis.

Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors' previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10-20 microg/ml, without evidence of accumulation. Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration. All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 +/- 25% of the time. With subsequent dosing, the target range was maintained 60 +/- 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 microg/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses. A rectal acetaminophen loading dose of 40 mg/kg followed by 20-mg/kg doses every 6 h results in serum concentrations centered at the target range of 10-20 microg/ml. There was large interindividual variability in pharmacokinetic characteristics. There was no evidence of accumulation during the 24-h sampling period.