The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes.

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies-for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

The potentials for incidental vocabulary acquisition from listening to computer science academic lectures: a higher education corpus-based case study from Macau.

Introduction: Universities in non-Anglophone countries are increasingly implementing English as the medium of instruction (EMI) lectures. There seems to be an assumption that students' performance on standardized English examinations can be equated with the lexical knowledge needed to comprehend EMI lectures regardless of discipline. For unknown words students encounter, it is assumed that they can be picked up through listening to these lectures. This potential for students to acquire unknown words incidentally while listening to these lectures has yet to be fully explored. Methods: This study addresses the potential of students incidentally acquiring vocabulary from listening to EMI lectures through corpus analyses of computer science lectures at one public university in Macau. Taking into consideration frequency, range, and lecturer explanation, corpus analyses of the transcripts of 28 computer science lectures (40 h 36 min) were conducted to determine the lexical knowledge needed for students to comprehend the lectures. The potential number of words these students could acquire through listening to the lectures was also uncovered through further analyses. Results: Results showed that L2 students need to have receptive knowledge of the most frequent 3,000 word families plus proper nouns and marginal words to reach beyond 95% lexical coverage. To reach 98% lexical coverage, 5,000 word families are needed. Considering frequency, range, and teacher explanation, we concluded that 30 new words could reasonably be incidentally acquired after listening to the 28 lectures. Discussion: These results indicate a need for EMI lecturers to consider the lexical knowledge of students and whether additional pedagogical techniques (i.e., vocabulary explanation) should be employed in content classrooms when lectures are delivered in English, especially for specialized fields such as computer science. Our results also draw attention to the importance of field specific vocabulary and the potential pitfalls of using blanket English language admissions criteria when admitting students to different academic programs.

Evaluation of Ibuprofen Prolonged Release of Biomedical PLA-PEG-PLA Hydrogel via Degradation Mechanism.

A micellar hydrogel has long been considered an intelligent hydrophobic drug delivery material. In this study, synthesized PLA1750-PEG1750-PLA1750 micellar hydrogel aims to encapsulate ibuprofen (IBU) in the core PLA hydrophobic of the micelle and prolong the drug release time by an injectable route. The structure and morphology of the PLA1750-PEG1750-PLA1750 copolymer hydrogel were demonstrated by 1H NMR and TEM data. The hydrogel also achieved a gel state at a high concentration of 25 wt.% under the physiological conditions of the body (37°C, pH 7.4). Besides, the biocompatibility test displayed that the hydrogel slightly affected mice after injection one week and fully recovered after four weeks. Furthermore, the in vitro degradation of the hydrogel showed apparent gel erosion after the first three weeks, which is related to the IBU release rate: slow for the first three weeks and then fast. As a result, the total drug release after three and four weeks was 18 wt.% and 41 wt.%, respectively. However, in the first 24 hours, the amount of the drug released was 10 wt.%, suggesting that the IBU drug diffused from the surface hydrogel to the buffer solution. These show that PLA1750-PEG1750-PLA1750 hydrogel can be a potential IBU drug delivery candidate.

Perineural Methylprednisolone Depot Formulation Decreases Opioid Consumption After Total Knee Arthroplasty.

Purpose: Opioid consumption after total knee arthroplasty (TKA) remains a challenge with single injection nerve blocks even with common local anesthetic adjuvants dexamethasone (DEX). This study aimed to investigate the effects of adding methylprednisolone acetate (MPA) to adductor canal blocks (ACB) and interspace between the popliteal artery and capsule of the posterior knee (iPACK) blocks on postoperative opioid consumption. Methods: A retrospective analysis was conducted on 100 consecutive TKA patients equally assigned into two groups, with one group receiving DEX through ACB and iPACK block and the other group receiving DEX and methylprednisolone acetate (DEX/MPA) through the same nerve blocks. The primary outcome was cumulative opioid consumption (oral milligram morphine equivalent, OME) during hospitalization for up to three days. Secondary outcomes included daily opioid consumption, highest rest and active pain scores, prosthetic knee joint active range of motion (AROM), laboratory studies including fasting serum glucose (FSG) and white blood cell count (WBC) on each postoperative day (POD), and length of hospital stay. Results: Cumulative opioid consumption was significantly lower in the DEX/MPA group vs DEX group (median difference (95% CI) = -45.3 (-80.5 to -10), P = 0.011). The highest rest and active pain scores were both significantly lower in the DEX/MPA group than in DEX group on POD 2 (least square mean difference (95% CI) = -1.3 (-2.3 to -0.4), P = 0.005 and -0.9 (-1.8 to -0.1), P = 0.031, respectively). Except on POD 1, FSG values were significantly lower in the DEX/MPA group (median difference (95% CI) = -22.5 (-36 to -8.9), P = 0.001). AROM, WBC, and length of stay were comparable between both groups. Conclusion: Compared to perineural DEX alone, the addition of MPA further decreases postoperative opioid consumption without clinically significant changes on FSG and WBC. Level of Evidence: III.

Incidental vocabulary acquisition from listening to English teacher education lectures: A case study from Macau higher education.

Some proponents of higher education English as a medium of instruction (EMI) have suggested listening to English lectures provides students the opportunity to incidentally acquire unknown words. A case study was designed to examine this assumption. First, the lexical profiles of 27 Introduction to English Language Teaching first-year undergraduate course lectures were computed to determine how many words students need to know for comprehension. Then an incoming year-1 undergraduate student with an English vocabulary size of 7,500 word families and mastery of the most frequent 3,000 word families listened to these lectures across 13.5 weeks with the purpose of measuring incidental acquisition gains of three aspects of word knowledge for ten targeted words. Lastly, the student's perceptions about listening to EMI lectures and potentials for this listening inducing incidental acquisition of word knowledge were gathered through a semi-structured interview. The lexical profiling of the entire corpus showed students need knowledge of the most frequent 4,000 English word families plus proper nouns and marginal words for 98% lexical coverage; however, some lectures present students with a more substantial lexical burden than the lectures overall. The student made the most gains in receptive meaning, followed by receptive form, and finally productive meaning. Content analysis of the interview transcript found seven themes representing the student's perception about listening to EMI lectures and their potential for inducing incidental vocabulary acquisition. While the student found listening to the EMI lectures challenging, he perceived the process as useful in preparing for university studies and a career as a secondary English teacher. The student perceived attention, topic, existing vocabulary knowledge, lecturer's native language, and lack of interaction with the lecturer to have moderated incidental learning of vocabulary through listening to English lectures. These results indicate a need to confirm whether incoming students' vocabulary knowledge meet the lexical demands of the EMI lectures given in the Macau context. Furthermore, pedagogical training on teacher talk strategies and orientation training for incoming students should both be provided to ensure students are receiving high quality instruction.

Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes.

Metformin, the most commonly prescribed anti-diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti-aging drug-the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose-dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.

Pharmacists leadership in a medication shortage response: Illustrative examples from a health system response to the COVID-19 crisis.

As medication experts, clinical pharmacists play an active and dynamic role in a medication shortage response. Supplementing existing guidelines with an actionable framework of discrete activities to support effective medication shortage responses can expand the scope of pharmacy practice and improve patient care. Dissemination of best practices and illustrative, networked examples from health systems can support the adoption of innovative solutions. In this descriptive report, we document the translation of published shortage mitigation guidelines into system success through broad pharmacist engagement and the adaption and implementation of targeted strategies. The profound, wide-reaching medication shortages that accompanied the coronavirus disease 2019 (COVID-19) pandemic are used to highlight coordinated but distinct practices and how they have been combined to expand the influence of the pharmacy enterprise.

Haploidentical Hematopoietic Stem Cell Transplant Using Post-transplant Cyclophosphamide: A Single-Center Initial Experience in Vietnam.

Aims and objectives: Haploidentical transplants constitute a potential alternative therapy for patients who urgently need transplantation in the absence of human leukocyte antigen-matched donors. We report a single-center experience regarding the initial results of haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) using post-transplant cyclophosphamide (PTCy) at the HCMC Blood Transfusion Hematology (BTH) Hospital. Methods: We conducted a retrospective case series study of 23 patients who underwent haplo-PBSCT using PTCy at the HCMC BTH Hospital between January 2014 and January 2021. The refined disease risk index (DRI) was used to stratify the outcomes. We evaluated the engraftment rate, graft-versus-host disease (GVHD), and complications during haploidentical transplantation. Overall survival (OS), disease-free survival (DFS), and GVHD-free relapse-free survival (GRFS) were assessed. Results: The majority of the patients in the present study were diagnosed with acute myeloid leukemia. All patients received reduced-intensity conditioning regimens. The engraftment rate was 86.9%. The median times to neutrophil and platelet engraftment were 17 and 31 days, respectively. Two patients (8.7%) reported severe acute GVHD (grade III-IV), while two patients (8.7%) had grade I-II acute GVHD. Three patients experienced limited chronic GVHD of the skin, requiring topical steroids. The most common complication was bloodstream infection (60.9%). Cytomegalovirus reactivation occurred in 19 patients (82.6%) and 17.4% developed hemorrhagic cystitis. The 1-year relapse rate was 32.5%. The cumulative incidence of non-relapse mortality at 1 year was 17.3%. The 1-year OS and DFS rates were 66.3% and 55.7%, respectively. The 1-year GRFS rate was 49.2%. A high/very high DRI score was associated with worse OS after haplo-PBSCT (P=0.038). Conclusion: Haploidentical transplant using PTCy is a feasible therapy for patients without suitably matched donors in Vietnam. Infection after transplantation remains a challenge and requires effective management.

Automated lifespan determination across Caenorhabditis strains and species reveals assay-specific effects of chemical interventions.

The goal of the Caenorhabditis Intervention Testing Program is to identify robust and reproducible pro-longevity interventions that are efficacious across genetically diverse cohorts in the Caenorhabditis genus. The project design features multiple experimental replicates collected by three different laboratories. Our initial effort employed fully manual survival assays. With an interest in increasing throughput, we explored automation with flatbed scanner-based Automated Lifespan Machines (ALMs). We used ALMs to measure survivorship of 22 Caenorhabditis strains spanning three species. Additionally, we tested five chemicals that we previously found extended lifespan in manual assays. Overall, we found similar sources of variation among trials for the ALM and our previous manual assays, verifying reproducibility of outcome. Survival assessment was generally consistent between the manual and the ALM assays, although we did observe radically contrasting results for certain compound interventions. We found that particular lifespan outcome differences could be attributed to protocol elements such as enhanced light exposure of specific compounds in the ALM, underscoring that differences in technical details can influence outcomes and therefore interpretation. Overall, we demonstrate that the ALMs effectively reproduce a large, conventionally scored dataset from a diverse test set, independently validating ALMs as a robust and reproducible approach toward aging-intervention screening.

Novel RNA-binding activity of NQO1 promotes SERPINA1 mRNA translation.

NAD(P)H: quinone oxidoreductase (NQO1) is essential for cell defense against reactive oxidative species, cancer, and metabolic stress. Recently, NQO1 was found in ribonucleoprotein (RNP) complexes, but NQO1-interacting mRNAs and the functional impact of such interactions are not known. Here, we used ribonucleoprotein immunoprecipitation (RIP) and microarray analysis to identify comprehensively the subset of NQO1 target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINA1 mRNA, encodes the serine protease inhibitor α-1-antitrypsin, A1AT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma. Biotin pulldown analysis indicated that NQO1 can bind the 3' untranslated region (UTR) and the coding region (CR) of SERPINA1 mRNA. NQO1 did not affect SERPINA1 mRNA levels; instead, it enhanced the translation of SERPINA1 mRNA, as NQO1 silencing decreased the size of polysomes forming on SERPINA1 mRNA and lowered the abundance of A1AT. Luciferase reporter analysis further indicated that NQO1 regulates SERPINA1 mRNA translation through the SERPINA1 3'UTR. Accordingly, NQO1-KO mice had reduced hepatic and serum levels of A1AT and increased activity of neutrophil elastase (NE), one of the main targets of A1AT. We propose that this novel mechanism of action of NQO1 as an RNA-binding protein may help to explain its pleiotropic biological effects.

Amprenavir-induced maculopapular exanthem followed by desensitization in a patient with late-stage human immunodeficiency virus.

BACKGROUND: Amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is approved for the treatment of HIV infection in combination with other antiretroviral agents in treatment-naive and experienced patients. Amprenavir is generally well tolerated. However, cutaneous hypersensitivity reactions to amprenavir occur in up to 28% of patients, with treatment discontinuation required in 3% of cases. OBJECTIVE: To report successful desensitization to amprenavir after the occurrence of a maculopapular exanthem in an HIV-infected patient with late-stage disease and limited antiretroviral treatment options. METHODS: Incremental doses of 0.025, 0.1, 0.25, 1, 2.5, 7.5, 25, 50, 100, 300, 600, and 1,200 mg of amprenavir oral solution were administered via percutaneous endoscopic gastrostomy tube at 20- to 30-minute intervals. RESULTS: The patient successfully tolerated amprenavir desensitization and has continued therapy without recurrence of rash at 19 months of follow-up. CONCLUSION: Desensitization may permit the continued use of amprenavir in HIV-positive patients with a history of amprenavir-induced maculopapular eruptions who have limited alternate treatment options.