Professional quality of life in animal research personnel is linked to retention & job satisfaction: A mixed-methods cross-sectional survey on compassion fatigue in the USA.

BACKGROUND: Working with research animals can be both rewarding and challenging. The rewarding part of the work is associated with understanding the necessity for animal research to improve the health of humans and animals and the knowledge that one can provide care and compassion for the animals. Challenges with animal research include witnessing stress/pain in animals necessitated by scientific requirements, end of study euthanasia, and societal stigmatization about animal research. These challenges could be compounded with more general workplace stresses, in turn, impacting job retention and satisfaction. However, these factors have yet to be formally evaluated. Therefore, the purpose of this survey was to comprehensively evaluate professional quality of life's correlation with key workplace metrics. METHODS: Six institutions were recruited to participate in a longitudinal intervention trial on compassion fatigue resiliency. This manuscript reports key baseline metrics from this survey. A cross-sectional mixed methods survey was developed to evaluate professional quality of life, job satisfaction, retention, and factors influencing compassion fatigue resiliency. Quantitative data were analyzed via general linear models and qualitative data were analyzed by theme. RESULTS: Baseline data was collected from 198 participants. Personnel who reported higher compassion satisfaction also reported higher retention and job satisfaction. Conversely, personnel who reported higher burnout also reported lower job satisfaction. In response to open-ended questions, participants said their compassion fatigue was impacted by institutional culture (70% of participants), animal research (58%), general mental health (41%), and specific compassion fatigue support (24%). CONCLUSIONS: In conclusion, these results show that professional quality of life is related to important operational metrics of job satisfaction and retention. Furthermore, compassion fatigue is impacted by factors beyond working with research animals, including institutional culture and general mental health support. Overall, this project provides rationale and insight for institutional support of compassion fatigue resiliency.

Cytosine base editing inhibits hepatitis B virus replication and reduces HBsAg expression in vitro and in vivo.

Chronic hepatitis B virus (HBV) infection remains a global health problem due to the lack of treatments that prevent viral rebound from HBV covalently closed circular (ccc)DNA. In addition, HBV DNA integrates in the human genome, serving as a source of hepatitis B surface antigen (HBsAg) expression, which impairs anti-HBV immune responses. Cytosine base editors (CBEs) enable precise conversion of a cytosine into a thymine within DNA. In this study, CBEs were used to introduce stop codons in HBV genes, HBs and Precore. Transfection with mRNA encoding a CBE and a combination of two guide RNAs led to robust cccDNA editing and sustained reduction of the viral markers in HBV-infected HepG2-NTCP cells and primary human hepatocytes. Furthermore, base editing efficiently reduced HBsAg expression from HBV sequences integrated within the genome of the PLC/PRF/5 and HepG2.2.15 cell lines. Finally, in the HBV minicircle mouse model, using lipid nanoparticulate delivery, we demonstrated antiviral efficacy of the base editing approach with a >3log10 reduction in serum HBV DNA and >2log10 reduction in HBsAg, and 4/5 mice showing HBsAg loss. Combined, these data indicate that base editing can introduce mutations in both cccDNA and integrated HBV DNA, abrogating HBV replication and silencing viral protein expression.

Free-Hand Intracerebroventricular Injections in Mice.

The investigation of neuroendocrine systems often requires the delivery of drugs, viruses, or other experimental agents directly into the brains of mice. An intracerebroventricular (ICV) injection allows the widespread delivery of the experimental agent throughout the brain (particularly in the structures near the ventricles). Here, methods for making free-hand ICV injections in adult mice are described. By using visual and tactile landmarks on the heads of mice, injections into the lateral ventricles can be made rapidly and reliably. The injections are made with a glass syringe held in the experimenter's hand and placed at approximate distances from the landmarks. Thus, this technique does not require a stereotaxic frame. Furthermore, this technique requires only brief isoflurane anesthesia, which permits the subsequent assessment of mouse behavior and/or physiology in awake, freely behaving mice. Free-hand ICV injection is a powerful tool for the efficient delivery of experimental agents into the brains of living mice and can be combined with other techniques such as frequent blood sampling, neural circuit manipulation, or in vivo recording to investigate neuroendocrine processes.

Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials.

INTRODUCTION: Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA. METHODS AND ANALYSIS: Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a 'go/no-go' decision is made by evaluating the posterior probability of the events of interests. ETHICS AND DISSEMINATION: The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication. TRIAL REGISTRATION NUMBER: ACTRN12619001042134, ACTRN12619001043123.

The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry.

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.

Outcomes for non-treatment-requiring infants evaluated for retinopathy of prematurity.

PURPOSE: To evaluate the rates of visually significant disorders in patients without treatment-requiring retinopathy of prematurity (ROP) at initial follow-up after completion of ROP examinations. METHODS: The medical records of all babies evaluated for retinopathy of prematurity between June 2015 and September 2020 were reviewed. Patients with documented gestational age, birth weight, and single versus multiple birth status who did not require ROP treatment and who followed-up with our institution's pediatric ophthalmologist were included. RESULTS: A total of 304 patients were included. Of these, 15 (4.9%) had strabismus (12 [4.0%] with esotropia, 3 [0.9%] with exotropia), 30 (9.9%) had myopia, 174 (57.2%) had hyperopia, 54 (18%) had astigmatism, 4 (1.3%) had amblyopia, 5 (1.6%) were labeled amblyopia suspects, 1 (0.3%) had congenital glaucoma, and 1 (0.3%) had congenital cataract. Nineteen (6.3%) had a condition requiring intervention at the first evaluation following completion of ROP examinations, and in 5 (2%), this was a condition that would typically not have been identified without evaluation by a pediatric ophthalmologist. CONCLUSIONS: In our population of infants evaluated for retinopathy of prematurity who did not require ROP treatment, the incidence of other ocular disorders requiring intervention at the first non-ROP evaluation was about 6%. This study highlights the need for further research that may aid in the creation of an evidence-based follow-up strategy for premature infants who never undergo ROP treatment.

Using refined methods to pick up mice: A survey benchmarking prevalence & beliefs about tunnel and cup handling.

Refined handling improves laboratory mouse welfare and research outcomes when compared to traditional tail handling, yet implementation does not seem to be widespread. Refined handling includes picking up a mouse using a tunnel or cupped hands. The aim of this study was to determine the current prevalence of and beliefs towards refined handling using the theory of planned behavior. It was predicted that refined handling prevalence is low compared to traditional handling methods, and its implementation is determined by individual and institutional beliefs. Research personnel were recruited via online convenience sampling through email listservs and social media. A total of 261 participants in diverse roles (e.g. veterinarians, managers, caretakers, researchers, etc.) responded primarily from the USA (79%) and academic institutions (61%) Participants were surveyed about their current use, knowledge, and beliefs about refined handling. Quantitative data were analyzed via descriptive statistics and generalised regression. Qualitative data were analyzed by theme. Research personnel reported low levels of refined handling implementation, with only 10% of participants using it exclusively and a median estimate of only 10% of institutional mice being handled with refined methods. Individually, participants had positive attitudes, neutral norms, and positive control beliefs about refined handling. Participants' intention to provide refined handling in the future was strongly associated with their attitudes, norms, and control beliefs (p<0.01). Participants believed barriers included jumpy mice, perceived incompatibility with restraint, lack of time, and other personnel. However, participants also believed refined handling was advantageous to mouse welfare, handling ease, personnel, and research. Although results from this survey indicate that current refined handling prevalence is low in this sample, personnel believe it has important benefits, and future use is associated with their beliefs about the practice. People who believed refined handling was good, felt pressure to use it, and were confident in their use reported higher implementation. Increased refined handling could be encouraged through education on misconceptions, highlighting advantages, and addressing important barriers.

Post-Prandial Cognitive and Blood Pressure Effects of a DHA-Rich Omega-3 Powder in Middle-Aged Males: A Pilot Study.

The use of omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplements is increasingly common among middle-aged and older adults. Users of ω-3 PUFA supplements often report using such supplements to support cognitive health, despite mixed findings reported within the ω-3 PUFA literature. To date, very few studies have explored cognitive effects in distinctly middle-aged (40 to 60 years) adults, and none have examined the acute effects (in the hours following a single dose) on cognitive performance. The current study evaluated whether a single dose of ω-3 PUFA (4020 mg docosahexaenoic acid and 720 mg eicosapentaenoic acid) influences cognitive performance and cardiovascular function in middle-aged males. Cognitive performance and cardiovascular function were assessed before and 3.5-4 h after consumption of a high dose of ω-3 PUFA (DHA + EPA) or placebo, incorporated into a standardized meal (i.e., single serve of Greek yogurt). In this study of middle-aged males, no significant differential treatment effects were observed for cognitive performance. However, a significant reduction in aortic systolic blood pressure (pre-dose to post-dose) was apparent following consumption of the ω-3 PUFA (DHA + EPA) treatment (mean difference = -4.11 mmHg, p = 0.004) but not placebo (mean difference = -1.39 mmHg, p = 0.122). Future replication in a sample comprising females, as well as patients with hypertension, is merited.

Analysis of Oral Anticoagulant Dosing and Adherence to Therapy Among Patients With Nonvalvular Atrial Fibrillation.

Importance: Although reduced doses of direct oral anticoagulants (DOACs) are approved for patients with nonvalvular atrial fibrillation (NVAF) at high risk of bleeding, little is known about dosing accuracy, particularly in patients with renal dysfunction. Objective: To determine whether underdosing of DOACs is associated with longitudinal adherence to anticoagulation. Design, Setting, and Participants: This retrospective cohort analysis used data from the Symphony Health claims data set. This national medical and prescription data set comprises 280 million patients and 1.8 million prescribers in the US. Patients included had at least 2 claims for NVAF between January 2015 and December 2017. The dates of analysis for this article were from February 2021 to July 2022. Exposures: This study included patients with CHA2DS2-VASc scores of 2 or higher who were treated with a dose of DOACs who did and did not meet label-specified criteria for dose reduction. Main Outcomes and Measures: Logistic regression models examined factors associated with off-label dosing (ie, dosing not recommended by US Food and Drug Administration [FDA] labeling), the association of creatinine clearance with recommended DOAC dosing, and the association of DOAC underdosing and excess dosing with 1-year adherence. Results: Among the 86 919 patients included (median [IQR] age, 74 [67-80] years; 43 724 men [50.3%]; 82 389 White patients [94.8%]), 7335 (8.4%) received an appropriately reduced dose, and 10 964 (12.6%) received an underdose not consistent with FDA recommendations, meaning that 59.9% (10 964 of 18 299) of those who received a reduced dose received an inappropriate dose. Patients who received off-label doses of DOACs were older (median [IQR] age, 79 [73-85] vs 73 [66-79] years) and had higher CHA2DS2-VASc scores (median [IQR], 5 [4-6] vs 4 [3-6]) compared with patients who received appropriate doses (as recommended by FDA labeling). Renal dysfunction, age, heart failure, and the prescribing clinician being in a surgical specialty were associated with dosing not recommended by FDA labeling. Almost one-third of patients (9792 patients [31.9%]) with creatinine clearance less than 60 mL per minute taking DOACs were either underdosed or excess-dosed not consistent with FDA recommendations. For every 10-unit decrease in creatinine clearance, the odds of the patient receiving an appropriately dosed DOAC was lower by 21%. Treatment with underdosed DOACs was associated with a lower likelihood of adherence (adjusted odds ratio, 0.88; 95% CI, 0.83-0.94) and higher risk of anticoagulation discontinuation (adjusted odds ratio, 1.20; 95% CI, 1.13-1.28) by 1 year. Conclusions and Relevance: In this study of oral anticoagulant dosing, DOAC dosing that did not follow FDA label recommendations was observed in a substantial number of patients with NVAF, occurred more frequently in patients with worse renal function, and was associated with less-consistent long-term anticoagulation. These results suggest a need for efforts to improve the quality of DOAC use and dosing.

A chromosome-scale reference of Chenopodium watsonii helps elucidate relationships within the North American A-genome Chenopodium species and with quinoa.

Quinoa (Chenopodium quinoa), an Andean pseudocereal, attained global popularity beginning in the early 2000s due to its protein quality, glycemic index, and high fiber, vitamin, and mineral contents. Pitseed goosefoot (Chenopodium berlandieri), quinoa's North American free-living sister species, grows on disturbed and sandy substrates across the North America, including saline coastal sands, southwestern deserts, subtropical highlands, the Great Plains, and boreal forests. Together with South American avian goosefoot (Chenopodium hircinum) they comprise the American tetraploid goosefoot complex (ATGC). Superimposed on pitseed goosefoot's North American range are approximately 35 AA diploids, most of which are adapted to a diversity of niche environments. We chose to assemble a reference genome for Sonoran A-genome Chenopodium watsonii due to fruit morphological and high (>99.3%) preliminary sequence-match similarities with quinoa, along with its well-established taxonomic status. The genome was assembled into 1377 scaffolds spanning 547.76 Mb (N50 = 55.14 Mb, L50 = 5), with 94% comprised in nine chromosome-scale scaffolds and 93.9% Benchmarking Universal Single-Copy Orthologs genes identified as single copy and 3.4% as duplicated. A high degree of synteny, with minor and mostly telomeric rearrangements, was found when comparing this taxon with the previously reported genome of South American C. pallidicaule and the A-subgenome chromosomes of C. quinoa. Phylogenetic analysis was performed using 10,588 single-nucleotide polymorphisms generated by resequencing a panel of 41 New World AA diploid accessions and the Eurasian H-genome diploid Chenopodium vulvaria, along with three AABB tetraploids previously sequenced. Phylogenetic analysis of these 32 taxa positioned the psammophyte Chenopodium subglabrum on the branch containing A-genome sequences from the ATGC. We also present evidence for long-range dispersal of Chenopodium diploids between North and South America.

The association of dietary and nutrient patterns on neurocognitive decline: A systematic review of MRI and PET studies.

BACKGROUND: As the global population ages, there has been a growing incidence of neurodegenerative diseases such as Alzheimer's. More recently, studies exploring the relationship between dietary patterns and neuroimaging outcomes have received particular attention. This systematic literature review provides a structured overview of the association between dietary and nutrient patterns on neuroimaging outcomes and cognitive markers in middle-aged to older adults. A comprehensive literature search was conducted to find relevant articles published from 1999 to date using the following databases Ovid MEDLINE, Embase, PubMed, Scopus and Web of Science. The inclusion criteria for the articles comprised studies reporting on the association between dietary patterns and neuroimaging outcomes, which includes both specific pathological hallmarks of neurodegenerative diseases such as Aß and tau and nonspecific markers such as structural MRI and glucose metabolism. The risk of bias was evaluated using the Quality Assessment tool from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The results were then organized into a summary of results table, collated based on synthesis without meta-analysis. After conducting the search, 6050 records were extracted and screened for eligibility, with 107 eligible for full-text screening and 42 articles ultimately being included in this review. The results of the systematic review indicate that there is some evidence suggesting that healthy dietary and nutrient patterns were associated with neuroimaging measures, indicative of a protective influence on neurodegeneration and brain ageing. Conversely, unhealthy dietary and nutrient patterns showed evidence pointing to decreased brain volumes, poorer cognition and increased Aß deposition. Future research should focus on sensitive neuroimaging acquisition and analysis methods, to study early neurodegenerative changes and identify critical periods for interventions and prevention. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no, CRD42020194444).

Corrigendum: The association between diet and cardio-metabolic risk on cognitive performance: A cross-sectional study of middle-aged Australian adults.

[This corrects the article DOI: 10.3389/fnut.2022.862475.].

Improved cytosine base editors generated from TadA variants.

Cytosine base editors (CBEs) enable programmable genomic C·G-to-T·A transition mutations and typically comprise a modified CRISPR-Cas enzyme, a naturally occurring cytidine deaminase, and an inhibitor of uracil repair. Previous studies have shown that CBEs utilizing naturally occurring cytidine deaminases may cause unguided, genome-wide cytosine deamination. While improved CBEs that decrease stochastic genome-wide off-targets have subsequently been reported, these editors can suffer from suboptimal on-target performance. Here, we report the generation and characterization of CBEs that use engineered variants of TadA (CBE-T) that enable high on-target C·G to T·A across a sequence-diverse set of genomic loci, demonstrate robust activity in primary cells and cause no detectable elevation in genome-wide mutation. Additionally, we report cytosine and adenine base editors (CABEs) catalyzing both A-to-I and C-to-U editing (CABE-Ts). Together with ABEs, CBE-Ts and CABE-Ts enable the programmable installation of all transition mutations using laboratory-evolved TadA variants with improved properties relative to previously reported CBEs.

Investigating the Effects of a Multinutrient Supplement on Cognition, Mood and Biochemical Markers in Middle-Aged Adults with 'Optimal' and 'Sub-Optimal' Diets: A Randomized Double Blind Placebo Controlled Trial.

Background: Previous randomized controlled trials examining cognitive and mood effects of combination multivitamin supplements in healthy, non-clinical adults have reported mixed results. One purported explanation for this is that the dietary status of participants at the start of supplement interventions may influence the magnitude of the effect of supplementation. Methods: In this study, we evaluated the effect of a multinutrient formula containing B group vitamins, Bacopa monniera and Ginkgo biloba on memory, attention, mood and biochemical markers of nutrient status in middle-aged adults (M = 52.84 years, n = 141) with 'optimal' and 'sub-optimal' diets over 12 weeks. We hypothesised that active supplementation would differentially improve memory and attention in those with a 'sub-optimal' diet. Results: Mixed model, repeated measures analysis revealed that, in comparison to placebo, active treatment was associated with significant increases in B vitamin status (B1, B6, B12). Regarding behavioural outcomes there was no significant benefit to memory (F(1, 113.51) = 0.53, p = 0.470) nor attention (F(1,113.77) = 1.89, p = 0.171) in the whole cohort. Contrary to our hypothesis, there was a significant beneficial effect of supplementation on attentional performance in individuals with an 'optimal' diet prior to supplementation (F(1,57.25) = 4.94, p = 0.030). In the absence of a main effect of supplementation across the entire cohort, there were also a number of significant three-way interactions (treatment by time by diet group) detected in secondary outcomes including lower state anxiety and mental fatigue in those with an 'optimal' diet. Conclusion: These findings suggest that the cognitive benefit of B vitamin and herbal supplementation may be dependent on diet quality, supporting the concepts of 'co-nutrient optimisation' and interdependency of nutrients. This warrants further investigation. This study advocates characterising the diet of participants prior to supplementation as it may influence the effect of a nutraceutical intervention.

Waking inactivity as a welfare indicator in laboratory mice: investigating postures, facial expressions and depression-like states.

Animal welfare assessment relies on valid and practical indicators of affect. In mice, the most widely used research vertebrates, lying still with eyes open, inactive-but-awake (IBA) in the home cage, has potential to be one such indicator. IBA is elevated in barren, conventional housing compared with well-resourced, enriched housing, and predicts immobility in Forced Swim Tests, a common measure of 'helplessness' in depression research. In Experiment 1, using females from three strains (C57BL/6, Balb/c and DBA/2), we first replicated past findings, confirming higher levels of IBA in conventional cages and a positive relationship between IBA and helplessness. We then extended this research to three other signs of depression: changes in weight and sleep, and reduced hippocampal volume. Here, IBA positively covaried with body mass index, with sleep in DBA/2s and conventionally housed BALB/cs, and negatively covaried with hippocampal volume in conventionally housed C57BL/6s. In Experiment 2, we sought to refine the phenotype of IBA to improve its accuracy as a welfare indicator. Here, scoring IBA performed in hunched postures appeared to improve its accuracy as an indicator in Balb/c mice. Additional research is now needed to further refine the phenotype of IBA and to confirm whether it reflects states consistent with depression, or instead other underlying poor welfare conditions.

Minimally invasive biomarkers in human and non-human primate evolutionary biology: Tools for understanding variation and adaptation.

BACKGROUND: The use of minimally invasive biomarkers (MIBs - physiological biomarkers obtained from minimally invasive sample types) has expanded rapidly in science and medicine over the past several decades. The MIB approach is a methodological strength in the field of human and non-human primate evolutionary biology (HEB). Among humans and our closest relatives, MIBs provide unique opportunities to document phenotypic variation and to operationalize evolutionary hypotheses. AIMS: This paper overviews the use of MIBs in HEB. Our objectives are to (1) highlight key research topics which successfully implement MIBs, (2) identify promising yet under-investigated areas of MIB application, and (3) discuss current challenges in MIB research, with suggestions for advancing the field. DISCUSSION AND CONCLUSIONS: A range of MIBs are used to investigate focal topics in HEB, including energetics and life history variation/evolution, developmental plasticity, and social status and dominance relationships. Nonetheless, we identify gaps in existing MIB research on traits such as physical growth and gut function that are central to the field. Several challenges remain for HEB research using MIBs, including the need for additional biomarkers and methods of assessment, robust validations, and approaches that are standardized across labs and research groups. Importantly, researchers must provide better support for adaptation and fitness effects in hypothesis testing (e.g., by obtaining complementary measures of energy expenditure, demonstrating redundancy of function, and performing lifetime/longitudinal analyses). We point to continued progress in the use of MIBs in HEB to better understand the past, present, and future of humans and our closest primate relatives.

Health-system specialty pharmacy role and outcomes: A review of current literature.

PURPOSE: Specialty medications can have life-altering outcomes for patients with complex diseases. However, their benefit relies on appropriate treatment selection, patients' ability to afford and initiate treatment, and ongoing treatment optimization based on patient response to therapy. Mounting research demonstrates the benefits of the health-system specialty pharmacies (HSSPs) in improving specialty medication access, affordability, and outcomes. The purpose of this rapid review is to describe the currently reported role and function of HSSP pharmacists and outcomes reported with use of the HSSP model, and to identify gaps in the literature where more information is needed to better understand the HSSP model and outcomes. SUMMARY: Current literature describes the role of HSSP pharmacists in facilitating patient access, affordability, and initiation and maintenance of specialty medications. Though it is clear HSSP pharmacists are involved in treatment monitoring, often through utilizing the electronic health record, more information is needed to elucidate the frequency, method, and extent of monitoring. Despite several valuable continuity of care services reported to be provided by HSSPs, the breadth and degree of standardization of these services remains unclear. There is minimal literature describing HSSP education and research involvement. HSSPs have reported significant benefits of this patient care model, as demonstrated by higher adherence and persistence; better clinical outcomes; financial benefits to patients, payers, and the health system; better quality of care; higher patient and provider satisfaction with services, and highly efficient specialty pharmacy services. More literature comparing clinical and diagnosis-related outcomes in HSSP versus non-HSSP patients is needed. CONCLUSION: HSSPs provide comprehensive, patient-centered specialty medication management that result in improved care across the continuum of the specialty patient journey and act as a valuable resource for specialty clinics and patients beyond medication management. Future research should build on the current description of HSSP services, how services affect patient outcomes, and the impact HSSP network restrictions.

The Association Between Diet and Cardio-Metabolic Risk on Cognitive Performance: A Cross-Sectional Study of Middle-Aged Australian Adults.

Adherence to different dietary patterns has been linked to the development of cognitive decline; yet little is known about whether this relationship is present in middle age. The current study aimed to explore the relationship between different dietary patterns, cognitive performance, and potential cardio-metabolic mechanisms for this relationship. Participants were recruited using a diet screening tool to ensure that the cohort had a range of diet quality ranging from relatively poor to relatively healthy. In a sample of 141 middle-aged adults (age: M = 52.84 years, SD = 6.87 years), multiple 24 h diet recalls were collected and used to score adherence to the Mediterranean diet, dietary approaches to stop hypertension (DASH) diet, and Mediterranean-DASH diet intervention for neurodegenerative delay (MIND) diet. Metabolic risk was assessed using the metabolic syndrome severity score (MetSSS) and arterial stiffness. Cognitive performance was assessed using the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB). Adherence to the MIND diet was significantly related to Stroop Processing domain (ß = 0.19, p = 0.035). None of the dietary patterns were significantly related to MetSSS or arterial stiffness. However, adherence to the DASH diet was significantly associated with two cardio-metabolic measures including lower augmentation index (ß = -0.17, p = 0.032) and lowered cholesterol (ß = -0.18, p = 0.041). Interestingly, two cardio-metabolic risk factors were also associated with better cognitive performance: MetSSS (ß = 0.21, p = 0.010) and waist circumference (ß = 0.22, p = 0.020). Together these findings suggest that diet in middle age may be important for cognitive functioning and cardio-metabolic risk. However, more research is needed in the form of randomized controlled trials to confirm the direction of these relationships.

Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL.

Allogeneic chimeric antigen receptor T-cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CARTs have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells, with between 90% and 99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). Using CBE, we developed 7CAR8, a CD7-directed allogeneic CART created using 4 simultaneous base edits. We show that CBE, unlike CRISPR-Cas9, does not impact T-cell proliferation, lead to aberrant DNA damage response pathway activation, or result in karyotypic abnormalities following multiplexed editing. We demonstrate 7CAR8 to be highly efficacious against T-cell acute lymphoblastic leukemia (T-ALL) using multiple in vitro and in vivo models. Thus, CBE is a promising technology for applications requiring multiplexed gene editing and can be used to manufacture quadruple-edited 7CAR8 cells, with high potential for clinical translation for relapsed and refractory T-ALL.