Cardiac fibroblasts in heart failure and regeneration.

In heart disease patients, myocyte loss or malfunction invariably leads to fibrosis, involving the activation and accumulation of cardiac fibroblasts that deposit large amounts of extracellular matrix. Apart from the vital replacement fibrosis that follows myocardial infarction, ensuring structural integrity of the heart, cardiac fibrosis is largely considered to be maladaptive. Much work has focused on signaling pathways driving the fibrotic response, including TGF-ß signaling and biomechanical strain. However, currently there are very limited options for reducing cardiac fibrosis, with most patients suffering from chronic fibrosis. The adult heart has very limited regenerative capacity. However, cardiac regeneration has been reported in humans perinatally, and reproduced experimentally in neonatal mice. Furthermore, model organisms such as the zebrafish are able to fully regenerate their hearts following massive cardiac damage into adulthood. Increasing evidence points to a transient immuno-fibrotic response as being key for cardiac regeneration to occur. The mechanisms at play in this context are changing our views on fibrosis, and could be leveraged to promote beneficial remodeling in heart failure patients. This review summarizes our current knowledge of fibroblast properties associated with the healthy, failing or regenerating heart. Furthermore, we explore how cardiac fibroblast activity could be targeted to assist future therapeutic approaches.

Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors.

PURPOSE: Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug-drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors. METHODS: Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted. RESULTS: Capivasertib-midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUCinf and Cmax was 1.13 (0.97-1.32) and 1.15 (0.99-1.33) for day 8 versus day 1, and 1.75 (1.50-2.05) and 1.25 (1.08-1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment. CONCLUSION: The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population. CLINICALTRIALS: gov: NCT04958226.

Neuropsychiatric symptoms of dementia in those with and without a recorded history of psychological trauma: A comparative study from an Australian dementia support service.

OBJECTIVE: To compare the number and severity of neuropsychiatric symptoms (NPS) and associated caregiver distress between those with and without a noted history of psychological trauma among those referred to a specialised national dementia NPS support service. METHODS: This was a 5-year retrospective observational study of records from the Dementia Support Australia NPS support service. NPS were reported by formal or informal caregivers at service entry using the Neuropsychiatric Inventory Nursing Home version or Questionnaire version. A history of psychological trauma was recorded in the person's social or medical history and/or endorsed as a contributor to NPS by a trained dementia consultant after a comprehensive clinical review. Regression was used to examine the impact of a recorded history of psychological trauma on NPS severity and associated caregiver distress, controlling for age and sex. RESULTS: Among 41,876 eligible referrals with dementia, 6% (n = 2529) had some reference in their records to a history of psychological trauma. Referrals with a recorded history of psychological trauma were rated with a higher rate of both NPS severity (mean = 12.0) and associated caregiver distress (mean = 16.5) at service entry than those without a recorded history of psychological trauma (means = 10.7 and 14.5, respectively). A recorded history of psychological trauma was associated with higher odds of psychotic symptoms, agitation/aggression, irritability, disinhibition, affective symptoms and night-time behaviours. CONCLUSIONS: Traumatic stress symptoms may represent a neglected target for intervention to reduce the impact of NPS in people with dementia.

Being Present and Meaningful Engagement for Aged Care Residents Living With Dementia: A Mixed-Methods Evaluation of Australian Care Worker's Experiences.

BACKGROUND AND OBJECTIVES: Meaningful engagement is essential for aged care residents living with dementia. Our knowledge pertaining to caring presence for residents living with dementia is limited. This study aims to understand care workers' experiences of providing care to residents, the challenges they face in being present with residents and support that enable them to be more present and provide person-centered care. RESEARCH DESIGN AND METHODS: A mixed-methods approach using surveys and semi-structured interviews with care workers from three Australian residential aged care homes was adopted. Surveys were analyzed using descriptive statistics. Open-ended survey responses and interviews were analyzed using thematic analysis. RESULTS: Twenty-six care workers completed surveys and a subset (n = 8) participated in interviews. Survey participants were largely positive about their role and reported that they loved caring for and making a difference in the lives of residents. Three themes emerged from interviews: (a) trust, connection, and the complexities of maintaining engagement; (b) time as gift and challenge; (c) organizational culture, structure and resources, and enabling carer presence. DISCUSSION AND IMPLICATIONS: Care workers in our study expressed their desire to be present with residents and stated that enablers such as meaningfully engaging with residents was one of the most enjoyable aspects of their work. Barriers such as staff shortages, competing demands of the role, and time-related impediments to being present were reported. Addressing challenges to being present with residents living with dementia is key to help avoiding poor care practices and resident outcomes.

Measuring the success of programmes of care for people living with dementia: a protocol for consensus building with consumers to develop a set of Core Outcome Measures for Improving Care (COM-IC).

INTRODUCTION: The Core Outcome Measures for Improving Care (COM-IC) project aims to deliver practical recommendations on the selection and implementation of a suite of core outcomes to measure the effectiveness of interventions for dementia care. METHODS AND ANALYSIS: COM-IC embeds a participatory action approach to using the Alignment-Harmonisation-Results framework for measuring dementia care in Australia. Using this framework, suitable core outcome measures will be identified, analysed, implemented and audited. The methods for analysing each stage will be codesigned with stakeholders, through the conduit of a Stakeholder Reference Group including people living with dementia, formal and informal carers, aged care industry representatives, researchers, clinicians and policy actors. The codesigned evaluation methods consider two key factors: feasibility and acceptability. These considerations will be tested during a 6-month feasibility study embedded in aged care industry partner organisations. ETHICS AND DISSEMINATION: COM-IC has received ethical approval from The University of Queensland (HREC 2021/HE001932). Results will be disseminated through networks established over the project, and in accordance with both the publication schedule and requests from the Stakeholder Reference Group. Full access to publications and reports will be made available through UQ eSpace (https://espace.library.uq.edu.au/), an open access repository hosted by The University of Queensland.

Nipbl Haploinsufficiency Leads to Delayed Outflow Tract Septation and Aortic Valve Thickening.

Cornelia de Lange Syndrome (CdLS) patients, who frequently carry a mutation in NIPBL, present an increased incidence of outflow tract (OFT)-related congenital heart defects (CHDs). Nipbl+/- mice recapitulate a number of phenotypic traits of CdLS patients, including a small body size and cardiac defects, but no study has specifically focused on the valves. Here, we show that adult Nipbl+/- mice present aortic valve thickening, a condition that has been associated with stenosis. During development, we observed that OFT septation and neural crest cell condensation was delayed in Nipbl+/- embryos. However, we did not observe defects in the deployment of the main lineages contributing to the semilunar valves. Indeed, endocardial endothelial-to-mesenchymal transition (EndMT), analysed via outflow tract explants, and neural crest migration, analysed via genetic lineage tracing, did not significantly differ in Nipbl+/- mice and their wild-type littermates. Our study provides the first direct evidence for valve formation defects in Nipbl+/- mice and points to specific developmental defects as an origin for valve disease in patients.

Comparing clinico-demographics and neuropsychiatric symptoms for immigrant and non-immigrant aged care residents living with dementia: a retrospective cross-sectional study from an Australian dementia-specific support service.

BACKGROUND: Neuropsychiatric symptoms of dementia such as agitation and aggression are common in people living with dementia. The presentation of neuropsychiatric symptoms is influenced by the cultural background of people living with dementia. Further, identifying factors contributing to neuropsychiatric symptoms may be complicated if people living with dementia are immigrants or from non-English-speaking backgrounds. Most of what is known about differences in neuropsychiatric symptoms between racial and ethnic groups living with dementia come from community-based samples. This study investigated differences in clinico-demographics and neuropsychiatric symptoms between immigrants and non-immigrants living with dementia in residential aged care homes who were referred to two Dementia Support Australia programs. METHODS: This was a retrospective observational cross-sectional study from 2018 to 2022 using data extracted from the Dementia Support Australia database. Immigrant status was identified by documented country of birth. We conducted exploratory subgroup analyses for English-speaking or non-English-speaking immigrants in comparison to non-immigrants. Neuropsychiatric Inventory and PainChek® were used to assess neuropsychiatric symptoms of dementia and pain, respectively. RESULTS: Of the 23,889 referrals, 36% were immigrants living with dementia. Immigrants were 0.8 years older than non-immigrants on average. Immigrants had a slightly higher prevalence of mixed dementia (9.5%) than non-immigrants (8.2%). Overall, the groups had no difference in the severity of neuropsychiatric symptoms and associated caregiver distress. However, there was a significant difference in the total number of neuropsychiatric inventory domains (Cohen's d = -0.06 [-0.09, - 0.02], p <.001) between non-English-speaking immigrants and non-immigrants. Immigrants were more likely to present with agitation/aggression, while non-immigrants were more likely to present with hallucinations. Factors contributing to neuropsychiatric symptoms were common between the groups, with language barriers and cultural considerations frequently endorsed for immigrants. CONCLUSION: This study reveals a mixed picture of neuropsychiatric symptoms between immigrants and non-immigrants. However, due to the exploratory nature of the hypotheses, our findings need to be replicated in future studies to confirm any conclusions. There is a need for increased awareness on the impact of culture and language on neuropsychiatric symptoms for people receiving residential care. Future studies investigating neuropsychiatric symptoms in different immigrant groups will help increase our understanding of neuropsychiatric symptoms for all people.

Exercise-induced hypohydration impairs 3 km treadmill-running performance in temperate conditions.

Research assessing exercise-induced hypohydration on running performance in a temperate environment is scarce. Given the weight-bearing nature of running, the negative effects of hypohydration might be offset by the weight-loss associated with a negative fluid balance. Therefore, this study investigated the effect of exercise-induced hypohydration on running performance in temperate conditions. Seventeen intermittent games players (age 22 ± 1 y; VO2peak 52.5 ± 4.1 mL∙kg-1∙min-1) completed preliminary and familiarisation trials, and two experimental trials consisting of 12 blocks of 6 min of running (65% VO2peak; preload) with 1 min passive rest in-between, followed by a 3 km time trial (TT). During the preload, subjects consumed minimal fluid (60 mL) to induce hypohydration (HYP) or water to replace 95% sweat losses (1622 ± 343 mL; EUH). Body mass loss (EUH -0.5 ± 0.3%; HYP -2.2 ± 0.4%; P < 0.001), and other changes indicative of hypohydration, including increased serum osmolality, heart rate, thirst sensation, and decreased plasma volume (P ≤ 0.022), were apparent in HYP by the end of the preload. TT performance was ~6% slower in HYP (EUH 900 ± 87 s; HYP 955 ± 110 s; P < 0.001). Exercise-induced hypohydration of ~2% body mass impaired 3 km running TT performance in a temperate environment.

Pharmacokinetics of the Akt Serine/Threonine Protein Kinase Inhibitor, Capivasertib, Administered to Healthy Volunteers in the Presence and Absence of the CYP3A4 Inhibitor Itraconazole.

Capivasertib is a potent, selective inhibitor of all 3 Akt isoforms (Akt1/2/3), and it is currently being tested in Phase III trials for the treatment of prostate and breast cancer. To investigate the effect of a cytochrome P450 3A4 (CYP3A4) inhibitor on the pharmacokinetics of capivasertib, a Phase I drug-drug interaction study of capivasertib and itraconazole was conducted in 11 healthy volunteers (median age, 54 years). The 8-day study had 3 stages: Participants received a single dose of capivasertib 80 mg in Stage 1, 4 doses of itraconazole 200 mg over 3 days in Stage 2, and a final dose of capivasertib 80 mg coadministered with itraconazole 200 mg in Stage 3. Capivasertib pharmacokinetics were examined in Stages 1 and 3. Itraconazole coadministration increased the maximum plasma concentration of capivasertib and total capivasertib exposure (area under the concentration-time curve from time of administration to infinity) by 1.70-fold (90% confidence interval, 1.56-1.86) and 1.95-fold (90% confidence interval, 1.82-2.10), respectively.

The effect of food and acid-reducing agents on the pharmacokinetic profile of capivasertib: Results from a randomized, crossover study.

AIMS: This two-part, adaptive study assessed the effect of food and an acid-reducing agent (rabeprazole) on the pharmacokinetics (PK) and safety of capivasertib, a potent AKT inhibitor, in clinical development for cancer treatment. METHODS: In Part 1, healthy participants (n = 24) were randomized to receive single-dose capivasertib after overnight fasting, a high-fat, high-calorie meal and with rabeprazole postovernight fasting in one of six treatment sequences. Based on Part 1 results, a new group of participants (n = 24) were randomized (Part 2) to receive capivasertib after overnight fasting, a low-fat, low-calorie meal and modified fasting (food restricted from 2 h before dosing to 1 h postdose) in one of six treatment sequences. Blood samples were collected for PK analyses. RESULTS: Following a high-fat, high-calorie meal, capivasertib exposure increased versus overnight fasting (geometric mean ratio [GMR] [90% confidence interval (CI)]: area under the concentration-time curve [AUCinf ] 1.32 [1.22, 1.43], maximum concentration [Cmax ] 1.23 [1.08, 1.41]), but was comparable to that postmodified fasting (GMR: AUCinf 1.13 [0.99, 1.29], Cmax 0.85 [0.70, 1.04]). AUCinf was similar and Cmax was lower with/without rabeprazole (GMR: AUCinf 0.94 [0.87, 1.02]), Cmax 0.73 [0.64, 0.84]). Capivasertib exposure was similar after a low-fat, low-calorie meal versus overnight fasting (GMR: AUCinf 1.14 [1.05, 1.25], Cmax 1.21 [0.99, 1.48]) or modified fasting (GMR: AUCinf 0.96 [0.88, 1.05], Cmax 0.86 [0.70, 1.06]). Safety was consistent with that in larger trials. CONCLUSIONS: This study demonstrates that administering capivasertib with food or acid-reducing agents does not lead to clinically relevant PK or safety profile changes.

UK Reference Intervals for Parathyroid Hormone Using Abbott Methods.

Background: Diagnosis of hyperparathyroidism requires measurement of parathyroid hormone (PTH) in the context of the plasma calcium and other factors, such as vitamin D status and renal function. Accurate classification depends upon an appropriate population reference interval. We examined local population plasma PTH reference intervals at four different UK sites using a common platform. Methods: Plasma PTH results were extracted from laboratory information systems at four different UK sites, all using the Abbott Architect i2000 method. We included only people with normal adjusted serum calcium, magnesium, vitamin D, and renal function. Following outlier rejection lower and upper reference limits were derived. Results: An overall reference interval for plasma PTH of 3.0-13.7 pmol/L was observed using a non-parametric approach compared to 2.9-14.1 pmol/L using a parametric approach, notably higher than the manufacturer's representative range of 1.6-7.2 pmol/L. We also noted statistically significant differences (p < 0.00001) between some sites with upper limits ranging from 11.5 to 15.8 pmol/L which may be due to different population characteristics of each group. Conclusion: Locally derived reference intervals may be beneficial for UK populations and revised upper thresholds are necessary when using the Abbott PTH method to avoid inappropriate classification of patients as having hyperparathyroidism.

Late-season corn stalk nitrate measurements across the US Midwest from 2006 to 2018.

The late-season Corn Stalk Nitrate Test (CSNT) is a well-known tool to help evaluate the after-the-fact performance of nitrogen management. The CSNT has the unique ability to distinguish between optimal and excessive corn nitrogen status, which makes it helpful for identifying the over-application of N so that farmers can adjust their future nitrogen decisions. This paper presents a multi-year and multi-location dataset of late-season corn stalk nitrate test measurements across the US Midwest from 2006 to 2018. The dataset consists of 32,025 corn stalk nitrate measurements from 10,675 corn fields. The nitrogen form, total N rate applied, US state, year of harvest, and climatic conditions are included for each corn field. When available, previous crop, manure source, tillage, and timing of N application are also informed. We provide a detailed description of the dataset to make it usable by the scientific community. Data are published through an R package and also available at the USDA National Agricultural Library Ag Data Commons repository and through an interactive website.

Improving quality in pastoral care using the Pastoral Care Activity Tracker (PCAT): A feasibility study of a digital tool within an Australian healthcare organization.

BACKGROUND: Activity reporting of Pastoral Care Coordinators (PCCs) is often inadequate within care settings because of suboptimal analog data collection methods. This study aims to render pastoral care activity reporting more efficient through digitizing data collection in pastoral care settings. METHODS: A one-year feasibility (pilot) study of a digital tool, the "Pastoral Care Activity Tracker" (PCAT) was conducted between June 1, 2020 and May 31, 2021 at HammondCare, an Australian nonprofit healthcare organization. Feasibility was measured using electronic activity logs collected by the tool and user feedback surveys by PCCs. RESULTS: Of the 43 PCCs working in the organization, 42 (97.7%) used the PCAT tool to complete the logging of 66,298 pastoral care activities (M [SD] = 1,578.5 [827.8] activities per PCC). Most activities were logged successfully (98.3%) and took less than one minute (89.5%). Survey responses (n = 20, 46.6%) indicated many PCCs found the PCAT more convenient (n = 15, 75.0%) and easier to use (n = 10, 50.0%) than paper-based method. CONCLUSIONS: PCCs found the PCAT to be feasible, favorable, and easier to use for report generation compared to paper-based methods. The feasibility of the PCAT improved pastoral care activity data capture, as perceived by PCCs.

A Phase I Study of Capivasertib in Combination With Abiraterone Acetate in Patients With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib - a potent, selective inhibitor of AKT1/2/3 - to approved abiraterone acetate therapy. METHODS: Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off). RESULTS: No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment. CONCLUSION: The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.

The regenerative response of cardiac interstitial cells.

Understanding how certain animals are capable of regenerating their hearts will provide much needed insights into how this process can be induced in humans in order to reverse the damage caused by myocardial infarction. Currently, it is becoming increasingly evident that cardiac interstitial cells play crucial roles during cardiac regeneration. To understand how interstitial cells behave during this process, we performed single-cell RNA sequencing of regenerating zebrafish hearts. Using a combination of immunohistochemistry, chemical inhibition, and novel transgenic animals, we were able to investigate the role of cell type-specific mechanisms during cardiac regeneration. This approach allowed us to identify a number of important regenerative processes within the interstitial cell populations. Here, we provide detailed insight into how interstitial cells behave during cardiac regeneration, which will serve to increase our understanding of how this process could eventually be induced in humans.

Examining barriers to participation in further and continuing education in Germany: Why a regional perspective is (still) important.

Further and continuing education is not only important for individual employability, but also for regional development. Therefore, improving participation in further and continuing education and removing barriers to participation are key concerns of regional education governance. The present study was conducted in a peripheral region of Rhineland-Palatinate in western Germany, where the annual participation rate in continuing education is relatively low compared to other geographic areas in Germany. This quantitative study was designed to understand: (1) To what extent do adult learners engage in continuing education within their habitual lifelong learning process? (2) Which circumstantial factors influence their participation in continuing education? And (3) What are the barriers hindering their participation? The authors found that for two-thirds of adult learners, a precondition for their enrolment in a continuing education course was the satisfaction of both work-related and private life-related factors. The authors' findings point towards the need for flexible study programmes which learners can fit to the demands of their work and life.

Analyse des obstacles à la participation à la formation continue en Allemagne : Pourquoi une perspective régionale est (encore) importante ­ L'éducation complémentaire et continue est importante non seulement pour l'employabilité des individus, mais aussi pour le développement régional. Par conséquent, l'amélioration de la participation à la formation continue et l'élimination des obstacles à la participation sont des préoccupations essentielles de la gouvernance régionale de l'éducation. La présente étude a été menée dans une région périphérique de la Rhénanie-Palatinat, dans l'ouest de l'Allemagne, où le taux de participation annuel à la formation continue est relativement faible par rapport à d'autres zones géographiques en Allemagne. Cette étude quantitative a été conçue pour comprendre : (1) Dans quelle mesure est-ce que les apprenants adultes s'engagent dans la formation continue dans le cadre de leur processus habituel d'apprentissage tout au long de la vie ? (2) Quels sont les facteurs circonstanciels qui influencent leur participation à la formation continue ? et (3) Quels sont les obstacles qui entravent leur participation ? Les auteurs ont constaté que pour deux tiers des apprenants adultes, une condition préalable à leur inscription à un cours de formation continue était la satisfaction de facteurs liés à la fois à leur vie professionnelle et à leur vie privée. Les conclusions des auteurs soulignent la nécessité de programmes d'études flexibles que les apprenants peuvent adapter aux exigences de leur travail et de leur vie personnelle.