Cancer risk following onset of type 2 diabetes in New Zealanders with impaired glucose tolerance over 25 years: a matched prospective cohort study.

BACKGROUND: In people with prediabetes, the link between developing type 2 diabetes (T2D) and cancer risk among those with impaired glucose tolerance (IGT) remains uncertain. We examined this association in IGT individuals from primary care in South and West Auckland, New Zealand, spanning 1994-2019, assessing 5- and 10-year cancer risks. METHODS: Study cohorts were extracted from the Diabetes Care Support Service in Auckland, New Zealand, linking it with national registries for death, cancer, hospital admissions, pharmaceutical claims, and socioeconomic status. We compared cancer risks in individuals with IGT newly diagnosed with or without T2D within a 1-5-year exposure window. Employing tapered matching and landmark analysis to address potential confounding effects, we formed comparative IGT cohorts. Weighted Cox regression models were then employed to assess the association between T2D onset and 5- and 10-year cancer risks. RESULTS: The study included 26,794 patients with IGT, with 629 newly diagnosed with T2D within 5 years and 13,007 without such a diagnosis. Those progressing to T2D had similar 5-year cancer risk but significantly higher 10-year risk (HR 1.35; 95% CI 1.09-1.68). This association was stronger in older individuals, the socioeconomically deprived, current smokers, those with worse metabolic measures, and lower renal function. Patients with IGT of NZ European ethnicity had lower 10-year cancer risk. CONCLUSIONS: T2D diagnosis influences cancer risk in individuals with IGT. Developing risk scores for high-risk IGT individuals and implementing cancer screening and structured diabetes prevention, especially in deprived or minority ethnic populations, is essential.

Hydrologic Connectivity Regulates Riverine N2O Sources and Dynamics.

Indirect nitrous oxide (N2O) emissions from streams and rivers are a poorly constrained term in the global N2O budget. Current models of riverine N2O emissions place a strong focus on denitrification in groundwater and riverine environments as a dominant source of riverine N2O, but do not explicitly consider direct N2O input from terrestrial ecosystems. Here, we combine N2O isotope measurements and spatial stream network modeling to show that terrestrial-aquatic interactions, driven by changing hydrologic connectivity, control the sources and dynamics of riverine N2O in a mesoscale river network within the U.S. Corn Belt. We find that N2O produced from nitrification constituted a substantial fraction (i.e., >30%) of riverine N2O across the entire river network. The delivery of soil-produced N2O to streams was identified as a key mechanism for the high nitrification contribution and potentially accounted for more than 40% of the total riverine emission. This revealed large terrestrial N2O input implies an important climate-N2O feedback mechanism that may enhance riverine N2O emissions under a wetter and warmer climate. Inadequate representation of hydrologic connectivity in observations and modeling of riverine N2O emissions may result in significant underestimations.

All-cause, premature, and cardiovascular death attributable to socioeconomic and ethnic disparities among New Zealanders with type 1 diabetes 1994-2019: a multi-linked population-based cohort study.

BACKGROUND: New Zealand (NZ) research into type 1 diabetes mellitus (T1DM) mortality can inform policy and future research. In this study we aimed to quantify the magnitude to which ethnicity and socioeconomic disparities influenced mortality at the population level among people with Type 1 diabetes (T1DM) in Auckland, New Zealand (NZ). METHODS: The cohort data were derived from the primary care diabetes audit program the Diabetes Care Support Service (DCSS), and linked with national primary care, pharmaceutical claims, hospitalisation, and death registration databases. People with T1DM enrolled in DCSS between 1994-2018 were included. All-cause, premature, and cardiovascular mortalities were estimated by Poisson regression models with adjustment for population-level confounders. The mortality rates ratio (MRR) was standardized against the DCSS type 2 diabetes population. Mortality rates were compared by ethnic group (NZ European (NZE) and non-NZE) and socioeconomic deprivation quintile. The population attributable fraction (PAF) was estimated for ethnic and socioeconomic disparities by Cox regression adjusting for demographic, lifestyle, and clinical covariates. The adjusted slope index inequality (SII) and relative index of inequality (RII) were used to measure the socioeconomic disparity in mortalities. RESULTS: Overall, 2395 people with T1DM (median age 34.6 years; 45% female; 69% NZE) were enrolled, among whom the all-cause, premature and CVD mortalities were 6.69 (95% confidence interval: 5.93-7.53), 3.30 (2.77-3.90) and 1.77 (1.39-2.23) per 1,000 person-years over 25 years. The overall MRR was 0.39 (0.34-0.45), 0.65 (0.52-0.80), and 0.31 (0.24-0.41) for all-cause, premature and CVD mortality, respectively. PAF attributable to ethnicity disparity was not significantly different for mortality. The adjusted PAF indicated that 25.74 (0.84-44.39)% of all-cause mortality, 25.88 (0.69-44.69)% of premature mortality, 55.89 (1.20-80.31)% of CVD mortality could be attributed to socioeconomic inequality. The SII was 8.04 (6.30-9.78), 4.81 (3.60-6.02), 2.70 (1.82-3.59) per 1,000 person-years and RII was 2.20 (1.94-2.46), 2.46 (2.09-2.82), and 2.53 (2.03-3.03) for all-cause, premature and CVD mortality, respectively. CONCLUSIONS: Our results suggest that socioeconomic disparities were responsible for a substantial proportion of all-cause, premature and CVD mortality in people with T1DM in Auckland, NZ. Reducing socioeconomic barriers to management and self-management would likely improve clinical outcomes.

Long-term impact of type 2 diabetes onset on dementia incidence rate among New Zealanders with impaired glucose tolerance: A tapered-matched landmark analysis over 25 years.

INTRODUCTION: We aimed to investigate the association between the onset of type 2 diabetes (T2D) and dementia incidence rates (IR) in the population with impaired glucose tolerance (IGT) identified in primary care in New Zealand (NZ) over 25 years. METHODS: Tapered matching and landmark analysis (accounting for immortal bias) were used to control for potential effects of known confounders. The association between T2D onset and 5- and 10-year IR of dementia was estimated by weighted Cox models. RESULTS: The onset of T2D was significantly associated with the 10-year IR of dementia, especially in the socioeconomically deprived, those of non-NZ European ethnicity, those currently smoking, and patients with higher metabolic measures. DISCUSSION: Our findings suggest that the onset of T2D is a significant risk factor for dementia in individuals with IGT. Dementia screening and structured diabetes prevention are vital in the population with IGT, particularly those from deprived or ethnic minority backgrounds. HIGHLIGHTS: Increased dementia incidence rate links with T2D onset in people with IGT. Significant incidence varied by ethnicity, socioeconomic status, and health factors. Results emphasize the diabetes manage and socioeconomic factors on dementia risk. Secondary analysis highlights the key role of vascular health in dementia prevention.

Mental health patients' preferences regarding restrictive interventions: An integrative review.

WHAT IS KNOWN ON THE SUBJECT?: The use of restrictive interventions is described as a violation of patients' rights and autonomy. It must only be used as a last resort to manage dangerous behaviour, to prevent or reduce the risk of mental health patients harming themselves or others. International mental health policy and legislation agree that when restrictive interventions are applied, the least restrictive alternative should be chosen. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: The results are ambiguous, as to which restrictive intervention is preferred over others, but there are tendencies towards the majority preferring observation, with mechanical restraint being the least preferred. To make the experience less intrusive and restrictive, certain factors are preferred, such as a more pleasant and humane seclusion room environment, staff communicating during the application and staff of same gender applying the intervention. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: When applying restrictive interventions, mental health professionals should consider environment, communication and duration factors that influence patient preferences, such as the opportunity to keep some personal items in the seclusion room, or, when using restraint, to communicate the reason and explain what is going to happen. More research is needed to clarify patients' preferences regarding restrictive interventions and their views on which are the least restrictive. Preferably, agreement is needed on standard measures, and global use of the same definition of restrictive interventions. ABSTRACT: INTRODUCTION: The use of restrictive interventions is a violation of patients' rights that causes physical and psychological harm and which is a well-known challenge globally. Mental health law and legislative principles and experts agree that when restrictive interventions are applied, the least restrictive alternative should be used. However, there is no consensus on what is the least restrictive alternative, especially from the patient perspective. AIM: To investigate the literature on mental health patients' preferences regarding restrictive interventions applied during admission to a psychiatric hospital. METHOD: An integrative review informed by the PRISMA statement and thematic analysis were undertaken. RESULTS: There were tendencies towards patients preferring observation and, for the majority, mechanical restraint was the least preferred restrictive intervention. Factors such as environment, communication and duration were found to influence patients' preferences. DISCUSSION: There is a lack of agreement on how best to measure patients' preferences and this complicates the choice of the least restrictive alternative. Nonetheless, our findings show that staff should consider environment, communication and duration when applying restrictive interventions. IMPLICATIONS FOR PRACTICE: More research on restrictive interventions and the least restrictive alternative is warranted, but agreement is needed on standard measures, and a standard global definition of restrictive interventions.

Promoting a Patient-Centered Understanding of Safety in Acute Mental Health Wards: A User-Centered Design Approach to Develop a Real-Time Digital Monitoring Tool.

BACKGROUND: Acute mental health services report high levels of safety incidents that involve both patients and staff. The potential for patients to be involved in interventions to improve safety within a mental health setting is acknowledged, and there is a need for interventions that proactively seek the patient perspective of safety. Digital technologies may offer opportunities to address this need. OBJECTIVE: This research sought to design and develop a digital real-time monitoring tool (WardSonar) to collect and collate daily information from patients in acute mental health wards about their perceptions of safety. We present the design and development process and underpinning logic model and programme theory. METHODS: The first stage involved a synthesis of the findings from a systematic review and evidence scan, interviews with patients (n=8) and health professionals (n=17), and stakeholder engagement. Cycles of design activities and discussion followed with patients, staff, and stakeholder groups, to design and develop the prototype tool. RESULTS: We drew on patient safety theory and the concepts of contagion and milieu. The data synthesis, design, and development process resulted in three prototype components of the digital monitoring tool (WardSonar): (1) a patient recording interface that asks patients to input their perceptions into a tablet computer, to assess how the ward feels and whether the direction is changing, that is, "getting worse" or "getting better"; (2) a staff dashboard and functionality to interrogate the data at different levels; and (3) a public-facing ward interface. The technology is available as open-source code. CONCLUSIONS: Recent patient safety policy and research priorities encourage innovative approaches to measuring and monitoring safety. We developed a digital real-time monitoring tool to collect information from patients in acute mental health wards about perceived safety, to support staff to respond and intervene to changes in the clinical environment more proactively.

Implementing and evaluating patient-focused safety technology on adult acute mental health wards.

WHAT IS KNOWN ON THE SUBJECT: Mental health wards can feel unsafe. We know that patients and staff have different ideas about what makes a hospital ward safe or unsafe. Patients are often the first to know when the atmosphere on a ward becomes tense, but often, no one asks them for their views. Patients and staff are experts and should be included in discussions about how to make wards safer. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE: We got together with some service users and staff, and made an app that helps patients to tell staff when they are not feeling safe on a mental health ward. We tried it out on six wards and we asked patients and staff what they thought. The app was easy to use and most people liked the look of it. Patients said staff did not talk with them enough and so they liked using the app. However, some staff said they could tell how patients were feeling without an app and so they did not need it. Ward managers told us that staff were often very busy and did not always have time to use the app. WHAT ARE THE IMPLICATIONS FOR PRACTICE: This app could help staff know straightaway when patients do not feel safe on the ward, so that they can act quickly to calm things down. To make the most of the app, staff need to get used to it and bring it into ward routines. ABSTRACT: INTRODUCTION: Safety improvement on mental health wards is of international concern. It should incorporate patient perspectives. AIM: Implementation and evaluation of 'WardSonar', a digital safety-monitoring tool for adult acute mental health wards, developed with stakeholders to communicate patients' real-time safety perceptions to staff. METHOD: Six acute adult mental health wards in England implemented the tool in 2022. Evaluation over 10 weeks involved qualitative interviews (34 patients, 33 staff), 39 focused ethnographic observations, and analysis of pen portraits. RESULTS: Implementation and evaluation of the WardSonar tool was feasible despite challenging conditions. Most patients valued the opportunity to communicate their immediate safety concerns, stating that staff had a poor understanding of them. Some staff said the WardSonar tool could help enhanced ward safety but recognised a need to incorporate its use into daily routines. Others said they did not need the tool to understand patients' safety concerns. DISCUSSION: Foreseeable challenges, including staff ambivalence and practical issues, appeared intensified by the post-COVID-19 context. IMPLICATIONS FOR PRACTICE: The WardSonar tool could improve ward safety, especially from patients' perspectives. Future implementation could support staff to use the real-time data to inform proactive safety interventions.

'Safer, Not Safe': Service Users' Experiences of Psychological Safety in Inpatient Mental Health Wards in the United Kingdom.

Research on patient safety in mental health settings is limited compared to physical healthcare settings. Recent qualitative studies have highlighted that patient safety is more than just physical safety but includes psychological safety. Traditionally, psychological safety has been defined as the belief that it is safe to take interpersonal risks, such as speaking up, without a fear of negative consequences. However, to date, it is not clear what constitutes psychological safety for service users of inpatient mental health settings. To understand this, we conducted 12 interviews with former inpatient mental health service users. Interviews were analysed with Reflexive Thematic Analysis, and five themes were developed. All themes had subthemes. Overall, we found that participants were more readily able to draw on situations where they felt psychologically unsafe, rather than safe. Psychological safety in service users was influenced by (1) healthcare staff attitudes and behaviours towards them, (2) their relationships with other service users, (3) whether they felt they had any control over their environment and medical decision-making regarding their care, (4) their experiences of physically safety, feeling listened to and believed and (5) access to meaningful occupation on the wards. These findings suggest that changes are needed to enhance inpatient mental health service users' general experiences of psychological safety. Further research will need to (1) further develop understanding of the concept of psychological safety for service users and (2) identify interventions, and such interventions should be co-designed with service users.

The LTAR Integrated Common Experiment at Upper Mississippi River Basin-Platteville.

Alternative agronomic practices are needed to address the various climatic, agronomic, edaphic, and water quality related challenges faced by the dairy farmers of the Driftless Area (DA) in the Upper Mississippi River Basin (UMRB). These practices should be innovative in nature, inclusive of regional stakeholders, and sustainable to meet the future food and climate related challenges of Wisconsin agriculture. Here, we outline our Integrated (grazing and cropland) Long-Term Agroecosystem Research Common Experiment at the University of Wisconsin-Platteville Pioneer Farm (UW-P PF) in the UMRB and describe our collaboration in this USDA network. In this field-scale experiment, we are comparing the conventional dairy production system common to this region (i.e., corn-on-corn [Zea mays L.] for 4 years, followed by alfalfa [Medicago sativa L.] for 3 years, with no cover crops) with two alternative dairy production systems-(1) soil health management with no-till, cover crops, and application of a novel manure-based nutrient-rich stable product, and (2) management intensive grazing-and rotational grazing on pastures established with diverse forage-legume mix. Meteorological, edaphic, hydrologic, and agronomic data are collected and analyzed at regular frequencies. Going forward, the experiment will continue as a form of stakeholder-driven adaptive research and receive evaluation on a regular basis to determine whether any changes are required to address the "real-world" challenges faced by the farmers in the Midwest.

A service-user digital intervention to collect real-time safety information on acute, adult mental health wards: the WardSonar mixed-methods study.

Background: Acute inpatient mental health services report high levels of safety incidents. The application of patient safety theory has been sparse, particularly concerning interventions that proactively seek patient perspectives. Objective(s): Develop and evaluate a theoretically based, digital monitoring tool to collect real-time information from patients on acute adult mental health wards about their perceptions of ward safety. Design: Theory-informed mixed-methods study. A prototype digital monitoring tool was developed from a co-design approach, implemented in hospital settings, and subjected to qualitative and quantitative evaluation. Setting and methods: Phase 1: scoping review of the literature on patient involvement in safety interventions in acute mental health care; evidence scan of digital technology in mental health contexts; qualitative interviews with mental health patients and staff about perspectives on ward safety. This, alongside stakeholder engagement with advisory groups, service users and health professionals, informed the development processes. Most data collection was virtual. Phase 1 resulted in the technical development of a theoretically based digital monitoring tool that collected patient feedback for proactive safety monitoring. Phase 2: implementation of the tool in six adult acute mental health wards across two UK NHS trusts; evaluation via focused ethnography and qualitative interviews. Statistical analysis of WardSonar data and routine ward data involving construction of an hour-by-hour data set per ward, permitting detailed analysis of the use of the WardSonar tool. Participants: A total of 8 patients and 13 mental health professionals participated in Phase 1 interviews; 33 staff and 34 patients participated in Phase 2 interviews. Interventions: Patients could use a web application (the WardSonar tool) to record real-time perceptions of ward safety. Staff could access aggregated, anonymous data to inform timely interventions. Results: Coronavirus disease 2019 restrictions greatly impacted the study. Stakeholder engagement permeated the project. Phase 1 delivered a theory-based, collaboratively designed digital tool for proactive patient safety monitoring. Phase 2 showed that the tool was user friendly and broadly acceptable to patients and staff. The aggregated safety data were infrequently used by staff. Feasibility depended on engaged staff and embedding use of the tool in ward routines. There is strong evidence that an incident leads to increased probability of further incidents within the next 4 hours. This puts a measure on the extent to which social/behavioural contagion persists. There is weak evidence to suggest that an incident leads to a greater use of the WardSonar tool in the following hour, but none to suggest that ward atmosphere predicts future incidents. Therefore, how often patients use the tool seems to send a stronger signal about potential incidents than patients' real-time reports about ward atmosphere. Limitations: Implementation was limited to two NHS trusts. Coronavirus disease 2019 impacted design processes including stakeholder engagement; implementation; and evaluation of the monitoring tool in routine clinical practice. Higher uptake could enhance validity of the results. Conclusions: WardSonar has the potential to provide a valuable route for patients to communicate safety concerns. The WardSonar monitoring tool has a strong patient perspective and uses proactive real-time safety monitoring rather than traditional retrospective data review. Future work: The WardSonar tool can be refined and tested further in a post Coronavirus disease 2019 context. Study registration: This study is registered as ISRCTN14470430. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR128070) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 14. See the NIHR Funding and Awards website for further award information.

Mental health wards can feel unsafe. We know that patients and staff have different ideas about what makes a hospital ward safe or unsafe. Patients are often the first to know when the atmosphere on a ward becomes tense but, often, no one asks them for input or feedback at the time. We worked with service users and staff to develop new technology to make it easy for patients to tell staff about changes in the ward atmosphere. We put everyone's ideas together and some technical developers then built a digital safety tool to use on a tablet computer. Patients put in anonymous information about the ward atmosphere and staff can read it straight away. We tested it on six adult acute mental health wards for 10 weeks. We asked patients and staff what they thought about the tool and we looked at how it was being used. Patients and staff liked the look of the tool on the tablet computer. Some staff said they did not need it because they could tell how patients were feeling, but patients told us that staff did not talk with them much and did not always know when patients were feeling tense. Coronavirus disease 2019 made life difficult on the wards. Most ward managers said the tool could be helpful, but they had not had time to get used to it on the wards. Occasionally, the tablet computers were out of action. Many staff tried hard to use the tool. Most patient information was gathered when it was calm, perhaps because staff were not too busy to help them. We found that this tool could help staff know about tensions on the ward, but they need to get used to it and bring it into ward routines.

Characteristics of surveillance systems for suicide and self-harm: A scoping review.

BACKGROUND: Suicide is a complex public health issue. Surveillance systems play a vital role in identifying trends and epidemiologic needs, informing public health strategies, and tailoring effective context-based suicide prevention interventions. AIM: To identify and summarise the characteristics of specific surveillance systems and general health behaviour that include data onsuicide and self-harm. METHOD: A scoping review following the JBI recommendations and PRISMA-ScR guidelines identified 29 relevant studies on suicide and self-harm surveillance systems. A systematic search was performed on Cinahl, Embase, Lilacs-Latin American and Caribbean Health Sciences Literature, PubMed-US National Library of Medicine, Scopus, and Google Scholar. The eligibility criteria include papers that use qualitative, quantitative or mixed methods with no restrictions on time or language. The following papers were excluded regarding euthanasia and assisted suicide, as well as papers that did not explicitly describe suicide, self-harm, and surveillance systems. Two researchers independently screened the materials for eligibility and extracted data from the included studies. Data analysis was conducted using content analysis. RESULTS: Twenty-nine references were included, and 30 surveillance systems were identified and classified into general health behaviour surveillance (n = 15) and specific systems for suicide and self-harm (n = 15). General health behaviour systems often operate at national data collection level, collecting non-fatal data in healthcare settings, mainly emergency departments. The specific systems exhibited greater variability in terms of context, involved actors, data collection level, data collection procedures, and case classification. Limitations found by the studies pointed mostly to case definitions and data quality. Co-production, intersectoral collaboration, clear case definition criteria and data standardisation are essential to improve surveillance systems for suicide and self-harm. CONCLUSIONS: This review identified the characteristics of surveillance systems for suicide and self-harm. Monitoring and evaluation are crucial for ongoing relevance and impact on prevention efforts.

American society for metabolic and bariatric surgery: intra-operative care pathway for minimally invasive Roux-en-Y gastric bypass.

BACKGROUND: Clinical care pathways help guide and provide structure to clinicians and providers to improve healthcare delivery and quality. The Quality Improvement and Patient Safety Committee (QIPS) of the American Society for Metabolic and Bariatric Surgery (ASMBS) has previously published care pathways for the performance of laparoscopic sleeve gastrectomy (LSG) and pre-operative care of patients undergoing Roux-en-Y gastric bypass (RYGB). OBJECTIVE: This current RYGB care pathway was created to address intraoperative care, defined as care occurring on the day of surgery from the preoperative holding area, through the operating room, and into the postanesthesia care unit (PACU). METHODS: PubMed queries were performed from January 2001 to December 2019 and reviewed according to Level of Evidence regarding specific key questions developed by the committee. RESULTS: Evidence-based recommendations are made for care of patients undergoing RYGB including the pre-operative holding area, intra-operative management and performance of RYGB, and concurrent procedures. CONCLUSIONS: This document may provide guidance based on recent evidence to bariatric surgeons and providers for the intra-operative care for minimally invasive RYGB.

RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia.

BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase­mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo. CONCLUSIONS: In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377.)

Effects of photon irradiation in the presence and absence of hindlimb unloading on the behavioral performance and metabolic pathways in the plasma of Fischer rats.

Introduction: The space environment astronauts experience during space missions consists of multiple environmental challenges, including microgravity. In this study, we assessed the behavioral and cognitive performances of male Fisher rats 2 months after sham irradiation or total body irradiation with photons in the absence or presence of simulated microgravity. We analyzed the plasma collected 9 months after sham irradiation or total body irradiation for distinct alterations in metabolic pathways and to determine whether changes to metabolic measures were associated with specific behavioral and cognitive measures. Methods: A total of 344 male Fischer rats were irradiated with photons (6 MeV; 3, 8, or 10 Gy) in the absence or presence of simulated weightlessness achieved using hindlimb unloading (HU). To identify potential plasma biomarkers of photon radiation exposure or the HU condition for behavioral or cognitive performance, we performed regression analyses. Results: The behavioral effects of HU on activity levels in an open field, measures of anxiety in an elevated plus maze, and anhedonia in the M&M consumption test were more pronounced than those of photon irradiation. Phenylalanine, tyrosine, and tryptophan metabolism, and phenylalanine metabolism and biosynthesis showed very strong pathway changes, following photon irradiation and HU in animals irradiated with 3 Gy. Here, 29 out of 101 plasma metabolites were associated with 1 out of 13 behavioral measures. In the absence of HU, 22 metabolites were related to behavioral and cognitive measures. In HU animals that were sham-irradiated or irradiated with 8 Gy, one metabolite was related to behavioral and cognitive measures. In HU animals irradiated with 3 Gy, six metabolites were related to behavioral and cognitive measures. Discussion: These data suggest that it will be possible to develop stable plasma biomarkers of behavioral and cognitive performance, following environmental challenges like HU and radiation exposure.