An economic evaluation of the Prioritising Responses Of Nurses To deteriorating patient Observations (PRONTO) clinical trial.

BACKGROUND: Early recognition and response to clinical deterioration reduce the frequency of in-hospital cardiac arrests, mortality, and unplanned intensive care unit (ICU) admissions. This study aimed to investigate the impact of the Prioritising Responses Of Nurses To deteriorating patient Observations (PRONTO) intervention on hospital costs and patient length of stay (LOS). METHOD: The PRONTO cluster randomised control trial was conducted to improve nurses' responses to patients with abnormal vital signs. Hospital data were collected pre-intervention (T0) at 6 months (T1) and 12 months (T2) post-intervention. The economic evaluation involved a cost-consequence analysis from the hospital's perspective. Generalised estimating equations were used to estimate the parameters for regression models of the difference in costs and LOS between study groups and time points. RESULTS: Hospital admission data for 6065 patients (intervention group, 3102; control group, 2963) were collected from four hospitals for T0, T1 and T2. The intervention cost was 69.61 A$ per admitted patient, including the additional intervention training for nurses and associated labour costs. The results showed cost savings and a shorter LOS in the intervention group between T0 - T1 and T0 - T2 (cost differences T0 - T1: -364 (95% CI -3,782; 3049) A$ and T0 - T2: -1,710 (95% CI -5,162; 1,742) A$; and LOS differences T0 - T1: -1.10 (95% CI -2.44; 0.24) days and T0 & T2: -2.18 (95% CI -3.53; -0.82) days). CONCLUSION: The results of the economic analysis demonstrated that the PRONTO intervention improved nurses' responses to patients with abnormal vital signs and significantly reduced hospital LOS by two days at 12 months in the intervention group compared to baseline. From the hospital's perspective, savings from reduced hospitalisations offset the costs of implementing PRONTO.

Nuclear receptor signaling via NHR-49/MDT-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues.

The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in Caenorhabditis elegans We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, an ortholog of mammalian peroxisome proliferator-activated receptor α (PPARα), regulates stress resilience and proteostasis downstream from embryo integrity and other pathways that influence lipid homeostasis and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing intertissue pathway in somatic cells, triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49, together with its coactivator, MDT-15, contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer. Our findings indicate that NHR-49 also contributes to stress resilience in other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting, and that increased NHR-49 activity is sufficient to improve proteostasis and stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

Cost of childhood severe pneumonia management in selected public inpatient care facilities in Bangladesh: a provider perspective.

OBJECTIVE: To estimate inpatient care costs of childhood severe pneumonia and its urban-rural cost variation, and to predict cost drivers. DESIGN: The study was nested within a cluster randomised trial of childhood severe pneumonia management. Cost per episode of severe pneumonia was estimated from a healthcare provider perspective for children who received care from public inpatient facilities. A bottom-up micro-costing approach was applied and data collected using structured questionnaire and review of the patient record. Multivariate regression analysis determined cost predictors and sensitivity analysis explored robustness of cost parameters. SETTING: Eight public inpatient care facilities from two districts of Bangladesh covering urban and rural areas. PATIENTS: Children aged 2-59 months with WHO-classified severe pneumonia. RESULTS: Data on 1252 enrolled children were analysed; 795 (64%) were male, 787 (63%) were infants and 59% from urban areas. Average length of stay (LoS) was 4.8 days (SD ±2.5) and mean cost per patient was US$48 (95% CI: US$46, US$49). Mean cost per patient was significantly greater for urban tertiary-level facilities compared with rural primary-secondary facilities (mean difference US$43; 95% CI: US$40, US$45). No cost variation was found relative to age, sex, malnutrition or hypoxaemia. Type of facility was the most important cost predictor. LoS and personnel costs were the most sensitive cost parameters. CONCLUSION: Healthcare provider cost of childhood severe pneumonia was substantial for urban located public health facilities that provided tertiary-level care. Thus, treatment availability at a lower-level facility at a rural location may help to reduce overall treatment costs.

Walking self-confidence and lower levels of anxiety are associated with meeting recommended levels of physical activity after hip fracture: a cross-sectional study.

PURPOSE: To explore whether psychological factors are associated with ability to meet recommended physical activity thresholds after hip fracture. MATERIALS AND METHODS: Cross-sectional observational study of 216 community-dwelling adults aged ≥65 years after hip fracture (mean age 79 SD 7 years, 70% female). Multiple ordinal regression analysis determined factors associated with meeting physical activity thresholds related to positive health outcomes: 4,400 and 7,100 daily steps. Explanatory variables were: walking self-confidence; falls self-efficacy; depression; anxiety; co-morbidities; previous gait aid use; nutritional status; age; and gender. RESULTS: Forty-three participants (20%) met the lower threshold of ≥4,400 to <7,100 steps and thirty participants (14%) met the upper threshold of ≥7,100 steps. Walking self-confidence was positively associated with meeting higher physical activity thresholds (adjusted odds ratio [AOR] 1.32: 95% CI 1.11 to 1.57, p = 0.002). Age (AOR 0.93: 95% CI 0.89 to 0.98, p = 0.003), DASS-21 anxiety score (AOR 0.81: 95% CI 0.69 to 0.94, p = 0.008) and comorbidity index score (AOR 0.52: 95% CI 0.36 to 0.72, p < 0.001) were negatively associated with meeting higher physical activity thresholds. CONCLUSION: Walking self-confidence and anxiety are potentially modifiable factors associated with meeting physical activity thresholds related to positive health outcomes after hip fracture.

Older people are often physically inactive after hip fracture, which can lead to negative health outcomes and increased risk of mortality.The potentially modifiable psychological factors of walking self-confidence and anxiety are associated with meeting recommended physical activity levels after hip fracture.Therapists should include assessment of psychological factors to help guide rehabilitation of patients after hip fracture.

The impact of maternal health on child's health outcomes during the first five years of child's life in countries with health systems similar to Australia: A systematic review.

INTRODUCTION: The first five years of life is an important developmental period that establishes the foundation for future health and well-being. Mothers play a primary role in providing emotional and physical nourishment during early childhood. This systematic review aims to explore the association between maternal health and child health in the first five years of the child's life. MATERIALS AND METHODS: As primary aims, we systematically synthesised published evidence relating to the first five years of life for associations between maternal health exposures (mental, physical and Health-Related Quality of Life (HRQoL) and child health outcomes (physical health, mental health, HRQoL and Health Service Use (HSU) /cost). As a secondary aim, we explored how the above associations vary between disadvantaged and non-disadvantaged populations. The search was limited to studies that published and collected data from 2010 to 2022. The systematic review was specific to countries with similar health systems to Australia. The search was conducted in MEDLINE, CINAHL, APA PsycINFO, GLOBAL HEALTH, and EMBASE databases. The quality of the included studies was assessed by The Effective Public Health Practice Project (EPHPP) tool. RESULTS: Thirteen articles were included in the final synthesis from the identified 9439 articles in the primary search. Six (46%) explored the association between maternal mental health and child's physical health, two (15%) explored maternal and child's physical health, one (8%) explored maternal and child's mental health, one (8%) explored maternal physical health and child's HRQoL, and three (23%) explored maternal mental health and child's HSU. We found an association between maternal health and child health (physical and mental) and HSU outcomes but no association between maternal health and child's overall HRQoL. The results for disadvantaged communities did not show any difference from the general population. DISCUSSION AND CONCLUSION: Our review findings show that maternal health influences the child's health in the first five years. However, the current evidence is limited, and the findings were primarily related to a specific maternal or child's health condition. There was no evidence of associations of child health outcomes in healthy mothers. There is an extensive research gap investigating maternal health exposures and child outcomes in quality of life and overall health.

Simulating the healthcare workforce impact and capacity for pancreatic cancer care in Victoria: a model-based analysis.

BACKGROUND: The incidence of pancreatic cancer is rising. With improvements in knowledge for screening and early detection, earlier detection of pancreatic cancer will continue to be more common. To support workforce planning, our aim is to perform a model-based analysis that simulates the potential impact on the healthcare workforce, assuming an earlier diagnosis of pancreatic cancer. METHODS: We developed a simulation model to estimate the demand (i.e. new cases of pancreatic cancer) and supply (i.e. the healthcare workforce including general surgeons, medical oncologists, radiation oncologists, pain medicine physicians, and palliative care physicians) between 2023 and 2027 in Victoria, Australia. The model compares the current scenario to one in which pancreatic cancer is diagnosed at an earlier stage. The incidence of pancreatic cancer in Victoria, five-year survival rates, and Victoria's population size were obtained from Victorian Cancer Registry, Cancer Council NSW, and Australian Bureau of Statistics respectively. The healthcare workforce data were sourced from the Australian Government Department of Health and Aged Care's Health Workforce Data. The model was constructed at the remoteness level. We analysed the new cases and the number of healthcare workforce by profession together to assess the impact on the healthcare workforce. RESULTS: In the status quo, over the next five years, there will be 198 to 220 stages I-II, 297 to 330 stage III, and 495 to 550 stage IV pancreatic cancer cases diagnosed annually, respectively. Assuming 20-70% of the shift towards pancreatic cancer's earlier diagnosis (shifting from stage IV to stages I-II pancreatic cancer within one year), the stages I-II cases could increase to 351 to 390 or 598 to 665 per year. The shift to early diagnosis led to substantial survival gains, translating into an additional 284 or 795 out of 5246 patients with pancreatic cancer remaining alive up to year 5 post-diagnosis. Workforce supply decreases significantly by the remoteness levels, and remote areas face a shortage of key medical professionals registered in delivering pancreatic cancer care, suggesting travel necessities by patients or clinicians. CONCLUSION: Improving the early detection and diagnosis of pancreatic cancer is expected to bring significant survival benefits, although there are workforce distribution imbalances in Victoria that may affect the ability to achieve the anticipated survival gain.

Cost-effectiveness of an inpatient nurse practitioner in heart failure.

AIMS: Heart failure (HF) nurse practitioners (NPs) are an important part of the HF specialist team, and their impact on the cost-effectiveness of their role is unknown. The aim of this study was to determine the cost-effectiveness of a HF NP inpatient service compared with current practice of no HF NP service from a health system perspective at 12 months and 3 years. METHODS AND RESULTS: We developed a Markov model to estimate costs, effects, and cost-effectiveness for hospitalized HF patients and seen by a HF NP service compared with usual care at 12 months and 3 years. Costs and effects were taken from a retrospective observational cohort study. Transition probabilities and utilities were derived from published studies. A total of 500 patients were included (250 patients in the HF NP service vs. 250 patients in usual care). Average age was 77.7 ± 11 years, and 54% were male. At 12 months, the HF NP group was cheaper and more effective compared with no HF NP [$23 031 vs. $25 111 (AUD), respectively; quality-adjusted life years (QALYs) were 0.68 in HF NP group compared with 0.66 in usual care]. The incremental cost-effectiveness ratio showed a savings of $109 474 per QALY gained at 12 months and a savings of $270 667 per QALY gained at 3 years in favour of the HF NP service. CONCLUSION: The HF NP service was cost-effective with lower costs and higher QALYs compared with no HF NP service. Economic evaluations alongside randomized controlled trials are warranted.

Homeostatic control of stearoyl desaturase expression via patched-like receptor PTR-23 ensures the survival of C. elegans during heat stress.

Organismal responses to temperature fluctuations include an evolutionarily conserved cytosolic chaperone machinery as well as adaptive alterations in lipid constituents of cellular membranes. Using C. elegans as a model system, we asked whether adaptable lipid homeostasis is required for survival during physiologically relevant heat stress. By systematic analyses of lipid composition in worms during and before heat stress, we found that unsaturated fatty acids are reduced in heat-stressed animals. This is accompanied by the transcriptional downregulation of fatty acid desaturase enzymes encoded by fat-1, fat-3, fat-4, fat-5, fat-6, and fat-7 genes. Conversely, overexpression of the Δ9 desaturase FAT-7, responsible for the synthesis of PUFA precursor oleic acid, and supplementation of oleic acid causes accelerated death of worms during heat stress. Interestingly, heat stress causes permeability defects in the worm's cuticle. We show that fat-7 expression is reduced in the permeability defective collagen (PDC) mutant, dpy-10, known to have enhanced heat stress resistance (HSR). Further, we show that the HSR of dpy-10 animals is dependent on the upregulation of PTR-23, a patched-like receptor in the epidermis, and that PTR-23 downregulates the expression of fat-7. Consequently, abrogation of ptr-23 in wild type animals affects its survival during heat stress. This study provides evidence for the negative regulation of fatty acid desaturase expression in the soma of C. elegans via the non-canonical role of a patched receptor signaling component. Taken together, this constitutes a skin-gut axis for the regulation of lipid desaturation to promote the survival of worms during heat stress.

Parent-Reported Child and Parent Quality of Life during COVID-19 Testing at an Australian Paediatric Hospital Outpatient Clinic: A Cross-Sectional Study.

Globally, we have seen a drop in adult and child quality of life (QOL) during the COVID-19 pandemic. However, little is known about adult or child QOL during the height of the pandemic in Australia and the impact of government-imposed restrictions, specifically attending school on-site versus home schooling. Our study aimed to establish if QOL in children and parents presenting to a Respiratory Infection Clinic in Victoria, Australia, for COVID-19 PCR testing differed from pre-pandemic population norms. We also explored whether on-site versus home schooling further impacted QOL. Following the child's test and prior to receiving results, consenting parents of children aged 6 to 17 years old completed the Child Health Utility 9 Dimension (CHU9D) instrument on their child's behalf. Parents of children aged birth to five years completed the EuroQOL 5-Dimension 5-Level (EQ-5D-5L) instrument on their own behalf (cross-sectional study). Data analyses utilised quantile regression, adjusting for the child's age, COVID-19 symptoms, gender and chronic health conditions. From July 2020 to November 2021, 2025 parents completed the CHU9D; the mean age for children was 8.41 years (±3.63 SD), and 48.4 per cent were female (n = 980/2025). In the same time period, 5751 parents completed the EQ-5D-5L; the mean age for children was 2.78 years (±1.74 SD), and 52.2 per cent were female (n = 3002/5751). Results showed that QOL scores were lower than pre-pandemic norms for 68 per cent of the CHU9D group and 60 per cent of the EQ-5D-5L group. Comparing periods of on-site to home schooling, there was no difference between the median QOL scores for both CHU9D (0.017, 95% CI -0.05 to 0.01) and EQ-5D-5L (0.000, 95% CI -0.002 to 0.002). Our large-scale study found that while QOL was reduced for children and parents at the point of COVID-19 testing during the pandemic, differing levels of government-imposed restrictions did not further impact QOL. These unique insights will inform decision-making in relation to COVID-19 and future pandemics.

Protocol for integrated solutions for healthy birth, growth and development: a cluster-randomised controlled trial to evaluate the effectiveness of a mixed nutrition intervention package in reducing child undernutrition in Lao People's Democratic Republic.

INTRODUCTION: While Lao People's Democratic Republic has seen economic gains in recent years, one-third of children aged 5 years and under are stunted. There is a need for evidence around clinically effective and cost-effective integrated nutrition-specific and nutrition-sensitive interventions in the local context. METHODS AND ANALYSIS: We aim to conduct a cluster-randomised control trial to test the effectiveness of an integrated package of community-based nutrition-specific and nutrition-sensitive interventions compared with the standard government package of nutrition actions. The trial will be in six districts within the province of Vientiane. We will recruit pregnant women in their third trimester and follow the children born to them every 6 months until 18 months of age. A total of 256 villages (serviced by 34 health centres) will be randomised to a control arm or an intervention arm using a minimisation algorithm. The primary outcome is the prevalence of stunting among children aged 6, 12 and 18 months. The secondary outcomes include prevalence of low birth weight and wasting among children aged 6, 12 and 18 months. Analyses for the primary and secondary outcomes will be conducted at the mother-infant dyad level and adjusted for the cluster randomisation. The difference in prevalence of low birth weight, wasting and stunting between control and intervention groups will be assessed using Pearson's χ2 tests and 95% CIs for the group difference, adjusted for clustering. ETHICS AND DISSEMINATION: The trial protocol was approved by the Alfred Human Research Ethic Committee (Ref: 227/16) and the Lao National Ethics Committee for Health Research (Ref: 81). The trial was registered with the Australian New Zealand Clinical Trials Registry on 28 April 2020 (ACTRN12620000520932). The results will be disseminated at different levels: study participants; the local community; other Lao stakeholders including policymakers; and an international audience. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry: ACTRN12620000520932.

Cost-Effectiveness of Osteoporosis Opportunistic Screening Using Computed Tomography in China.

OBJECTIVES: Underutilization and insufficient availability of dual-energy X-ray absorptiometry (DXA) in diagnosing osteoporosis in China could be changed by adopting unindicated quantitative computed tomography. We aimed to assess the cost-effectiveness of quantitative computed tomography (QCT) as a screening tool for osteoporosis in China. METHODS: A Markov microsimulation model was developed to assess the long-term costs and quality-adjusted life-years (QALYs) saved associated with 2 examinations as opportunistic screening for osteoporosis in a general population without prior histories of fracture. The diagnostic performance of both examinations was incorporated into the model. In lifetime modeling, opportunistically screened people may face the risk of experiencing hip, vertebral, and wrist fractures depending on their osteoporosis, age, and sex. Model parameters were informed by published literature. RESULTS: The base-case result showed that QCT was associated with higher costs ($6054 vs $5883) and higher benefits (10.081 vs 10.071 QALYs) in comparison with DXA, making QCT a cost-effective option for opportunistic screening (incremental cost-effectiveness ratio of US $16 430/QALY). Screening with QCT led to fewer fractures over the lifetime simulation: for every 10 000 people screened, 129 fractures (32 hip, 78 vertebral, and 19 wrist fractures) could be avoided because of the early initiation of antiosteoporotic treatment. CONCLUSIONS: Using QCT to screen people for osteoporosis is more cost-effective than standard practice in China, where access to DXA is minimal. This finding could support opportunistic osteoporosis screening using QCT in other countries with similar status.

Impact of the Medicare Benefits Schedule Rebate (MBSR) freeze on General Practice (GP) use: multivariable regression analysis.

BACKGROUND: In 2015, the Australian government froze the Medicare Benefits Schedule Rebate (MBSR) for General Practitioner (GP) service use. This paper aimed to explore the impact of the MBSR freeze on the demand for GP services in Victoria, Australia, for three years, from 2014 to 2016. METHOD: Annual data on GP service utilisation by the Victorian State Statistical Area Level 3 (SA3) were analysed using 2015 as the reference year (MBSR freeze year). We compared annual per-person GP service use before and after the MBSR freeze for each SA3. Socioeconomic Indexes for Areas (SEIFA) scores and regions of Victoria (Greater Melbourne and the Rest of Victoria) were used to identify the most disadvantaged SA3s in Victoria. We conducted a multivariable regression analysis for the number of GP services per patient by SA3, controlling for regions of Victoria, the number of GP services, the proportion of bulk-billed visits, age group, gender and year. FINDINGS: After adjusting for age group, gender, region, SEIFA, the number of GPs and the proportion of bulk-billed GP visits, mean GP services per person per year declined steadily between 2014 and 2016, with a 3% or 0.11 visit (-0.114, 95%CI: -0.134; -0.094, P = < 0.001) reduction in mean utilisation in 2016 compared to 2014. In disadvantaged SA3s, there was a fall in the number of GP services that were bulk-billed during and after the MBSR freeze compared to 2014, and this fall was large in LOW SEIFA SA3s, with a reduction in 17% of mean bulk-billed GP services. CONCLUSION: The MBSR freeze for GP consultations in 2015 resulted in a reduction in the annual per capita demand for GP visits, with the impact of reduced demand more significant in lower socioeconomic and regional/rural areas. The GP funding policies must consider the demand differences by social-economic status and location.

Cost-effectiveness of personalised telehealth intervention for chronic disease management: A pilot randomised controlled trial.

OBJECTIVE: The study aims to assess the cost-effectiveness of a personalised telehealth intervention to manage chronic disease in the long run. METHOD: The Personalised Health Care (PHC) pilot study was a randomised trial with an economic evaluation alongside over 12 months. From a health service perspective, the primary analysis compared the costs and effectiveness of PHC telehealth monitoring with usual care. An incremental cost-effectiveness ratio was calculated based on costs and health-related quality of life. The PHC intervention was implemented in the Barwon Health region, Geelong, Australia, for patients with a diagnosis of COPD and/or diabetes who had a high likelihood of hospital readmission over 12 months. RESULTS: When compared to usual care at 12 months, the PHC intervention cost AUD$714 extra per patient (95%CI -4879; 6308) with a significant improvement of 0.09 in health-related quality of life (95%CI: 0.05; 0.14). The probability of PHC being cost-effective by 12 months was close to 65%, at willingness to pay a threshold of AUD$50,000 per quality-adjusted life year. CONCLUSION: Benefits of PHC to patients and the health system at 12 months translated to a gain in quality-adjusted life years with a non-significant cost difference between the intervention and control groups. Given the relatively high set-up costs of the PHC intervention, the program may need to be offered to a larger population to achieve cost-effectiveness. Long-term follow-up is required to assess the real health and economic benefits over time.

Vital sign assessment and nursing interventions in medical and surgical patients with rapid response system triggers.

AIM(S): To explore vital sign assessment (both complete and incomplete sets of vital signs), and escalation of care per policy and nursing interventions in response to clinical deterioration. DESIGN: This cohort study is a secondary analysis of data from the Prioritising Responses of Nurses To deteriorating patient Observations cluster randomised controlled trial of a facilitation intervention on nurses' vital sign measurement and escalation of care for deteriorating patients. METHODS: The study was conducted in 36 wards at four metropolitan hospitals in Victoria, Australia. Medical records of all included patients from the study wards during three randomly selected 24-h periods within the same week were audited at three time points: pre-intervention (June 2016), and at 6 (December 2016) and 12 months (June 1017) post-intervention. Descriptive statistics were used to summarise the study data, and relationships between variables were examined using chi-square test. RESULTS: A total of 10,383 audits were conducted. At least one vital sign measurement was documented every 8 h in 91.6% of audits, and a complete set of vital signs was documented every 8 h in 83.1% of audits. There were pre-Medical Emergency Team, Medical Emergency Team or Cardiac Arrest Team triggers in 25.8% of audits. When triggers were present, a rapid response system call occurred in 26.8% of audits. There were 1350 documented nursing interventions in audits with pre-Medical Emergency Team (n = 2403) or Medical Emergency Team triggers (n = 273). One or more nursing interventions were documented in 29.5% of audits with pre-Medical Emergency Team triggers and 63.7% of audits with Medical Emergency Team triggers. CONCLUSION: When rapid response system triggers were documented, there were gaps in escalation of care per policy; however, nurses undertook a range of interventions within their scope of practice in response to clinical deterioration. RELEVANCE TO CLINICAL PRACTICE: Medical and surgical ward nurses in acute care wards frequently engage in vital sign assessment. Interventions by medical and nurgical nurses may occur prior to, or in parallel with calling the rapid response system. Nursing interventions are a key but under-recognised element of the organisational response to deteriorating patients. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Nurses engage in a range of nursing interventions to manage deteriorating patients, (aside from rapid response system activation) that are not well understood, nor well described in the literature to date. IMPACT: This study addresses the gap in the literature regarding nurses' management of deteriorating patients within their scope of practice (aside from RRS activation) in real world settings. When rapid response system triggers were documented, there were gaps in escalation of care per policy; however, nurses undertook a range of interventions within their scope of practice in response to clinical deterioration. The results of this research are relevant to nurses working on medical and surgical wards. REPORTING METHOD: The trial was reported according to the Consolidated Standards of Reporting Trials extension for Cluster Trials recommendations, and this paper is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology Statement. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Dihydroxy-Metabolites of Dihomo-γ-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA dihomo-γ-linolenic acid (DGLA) specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH (CYP, cytochrome P450; EH, epoxide hydrolase), representing a new class of lipid metabolites that induce neurodegeneration via ferroptosis.

Nuclear receptor signaling via NHR-49/MDT-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues.

The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in C. elegans. We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, a functional homolog of mammalian peroxisome proliferator-activated receptor alpha (PPARα), regulates stress resilience and proteostasis downstream of embryo integrity and other pathways that influence lipid homeostasis, and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing inter-tissue pathway in somatic tissues, also triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49 together with its co-activator MDT-15 contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer as well as by other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting. Further, we show that increased NHR-49 activity is sufficient to suppress polyglutamine aggregation and improve stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis.

Ferroptosis is a form of regulated cell death that is intricately linked to cellular metabolism. In the forefront of research on ferroptosis, the peroxidation of polyunsaturated fatty acids has emerged as a key driver of oxidative damage to cellular membranes leading to cell death. Here, we review the involvement of polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), lipid remodeling enzymes and lipid peroxidation in ferroptosis, highlighting studies revealing how using the multicellular model organism Caenorhabditis elegans contributes to the understanding of the roles of specific lipids and lipid mediators in ferroptosis.

Dihydroxy-Metabolites of Dihomo-gamma-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA, dihomo gamma linolenic acid (DGLA), specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH, representing a new class of lipid metabolite that induces neurodegeneration via ferroptosis.

Carbon uptake in Eurasian boreal forests dominates the high-latitude net ecosystem carbon budget.

Arctic-boreal landscapes are experiencing profound warming, along with changes in ecosystem moisture status and disturbance from fire. This region is of global importance in terms of carbon feedbacks to climate, yet the sign (sink or source) and magnitude of the Arctic-boreal carbon budget within recent years remains highly uncertain. Here, we provide new estimates of recent (2003-2015) vegetation gross primary productivity (GPP), ecosystem respiration (Reco ), net ecosystem CO2 exchange (NEE; Reco - GPP), and terrestrial methane (CH4 ) emissions for the Arctic-boreal zone using a satellite data-driven process-model for northern ecosystems (TCFM-Arctic), calibrated and evaluated using measurements from >60 tower eddy covariance (EC) sites. We used TCFM-Arctic to obtain daily 1-km2 flux estimates and annual carbon budgets for the pan-Arctic-boreal region. Across the domain, the model indicated an overall average NEE sink of -850 Tg CO2 -C year-1 . Eurasian boreal zones, especially those in Siberia, contributed to a majority of the net sink. In contrast, the tundra biome was relatively carbon neutral (ranging from small sink to source). Regional CH4 emissions from tundra and boreal wetlands (not accounting for aquatic CH4 ) were estimated at 35 Tg CH4 -C year-1 . Accounting for additional emissions from open water aquatic bodies and from fire, using available estimates from the literature, reduced the total regional NEE sink by 21% and shifted many far northern tundra landscapes, and some boreal forests, to a net carbon source. This assessment, based on in situ observations and models, improves our understanding of the high-latitude carbon status and also indicates a continued need for integrated site-to-regional assessments to monitor the vulnerability of these ecosystems to climate change.

Pan-Arctic soil moisture control on tundra carbon sequestration and plant productivity.

Long-term atmospheric CO2 concentration records have suggested a reduction in the positive effect of warming on high-latitude carbon uptake since the 1990s. A variety of mechanisms have been proposed to explain the reduced net carbon sink of northern ecosystems with increased air temperature, including water stress on vegetation and increased respiration over recent decades. However, the lack of consistent long-term carbon flux and in situ soil moisture data has severely limited our ability to identify the mechanisms responsible for the recent reduced carbon sink strength. In this study, we used a record of nearly 100 site-years of eddy covariance data from 11 continuous permafrost tundra sites distributed across the circumpolar Arctic to test the temperature (expressed as growing degree days, GDD) responses of gross primary production (GPP), net ecosystem exchange (NEE), and ecosystem respiration (ER) at different periods of the summer (early, peak, and late summer) including dominant tundra vegetation classes (graminoids and mosses, and shrubs). We further tested GPP, NEE, and ER relationships with soil moisture and vapor pressure deficit to identify potential moisture limitations on plant productivity and net carbon exchange. Our results show a decrease in GPP with rising GDD during the peak summer (July) for both vegetation classes, and a significant relationship between the peak summer GPP and soil moisture after statistically controlling for GDD in a partial correlation analysis. These results suggest that tundra ecosystems might not benefit from increased temperature as much as suggested by several terrestrial biosphere models, if decreased soil moisture limits the peak summer plant productivity, reducing the ability of these ecosystems to sequester carbon during the summer.