Novel palm shortening substitute using a combination of rapeseed oil, linseed meal and beta-glucan.

This study investigated the potential of a novel sustainable ingredient composed of rapeseed oil, linseed meal and beta-glucan (PALM-ALT) to mimic palm shortening functionality in cake. The combined functional properties of linseed meal and beta-glucan led to stable semi-solid emulsion-gels (20-31 µm oil droplet size, 105-115 Pa.s viscosity and 60-65 Pa yield stress). PALM-ALT contained 25 and 88% less total and saturated fat than palm shortening, whilst PALM-ALT cakes contained 26 and 75% less total and saturated fat than the palm-based control. PALM-ALT cakes matched the flavour profile of the palm-based control, while rapeseed oil cakes tasted more sour and less sweet than the control (p < 0.05). PALM-ALT cakes proved less hard and more cohesive than the control (p < 0.05), with 100% of the consumer panel preferring PALM-ALT formulations. This study demonstrated the unique potential of PALM-ALT as healthier, sustainable and competitive alternative to palm shortening.

Senescent glia link mitochondrial dysfunction and lipid accumulation.

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery.

The blood-brain barrier (BBB) is a critical interface separating the central nervous system from the peripheral circulation, ensuring brain homeostasis and function. Recent research has unveiled a profound connection between the BBB and circadian rhythms, the endogenous oscillations synchronizing biological processes with the 24-hour light-dark cycle. This review explores the significance of circadian rhythms in the context of BBB functions, with an emphasis on substrate passage through the BBB. Our discussion includes efflux transporters and the molecular timing mechanisms that regulate their activities. A significant focus of this review is the potential implications of chronotherapy, leveraging our knowledge of circadian rhythms for improving drug delivery to the brain. Understanding the temporal changes in BBB can lead to optimized timing of drug administration, to enhance therapeutic efficacy for neurological disorders while reducing side effects. By elucidating the interplay between circadian rhythms and drug transport across the BBB, this review offers insights into innovative therapeutic interventions.

Age-regulated cycling metabolites are relevant for behavior.

Circadian cycles of sleep:wake and gene expression change with age in all organisms examined. Metabolism is also under robust circadian regulation, but little is known about how metabolic cycles change with age and whether these contribute to the regulation of behavioral cycles. To address this gap, we compared cycling of metabolites in young and old Drosophila and found major age-related variations. A significant model separated the young metabolic profiles by circadian timepoint, but could not be defined for the old metabolic profiles due to the greater variation in this dataset. Of the 159 metabolites measured in fly heads, we found 17 that cycle by JTK analysis in young flies and 17 in aged. Only four metabolites overlapped in the two groups, suggesting that cycling metabolites are distinct in young and old animals. Among our top cyclers exclusive to young flies were components of the pentose phosphate pathway (PPP). As the PPP is important for buffering reactive oxygen species, and overexpression of glucose-6-phosphate dehydrogenase (G6PD), a key component of the PPP, was previously shown to extend lifespan in Drosophila, we asked if this manipulation also affects sleep:wake cycles. We found that overexpression in circadian clock neurons decreases sleep in association with an increase in cellular calcium and mitochondrial oxidation, suggesting that altering PPP activity affects neuronal activity. Our findings elucidate the importance of metabolic regulation in maintaining patterns of neural activity, and thereby sleep:wake cycles.

Glucose Challenge Uncovers Temporal Fungibility of Metabolic Homeostasis Throughout the Day.

Rhythmicity is a central feature of behavioral and biological processes including metabolism, however, the mechanisms of metabolite cycling are poorly understood. A robust oscillation in a network of key metabolite pathways downstream of glucose is described in humans, then these pathways mechanistically probed through purpose-built 13C6-glucose isotope tracing in Drosophila every 4h. A temporal peak in biosynthesis was noted by broad labelling of pathways downstream of glucose in wild-type flies shortly following lights on. Krebs cycle labelling was generally increased in a hyperactive mutant (fumin) along with glycolysis labelling primarily observed at dawn. Surprisingly, neither underlying feeding rhythms nor the presence of food explains the rhythmicity of glucose processing across genotypes. These results are consistent with clinical data demonstrating detrimental effects of mis-timed energy intake. This approach provides a window into the dynamic range of metabolic processing ability through the day and mechanistic basis for exploring circadian metabolic homeostasis in disease states.

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.

Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in an in vitro mouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

Evidence for a role of human blood-borne factors in mediating age-associated changes in molecular circadian rhythms.

Aging is associated with a number of physiologic changes including perturbed circadian rhythms; however, mechanisms by which rhythms are altered remain unknown. To test the idea that circulating factors mediate age-dependent changes in peripheral rhythms, we compared the ability of human serum from young and old individuals to synchronize circadian rhythms in culture. We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals and used the serum to synchronize cultured fibroblasts. We found that young and old sera are equally competent at driving robust ~24h oscillations of a luciferase reporter driven by clock gene promoter. However, cyclic gene expression is affected, such that young and old sera drive cycling of different genes. While genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions, genes identified by STRING and IPA analyses as associated with oxidative phosphorylation and Alzheimer's Disease lose rhythmicity in the aged condition. Also, the expression of cycling genes associated with cholesterol biosynthesis increases in the cells entrained with old serum. We did not observe a global difference in the distribution of phase between groups, but find that peak expression of several clock controlled genes (PER3, NR1D1, NR1D2, CRY1, CRY2, and TEF) lags in the cells synchronized with old serum. Taken together, these findings demonstrate that age-dependent blood-borne factors affect peripheral circadian rhythms in cells and have the potential to impact health and disease via maintaining or disrupting rhythms respectively.

Predicting Functional Dependency in Patients with Disorders of Consciousness: A TBI-Model Systems and TRACK-TBI Study.

OBJECTIVE: It is not currently possible to predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI). Our objective was to fit and externally validate a prediction model for 1-year dependency in patients with DoC ≥ 2 weeks after TBI. METHODS: We included adults with TBI enrolled in TBI Model Systems (TBI-MS) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) studies who were not following commands at rehabilitation admission or 2 weeks post-injury, respectively. We fit a logistic regression model in TBI-MS and validated it in TRACK-TBI. The primary outcome was death or dependency at 1 year post-injury, defined using the Disability Rating Scale. RESULTS: In the TBI-MS Discovery Sample, 1,960 participants (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria, and 406 (27%) were dependent 1 year post-injury. In a TBI-MS held out cohort, the dependency prediction model's area under the receiver operating characteristic curve was 0.79 (95% CI 0.74-0.85), positive predictive value was 53% and negative predictive value was 86%. In the TRACK-TBI external validation (n = 124, age 40 [16] years, 77% male, 81% white), the area under the receiver operating characteristic curve was 0.66 (0.53, 0.79), equivalent to the standard IMPACTcore + CT score (p = 0.8). INTERPRETATION: We developed a 1-year dependency prediction model using the largest existing cohort of patients with DoC after TBI. The sensitivity and negative predictive values were greater than specificity and positive predictive values. Accuracy was diminished in an external sample, but equivalent to the IMPACT model. Further research is needed to improve dependency prediction in patients with DoC after TBI. ANN NEUROL 2023;94:1008-1023.

Effectiveness of chatbots on COVID vaccine confidence and acceptance in Thailand, Hong Kong, and Singapore.

Chatbots have become an increasingly popular tool in the field of health services and communications. Despite chatbots' significance amid the COVID-19 pandemic, few studies have performed a rigorous evaluation of the effectiveness of chatbots in improving vaccine confidence and acceptance. In Thailand, Hong Kong, and Singapore, from February 11th to June 30th, 2022, we conducted multisite randomised controlled trials (RCT) on 2,045 adult guardians of children and seniors who were unvaccinated or had delayed vaccinations. After a week of using COVID-19 vaccine chatbots, the differences in vaccine confidence and acceptance were compared between the intervention and control groups. Compared to non-users, fewer chatbot users reported decreased confidence in vaccine effectiveness in the Thailand child group [Intervention: 4.3 % vs. Control: 17%, P = 0.023]. However, more chatbot users reported decreased vaccine acceptance [26% vs. 12%, P = 0.028] in Hong Kong child group and decreased vaccine confidence in safety [29% vs. 10%, P = 0.041] in Singapore child group. There was no statistically significant change in vaccine confidence or acceptance in the Hong Kong senior group. Employing the RE-AIM framework, process evaluation indicated strong acceptance and implementation support for vaccine chatbots from stakeholders, with high levels of sustainability and scalability. This multisite, parallel RCT study on vaccine chatbots found mixed success in improving vaccine confidence and acceptance among unvaccinated Asian subpopulations. Further studies that link chatbot usage and real-world vaccine uptake are needed to augment evidence for employing vaccine chatbots to advance vaccine confidence and acceptance.

Predicting Functional Dependency in Patients with Disorders of Consciousness: A TBI-Model Systems and TRACK-TBI Study.

Importance: There are currently no models that predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI). Objective: Fit, test, and externally validate a prediction model for 1-year dependency in patients with DoC 2 or more weeks after TBI. Design: Secondary analysis of patients enrolled in TBI Model Systems (TBI-MS, 1988-2020, Discovery Sample) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI, 2013-2018, Validation Sample) and followed 1-year post-injury. Setting: Multi-center study at USA rehabilitation hospitals (TBI-MS) and acute care hospitals (TRACK-TBI). Participants: Adults with TBI who were not following commands at rehabilitation admission (TBI-MS; days post-injury vary) or 2-weeks post-injury (TRACK-TBI). Exposures: In the TBI-MS database (model fitting and testing), we screened demographic, radiological, clinical variables, and Disability Rating Scale (DRS) item scores for association with the primary outcome. Main Outcome: The primary outcome was death or complete functional dependency at 1-year post-injury, defined using a DRS-based binary measure (DRS Depend ), indicating need for assistance with all activities and concomitant cognitive impairment. Results: In the TBI-MS Discovery Sample, 1,960 subjects (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria and 406 (27%) were dependent at 1-year post-injury. A dependency prediction model had an area under the receiver operating characteristic curve (AUROC) of 0.79 [0.74, 0.85], positive predictive value of 53%, and negative predictive value of 86% for dependency in a held-out TBI-MS Testing cohort. Within the TRACK-TBI external validation sample (N=124, age 40 [16], 77% male, 81% white), a model modified to remove variables not collected in TRACK-TBI, had an AUROC of 0.66 [0.53, 0.79], equivalent to the gold-standard IMPACT core+CT score (0.68; 95% AUROC difference CI: -0.2 to 0.2, p=0.8). Conclusions and Relevance: We used the largest existing cohort of patients with DoC after TBI to develop, test and externally validate a prediction model of 1-year dependency. The model’s sensitivity and negative predictive value were greater than specificity and positive predictive value. Accuracy was diminished in an external sample, but equivalent to the best-available models. Further research is needed to improve dependency prediction in patients with DoC after TBI.

Strategies to improve the experience of patients with brain tumors in the inpatient rehabilitation setting: development of a care coordination checklist.

PURPOSE: To develop a checklist to facilitate coordination of care and communication of patients with brain tumors and assess the benefit of the checklist using a quality improvement survey. MATERIALS AND METHODS: Rehabilitation teams are challenged to respond to the unique needs of patients with brain tumors as this population requires coordinated care across multiple disciplines with frequent communication. To improve care of this patient population in an IRF setting, we developed a novel checklist using a multidisciplinary team of clinicians. Our checklist aims to improve communication between multiple treatment teams, achieve appropriate goals during the IRF stay, involve services as needed and arrange post-discharge services for patients with brain tumors. We then used a quality improvement survey among clinicians to assess the efficacy and general opinion of the checklist. RESULTS: A total of 15 clinicians completed the survey. 66.7% felt that the checklist improved care delivery, and 66.7% felt the checklist improved communication between providers internally and with external institutions. More than half felt the checklist improved the patient experience and care delivery. CONCLUSIONS: A care coordination checklist has the potential to address the unique challenges experienced by patients with brain tumors to improve overall care for this population.IMPLICATIONS FOR REHABILITATIONSuccessful clinical care and rehabilitation of patients with brain tumors requires the coordinated efforts of an interdisciplinary team that often spans multiple care settings.A care coordination checklist has the potential to address the unique challenges experienced by patients with brain tumors to improve overall care for this population in the inpatient rehabilitation setting.

Unintentional injuries among children with developmental disabilities are a public health challenge in China.

Child injury is a significant global health issue that contributes to both morbidity and mortality in children. Children with developmental disabilities are at a high risk for injuries due to a combination of environmental barriers and health conditions. However, little research has assessed the prevalence of injuries among this population in China. Using administrative data from a micro insurance programme for children with developmental disabilities (such as autism, intellectual disability, cerebral palsy and Down syndrome) under the age of 19, we estimated the risk of unintentional injuries reported in insurance claims. Between 2017 and 2020, there were 190 insurance claims (0.53%) reporting nonfatal unintentional injuries and six reporting fatal injuries. The cumulative hazard rate of unintentional injuries by the end of 1 year is 1.21% and is negatively associated with children's age. These findings suggest the need for increased safety support for children with developmental disabilities, particularly in early childhood.

Ecdysone acts through cortex glia to regulate sleep in Drosophila.

Steroid hormones are attractive candidates for transmitting long-range signals to affect behavior. These lipid-soluble molecules derived from dietary cholesterol easily penetrate the brain and act through nuclear hormone receptors (NHRs) that function as transcription factors. To determine the extent to which NHRs affect sleep:wake cycles, we knocked down each of the 18 highly conserved NHRs found in Drosophila adults and report that the ecdysone receptor (EcR) and its direct downstream NHR Eip75B (E75) act in glia to regulate the rhythm and amount of sleep. Given that ecdysone synthesis genes have little to no expression in the fly brain, ecdysone appears to act as a long-distance signal and our data suggest that it enters the brain more at night. Anti-EcR staining localizes to the cortex glia in the brain and functional screening of glial subtypes revealed that EcR functions in adult cortex glia to affect sleep. Cortex glia are implicated in lipid metabolism, which appears to be relevant for actions of ecdysone as ecdysone treatment mobilizes lipid droplets (LDs), and knockdown of glial EcR results in more LDs. In addition, sleep-promoting effects of exogenous ecdysone are diminished in lsd-2 mutant flies, which are lean and deficient in lipid accumulation. We propose that ecdysone is a systemic secreted factor that modulates sleep by stimulating lipid metabolism in cortex glia.

Behaviourally informed, patient-led interventions to reduce missed appointments in general practice: a 12-month implementation study.

BACKGROUND: Scalable, positive, behaviourally informed interventions may help people remember to attend their primary care appointment or cancel in good time, but have not yet been implemented long term. AIM: To examine effects of social norms and making active commitments on missed and cancelled appointments in primary care over 12 months and explore implementation factors. DESIGN AND SETTING: A mixed-methods design evaluation and implementation study led by a Patient Participation Group (PPG) member in a large GP practice in the West Midlands. METHODS: Following a 6-month baseline, waiting room notices were redesigned to emphasise positive social norms for desired behaviours. When booking appointments, receptionists were trained to invite patients to (i) verbally actively commit to cancelling if needed; (ii) write down their own appointment details. Monthly missed appointments (MAs) and cancellations were statistically compared with baseline averages and seasonally equivalent months. To explore implementation, reception staff completed a knowledge, attitude, and behaviour questionnaire at 9 months, analysed descriptively. Study team field notes were thematically analysed. RESULTS: Across 12 intervention months there was a mean of 37.67 fewer MAs per month (20% reduction) and 102.66 more cancellations (21.07% increase) compared with 6-month baseline means [MAs t(11) = -6.15, P < 0.001; cancellations t(11) = 3.637, P = 0.004] with statistically significant differences in seasonally equivalent months [MAs t(5) = -4.65, P = 0.006; cancellations t(5) = 3.263, P = 0.022]. Receptionists (n = 12) reported implementing the strategies except when facing pressures; knowledge and attitudes varied. CONCLUSIONS: Behaviourally informed interventions reduced primary care MAs longer term; PPGs and practice teams can work together on quality improvement projects with support from leaders to prioritise and embed new practices.

A Regional Health System Journey from Volume to Value: Roadmap to the Recognition as a 15 Top Health System in the USA for Quality Excellence.

The 15 Top Health System program, an IBM Watson study, objectively measures health systems' performance overall on an annual basis using publicly reported data available from the Center for Medicare and Medicaid Services (CMS) and state data banks. Genesis Health System was recognized as an IBM Watson Health 15 Top Health System for two consecutive years in 2020 and 2021. A system-based approach with a "physician-lead, professionally-managed" framework, led to accomplishing the 15 Top Health System. The steps needed included adoption of the IBM Watson database to determine current status of certain key performance indicators, establishing a clinical effectiveness program and governance structure, and adopting Lean methodologies to analyze and determine appropriate interventions with long-term solution. The desire and willingness to accomplish this ambitious goal start with adoption by the Board and the administration of the health system while supplying appropriate financial and human resources that are dedicated to the success of the journey. In this manuscript, we describe the journey and steps implemented to accomplish the outcomes that led to the recognition as a 15 Top Health System for quality excellence.

Battle of Polio eradication in the Western Pacific Region in the transition to COVID-19 endemicity

The Polio eradication campaign has been set back substantially since 2020 due to the COVID-19 pandemic. Recent detections of poliovirus transmission in multiple high-income countries suggest suboptimal population immunity in many parts of the world even though polio vaccination has been included in routine childhood immunization for decades. We reviewed polio vaccination schedules and vaccine uptake in the Western Pacific Region countries and assessed the potential shortfall in population immunity against polio resurgence across these populations. In addition, we conducted a repeated cross-sectional study between 2021 and 2022 in the Western Pacific Region to understand factors contributing to polio vaccine hesitancy. Our results reveal potential shortfalls in population immunity against polio in Western Pacific Region and provide insights into how vaccination programs and campaigns can be strengthened to ensure continual progress towards polio eradication.