Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Percutaneous Closure of an Iatrogenic Intracardiac Shunt in Treating Torrential Tricuspid Regurgitation.

A patient presented with severe right heart failure due to a large LV-to-RA shunt with left-to-right shunting and torrential tricuspid regurgitation 6-weeks following surgical sub-aortic stenosis resection. Retrograde delivery of an Occlutech ventricular septal defect device produced instantaneous resolution of shunt, reduction in tricuspid regurgitation, and impressive diuresis of 28 kg.

CHRISTMAS: Chiral Pair Isobaric Labeling Strategy for Multiplexed Absolute Quantitation of Enantiomeric Amino Acids.

Amino acids (AAs) in the d-form are involved in multiple pivotal neurological processes, although their l-enantiomers are most commonly found. Mass spectrometry-based analysis of low-abundance d-AAs has been hindered by challenging enantiomeric separation from l-AAs, low sensitivity for detection, and lack of suitable internal standards for accurate quantification. To address these critical gaps, N,N-dimethyl-l-leucine (l-DiLeu) tags are first validated as novel chiral derivatization reagents for chromatographic separation of 20 pairs of d/l-AAs, allowing the construction of a 4-plex isobaric labeling strategy for enantiomer-resolved quantification through single step tagging. Additionally, the creative design of N,N-dimethyl-d-leucine (d-DiLeu) reagents offers an alternative approach to generate analytically equivalent internal references of d-AAs using d-DiLeu-labeled l-AAs. By labeling cost-effective l-AA standards using paired d- and l-DiLeu, this approach not only enables absolute quantitation of both d-AAs and l-AAs from complex biological matrices with enhanced precision but also significantly boosts the combined signal intensities from all isobaric channels, greatly improving the detection and quantitation of low-abundance AAs, particularly d-AAs. We term this quantitative strategy CHRISTMAS, which stands for chiral pair isobaric labeling strategy for multiplexed absolute quantitation. Leveraging the ion mobility collision cross section (CCS) alignment, interferences from coeluting isomers/isobars are effectively filtered out to provide improved quantitative accuracy. From wild-type and Alzheimer's disease (AD) mouse brains, we successfully quantified 20 l-AAs and 5 d-AAs. The significant presence and differential trends of certain d-AAs compared to those of their l-counterparts provide valuable insights into the involvement of d-AAs in aging, AD progression, and neurodegeneration.

Protein restriction slows the development and progression of Alzheimer's disease in mice.

Over the last decade, it has become evident that dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and we and others have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice. We found that PR induces sex-specific alterations in circulating metabolites and in the brain lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

The need to strengthen the evaluation of the impact of Artificial Intelligence-based decision support systems on healthcare provision.

Despite the renewed interest in Artificial Intelligence-based clinical decision support systems (AI-CDS), there is still a lack of empirical evidence supporting their effectiveness. This underscores the need for rigorous and continuous evaluation and monitoring of processes and outcomes associated with the introduction of health information technology. We illustrate how the emergence of AI-CDS has helped to bring to the fore the critical importance of evaluation principles and action regarding all health information technology applications, as these hitherto have received limited attention. Key aspects include assessment of design, implementation and adoption contexts; ensuring systems support and optimise human performance (which in turn requires understanding clinical and system logics); and ensuring that design of systems prioritises ethics, equity, effectiveness, and outcomes. Going forward, information technology strategy, implementation and assessment need to actively incorporate these dimensions. International policy makers, regulators and strategic decision makers in implementing organisations therefore need to be cognisant of these aspects and incorporate them in decision-making and in prioritising investment. In particular, the emphasis needs to be on stronger and more evidence-based evaluation surrounding system limitations and risks as well as optimisation of outcomes, whilst ensuring learning and contextual review. Otherwise, there is a risk that applications will be sub-optimally embodied in health systems with unintended consequences and without yielding intended benefits.

The ethical challenges of personalized digital health.

Personalized digital health systems (pHealth) bring together in sharp juxtaposition very different yet hopefully complementary moral principles in the shared objectives of optimizing health care and the health status of individual citizens while maximizing the application of robust clinical evidence through harnessing powerful and often complex modern data-handling technologies. Principles brought together include respecting the confidentiality of the patient-clinician relationship, the need for controlled information sharing in teamwork and shared care, benefitting from healthcare knowledge obtained from real-world population-level outcomes, and the recognition of different cultures and care settings. This paper outlines the clinical process as enhanced through digital health, reports on the examination of the new issues raised by the computerization of health data, outlines initiatives and policies to balance the harnessing of innovation with control of adverse effects, and emphasizes the importance of the context of use and citizen and user acceptance. The importance of addressing ethical issues throughout the life cycle of design, provision, and use of a pHealth system is explained, and a variety of situation-relevant frameworks are presented to enable a philosophy of responsible innovation, matching the best use of enabling technology with the creation of a culture and context of trustworthiness.

Intracellular Citrate/acetyl-CoA flux and endoplasmic reticulum acetylation: Connectivity is the answer.

BACKGROUND: Key cellular metabolites reflecting the immediate activity of metabolic enzymes as well as the functional metabolic state of intracellular organelles can act as powerful signal regulators to ensure the activation of homeostatic responses. The citrate/acetyl-CoA pathway, initially recognized for its role in intermediate metabolism, has emerged as a fundamental branch of this nutrient-sensing homeostatic response. Emerging studies indicate that fluctuations in acetyl-CoA availability within different cellular organelles and compartments provides substrate-level regulation of many biological functions. A fundamental aspect of these regulatory functions involves Nε-lysine acetylation. SCOPE OF REVIEW: Here, we will examine the emerging regulatory functions of the citrate/acetyl-CoA pathway and the specific role of the endoplasmic reticulum (ER) acetylation machinery in the maintenance of intracellular crosstalk and homeostasis. These functions will be analyzed in the context of associated human diseases and specific mouse models of dysfunctional ER acetylation and citrate/acetyl-CoA flux. A primary objective of this review is to highlight the complex yet integrated response of compartment- and organelle-specific Nε-lysine acetylation to the intracellular availability and flux of acetyl-CoA, linking this important post-translational modification to cellular metabolism. MAJOR CONCLUSIONS: The ER acetylation machinery regulates the proteostatic functions of the organelle as well as the metabolic crosstalk between different intracellular organelles and compartments. This crosstalk enables the cell to impart adaptive responses within the ER and the secretory pathway. However, it also enables the ER to impart adaptive responses within different cellular organelles and compartments. Defects in the homeostatic balance of acetyl-CoA flux and ER acetylation reflect different but converging disease states in humans as well as converging phenotypes in relevant mouse models. In conclusion, citrate and acetyl-CoA should not only be seen as metabolic substrates of intermediate metabolism but also as signaling molecules that direct functional adaptation of the cell to both intracellular and extracellular messages. Future discoveries in CoA biology and acetylation are likely to yield novel therapeutic approaches.

BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors.

Multiple tumor types overexpress Nectin-4 and the antibody-drug conjugate (ADC), enfortumab vedotin (EV) shows striking efficacy in clinical trials for metastatic urothelial cancer, which expresses high levels of Nectin-4, validating Nectin-4 as a clinical target for toxin delivery in this indication. Despite excellent data in urothelial cancer, little efficacy data are reported for EV in other Nectin-4 expressing tumors and EV therapy can produce significant toxicities in many patients, frequently leading to discontinuation of treatment. Thus, additional approaches to this target with the potential to extend utility and reduce toxicity are warranted. We describe the preclinical development of BT8009, a "Bicycle Toxin Conjugate" (BTC) consisting of a Nectin-4-binding bicyclic peptide, a cleavable linker system and the cell penetrant toxin mono-methylauristatin E (MMAE). BT8009 shows significant antitumor activity in preclinical tumor models, across a variety of cancer indications and is well tolerated in preclinical safety studies. In several models, it shows superior or equivalent antitumor activity to an EV analog. As a small hydrophilic peptide-based drug BT8009 rapidly diffuses from the systemic circulation, through tissues to penetrate the tumor and target tumor cells. It is renally eliminated from the circulation, with a half-life of 1-2 hours in rat and non-human primate. These physical and PK characteristics differentiate BT8009 from ADCs and may provide benefit in terms of tumor penetration and reduced systemic exposure. BT8009 is currently in a Phase 1/2 multicenter clinical trial across the US, Canada, and Europe, enrolling patients with advanced solid tumors associated with Nectin-4 expression.

Comparative analysis of pre-Covid19 child immunization rates across 30 European countries and identification of underlying positive societal and system influences.

This study provides a macro-level societal and health system focused analysis of child vaccination rates in 30 European countries, exploring the effect of context on coverage. The importance of demography and health system attributes on health care delivery are recognized in other fields, but generally overlooked in vaccination. The analysis is based on correlating systematic data built up by the Models of Child Health Appraised (MOCHA) Project with data from international sources, so as to exploit a one-off opportunity to set the analysis within an overall integrated study of primary care services for children, and the learning opportunities of the 'natural European laboratory'. The descriptive analysis shows an overall persistent variation of coverage across vaccines with no specific vaccination having a low rate in all the EU and EEA countries. However, contrasting with this, variation between total uptake per vaccine across Europe suggests that the challenge of low rates is related to country contexts of either policy, delivery, or public perceptions. Econometric analysis aiming to explore whether some population, policy and/or health system characteristics may influence vaccination uptake provides important results-GDP per capita and the level of the population's higher education engagement are positively linked with higher vaccination coverage, whereas mandatory vaccination policy is related to lower uptake rates. The health system characteristics that have a significant positive effect are a cohesive management structure; a high nurse/doctor ratio; and use of practical care delivery reinforcements such as the home-based record and the presence of child components of e-health strategies.

Performance of Cardiac MRI in Pediatric and Adult Patients with Fontan Circulation.

Cardiac MRI has become a widely accepted standard for anatomic and functional assessment of complex Fontan physiology, because it is noninvasive and suitable for comprehensive follow-up evaluation after Fontan completion. The use of cardiac MRI in pediatric and adult patients after completion of the Fontan procedure are described, and a practical and experience-based cardiac MRI protocol for evaluating these patients is provided. The current approach and study protocol in use at the authors' institution are presented, which address technical considerations concerning sequences, planning, and optimal image acquisition in patients with Fontan circulation. Additionally, for each sequence, the information that can be obtained and guidance on how to integrate it into clinical decision-making is discussed. Keywords: Pediatrics, MRI, MRI Functional Imaging, Heart, Congenital © RSNA, 2022.

The Role of Formative Evaluation in Promoting Digitally-based Health Equity and Reducing Bias for Resilient Health Systems: The Case of Patient Portals.

OBJECTIVES: Patient portals are increasingly implemented to improve patient involvement and engagement. We here seek to provide an overview of ways to mitigate existing concerns that these technologies increase inequity and bias and do not reach those who could benefit most from them. METHODS: Based on the current literature, we review the limitations of existing evaluations of patient portals in relation to addressing health equity, literacy and bias; outline challenges evaluators face when conducting such evaluations; and suggest methodological approaches that may address existing shortcomings. RESULTS: Various stakeholder needs should be addressed before deploying patient portals, involving vulnerable groups in user-centred design, and studying unanticipated consequences and impacts of information systems in use over time. CONCLUSIONS: Formative approaches to evaluation can help to address existing shortcomings and facilitate the development and implementation of patient portals in an equitable way thereby promoting the creation of resilient health systems.

Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology.

N ε-lysine acetylation within the lumen of the endoplasmic reticulum is a recently characterized protein quality control system that positively selects properly folded glycoproteins in the early secretory pathway. Overexpression of the endoplasmic reticulum acetyl-CoA transporter AT-1 in mouse forebrain neurons results in increased dendritic branching, spine formation and an autistic-like phenotype that is attributed to altered glycoprotein flux through the secretory pathway. AT-1 overexpressing neurons maintain the cytosolic pool of acetyl-CoA by upregulation of SLC25A1, the mitochondrial citrate/malate antiporter and ATP citrate lyase, which converts cytosolic citrate into acetyl-CoA. All three genes have been associated with autism spectrum disorder, suggesting that aberrant cytosolic-to-endoplasmic reticulum flux of acetyl-CoA can be a mechanistic driver for the development of autism spectrum disorder. We therefore generated a SLC25A1 neuron transgenic mouse with overexpression specifically in the forebrain neurons. The mice displayed autistic-like behaviours with a jumping stereotypy. They exhibited increased steady-state levels of citrate and acetyl-CoA, disrupted white matter integrity with activated microglia and altered synaptic plasticity and morphology. Finally, quantitative proteomic and acetyl-proteomic analyses revealed differential adaptations in the hippocampus and cortex. Overall, our study reinforces the connection between aberrant cytosolic-to-endoplasmic reticulum acetyl-CoA flux and the development of an autistic-like phenotype.

ATase inhibition rescues age-associated proteotoxicity of the secretory pathway.

Malfunction of autophagy contributes to the progression of many chronic age-associated diseases. As such, improving normal proteostatic mechanisms is an active target for biomedical research and a key focal area for aging research. Endoplasmic reticulum (ER)-based acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy. ER acetylation is ensured by two ER-membrane bound acetyltransferases, ATase1 and ATase2. Here, we show that ATase inhibitors can rescue ongoing disease manifestations associated with the segmental progeria-like phenotype of AT-1 sTg mice. We also describe a pipeline to reliably identify ATase inhibitors with promising druggability properties. Finally, we show that successful ATase inhibitors can rescue the proteopathy of a mouse model of Alzheimer's disease. In conclusion, our study proposes that ATase-targeting approaches might offer a translational pathway for many age-associated proteopathies affecting the ER/secretory pathway.

SLC13A5/sodium-citrate co-transporter overexpression causes disrupted white matter integrity and an autistic-like phenotype.

Endoplasmic reticulum-based N ɛ-lysine acetylation serves as an important protein quality control system for the secretory pathway. Dysfunctional endoplasmic reticulum-based acetylation, as caused by overexpression of the acetyl coenzyme A transporter AT-1 in the mouse, results in altered glycoprotein flux through the secretory pathway and an autistic-like phenotype. AT-1 works in concert with SLC25A1, the citrate/malate antiporter in the mitochondria, SLC13A5, the plasma membrane sodium/citrate symporter and ATP citrate lyase, the cytosolic enzyme that converts citrate into acetyl coenzyme A. Here, we report that mice with neuron-specific overexpression of SLC13A5 exhibit autistic-like behaviours with a jumping stereotypy. The mice displayed disrupted white matter integrity and altered synaptic structure and function. Analysis of both the proteome and acetyl-proteome revealed unique adaptations in the hippocampus and cortex, highlighting a metabolic response that likely plays an important role in the SLC13A5 neuron transgenic phenotype. Overall, our results support a mechanistic link between aberrant intracellular citrate/acetyl coenzyme A flux and the development of an autistic-like phenotype.

Identifying and addressing digital health risks associated with emergency pandemic response: Problem identification, scoping review, and directions toward evidence-based evaluation.

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic has accelerated digital health applications in multifaceted disease management dimensions. This study aims (1) to identify risk issues relating to the rapid development and redeployment of COVID-19 related e-health systems, in primary care, and in the health ecosystems interacting with it and (2) to suggest evidence-based evaluation directions under emergency response. METHOD: After initial brainstorming of digital health risks posed in this pandemic, a scoping review method was adopted to collect evidence across databases of PubMed, CINAHL, and EMBASE. Peer-review publications, reports, news sources, and websites that credibly identified the challenges relating digital health scaled for COVID-19 were scrutinized. Additional supporting materials were obtained through snowball sampling and the authors' global digital health networks. Studies satisfying the selection criteria were charted based on their study design, primary care focus, and coverage of e-health areas of risk. RESULTS: Fifty-eight studies were mapped for qualitative synthesis. Five identified digital health risk areas associated with the pandemic were governance, system design and coordination, information access, service provision, and user (professional and public) reception. We observed that rapid digital health responses may embed challenges in health system thinking, the long-term development of digital health ecosystems, and interoperability of health IT infrastructure, with concomitant weaknesses in existing evaluation theories. CONCLUSION: Through identifying digital health risks posed during the pandemic, this paper discussed potential directions for next-generation informatics evaluation development, to better prepare for the post-COVID-19 era, a new future epidemic, or other unforeseen global health emergencies. An updated evidence-based approach to health informatics is essential to gain public confidence in digital health across primary and other health sectors.

A commitment to marginalized children in the European Union: The hope and challenges of the EU Child Guarantee.

While children in general are usually seen as a societal priority, many children are disadvantaged by marginalization, with adverse effects on health and development. Following feasibility studies, the European Commission has now adopted a formal Child Guarantee of service access. This paper links the Feasibility Studies to other reports on the need to address marginalized and institutionalized children. The problems in identifying and quantifying such children are outlined, as are the challenges of planning for these groups of children and the difficulty of finding universal definitions and data. This European Union initiative is timely, given that around a quarter of European children are marginalized, while the effects of Covid-19 will add to this marginalization.

Factors influencing the uptake of evidence in child health policy-making: results of a survey among 23 European countries.

BACKGROUND: The ability to successfully transfer knowledge across international boundaries to improve health across the European Region is dependent on an in-depth understanding of the many factors involved in policy creation. Across countries we can observe various approaches to evidence usage in the policy-making process. This study, which was a part of the Models of Child Health Appraised (MOCHA) project assessing patterns of children's primary care in Europe, focused on how and what kind of evidence is used in child health policy-making processes in European countries and how it is applied to inform policy and practice. METHOD: In this study, a qualitative approach was used. The data were analysed in accordance with the thematic analysis protocol. The MOCHA project methodology relies on experienced country agents (CA) recruited for the project and paid to deliver child health data in each of 30 European countries. CAs are national experts in the child health field who defined the country-specific structured information and data. A questionnaire designed as a semi-structured survey instrument asked CAs to indicate the sources of evidence used in the policy-making process and what needed to be in place to support evidence uptake in policy and practice. RESULTS: In our data we observed two approaches to evidence usage in child health policy formulation. The scientific approach in our understanding refers to the so-called bottom-up initiatives of academia which identify and respond to the population's needs. Institutional approaches can be informed by scientific resources as well; however, the driving forces here are governmental institutions, whose decisions and choices are based not only on the population needs but also on political, economic and organizational factors. The evidence used in Europe can also be of an external or internal nature. Various factors can affect the use of evidence in child health policy-making. Facilitators are correlated with strong scientific culture development, whereas barriers are defined by a poor tradition of implementing changes based on reliable evidence. CONCLUSIONS: Focusing on the facilitators and actively working to reduce the barriers can perceivably lead to faster and more robust policy-making, including the development of a culture of scientific grounding in policy creation.

When Covid-19 first struck: Analysis of the influence of structural characteristics of countries - technocracy is strengthened by open democracy.

CONTEXT: The Covid-19 pandemic hit the developed world differentially due to accidental factors, and countries had to respond rapidly within existing resources, structures, and processes to manage totally new health challenges. This study aimed to identify which pre-existing structural factors facilitated better outcomes despite different starting points, as understanding of the relative impact of structural aspects should facilitate achieving optimal forward progress. METHODS: Desk study, based on selecting and collecting a range of measures for 48 representative characteristics of 42 countries' demography, society, health system, and policy-making profiles, matched to three pandemic time points. Different analytic approaches were employed including correlation, multiple regression, and cluster analysis in order to seek triangulation. FINDINGS: Population structure (except country size), and volume and nature of health resources, had only minor links to Covid impact. Depth of social inequality, poverty, population age structure, and strength of preventive health measures unexpectedly had no moderating effect. Strongest measured influences were population current enrolment in tertiary education, and country leaders' strength of seeking scientific evidence. The representativeness, and by interpretation the empathy, of government leadership also had positive effects. CONCLUSION: Strength of therapeutic health system, and indeed of preventive health services, surprisingly had little correlation with impact of the pandemic in the first nine months measured in death- or case-rates. However, specific political system features, including proportional representation electoral systems, and absence of a strong single party majority, were consistent features of the most successful national responses, as was being of a small or moderate population size, and with tertiary education facilitated. It can be interpreted that the way a country was lead, and whether leadership sought evidence and shared the reasoning behind resultant policies, had notable effects. This has significant implications within health system development and in promoting the population's health.