Who is supporting the parents during their child's cancer treatment? A qualitative study through the lens of compassion.

PURPOSE: Parents of children/adolescents with cancer are placed in a state of severe suffering due to serious concerns, fears, and radical daily life changes. Human support is an important source of support for successful coping. This study explored fundamental aspects of parents' daily, social, and personal life during their child's treatment to deepen our understanding of 'who' plays a significant role in supporting parents, and how, and to what extent this support is provided. METHODS: This qualitative study was undertaken in a compassion paradigm, designed and guided by Heidegger's and Gadamer's philosophy and compassionate methods. Data were generated through ethnographic observations (144 h), focus group interviews (n = 2), and individual/couple interviews (n = 16) at two Danish hospitals. Inductive content analysis was used to analyse data. RESULTS: Overall, support from peers, health professionals, and social networks constituted significant sources of support. Especially peers and health professionals had a continuous support role, which was fundamental for establishing interpersonal closeness and relieving suffering. Sharing responsibilities between parents and among social networks seemed to ease the emotional and practical burden. However, to ensure effectiveness, social networks must be available, outreach, and responsive to needs. Moreover, parents disclosed little self-awareness and resources and options for self-care due to a combination of lack of awareness, time, and space in the hospitals. CONCLUSION: Safeguarding interpersonal and interparental understanding and closeness in parental care is essential. One way is building resilience and a broader human-to-human-based safety net around the family, including social networks and professional psychosocial support, advantageously using compassion.

Economic evaluations of telepharmacy services in non-cancer settings: A systematic review.

BACKGROUND: Telepharmacy is the provision of pharmacy services from a distance to a patient using telecommunications and other technologies. There has been limited research investigating the cost-effectiveness of telepharmacy services. OBJECTIVE: To provide a comprehensive review and narrative synthesis of the available economic evidence on telepharmacy services in non-cancer settings. METHOD: A systematic literature search of four databases including PubMed, Embase, CINAHL, and EconLit was undertaken to identify economic evaluations comparing telepharmacy services to standard pharmacy care. Abstracts and full texts were screened by two independent reviewers for inclusion against the eligibility criteria. Key economic findings were extracted from included articles to determine the cost-effectiveness of the reported telepharmacy services. RESULTS: The review included six studies; two were cost-minimisation analyses, three were cost effectiveness analyses (CEA) and one study conducted both a CEA and cost-utility analysis. Telepharmacy services predominantly relied upon telephone modes of communication, with three that used remote patient monitoring. These services managed a variety of clinical situations which included newly initiated antibiotics, antiretroviral therapy management, and medications for chronic conditions, as well as hypertension management. Articles were of relatively high reporting quality, scoring an average of 83% on the Consolidated Health Economics Reporting Standards checklist. Four of the six studies reported that telepharmacy was less costly than usual care, with two that reported telepharmacy as cost-effective to the healthcare system according to a specified cost-effectiveness threshold. CONCLUSIONS: Overall, this review demonstrates that there is emerging evidence that telepharmacy services can be cost-effective compared with standard care in non-cancer settings. Further research is needed to complement these findings, particularly reflecting the increased uptake of telehealth and telepharmacy services since the onset of the Coronavirus disease pandemic.

Patient and families' perspectives on telepalliative care: A systematic integrative review.

BACKGROUND: Telepalliative care is increasingly used in palliative care, but has yet to be examined from a patient and family perspective. A synthesis of evidence may provide knowledge on how to plan and provide telepalliative care that caters specifically to patients and families' needs. OBJECTIVE: To synthesise evidence on patients and families' perspectives on telepalliative care. DESIGN: A systematic integrative review (PROSPERO #CRD42022301206) reported in accordance with PRISMA 2020 guidelines. Inclusion criteria; primary peer-reviewed studies published 2011-2022, patient and family perspective, >18 years, telepalliative care and English/Danish language. Quality was appraised using the mixed-methods appraisal tool, version 2020. Guided by Toronto and Remington, data were extracted, thematically analysed and synthesised. DATA SOURCES: MEDLINE, EMBASE, PsycINFO and CINAHL were searched in March 2022 and updated in February 2023. RESULTS: Forty-four studies were included. Analysis revealed five themes; the effect of the Covid-19 pandemic on telepalliative care, adding value for patients and families, synchronous and asynchronous telepalliative care, the integration of telepalliative care with other services and the tailoring and timing of telepalliative care. CONCLUSION: Enhanced access to care and convenience, as attributes of telepalliative care, are highly valued. Patients and families have varying needs during the illness trajectory that may be addressed by early integration of telepalliative care based on models of care that are flexible and combine synchronous and asynchronous solutions. Further research should examine telepalliative care in a post-pandemic context, use of models of care and identify meaningful outcome measures from patient and family perspectives for evaluation of telepalliative care.

Telehealth adoption in cancer clinical trials: An Australian perspective.

INTRODUCTION: Cancer clinical trials have traditionally occurred in-person. However, the COVID-19 pandemic has forced adaptions of all aspects of cancer care (including clinical trials) so they can be delivered remotely. We aimed to quantify and qualify current use of telehealth and how it can be further improved and routinely integrated into cancer clinical trials in Australia. METHODS: We used a mixed-method study design, involving surveys of 14 multi-site Collaborative Cancer Clinical Trial Groups members across Australia (n = 98) and qualitative interviews with trial administrators and clinicians (n = 21). RESULTS: The results of our study indicated a strong willingness to use telehealth for certain transactions of clinical trials because it was perceived as a way of increasing efficiency and reach of services. Hybrid models (including telehealth and in-person methods), which considered transaction, cancer type, and patient preferences were most favorable. Additionally, telehealth allowed for greater equity to access and reduced trial burden but interestingly had little effect on increased diversity and recruitment. Factors influencing telehealth service implementation and uptake included communication among trial stakeholders, training, and learning from the experience of others in the clinical trials community. CONCLUSION: Many but not all aspects of clinical trial care are appropriate to be delivered via telehealth. A hybrid approach provides flexibility to trial delivery and may support greater equity of access to trials in the future. Our findings and actionable recommendations support the need for greater planning, training, and guidelines to enable telehealth to be better integrated into clinical trials. Opportunities exist to expand the use of remote patient monitoring to enable more objective data collection from trial participants in the future.

Cancer care and management during COVID-19: A comparison of in-person, video and telephone consultations.

In Australia, the COVID-19 pandemic has resulted in the exponential growth in the delivery of telehealth services. Medicare data indicates that the majority of telehealth consultations have used the telephone, despite the known benefits of using video. The aim of this study was to understand the perceived quality and effectiveness of in-person, telephone and videoconsultations for cancer care. Data was collected via online surveys with consumers (n = 1162) and health professionals (n = 59), followed by semi-structured interviews with telehealth experienced health professionals (n = 22) and consumers (n = 18). Data were analysed using descriptive statistics and significance was tested using the chi-square test. A framework analysis and thematic analysis were used for qualitative data. Results indicate telehealth is suitable for use across the cancer care pathway. However, consumers and health professionals perceived videoconsultations facilitated visual communication and improved patients' quality of care. The telephone was appropriate for short transactional consultations such as repeat prescriptions. Consumers were rarely given the choice of consultation modality. The choice of modality depended on a range of factors such as the type of consultation and stage of cancer care. Hybrid models of care utilising in-person, video and telephone should be developed and requires further guidance to promote the adoption of telehealth in cancer care.

Costs to the Medicare Benefits Schedule for general practitioner consultations: A time-series analysis.

The COVID-19 pandemic was a catalyst for the introduction of additional telehealth funding (telehealth item numbers) for general practitioner (GP) consultations through the Medicare Benefits Schedule (MBS) in Australia. This study evaluated the impact of telehealth funding on costs to the MBS for GP consultations from January 2017 to December 2021. An interrupted time series analysis assessed MBS costs (initial and monthly growth) for GP consultations (in-person, videoconference, telephone) before and after additional telehealth item numbers were introduced. From January 2017 to February 2020, total MBS costs for GP consultations were, on average, $545 million per month compared to $592 million per month from March 2020 to December 2021. There was an initial cost increase of approximately $39 million in the first month after additional telehealth funding was introduced (p = 0.0001). Afterwards, there was no significant change in monthly costs (p = 0.539). The introduction of additional MBS telehealth funding increased overall MBS costs for GP consultations. This increased cost for GP telehealth services could save costs to society if it translates into improved continuity of care, decreased hospitalisations, reduced productivity losses and improved patient outcomes. Future policy reform should incorporate a cost-benefit analysis to determine if increased MBS costs for GP consultations are a good investment.

Digital health experiences reported in chronic disease management: An umbrella review of qualitative studies.

INTRODUCTION: Digital health interventions can be useful for the management of chronic disease. The aim of this study was to draw out universal themes to understand how people with chronic conditions experience digital health services, programmes, and interventions, and consequently, better inform future digital health delivery. METHODS: An umbrella review was conducted to identify qualitative systematic reviews reporting digital health experiences in chronic disease. Themes for each included review were independently extracted and appraised by two review authors. Data analysis was conducted using the Constant Comparative method. RESULTS: Twenty-two systematic reviews containing 240 individual studies were selected for inclusion. Mental health was the most common condition (n = 5, 23%), followed by cancer (n = 4, 18%) or a combination of chronic diseases (n = 4, 18%). Common themes across the conditions were categorised under nine headings, including: (i) participation and engagement (strong usability and engagement vs reluctance to use digital health when these concepts are ignored), (ii) trust, confidence, and competence (users felt reassured, however technology illiteracy led to a perceived lack of control), (iii) perceived value, perceived effectiveness, transaction cost (gained from efficient aspects of digital health, but also lost through the burden of keeping up with data entry), (iv) perceived care quality (requiring tailoring and fostering motivation), (v) barriers and threats (related to technology risks and challenges), (vi) health outcomes (improved self-management capability), (vii) relationships (improved participant-health professional interaction, but interpersonal aspects such as face-to-face contact were lacking), (viii) unplanned benefit (where digital health often led to users feeling more empowered in their health journey), and (ix) diversity of experiences (reflecting ambivalence of experiences and discipline-specific experiences). CONCLUSION: People with chronic conditions perceive digital health provides feelings of reassurance and the ability to self-manage their condition. While there is ambivalence across the participant experiences reported within the major themes, this umbrella review has outlined a need for future interventions that are user-friendly, flexible, and tailored to individual users. This will be best achieved through a co-design model, with the consumer actively involved in the planning and design of digital health products and services.

The impact of telehealth policy changes on general practitioner consultation activity in Australia: a time-series analysis.

Objective To examine the impact of telehealth policy changes on general practitioner (GP) consultation activity in Australia, during the coronavirus disease 2019 (COVID-19) pandemic, from January 2019 to December 2021. Methods An interrupted time-series analysis was conducted to analyse the impact of two major policy changes, introduced through the Medicare Benefits Schedule (MBS), on GP consultation (in-person, videoconference, telephone) activity. The first policy change was the introduction of additional COVID-19 telehealth funding through the MBS on 30 March 2020. The second policy change was the limitation on telephone consultation length to under 20 min on 1 July 2021. The rate of GP telehealth provision and activity was compared between pre-and post-intervention periods, separated by these MBS policy changes. Results After the first policy change, there was a significant increase in telehealth provision, with a simultaneous decrease in in-person consultations (P < 0.0001). However, telehealth provision decreased in the months following this first policy change (P < 0.0001), while in-person activity increased. After the second policy change, the initial videoconference provision increased (P < 0.0001). However, all telehealth activity decreased afterwards. In the months following the second policy change, the decrease in monthly activity for in-person (P = 0.700), telephone (0.199) and videoconference (P = 0.178) consultations was not significant. Conclusions The introduction of additional telehealth funding and limitations on telephone consultation length encouraged the initial provision and growth of telehealth services. However, these policy changes did not sustain the long-term upward trajectory of telehealth activity. Telehealth policies should increase opportunities for appropriate and sustainable GP telehealth services.

Increase in telemental health services on the Medicare Benefits Schedule after the start of the coronavirus pandemic: data from 2019 to 2021.

Objective To describe the change in telemental health service volume that resulted from the introduction of the Medicare Benefits Schedule (MBS) item numbers in 2020 for services provided by psychologists and psychiatrists in Australia for a 3-year period, from January 2019 to December 2021. Methods Quarterly MBS activity and cost data for mental health services provided by consultant psychiatrists, clinical psychologists, and psychologists between January 2019 and December 2021 were extracted from the MBS statistics website. Data were grouped by profession and delivery mode (in-person, telephone or videoconference) and reported using activity counts. Descriptive analysis and interrupted time-series regression analysis were conducted. Specific descriptive explorations were also conducted for psychiatrists, including: new client consultations, review or general consultations, and group consultations. Results The delivery of mental health services by telehealth (telemental health) during the pandemic has increased (P < 0.0001). When the pandemic started in March 2020, telemental health services provided by psychiatrists and psychologists increased from a combined 1-2% per quarter to 29% videoconference and 20% telephone in quarter two 2020. After the onset of the pandemic, videoconference remained the primary form of telehealth for these professions. However, the telephone accounted for approximately a third of the telehealth activity after the new item numbers were introduced. Conclusion Telemental health services are more likely to be conducted by videoconference than by telephone. The observed increase in telehealth service activity confirms how crucial appropriate funding models are to the sustainability of telehealth services in Australia. The growth in telehealth was used to support people with mental health conditions in Australia.

Protocol for an integrative review: patient and families' perspectives on telehealth in palliative care.

INTRODUCTION: Increases in the use of telehealth in palliative care (telepalliative care) prior to, and during, the COVID-19 pandemic have resulted in a proliferation of studies on the topic. While knowledge is building on how providers and recipients adapt to telepalliative care, no reviews have, as of yet, examined telepalliative care from a patient and family perspective. Therefore, the aim of this integrative review is to explore patients and families' perspectives on telepalliative. METHODS AND ANALYSIS: An integrative review will be performed inspired by the methodology of Remmington and Toronto from March 2022 to December 2022. Medline, Embase, PsycINFO and CINAHL will be searched for primary peer-reviewed studies that describe telepalliative care from patient and families' perspectives. Limiters will be used for age; 18 years+, time; 10 years, and language; English and Danish. Hand searches of authors of included articles and reference lists of included articles will be performed. Two reviewers will independently screen and appraise selected articles using the Mixed Method Appraisal Tool. Conflicts will be resolved through discussions with a third reviewer. Data will be extracted independently by two reviewers into a data matrix with predefined headings and analysed using thematic analysis. Findings will be reported thematically, summarised into a thematic synthesis and discussed in relation to relevant literature. ETHICS AND DISSEMINATION: Ethical approval is not required for this review. Results will be published in an international peer-reviewed journal and presented at a relevant international conference. Reporting of this protocol was guided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol checklist and prospectively reported to PROSPERO (CRD42022301206).

Enhancing a community palliative care service with telehealth leads to efficiency gains and improves job satisfaction.

Telepalliative care services enable clinicians to provide essential palliation services to people with a life-limiting illness in or closer to home. This study aims to explore the costs, service activity and staff experiences resulting from the introduction of telehealth in a community palliative care service in Queensland, Australia. Pre- and post-activity and cost data from the 2016-2017 and 2019-2020 financial years were examined and staff members interviewed. Accounting for inflation and standard wage increases, the labour costs before and after the addition of telehealth were approximately equal. There were small variations in non-labour costs, but these were not directly attributable to the expansion of the telehealth services. Overall, the service activity increased by 189% for standard doctor and nurse consultations, due to the increased efficiency of telehealth compared to the previous outreach (travel) model. Thematic analysis of the staff interview data generated an overarching theme of Increased Job Satisfaction which staff attributed to the patient-centred nature of the telepalliative care service, the increased peer support and increased professional development. Compared with the traditional in-person service, the new telehealth-supported model resulted in equivalent costs, greater efficiency by allowing palliative care to reach more patients and improved staff job satisfaction.

Specialist consultation activity and costs in Australia: Before and after the introduction of COVID-19 telehealth funding.

This study describes and analyses the Medicare Benefits Schedule (MBS) activity and cost data for specialist consultations in Australia, as a result of the coronavirus disease 2019 (COVID-19) pandemic. To achieve this, activity and cost data for MBS specialist consultations conducted from March 2019 to February 2021 were analysed month-to-month. MBS data for in-person, videoconference and telephone consultations were compared before and after the introduction of COVID-19 MBS telehealth funding in March 2020. The total number of MBS specialist consultations claimed per month did not differ significantly before and after the onset of COVID-19 (p = 0.717), demonstrating telehealth substitution of in-person care. After the introduction of COVID-19 telehealth funding, the average number of monthly telehealth consultations increased (p < 0.0001), representing an average of 19% of monthly consultations. A higher proportion of consultations were provided by telephone when compared to services delivered by video. Patient-end services did not increase after the onset of COVID-19, signifying a divergence from the historical service delivery model. Overall, MBS costs for specialist consultations did not vary significantly after introducing COVID-19 telehealth funding (p = 0.589). Telehealth consultations dramatically increased during COVID-19 and patients continued to receive specialist care. After the onset of COVID-19, the cost per telehealth specialist consultation was reduced, resulting in increased cost efficiency to the MBS.

Nucleotide-binding sites can enhance N-acylation of nearby protein lysine residues.

Acyl-CoAs are reactive metabolites that can non-enzymatically S-acylate and N-acylate protein cysteine and lysine residues, respectively. N-acylation is irreversible and enhanced if a nearby cysteine residue undergoes an initial reversible S-acylation, as proximity leads to rapid S → N-transfer of the acyl moiety. We reasoned that protein-bound acyl-CoA could also facilitate S → N-transfer of acyl groups to proximal lysine residues. Furthermore, as CoA contains an ADP backbone this may extend beyond CoA-binding sites and include abundant Rossmann-fold motifs that bind the ADP moiety of NADH, NADPH, FADH and ATP. Here, we show that excess nucleotides decrease protein lysine N-acetylation in vitro. Furthermore, by generating modelled structures of proteins N-acetylated in mouse liver, we show that proximity to a nucleotide-binding site increases the risk of N-acetylation and identify where nucleotide binding could enhance N-acylation in vivo. Finally, using glutamate dehydrogenase as a case study, we observe increased in vitro lysine N-malonylation by malonyl-CoA near nucleotide-binding sites which overlaps with in vivo N-acetylation and N-succinylation. Furthermore, excess NADPH, GTP and ADP greatly diminish N-malonylation near their nucleotide-binding sites, but not at distant lysine residues. Thus, lysine N-acylation by acyl-CoAs is enhanced by nucleotide-binding sites and may contribute to higher stoichiometry protein N-acylation in vivo.

Queensland Telepaediatric Service: A Review of the First 15 Years of Service.

In November 2000, the Queensland Telepaediatric Service (QTS) was established in Brisbane, Australia, to support the delivery of telehealth services to patients and clinicians in regional and remote locations. The QTS was built on a centralized coordination model, where telehealth services could be effectively managed by a dedicated telehealth coordinator. In doing so, telehealth referral and consultation processes were efficient and clinicians felt better supported as they adjusted to new processes for engaging with patients. We have conducted a retrospective review of activity associated with the QTS and summarized key activities which have arisen from this extensive program of work. Telehealth service records and associated publications were used to describe the evolution of the QTS over a 15-year period. From November 2000 to March 2016, 23,054 telehealth consultations were delivered for 37 pediatric clinical specialties. The most common service areas included child and youth mental health, neurology, burns care, surgery, and ear nose and throat services. A range of different telehealth service models were developed to align with different clinical service needs and location of services. Whilst most work involved video consultation between hospitals, some services involved the delivery of telehealth services into the home, schools or community health centres. Despite its longevity, the QTS was not immune to the usual challenges associated with telehealth implementation, service redesign and sustainability. Experience reported from the QTS will be useful for other health services seeking to develop comprehensive telehealth services in a rapidly changing healthcare environment.

Models of care in tele-ophthalmology: A scoping review.

The objective of this review was to identify and describe telehealth models of care for ophthalmic services. We conducted a scoping review of the literature to identify how ophthalmic care can be delivered by telehealth. We searched the PubMed database to identify relevant articles which were screened based on pre-defined inclusion criteria. For included articles, data were extracted, categorised and analysed. Synthesis of findings was performed narratively. The scoping review included 78 articles describing 62 discrete tele-ophthalmic models of care. Tele-ophthalmic models of care can be used for consultative service, screening, triage and remote supervision. The majority of services were for general eye care and triage ( n = 17; 26%) or emergency services ( n = 8; 12%). The most common conditions for disease-specific models of care were diabetic retinopathy ( n = 14; 21%), and glaucoma ( n = 8; 12%). Most models of care involved local clinicians capturing images and transmitting them to an ophthalmologist for assessment. This scoping review demonstrated tele-ophthalmology to be feasible for consultation, screening, triage and remote supervision applications across a broad range of ophthalmic conditions. A large number of models of care have been identified and described in this review. Considerable collaboration between patient-end clinicians and substantial infrastructure is typically required for tele-ophthalmology.

Screening of candidate substrates and coupling ions of transporters by thermostability shift assays.

Substrates of most transport proteins have not been identified, limiting our understanding of their role in physiology and disease. Traditional identification methods use transport assays with radioactive compounds, but they are technically challenging and many compounds are unavailable in radioactive form or are prohibitively expensive, precluding large-scale trials. Here, we present a high-throughput screening method that can identify candidate substrates from libraries of unlabeled compounds. The assay is based on the principle that transport proteins recognize substrates through specific interactions, which lead to enhanced stabilization of the transporter population in thermostability shift assays. Representatives of three different transporter (super)families were tested, which differ in structure as well as transport and ion coupling mechanisms. In each case, the substrates were identified correctly from a large set of chemically related compounds, including stereo-isoforms. In some cases, stabilization by substrate binding was enhanced further by ions, providing testable hypotheses on energy coupling mechanisms.

The Causes and Consequences of Nonenzymatic Protein Acylation.

Thousands of protein acyl modification sites have now been identified in vivo. However, at most sites the acylation stoichiometry is low, making functional enzyme-driven regulation in the majority of cases unlikely. As unmediated acylation can occur on the surface of proteins when acyl-CoA thioesters react with nucleophilic cysteine and lysine residues, slower nonenzymatic processes likely underlie most protein acylation. Here, we review how nonenzymatic acylation of nucleophilic lysine and cysteine residues occurs; the factors that enhance acylation at particular sites; and the strategies that have evolved to limit protein acylation. We conclude that protein acylation is an unavoidable consequence of the central role of reactive thioesters in metabolism. Finally, we propose a hypothesis for why low-stoichiometry protein acylation is selected against by evolution and how it might contribute to degenerative processes such as aging.

Proximal Cysteines that Enhance Lysine N-Acetylation of Cytosolic Proteins in Mice Are Less Conserved in Longer-Living Species.

Acetyl-coenzyme A (CoA) is an abundant metabolite that can also alter protein function through non-enzymatic N-acetylation of protein lysines. This N-acetylation is greatly enhanced in vitro if an adjacent cysteine undergoes initial S-acetylation, as this can lead to S→N transfer of the acetyl moiety. Here, using modeled mouse structures of 619 proteins N-acetylated in mouse liver, we show lysine N-acetylation is greater in vivo if a cysteine is within ∼10 Å. Extension to the genomes of 52 other mammalian and bird species shows pairs of proximal cysteine and N-acetylated lysines are less conserved, implying most N-acetylation is detrimental. Supporting this, there is less conservation of cytosolic pairs of proximal cysteine and N-acetylated lysines in species with longer lifespans. As acetyl-CoA levels are linked to nutrient supply, these findings suggest how dietary restriction could extend lifespan and how pathologies resulting from dietary excess may occur.

Pathogenic mutations of the human mitochondrial citrate carrier SLC25A1 lead to impaired citrate export required for lipid, dolichol, ubiquinone and sterol synthesis.

Missense mutations of the human mitochondrial citrate carrier, encoded by the SLC25A1 gene, lead to an autosomal recessive neurometabolic disorder characterised by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development, often resulting in early death. Here, we have measured the effect of all twelve known pathogenic mutations on the transport activity. The results show that nine mutations abolish transport of citrate completely, whereas the other three reduce the transport rate by >70%, indicating that impaired citrate transport is the most likely primary cause of the disease. Some mutations may be detrimental to the structure of the carrier, whereas others may impair key functional elements, such as the substrate binding site and the salt bridge network on the matrix side of the carrier. To understand the consequences of impaired citrate transport on metabolism, the substrate specificity was also determined, showing that the human citrate carrier predominantly transports citrate, isocitrate, cis-aconitate, phosphoenolpyruvate and malate. Although D-2- and L-2 hydroxyglutaric aciduria is a metabolic hallmark of the disease, it is unlikely that the citrate carrier plays a significant role in the removal of hydroxyglutarate from the cytosol for oxidation to oxoglutarate in the mitochondrial matrix. In contrast, computer simulations of central metabolism predict that the export of citrate from the mitochondrion cannot be fully compensated by other pathways, restricting the cytosolic production of acetyl-CoA that is required for the synthesis of lipids, sterols, dolichols and ubiquinone, which in turn explains the severe disease phenotypes.

MitoCore: a curated constraint-based model for simulating human central metabolism.

BACKGROUND: The complexity of metabolic networks can make the origin and impact of changes in central metabolism occurring during diseases difficult to understand. Computer simulations can help unravel this complexity, and progress has advanced in genome-scale metabolic models. However, many models produce unrealistic results when challenged to simulate abnormal metabolism as they include incorrect specification and localisation of reactions and transport steps, incorrect reaction parameters, and confounding of prosthetic groups and free metabolites in reactions. Other common drawbacks are due to their scale, making them difficult to parameterise and simulation results hard to interpret. Therefore, it remains important to develop smaller, manually curated models. RESULTS: We present MitoCore, a manually curated constraint-based computer model of human metabolism that incorporates the complexity of central metabolism and simulates this metabolism successfully under normal and abnormal physiological conditions, including hypoxia and mitochondrial diseases. MitoCore describes 324 metabolic reactions, 83 transport steps between mitochondrion and cytosol, and 74 metabolite inputs and outputs through the plasma membrane, to produce a model of manageable scale for easy interpretation of results. Its key innovations include a more accurate partitioning of metabolism between cytosol and mitochondrial matrix; better modelling of connecting transport steps; differentiation of prosthetic groups and free co-factors in reactions; and a new representation of the respiratory chain and the proton motive force. MitoCore's default parameters simulate normal cardiomyocyte metabolism, and to improve usability and allow comparison with other models and types of analysis, its reactions and metabolites have extensive annotation, and cross-reference identifiers from Virtual Metabolic Human database and KEGG. These innovations-including over 100 reactions absent or modified from Recon 2-are necessary to model central metabolism more accurately. CONCLUSION: We anticipate MitoCore as a research tool for scientists, from experimentalists looking to interpret their data and test hypotheses, to experienced modellers predicting the consequences of disease or using computationally intensive methods that are infeasible with larger models, as well as a teaching tool for those new to modelling and needing a small, manageable model on which to learn and experiment.