Training needs for staff providing remote services in general practice: a mixed-methods study.

BACKGROUND: Contemporary general practice includes many kinds of remote encounter. The rise in telephone, video and online modalities for triage and clinical care requires clinicians and support staff to be trained, both individually and as teams, but evidence-based competencies have not previously been produced for general practice. AIM: To identify training needs, core competencies, and learning methods for staff providing remote encounters. DESIGN AND SETTING: Mixed-methods study in UK general practice. METHOD: Data were collated from longitudinal ethnographic case studies of 12 general practices; a multi-stakeholder workshop; interviews with policymakers, training providers, and trainees; published research; and grey literature (such as training materials and surveys). Data were coded thematically and analysed using theories of individual and team learning. RESULTS: Learning to provide remote services occurred in the context of high workload, understaffing, and complex workflows. Low confidence and perceived unmet training needs were common. Training priorities for novice clinicians included basic technological skills, triage, ethics (for privacy and consent), and communication and clinical skills. Established clinicians' training priorities include advanced communication skills (for example, maintaining rapport and attentiveness), working within the limits of technologies, making complex judgements, coordinating multi-professional care in a distributed environment, and training others. Much existing training is didactic and technology focused. While basic knowledge was often gained using such methods, the ability and confidence to make complex judgements were usually acquired through experience, informal discussions, and on-the-job methods such as shadowing. Whole-team training was valued but rarely available. A draft set of competencies is offered based on the findings. CONCLUSION: The knowledge needed to deliver high-quality remote encounters to diverse patient groups is complex, collective, and organisationally embedded. The vital role of non-didactic training, for example, joint clinical sessions, case-based discussions, and in-person, whole-team, on-the-job training, needs to be recognised.

Patient safety in remote primary care encounters: multimethod qualitative study combining Safety I and Safety II analysis.

BACKGROUND: Triage and clinical consultations increasingly occur remotely. We aimed to learn why safety incidents occur in remote encounters and how to prevent them. SETTING AND SAMPLE: UK primary care. 95 safety incidents (complaints, settled indemnity claims and reports) involving remote interactions. Separately, 12 general practices followed 2021-2023. METHODS: Multimethod qualitative study. We explored causes of real safety incidents retrospectively ('Safety I' analysis). In a prospective longitudinal study, we used interviews and ethnographic observation to produce individual, organisational and system-level explanations for why safety and near-miss incidents (rarely) occurred and why they did not occur more often ('Safety II' analysis). Data were analysed thematically. An interpretive synthesis of why safety incidents occur, and why they do not occur more often, was refined following member checking with safety experts and lived experience experts. RESULTS: Safety incidents were characterised by inappropriate modality, poor rapport building, inadequate information gathering, limited clinical assessment, inappropriate pathway (eg, wrong algorithm) and inadequate attention to social circumstances. These resulted in missed, inaccurate or delayed diagnoses, underestimation of severity or urgency, delayed referral, incorrect or delayed treatment, poor safety netting and inadequate follow-up. Patients with complex pre-existing conditions, cardiac or abdominal emergencies, vague or generalised symptoms, safeguarding issues, failure to respond to previous treatment or difficulty communicating seemed especially vulnerable. General practices were facing resource constraints, understaffing and high demand. Triage and care pathways were complex, hard to navigate and involved multiple staff. In this context, patient safety often depended on individual staff taking initiative, speaking up or personalising solutions. CONCLUSION: While safety incidents are extremely rare in remote primary care, deaths and serious harms have resulted. We offer suggestions for patient, staff and system-level mitigations.

Pharmaceutical Company Targets and Strategies to Address Climate Change: Content Analysis of Public Reports from 20 Pharmaceutical Companies.

The pharmaceutical industry produces a large proportion of health system greenhouse gas (GHG) emissions, contributing to climate change. This urgently needs to be addressed. We aimed to examine pharmaceutical company climate change targets, GHG emissions, and strategies to reduce them. We performed content analysis of the 20 largest pharmaceutical companies' publicly available 2020/2021 reports, focusing on extracting information on their reported climate change targets, GHG emissions (and whether companies had demonstrated any reduction in emissions over their reporting period), and strategies being implemented to reduce company emissions and meet their targets. Nineteen companies have committed to reducing GHG emissions, ten to carbon neutrality and eight to net zero emissions between 2025 and 2050. Companies showed largely favorable reductions in scope 1 (in-house) and scope 2 (purchased energy), with variable results in scope 3 (supply chain) emissions. Strategies to reduce emissions included optimizing manufacturing and distribution, and responsible sourcing of energy, water, and raw materials. Pharmaceutical companies are setting climate change targets and reporting reduced emissions via a range of strategies. This varies, with scope to track actions and accountability to targets, improve consistency of reporting, especially of scope 3 emissions, and collaborate on novel solutions. There is need for further mixed methods research on progress with achieving reported climate change targets, as well as implementation of strategies to reduce emissions within the pharmaceutical industry.

Using Patient Perspectives to Inform Better Clinical Trial Design and Conduct: Current Trends and Future Directions.

The approach to patient engagement (PE) in drug development has changed rapidly due to many factors, including the complexity of innovative drugs and the need to demonstrate outcomes of relevance to patients, the desire to show 'value add' of PE, and the pandemic-related changes to how clinical trials are run, e.g., decentralised studies. In parallel, there have been changes in technology-assisted ways of running clinical trials, capturing patient health outcomes and preferences, an increasing societal demand for diversity and inclusion, and efforts to improve clinical trial efficiency, transparency, and accountability. Organisations are beginning to monitor PE activities and outcomes more effectively to learn and inform future PE strategies. As a result, these factors are facilitating the incorporation of patients' lived experience, preferences and needs into the design and running of clinical trials more than ever before. In this paper, the authors reflect upon these last few years, the emerging trends and their drivers, and where we may expect PE in clinical research to progress in the near future.

Remote care in UK general practice: baseline data on 11 case studies.

Background: Accessing and receiving care remotely (by telephone, video or online) became the default option during the coronavirus disease 2019 (COVID-19) pandemic, but in-person care has unique benefits in some circumstances. We are studying UK general practices as they try to balance remote and in-person care, with recurrent waves of COVID-19 and various post-pandemic backlogs. Methods: Mixed-methods (mostly qualitative) case study across 11 general practices. Researchers-in-residence have built relationships with practices and become familiar with their contexts and activities; they are following their progress for two years via staff and patient interviews, documents and ethnography, and supporting improvement efforts through co-design. In this paper, we report baseline data. Results: Reflecting our maximum-variety sampling strategy, the 11 practices vary in size, setting, ethos, staffing, population demographics and digital maturity, but share common contextual features-notably system-level stressors such as high workload and staff shortages, and UK's technical and regulatory infrastructure. We have identified both commonalities and differences between practices in terms of how they: 1] manage the 'digital front door' (access and triage) and balance demand and capacity; 2] strive for high standards of quality and safety; 3] ensure digital inclusion and mitigate wider inequalities; 4] support and train their staff (clinical and non-clinical), students and trainees; 5] select, install, pilot and use technologies and the digital infrastructure which support them; and 6] involve patients in their improvement efforts. Conclusions: General practices' responses to pandemic-induced disruptive innovation appear unique and situated. We anticipate that by focusing on depth and detail, this longitudinal study will throw light on why a solution that works well in one practice does not work at all in another. As the study unfolds, we will explore how practices achieve timely diagnosis of urgent or serious illness and manage continuity of care, long-term conditions and complex needs.

We describe early results from the Remote by Default 2 study, which is following 11 UK general practices for two years as they introduce various kinds of remote appointment booking and clinical consultations. We have been using interviews and ethnography (watching real-world activities), and analysing documents (such as practice reports and websites) to prepare case studies of the 11 practices, which vary widely in size, ethos, geographical location, practice population and digital maturity. Our initial interviews identified the following cross-cutting themes, which showed both commonalities and differences across the 11 practices: - The 'digital front door' (patients gaining access using digital portals), which was used to a greater or lesser extent in all practices; some found these systems frustrating and inefficient.- Quality and safety. Staff were concerned about the risk of missing an important diagnosis when consulting remotely, and felt that digitisation could threaten continuity of care.- Digital inclusion. All practices were keen to ensure that patients who lacked digital devices or skills were not disadvantaged; this goal was achieved in different ways (and to different degrees) in different settings.- Staff support and training. Some practices are finding current workload unsustainable due to (among other things) rising patient demand, unfilled staff posts, a post-pandemic backlog of unmet need, and task-shifting from secondary care. Digitisation appears to have increased workload in most practices.- Technologies and infrastructure. The IT infrastructure in each practice had grown in a particular way over time, and was in this sense 'path-dependent' (hence, not easily changed). In conclusion, different practices are responding to the 'disruptive innovation' of digital technologies in very different ways, reflecting their different practice populations, settings and priorities. We plan to follow the above themes over time and explore additional themes including the experience and role of patients.

Protocol: Remote care as the 'new normal'? Multi-site case study in UK general practice.

Background: Following a pandemic-driven shift to remote service provision, UK general practices offer telephone, video or online consultation options alongside face-to-face. This study explores practices' varied experiences over time as they seek to establish remote forms of accessing and delivering care. Methods: This protocol is for a mixed-methods multi-site case study with co-design and national stakeholder engagement. 11 general practices were selected for diversity in geographical location, size, demographics, ethos, and digital maturity. Each practice has a researcher-in-residence whose role is to become familiar with its context and activity, follow it longitudinally for two years using interviews, public-domain documents and ethnography, and support improvement efforts. Research team members meet regularly to compare and contrast across cases. Practice staff are invited to join online learning events. Patient representatives work locally within their practice patient involvement groups as well as joining an online patient learning set or linking via a non-digital buddy system. NHS Research Ethics Approval has been granted. Governance includes a diverse independent advisory group with lay chair. We also have policy in-reach (national stakeholders sit on our advisory group) and outreach (research team members sit on national policy working groups). Results anticipated: We expect to produce rich narratives of contingent change over time, addressing cross-cutting themes including access, triage and capacity; digital and wider inequities; quality and safety of care (e.g. continuity, long-term condition management, timely diagnosis, complex needs); workforce and staff wellbeing (including non-clinical staff, students and trainees); technologies and digital infrastructure; patient perspectives; and sustainability (e.g. carbon footprint). Conclusion: By using case study methods focusing on depth and detail, we hope to explain why digital solutions that work well in one practice do not work at all in another. We plan to inform policy and service development through inter-sectoral network-building, stakeholder workshops and topic-focused policy briefings.

The pandemic required general practices to introduce remote (phone, video and email) consultations. That policy undoubtedly saved lives at the time but there are also clear benefits of face-to-face consultations in some circumstances, and the exact role of remote care still needs to be worked out. Despite best efforts, remote care tends to worsen health inequities (people who were poor or less well educated are less able to access and navigate the system and secure the type of appointment they need or prefer). Workstream 1: We will look at 11 GP surgeries across England, Scotland and Wales. We have selected a variety of sites: urban and rural, serving a range of different communities. Each surgery has a different approach to technology. A researcher from our team will work alongside surgery staff to learn what methods and technologies each practice uses to deliver care. They will gather information (mostly qualitative) about how different technological solutions are playing out over time. Workstream 2: Many people experience barriers to accessing care when it is done through technology. This could be because they lack understanding of how to do it, don't have the right equipment, can't afford data, or other reasons. We will ask patients about their experiences and work with them and staff to develop ideas about how to overcome barriers. Workstream 3: We will take what we have learnt in Workstreams 1 and 2 to make suggestions to inform national stakeholders and to influence policymakers. Patients and members of the public helped shape the research design. They continue to help guide our research by reading our reports, giving us their opinions and advising on how best to share our research so everyone can benefit from what we have learnt. Our governance panel is chaired by a member of the public.

Planning and Evaluating Remote Consultation Services: A New Conceptual Framework Incorporating Complexity and Practical Ethics.

Establishing and running remote consultation services is challenging politically (interest groups may gain or lose), organizationally (remote consulting requires implementation work and new roles and workflows), economically (costs and benefits are unevenly distributed across the system), technically (excellent care needs dependable links and high-quality audio and images), relationally (interpersonal interactions are altered), and clinically (patients are unique, some examinations require contact, and clinicians have deeply-held habits, dispositions and norms). Many of these challenges have an under-examined ethical dimension. In this paper, we present a novel framework, Planning and Evaluating Remote Consultation Services (PERCS), built from a literature review and ongoing research. PERCS has 7 domains-the reason for consulting, the patient, the clinical relationship, the home and family, technologies, staff, the healthcare organization, and the wider system-and considers how these domains interact and evolve over time as a complex system. It focuses attention on the organization's digital maturity and digital inclusion efforts. We have found that both during and beyond the pandemic, policymakers envisaged an efficient, safe and accessible remote consultation service delivered through state-of-the art digital technologies and implemented via rational allocation criteria and quality standards. In contrast, our empirical data reveal that strategic decisions about establishing remote consultation services, allocation decisions for appointment type (phone, video, e-, face-to-face), and clinical decisions when consulting remotely are fraught with contradictions and tensions-for example, between demand management and patient choice-leading to both large- and small-scale ethical dilemmas for managers, support staff, and clinicians. These dilemmas cannot be resolved by standard operating procedures or algorithms. Rather, they must be managed by attending to here-and-now practicalities and emergent narratives, drawing on guiding principles applied with contextual judgement. We complement the PERCS framework with a set of principles for informing its application in practice, including education of professionals and patients.

Sustaining Meaningful Patient Engagement Across the Lifecycle of Medicines: A Roadmap for Action.

BACKGROUND: There is increased recognition that incorporating patients' perspectives and insights into the medicines development process results in better health outcomes and benefits for all involved stakeholders. Despite the increased interest and the existence of frameworks and practical recommendations, patient engagement (PE) is not yet considered standard practice. The objective of this work was to provide a roadmap to support systematic change in all stakeholder organisations involved in medicines development across Europe, patients and patient organisations, medicines developers, academia, regulatory authorities, Health Technology Assessment bodies, payers, policy-makers and public research funders, to sustain PE practices. METHODS: A mixed-methods approach was used by the EU-funded Innovative Medicines Initiative PARADIGM Consortium to co-develop the sustainability roadmap including background work to identify success factors and scenarios for sustainable PE. The roadmap development was based on the Theory of Change concept and populated with findings from (1) interviews with national/ and international institutions with the potential to increase PE uptake by other stakeholders; (2) multi-stakeholder workshops and webinars; and (3) consultations with specific stakeholder groups, Consortium members and a consultative body formed by international PE initiatives. RESULTS: This roadmap sets strategic goals for the PE community to achieve meaningful and systematic PE through changes in the culture, processes and resources of stakeholder organisations. It brings in key PARADIGM outputs to work in a coordinated fashion with existing frameworks and mechanisms to achieve system-wide sustained PE. CONCLUSIONS: The roadmap provides a framework for all stakeholders to take collective action within their organisations and across Europe to implement PE in a sustainable manner.

Understanding multi-stakeholder needs, preferences and expectations to define effective practices and processes of patient engagement in medicine development: A mixed-methods study.

BACKGROUND: The holistic evolution of patient engagement in medicines development requires a more detailed understanding of the needs of all involved stakeholders, and one that better accounts for the specific needs of some potentially vulnerable patient populations and key stages in medicines development. OBJECTIVE: The purpose of this convergent mixed-methods study was to better understand the needs of different stakeholders concerning patient engagement at three key stages in medicines development: research priority setting, clinical trial design and early dialogues with Health Technology Assessment bodies and regulators. DESIGN: This study brought together findings from three sources: i) an online questionnaire, ii) face-to-face consultations with two potentially vulnerable patient populations, a workshop with Health Technology Assessment bodies, and iii) three-step modified Delphi methodology. RESULTS: Overall stakeholders still need additional varied support mechanisms to undertake, sustain or measure value of patient engagement. Health Technology Assessment bodies need better rationale for patient engagement in early dialogue and tools to support its implementation. Improved awareness and understanding of the need and value that involving patients, who are often considered as potentially vulnerable, can bring is needed, as is better accommodation of their specific needs. Similarly, weighted Delphi categories were as follows: aims and objectives, and sustainability. Several additional themes were common across the three key stages in medicines development. CONCLUSION: This broad-reaching study provides the blocks needed to build a framework for patient engagement in medicines development. PATIENT OR PUBLIC CONTRIBUTION: Patients were involved in review and interpretation of data.

Achieving Spread, Scale Up and Sustainability of Video Consulting Services During the COVID-19 Pandemic? Findings From a Comparative Case Study of Policy Implementation in England, Wales, Scotland and Northern Ireland.

Requirements for physical distancing as a result of COVID-19 and the need to reduce the risk of infection prompted policy supporting rapid roll out of video consulting across the four nations of the UK-England, Northern Ireland, Scotland and Wales. Drawing on three studies of the accelerated implementation and uptake of video consulting across the four nations, we present a comparative and interpretive policy analysis of the spread and scale-up of video consulting during the pandemic. Data include interviews with 59 national level stakeholders, 55 health and social care staff and 30 patients, 20 national documents, responses to a UK-wide survey of NHS staff and analysis of routine activity data. Sampling ensured variations in geography, clinical context and adoption progress across the combined dataset. Comparative analysis was guided by theory on policy implementation and crisis management. The pandemic provided a "burning platform" prompting UK-wide policy supporting the use of video consulting in health care as a critical means of managing the risk of infection and a standard mode of provision. This policy push facilitated interest in video consulting across the UK. There was, however, marked variation in how this was put into practice across the four nations. Pre-existing infrastructure, policies and incentives for video consulting in Scotland, combined with a collaborative system-level approach, a program dedicated to developing video-based services and resourcing and supporting staff to deliver them enabled widespread buy-in and rapid spread. In England, Wales and Northern Ireland, pre-existing support for digital health (e.g., hardware, incentives) and virtual care, combined with reduced regulation and "light touch" procurement managed to override some (but by no means all) cultural barriers and professional resistance to implementing digital change. In Northern Ireland and Wales, limited infrastructure muted spread. In all three countries, significant effort at system level to develop, review and run video consulting programs enabled a substantial number of providers to change their practice, albeit variably across settings. Across all four nations ongoing uncertainty, potential restructuring and tightening of regulations, along with difficulties inherent in addressing inequalities in digital access, raise questions about the longer-term sustainability of changes to-date.

Medicines Adaptive Pathways to Patients: Why, When, and How to Engage?

Medicines Adaptive Pathways to Patients (MAPPs) seeks to foster access to novel beneficial treatments for the right patient groups at the earliest appropriate time in the product life-span, in a sustainable fashion. We summarize the MAPPs engagement process and critical questions to be asked at each milestone of the product life-span. These considerations are of relevance for regulatory and access pathways that strive to address the "evidence vs. access" conundrum.

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents.

BACKGROUND: Cerebral Palsy (CP) is the most common physical pediatric neurodevelopmental disorder and spastic diplegic injury is its most frequent subtype. CP results in substantial neuromotor and cognitive impairments that have significant socioeconomic impact. Despite this, its underlying pathophysiological mechanisms and etiology remain incompletely understood. Furthermore, there is a need for clinically relevant injury models, which a) reflect the heterogeneity of the condition and b) can be used to evaluate new translational therapies. To address these key knowledge gaps, we characterized a chronic placental insufficiency (PI) model, using bilateral uterine artery ligation (BUAL) of dams. This injury model results in intrauterine growth restriction (IUGR) in pups, and animals recapitulate the human phenotype both in terms of neurobehavioural and anatomical deficits. METHODS: Effects of BUAL were studied using luxol fast blue (LFB)/hematoxylin & eosin (H&E) staining, immunohistochemistry, quantitative Magnetic Resonance Imaging (MRI), and Catwalk neurobehavioural tests. RESULTS: Neuroanatomical analysis revealed regional ventricular enlargement and corpus callosum thinning in IUGR animals, which was correlated with the extent of growth restriction. Olig2 staining revealed reductions in oligodendrocyte density in white and grey matter structures, including the corpus callosum, optic chiasm, and nucleus accumbens. The caudate nucleus, along with other brain structures such as the optic chiasm, internal capsule, septofimbrial and lateral septal nuclei, exhibited reduced size in animals with IUGR. The size of the pretectal nucleus was reduced only in moderately injured animals. MAG/NF200 staining demonstrated reduced myelination and axonal counts in the corpus callosum of IUGR animals. NeuN staining revealed changes in neuronal density in the hippocampus and in the thickness of hippocampal CA2 and CA3 regions. Diffusion weighted imaging (DWI) revealed regional white and grey matter changes at 3 weeks of age. Furthermore, neurobehavioural testing demonstrated neuromotor impairments in animals with IUGR in paw intensities, swing speed, relative print positions, and phase dispersions. CONCLUSIONS: We have characterized a rodent model of IUGR and have demonstrated that the neuroanatomical and neurobehavioural deficits mirror the severity of the IUGR injury. This model has the potential to be applied to examine the pathobiology of and potential therapeutic strategies for IUGR-related brain injury. Thus, this work has potential translational relevance for the study of CP.

Systemic pro-inflammatory cytokine status following therapeutic hypothermia in a piglet hypoxia-ischemia model.

BACKGROUND: Inflammatory cytokines are implicated in the pathogenesis of perinatal hypoxia-ischemia (HI). The influence of hypothermia (HT) on cytokines after HI is unclear. Our aim was to assess in a piglet asphyxia model, under normothermic (NT) and HT conditions: (i) the evolution of serum cytokines over 48 h and (ii) cerebrospinal fluid (CSF) cytokine levels at 48 h; (iii) serum pro/anti-inflammatory cytokine profile over 48 h and (iv) relation between brain injury measured by magnetic resonance spectroscopy (MRS) and brain TUNEL positive cells with serum cytokines, serum pro/anti-inflammatory cytokines and CSF cytokines. METHODS: Newborn piglets were randomized to NT (n = 5) or HT (n = 6) lasting 2-26 h after HI. Serum samples were obtained 4-6 h before, during and at 6-12 h intervals after HI; CSF was obtained at 48 h. Concentrations of interleukin (IL)-1ß, -4, -6, -8, -10 and TNF-α were measured and pro/anti-inflammatory status compared between groups. White matter and thalamic voxel lactate/N-acetyl aspartate (Lac/NAA) (a measure of both oxidative metabolism and neuronal loss) were acquired at baseline, after HI and at 24 and 36 h. RESULTS: Lac/NAA was reduced at 36 h with HT compared to NT (p = 0.013 basal ganglia and p = 0.033 white matter). HT showed lower serum TNF-α from baseline to 12 h (p < 0.05). Time-matched (acquired within 5 h of each other) serum cytokine and MRS showed correlations between Lac/NAA and serum IL-1ß and IL-10 (all p < 0.01). The pro/anti-inflammatory ratios IL-1ß/IL-10, IL-6/IL-10, IL-4/IL-10 and IL-8/IL-10 were similar in NT and HT groups until 36 h (24 h for IL-6/IL-10); after this, 36 h pro/anti-inflammatory cytokine ratios in the serum were higher in HT compared to NT (p < 0.05), indicating a pro-inflammatory cytokine surge after rewarming in the HT group. In the CSF at 48 h, IL-8 was lower in the HT group (p < 0.05). At 48 h, CSF TNF-α correlated with Lac/NAA (p = 0.02) and CSF IL-8 correlated with white matter TUNEL positive cell death (p = 0.04). CONCLUSIONS: Following cerebral HI, there was a systemic pro-inflammatory surge after rewarming in the HT group, which is counterintuitive to the putative neuroprotective effects of HT. While serum cytokines were variable, elevations in CSF inflammatory cytokines at 48 h were associated with MRS Lac/NAA and white matter cell death.

Brain cell death is reduced with cooling by 3.5°C to 5°C but increased with cooling by 8.5°C in a piglet asphyxia model.

BACKGROUND AND PURPOSE: In infants with moderate to severe neonatal encephalopathy, whole-body cooling at 33°C to 34°C for 72 hours is standard care with a number needed to treat to prevent a adverse outcome of 6 to 7. The precise brain temperature providing optimal neuroprotection is unknown. METHODS: After a quantified global cerebral hypoxic-ischemic insult, 28 piglets aged <24 hours were randomized (each group, n=7) to (1) normothermia (38.5°C throughout) or whole-body cooling 2 to 26 hours after insult to (2) 35°C, (3) 33.5°C, or (4) 30°C. At 48 hours after hypoxia-ischemia, delayed cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and cleaved caspase 3) and microglial ramification (ionized calcium-binding adapter molecule 1) were evaluated. RESULTS: At 48 hours after hypoxia-ischemia, substantial cerebral injury was found in the normothermia and 30°C hypothermia groups. However, with 35°C and 33.5°C cooling, a clear reduction in delayed cell death and microglial activation was observed in most brain regions (P<0.05), with no differences between 35°C and 33.5°C cooling groups. A protective pattern was observed, with U-shaped temperature dependence in delayed cell death in periventricular white matter, caudate nucleus, putamen, hippocampus, and thalamus. A microglial activation pattern was also seen, with inverted U-shaped temperature dependence in periventricular white matter, caudate nucleus, internal capsule, and hippocampus (all P<0.05). CONCLUSIONS: Cooling to 35°C (an absolute drop of 3.5°C as in therapeutic hypothermia protocols) or to 33.5°C provided protection in most brain regions after a cerebral hypoxic-ischemic insult in the newborn piglet. Although the relatively wide therapeutic range of a 3.5°C to 5°C drop in temperature reassured, overcooling (an 8.5°C drop) was clearly detrimental in some brain regions.

Adult-derived pluripotent stem cells.

The global incidence of spinal cord injury (SCI) is 15-40 cases per million people, with the socioeconomic and healthcare costs amounting to nearly $10 billion per annum in the USA alone. Despite substantial advances in medical care and surgical technology, many patients with SCI still experience significant long-term neurologic disability. Cellular transplantation offers a promising therapy to address the multifactorial nature of SCI in both the subacute and chronic phase of the injury to promote central nervous system repair and regeneration and to augment existing therapies. Adult-derived stem cells are the least ethically challenging stem cells but, until recently, a major hurdle has been inducing pluripotency to generate the required neural lineages. Improved generation and transfection techniques, combined with positive experimental outcomes in SCI models, suggest that adult-derived induced pluripotent stem cells could be a genuine alternative to embryonic stem cells for clinical treatments. For translation from bench to bedside, the efficacy of induced pluripotent stem cell-derived neural stem and progenitor cells in suitable SCI models needs to be validated further and backed up with rigorous early-stage clinical trials.

Comparison of three hypothermic target temperatures for the treatment of hypoxic ischemia: mRNA level responses of eight genes in the piglet brain.

Hypothermia can reduce neurodevelopmental disabilities in asphyxiated newborn infants. However, the optimal cooling temperature for neuroprotection is not well defined. We studied the effects of transient piglet brain hypoxic ischemia (HI) on transcriptional activity of eight genes and if mRNA level alterations could be counteracted by whole body cooling to 35, 33.5 or 30 °C. BDNF mRNA was globally upregulated by the insult, and none of the cooling temperatures counteracted this change. In contrast, MANF mRNA was downregulated, and these changes were modestly counteracted in different brain regions by hypothermic treatment at 33.5 °C, while 30 °C aggravated the MANF mRNA loss. MAP2 mRNA was markedly downregulated in all brain regions except striatum, and cooling to 33.5 °C modestly counteract this downregulation in the cortex cerebri. There was a tendency for GFAP mRNA levels in core, but not mantle regions to be downregulated and for these changes to be modestly counteracted by cooling to 33.5 or 35 °C. Cooling to 30 °C caused global GFAP mRNA decrease. HSP70 mRNA tended to become upregulated by HI and to be more pronounced in cortex and CA1 of hippocampus during cooling to 33.5 °C. We conclude that HI causes alterations of mRNA levels of many genes in superficial and deep piglet brain areas. Some of these changes may be beneficial, others detrimental, and lowering body temperature partly counteracts some, but not all changes. There may be general differences between core and mantle regions, as well as between the different cooling temperatures for protection. Comparing the three studied temperatures, cooling to 33.5 °C, appears to provide the best cooling temperature compromise.

The potential for stem cells in cerebral palsy--piecing together the puzzle.

The substantial socioeconomic burden of a diagnosis of cerebral palsy, coupled with a positive anecdotal and media spin on stem cell treatments, drives many affected families to seek information and treatment outside of the current clinical and scientific realm. Preclinical studies using several types of stem and adult cells--including mesenchymal stem cells, neural precursor cells, olfactory ensheathing glia and Schwann cells--have demonstrated some regenerative and functional efficacy in neurologic paradigms. This paper describes the most common cell types investigated for transplant in vivo and summarizes the current state of early-phase clinical trials. It investigates the most relevant and promising coadministered therapies, including rehabilitation, drug targeting, magnetic stimulation, and bioengineering approaches. We highlight the need for adjunctive combinatorial strategies to successfully transfer stem cell treatments from bench to bedside.

The potential for stem cell therapies to have an impact on cerebral palsy: opportunities and limitations.

Cerebral palsy (CP) is a chronic childhood disorder described by a group of motor and cognitive impairments and results in a substantial socio-economic burden to the individual, family, and healthcare system. With no effective biological interventions, therapies for CP are currently restricted to supportive and management strategies. Cellular transplantation has been suggested as a putative intervention for neural pathology, as mesenchymal and neural stem cells, as well as olfactory ensheathing glia and Schwann cells, have shown some regenerative and functional efficacy in experimental central nervous system disorders. This review describes the most common cell types investigated and delineates their purported mechanisms in vivo. Furthermore, it provides a cogent summary of both current early-phase clinical trials using neural precursor cells (NPCs) and the state of stem cell therapies for neurodegenerative conditions. Although NPCs are perhaps the most promising candidates for cell replacement therapy in the context of CP, much still remains to be understood regarding safety, efficacy, timing, dose, and route of transplantation, as well as the capacity for combinatorial strategies.

Methyl-isobutyl amiloride reduces brain Lac/NAA, cell death and microglial activation in a perinatal asphyxia model.

Na⁺/H⁺ exchanger (NHE) blockade attenuates the detrimental consequences of ischaemia and reperfusion in myocardium and brain in adult and neonatal animal studies. Our aim was to use magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry to investigate the cerebral effects of the NHE inhibitor, methyl isobutyl amiloride (MIA) given after severe perinatal asphyxia in the piglet. Eighteen male piglets (aged < 24 h) underwent transient global cerebral hypoxia-ischaemia and were randomized to (i) saline placebo; or (ii) 3 mg/kg intravenous MIA administered 10 min post-insult and 8 hourly thereafter. Serial phosphorus-31 (³¹P) and proton (¹H) MRS data were acquired before, during and up to 48 h after hypoxia-ischaemia and metabolite-ratio time-series Area under the Curve (AUC) calculated. At 48 h, histological and immunohistochemical assessments quantified regional tissue injury. MIA decreased thalamic lactate/N-acetylaspartate and lactate/creatine AUCs (both p < 0.05) compared with placebo. Correlating with improved cerebral energy metabolism, transferase mediated biotinylated d-UTP nick end-labelling (TUNEL) positive cell density was reduced in the MIA group in cerebral cortex, thalamus and white matter (all p < 0.05) and caspase 3 immunoreactive cells were reduced in pyriform cortex and caudate nucleus (both p < 0.05). Microglial activation was reduced in pyriform and midtemporal cortex (both p < 0.05). Treatment with MIA starting 10 min after hypoxia-ischaemia was neuroprotective in this perinatal asphyxia model.

Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model.

Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain (31)P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic-induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain (31)P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.