David J. Heslop

Noxious activation of spinal or vagal afferents evokes distinct patterns of fos-like immunoreactivity in the ventrolateral periaqueductal gray of unanaesthetised rats

The consequences of a severe traumatic injury--deep pain and haemorrhage--usually evoke a passive emotional coping reaction characterised by: quiescence and immobility, decreased vigilance, hypotension and bradycardia. Results of studies utilising microinjections of excitatory amino acids suggest that passive coping reactions are mediated, at least in part, by activation of the midbrain, ventrolateral periaqueductal gray (vlPAG) region. Further, experiments in anaesthetised rats, using the expression of the immediate-early gene, c-fos, as a marker of neuronal activation, report that pain arising from muscles, joints or viscera selectively activates the vlPAG. Anaesthesia alone, however, evokes substantial Fos-like immunoreactivity (IR) within the vlPAG and this may have obscured any differences in patterns of Fos expression following noxious deep somatic versus noxious visceral activation. In these experiments, in unanaesthetised rats, the effects of noxious spinal versus noxious vagal primary afferent activation were re-examined and distinct rostrocaudal patterns of Fos-expression were observed. Specifically: (i) injection of algesic substances into muscle, which preferentially activates spinal afferents, evoked Fos expression predominantly within the caudal vlPAG; whereas, (ii) noxious manipulations whose effects are mediated by (cardiopulmonary) vagal activation evoked preferential Fos-expression within the rostral vlPAG. On the other hand, hypotensive haemorrhage evoked substantial Fos expression along the entire rostrocaudal extent of the vlPAG, a finding which fits with suggestions that haemorrhagic shock is triggered by a combination of: (i) spinally-relayed nociceptive signals originating from ischaemic tissue, and (ii) vagally-relayed signals reflecting poor cardiac filling.

Haemorrhage-evoked compensation and decompensation are mediated by distinct caudal midline medullary regions in the urethane-anaesthetised rat

Previous research using microinjections of excitatory amino acids suggested that the caudal midline medulla (including nucleus raphe obscurus and nucleus raphe pallidus) contained a mixed population of sympathoexcitatory and sympathoinhibitory neurones. The results of this study indicate that different anaesthetic regimes (urethane versus halothane) determine whether sympathoexcitatory (urethane only) or sympathoinhibitory (halothane only) responses are evoked by stimulation within distinct caudal midline medullary regions. In addition, anaesthetic regimes also affect the caudal midline medullary-mediated response to haemorrhage. Specifically, under conditions of urethane anaesthesia, inactivation (lignocaine) of the midline medullary region immediately caudal to the obex, prematurely triggered and dramatically potentiated the hypotension and bradycardia evoked by 15% haemorrhage; whereas under halothane anaesthesia, inactivation of the same region had no effect. In contrast, under urethane anaesthesia, inactivation of the midline medullary region immediately rostral to the obex, delayed the onset of the hypotension and bradycardia to 15% haemorrhage; inactivation of the same region under halothane anaesthesia blocked haemorrhage-evoked hypotension and bradycardia. Our findings indicate that topographically distinct parts of the caudal midline medulla contain neurones (i) that differentially regulate the timing and magnitude of the compensatory (normotensive) versus decompensatory (hypotensive) phases of the response to haemorrhage; and (ii) whose activity is altered by urethane versus halothane anaesthesia.

Haemorrhage‐evoked decompensation and recompensation mediated by distinct projections from rostral and caudal midline medulla in the rat

The haemodynamic response to blood loss consists of three phases: (i) an initial compensatory phase during which resting arterial pressure is maintained; (ii) a decompensatory phase characterized by a sudden, life‐threatening hypotension and bradycardia; and (iii) if blood loss ceases, a recompensatory phase during which arterial pressure returns to normal. Previous research indicates that topographically distinct, rostral and caudal parts of the caudal midline medulla (CMM) contain neurons that differentially regulate the timing and magnitude of each of the three phases. Specifically, decompensation depends critically on the integrity of the rostral CMM; whereas compensation and recompensation depend upon the integrity of the caudal CMM. This study aimed to determine, using retrograde and anterograde tracing techniques, if the rostral and caudal CMM gave rise to different sets of projections to the major cardiovascular region of the ventrolateral medulla (VLM) and spinal cord. It was found that rostral and caudal CMM each have projections of varying density to the region containing bulbospinal (presympathetic) motor neurons in the rostral VLM and preganglionic sympathetic motor neurons in the intermediolateral cell column of the spinal cord. Via these projections vasomotor tone and hence arterial pressure can be regulated. More strikingly: (i) consistent with a role in mediating bradycardia during decompensation, the rostral CMM projects uniquely to VLM regions containing vagal cardiac motor neurons; and (ii) consistent with its role in mediating recompensation, the caudal CMM projects uniquely onto tyrosine hydroxylase‐containing, caudal VLM (A1) neurons whose activity mediates vasopressin release, on which recompensation depends.

Does Zika Virus Cause Microcephaly - Applying the Bradford Hill Viewpoints

Introduction: Zika virus has been documented since 1952, but been associated with mild, self-limiting disease. Zika virus is classified as an arbovirus from a family of Flaviviridae and primarily spread by Aedes Aegypti mosquitos. However, in a large outbreak in Brazil in 2015, Zika virus has been associated with microcephaly. Methods: In this review we applied the Bradford-Hill viewpoints to investigate the association between Zika virus and microcephaly. We examined historical studies, available data and also compared historical rates of microcephaly prior to the Zika virus outbreak. The available evidence was reviewed against the Bradford Hill viewpoints. Results: All the nine criteria were met to varying degrees: strength of association, consistency of the association, specificity, temporality, plausibility, coherence, experimental evidence, biological gradient and analogy. Conclusion: Using the Bradford Hill Viewpoints as an evaluation framework for causation is highly suggestive that the association between Zika virus and microcephaly is causal. Further studies using animal models on the viewpoints which were not as strongly fulfilled would be helpful.

Translation of Real-Time Infectious Disease Modeling into Routine Public Health Practice

Infectious disease dynamic modeling can support outbreak emergency responses. We conducted a workshop to canvas the needs of stakeholders in Australia for practical, real-time modeling tools for infectious disease emergencies. The workshop was attended by 29 participants who represented government, defense, general practice, and academia stakeholders. We found that modeling is underused in Australia and its potential is poorly understood by practitioners involved in epidemic responses. The development of better modeling tools is desired. Ideal modeling tools for operational use would be easy to use, clearly indicate underlying parameterization and assumptions, and assist with policy and decision making.

Converging and emerging threats to health security

Advances in biological sciences have outpaced regulatory and legal frameworks for biosecurity. Simultaneously, there has been a convergence of scientific disciplines such as synthetic biology, data science, advanced computing and many other technologies, which all have applications in health. For example, advances in cybercrime methods have created ransomware attacks on hospitals, which can cripple health systems and threaten human life. New kinds of biological weapons which fall outside of traditional Cold War era thinking can be created synthetically using genetic code. These convergent trajectories are dramatically expanding the repertoire of methods which can be used for benefit or harm. We describe a new risk landscape for which there are few precedents, and where regulation and mitigation are a challenge. Rapidly evolving patterns of technology convergence and proliferation of dual-use risks expose inadequate societal preparedness. We outline examples in the areas of biological weapons, antimicrobial resistance, laboratory security and cybersecurity in health care. New challenges in health security such as precision harm in medicine can no longer be addressed within the isolated vertical silo of health, but require cross-disciplinary solutions from other fields. Nor can they cannot be managed effectively by individual countries. We outline the case for new cross-disciplinary approaches in risk analysis to an altered risk landscape.

Publicly available software tools for decision-makers during an emergent epidemic—Systematic evaluation of utility and usability

Epidemics and emerging infectious diseases are becoming an increasing threat to global populations-challenging public health practitioners, decision makers and researchers to plan, prepare, identify and respond to outbreaks in near real-timeframes. The aim of this research is to evaluate the range of public domain and freely available software epidemic modelling tools. Twenty freely utilisable software tools underwent assessment of software usability, utility and key functionalities. Stochastic and agent based tools were found to be highly flexible, adaptable, had high utility and many features, but low usability. Deterministic tools were highly usable with average to good levels of utility.

Addressing unwarranted clinical variation: A rapid review of current evidence

INTRODUCTION Unwarranted clinical variation (UCV) can be described as variation that can only be explained by differences in health system performance. There is a lack of clarity regarding how to define and identify UCV and, once identified, to determine whether it is sufficiently problematic to warrant action. As such, the implementation of systemic approaches to reducing UCV is challenging. A review of approaches to understand, identify, and address UCV was undertaken to determine how conceptual and theoretical frameworks currently attempt to define UCV, the approaches used to identify UCV, and the evidence of their effectiveness. DESIGN Rapid evidence assessment (REA) methodology was used. DATA SOURCES A range of text words, synonyms, and subject headings were developed for the major concepts of unwarranted clinical variation, standards (and deviation from these standards), and health care environment. Two electronic databases (Medline and Pubmed) were searched from January 2006 to April 2017, in addition to hand searching of relevant journals, reference lists, and grey literature. DATA SYNTHESIS Results were merged using reference-management software (Endnote) and duplicates removed. Inclusion criteria were independently applied to potentially relevant articles by 3 reviewers. Findings were presented in a narrative synthesis to highlight key concepts addressed in the published literature. RESULTS A total of 48 relevant publications were included in the review; 21 articles were identified as eligible from the database search, 4 from hand searching published work and 23 from the grey literature. The search process highlighted the voluminous literature reporting clinical variation internationally; yet, there is a dearth of evidence regarding systematic approaches to identifying or addressing UCV. CONCLUSION Wennbergs classification framework is commonly cited in relation to classifying variation, but no single approach is agreed upon to systematically explore and address UCV. The instances of UCV that warrant investigation and action are largely determined at a systems level currently, and stakeholder engagement in this process is limited. Lack of consensus on an evidence-based definition for UCV remains a substantial barrier to progress in this field.