Pain permeates childhood and remains inadequately and/or inconsistently managed. Existing research and clinical practice guidelines have largely focused on factors influencing the immediate experience of pain. The need for and benefits of preparing children for future pain  has been well established. Despite being a robust predictor of future pain and distress, memories of past painful experiences remain overlooked in pediatric pain management. Just as autobiographical memories prepare us for the future, children’s memories for past pain can be harnessed to prepare children for future painful experiences. Children’s pain memories are malleable and can be reframed to be less distressing, thus reducing anticipatory distress and promoting self-efficacy. Parents are powerful agents of change in the context of pediatric pain and valuable historians of children’s past painful experiences. They can alter children’s pain memories to be less distressing simply by talking, or reminiscing, about past pain. This narrative review summarizes existing research on parent–child reminiscing in the context of acute and chronic pediatric pain and argues for incorporation of parent–child reminiscing elements into preparatory interventions for painful procedures. Pain is an inherent part of childhood. From birth, as a part of standard healthcare, children undergo numerous painful procedures . The World Health Organization recommends that all children receive 10 or more routine immunizations by the age of 1 year . Pediatrimmediate experience of pain. Clinical interventions mirror this trend and guide the management of the child’s immediate pain experience. For example, the clinical practice guidelines on pain mitigation during vaccine injections recommends the “5P” approach , where most of the techniques focus on pain during vaccinations [There has been notable progress in pediatric pain management. Yet pediatric pain remains inadequately and/or inconsistently managed . Existininations .past pain robustly predicts future distress and pain [The importance of addressing future pain before it occurs  has been well established . Preparaand pain ,12, suchand pain ,14 for hand pain . Thus, cParents impact children’s pain experiences and can play an active role in reducing pain and distress before, during, and after painful experiences. Although current clinical practice guidelines  recommenThis narrative review argues for incorporating parent–child reminiscing into preparatory interventions. Following a brief overview of conceptual models of preparation and information provision, as well as a review of the malleability of children’s memories for pain and parent–child reminiscing about past pain, the current paper elaborates on the benefits and risks of parent–child reminiscing as used in preparing children for painful procedures in the context of acute  pain. This review also summarizes the available evidence of children’s memories for and parent–child reminiscing about pediatric chronic pain, as well as the applicability of reminiscing-enhanced preparation in the context of pediatric chronic pain. We conclude the review with a future research agenda to examine the efficacy of parent–child reminiscing in preparatory interventions.and are easy to implement in healthcare settings. Preparatory interventions for painful procedures reduce children’s levels of pre-procedural distress as well as their level of experienced pain [Information provision and preparation of children for painful procedures are guided by two key goals: (1) to provide children with information about the procedure; (2) to teach or remind children about effective coping skills . Prepariced pain ,25,26.Central to understanding the merit of preparation and information provision is the concept of self-regulation, or one’s ability plan and adapt one’s behavior to reach an optimal outcome . Self-reFor young children, the development of self-regulation is non-linear and undergoes critical changes in early childhood  . Young cstressful future events, Miller [Another key aspect to consider is the degree of predictability that contributes to the individual’s self-efficacy, or one’s belief that they are able to deal with the situation. With regards to , Miller  highlighThe role of past experiences in preparation for future events is complemented by schema theories. Past experiences are crystallized into schemata, or general frameworks, that organize and store memories . PreparaJaaniste and colleagues combined the self-regulation and schema theories into the Information Provision Theory that details how preparatory information interacts with children’s past experiences to change the appraisal of, and reactions to, future medical procedures . AccordiIn summary, past experiences and associated memories play a key role in preparing children for future painful procedures. Preparation relies on coping and emotion regulation skills that children have learned and practiced in the past. Information provision and preparation activate children’s health- and pain-related schemata; yet those schemata may be negatively altered by previous experiences and need to be changed to be less distressing. Thus, preparing children for future pain should necessarily consider past pain and memories for it. Yet, existing preparatory interventions have not targeted children’s memories for past experiences, nor have they harnessed the malleable nature of autobiographical memories. In the next sections, we review key factors that shape children’s memories for pain and elaborate on how parent–child reminiscing can be used to alter those memories and interact with preparatory information to reduce children’s pain-related distress.Poorly managed acute pain is long remembered and results in an array of detrimental sequelae. For instance, 3-year-old children remembered their visit to an emergency department following an injury up to 10 years later . ChildreMemory biases are defined as higher  or lower  levels of recalled pain as compared to initial/earlier reports. For young children, recall of acute experimental pain has been demonstrated to be a more robust predictor of future pain intensity as compared to the initial pain report . NegativThe social factors influencing pain and memories for pain are a subject of an emerging, timely, and provocative discussion in the pain community. The social aspects of the pain experience have only recently been added as a note to the revised International Association for the Study of Pain definition of pain  . AlthougThe broader field of developmental psychology has long demonstrated the pivotal role that parent–child reminiscing plays in children’s developmental trajectories. These parent–child narrative exchanges about past autobiographical pleasant and/or distressing events create a unique and influential milieu that allows children to share their recollection of past events and co-construct a meaningful and coherent account of the past together with their parents. Indeed, as Eric Kandel put it, “Recall of memory is a creative process. What the brain stores is thought to be only a core memory. Upon recall, this core memory is then elaborated upon, reconstructed, with subtractions, additions, elaborations, and distortions” . Basic aParent–child reminiscing shapes children’s autobiographical memory development. Young children of mothers who reminisced with them using open-ended questions containing novel emotion-rich details  demonstrated better developed autobiographical memory skills at 3.5 years of age  ,60. ElabA substantial amount of reminiscing research has focused on children’s memories of positive events . Yet it is parent–child reminiscing about past distressing events  that is particularly powerful and beneficial . As distWhile implicit memories  can be formed from birth, it is the explicit memory system  that expands dramatically during the toddler and preschool years. Starting from the age of 3 years, children are rapidly developing the cognitive and verbal capacities that are needed to form, elicit, and discuss explicit memories of past pain. The first pain-related words  appear in vocabularies of 17–18-month-old children; the pain vocabulary expands and develops during preschool years . PreschoAn emerging body of research has demonstrated the unique characteristics of parent–child reminiscing about past pain and its role in the development of children’s memories for pain. A recent observational study of preschool-aged children who underwent an outpatient surgery  demonstrated distinctive patterns of parent–child reminiscing about past painful versus sad events. When discussing the surgery versus a sad event, parents used reminiscing elements that characterized a topic-switching  reminiscing style. Specifically, parents used fewer explanations, open-ended questions containing new details, and words associated with negative emotions . These rTo date, there has been only one study investigating the role of parent–child reminiscing about past painful events and children’s pain memory biases . Young cThe parent reminiscing style is malleable and can be changed using simple narrative interventions. For example, parents of young children were taught to reminisce using more open-ended questions and emotion-rich language . Their cJust as parent–child reminiscing is malleable, so too are young children’s memories for pain. Given the critical importance of biased pain memories in children’s future pain trajectories  , there hMemory reframing can serve to reduce children’s anticipatory distress. Yet, only one of the memory reframing interventions addressed its influence on future pain-related distress. Chen and colleagues measured the effect of their memory reframing intervention on the levels of children’s anticipatory distress in the context of repeated lumbar punctures for cancer treatment . ChildreTo date, memory reframing interventions have all been conducted by adult researchers. Parents, who are powerful, yet underutilized, agents of change and valuable historians in the context of children’s memories, have not yet been involved in the delivery of memory reframing interventions . The onlIt is important to consider individual differences that influence children’s memories for pain. As posited by cognitive theories, anxiety and anxiety-related constructs play a pivotal role in development of memory biases, such that individuals with higher levels of anxiety preferentially attend and recall threatening information . For exaAs outlined in the sections above, preparing children for future painful events necessarily relies on their memories for past pain that are malleable, susceptible to distortions, and can be altered to be less distressing. One way of altering children’s memories for pain is by reminiscing with them about past painful events and highlighting positive aspects of the experience, helping them re-appraise any distressing and/or negatively biased memories, and reminding them about coping strategies they used to increase self-efficacy. Parent–child reminiscing about past pain can be readily incorporated in preparatory interventions and enhance specific aspects of the interventions.First, an elaborative parent reminiscing style  may refine and add to children’s existing pain-related schemata. Children who are distressed during painful procedures remember fewer details about the procedure . FurtherSecond, young children may shift their self-regulation from higher-order cognitive to emotion regulation strategies. A stranger  providing information to a young patient may not pick up on the child’s distress and/or the need for emotion regulation. The elaborative reminiscing style has been linked to children’s better-developed emotion regulation skills . EmotionThird, parent–child reminiscing promotes parents’ involvement in pediatric pain management. Parents are highly capable and efficacious preparatory interventionists . The priParent–child reminiscing should be implemented in preparatory interventions with a degree of caution. First, when talking about past pain, parents tend to use the elements of the topic-switching reminiscing style  . Repeateaccurate sensory information . At times, expected levels of pain may be moderate to severe, yet a child may have an inaccurate estimation of the expected pain, particularly in cases of novel procedures [and children who expected low levels of pain adjusted their expected pain to moderate) [Another factor to consider is a potential incongruence between the degree of pain that the child expects, based on reminiscing, and their actual experiences during a procedure. A key part of preparatory interventions is the provision of ocedures . In a troderate) . Furtheroderate) . It is aoderate) , parentsFinally, schemata theories posit that using pain-related words may activate children’s pain-related schemata, such that children may be expecting, and preferentially attending to, pain and pain-related stimuli in the environment. A recent study demonstrated that frequent use of pain-related words when reminiscing about past post-surgical pain resulted in children remembering their pain in a negatively biased way . Thus, wThis area of inquiry is ripe for future empirical investigation and clinical innovation. The research agenda is to examine several aspects of incorporating parent–child reminiscing into preparatory interventions. First, pilot trials need to assess the feasibility and acceptability of including parent–child reminiscing into preparation for painful procedures in healthcare and community  settings. Comparative efficacy trials should investigate whether reminiscing-enhanced preparation is superior to preparation alone. Research should also examine the efficacy and comparative effectiveness of differently timed and combined interventions. For example, it could be that reminiscing after a painful procedure combined with reminiscing before the next painful procedure is more effective than reminiscing just before or just after the procedure alone. We would hypothesize that a combination of repeated reminiscing and provision of preparatory information would result in the greatest decreases in procedural pain.Second, preparatory interventions often involve various media . In addition to reminiscing principles, existing memory reframing interventions use visual tokens to remind children about their coping skills and self-efficacy  and child sex differences as potential moderators in reminiscing-enhanced preparation. Information provision trials have not reported any differences in response to the intervention as a function of child sex. There are potential differences between fathers and mothers regarding information provision. Males focus on and engage in information-based communication, whereas females focus on providing emotional support ,86. FurtFuture research should examine other potential moderators of reminiscing-enhanced preparatory interventions. Individual differences that are influential in the formation of pain memories and cognitive schemata about pain are likely to impact the efficacy of reminiscing-enhanced interventions. Children who tend to develop negatively biased memories for pain may benefit more from the combination of memory reframing reminiscing and information provision, as compared to children with accurate or positively biased pain memories. Children with high levels of anxiety-related constructs  may develop distressing pain memories that are resistant to change as a result of one instance of reminiscing, and a preparatory intervention may trigger those distressing pain memories, leading to anticipatory distress. These children may benefit from repeated reminiscing interventions in combination with reminiscing-enhanced preparation to alter anxiety-driven distressing memories. For children with low levels of self-efficacy, reminiscing about past pain and preparation for future procedures will likely need to repeatedly emphasize and enhance their pain-related self-efficacy .A prominent area of future research concerns the use of parent–child reminiscing in the context of pediatric chronic pain and preparation of youth living with chronic pain for painful exercises and procedures. The role, origin, and prognostic value of pain memories in the context of primary pain disorders  is unclear. The existing studies of memory in the context of pediatric chronic pain utilized methods from acute pain memory research  and focused on the accuracy of and biases in pain recall ,88,89). Reminiscing also has the potential to improve care through novel intervention strategies. For example, reminiscing may be used to encourage participation in nonpharmacologic treatments for chronic pain. Physiotherapy and exercise therapy are among the most effective nonpharmacological strategies for managing pediatric chronic pain and are a key component of multidisciplinary rehabilitation programs . HoweverPreparation and information provision in the context of pediatric pain is a burgeoning area of inquiry that has contributed to, and holds enormous potential to enhance, pediatric pain management. To date, preparation of children for painful procedures has focused on the management of initial expectations, refinement of and adjusting existing health- and pain-related schemata, and modifying appraisals of future pain procedures. The existing preparatory interventions have not yet utilized or targeted children’s past experiences and past learning, which forms the basis for children’s pain-specific expectations and schemas. Only a few preparation techniques involve parents, who are underutilized agents and overlooked stakeholders in the pediatric pain context. Parent–child reminiscing about past painful experiences represents a unique ready-to-implement preparatory intervention technique. Parent–child reminiscing about past pain has unharnessed potential to remind children about positive aspects of their past painful experiences, highlight the most effective coping skills that children and/or parents used in the past, and reframe any negatively biased or distressing memories for past pain that children may have. Needle procedures are a prime context to apply the principles of parent–child reminiscing as a preparatory intervention. Nearly every child has experienced needle-related pain; therefore, parents can reminisce with their children about past needle procedures at any point and reframe any negatively biased memories and, in doing so, parents can prepare their children for future needle procedures. Novel painful procedures  may require more generalized reminiscing about past pain with a focus on coping strategies and children’s pain-specific self-efficacy. By fostering self-efficacy and accurate and positive memories, this simple language-based intervention holds potential for not only improving future pain experiences but also reducing avoidance of healthcare and vaccine hesitancy. In the context of pediatric chronic pain, reminiscing may increase a youth’s willingness and readiness to engage in therapeutic yet painful interventions  and activities of daily living. Thus, parent–child reminiscing creates a safe and empowering context for children to face and deal with future pain and pain-related distress and, hopefully, for them to experience pain and distress to a lesser degree.


New therapeutic strategies and paradigms are direly needed for the treatment of cancer. While the surgical removal of tumors is favored in most cancer treatment plans, resection options are often limited based on tumor localization. Over the last two decades, multiple tumor ablation strategies have emerged as promising stand-alone or combination therapeutic options for patients. These strategies are often employed to treat tumors in areas where surgical resection is not possible or where chemotherapeutics have proven ineffective. The type of cell death induced by the ablation modality is a critical aspect of therapeutic success that can impact the efficacy of the treatment and systemic anti-tumor immune system responses. Electroporation-based ablation technologies include electrochemotherapy, irreversible electroporation, and other modalities that rely on pulsed electric fields to create pores in cell membranes. These pores can either be reversible or irreversible depending on the electric field parameters and can induce cell death either alone or in combination with a therapeutic agent. However, there have been many controversial findings among these technologies as to the cell death type initiated, from apoptosis to pyroptosis. As cell death mechanisms can impact treatment side effects and efficacy, we review the main types of cell death induced by electroporation-based treatments and summarize the impact of these mechanisms on treatment response. We also discuss potential reasons behind the variability of findings such as the similarities between cell death pathways, differences between cell-types, and the variation in electric field strength across the treatment area. Despite improvements in survival and quality of life provided by current therapeutic practices, cancer death rates remain unacceptably high . New treExtensive investigations have explored the mechanisms underlying cell death induced by pore formation and homeostasis loss following electroporation-based tumor ablation treatments , 12. HowCell death can diverge into many pathways, eliciting a large range of responses . Each paApoptosis is one of the most commonly mentioned forms of cell death in electroporation-based ablations –28. GeneNecrosis lies opposite of apoptosis and involves rapid cell death. Necrosis is typically induced by sudden loss in cell homeostasis, such as rapid osmolarity or temperature changes, influx of calcium into the cell or mitochondrial spaces, or mechanical tissue damages that can lead to autolysis . It shouNecrosis is often referred to as accidental or lytic cell death and is characterized by the breakdown of the cell membrane and the release of large amounts of damage-associated molecular patterns (DAMPs) , 41. FurPyroptosis is one of twelve identified subclasses of regulated cell death and displays high local inflammatory responses distinct from necrosis . TraditiIn addition to pyroptosis, a fourth major regulated cell death routine termed necroptosis has also been described following irreversible electroporation. Necroptosis is also termed programmed necrosis or alternative necrosis and has features characteristic to both apoptosis and necrosis. Necroptosis is triggered by perturbations of extracellular or intracellular homeostasis and does not induce a quick, automatic lysis of the cell . Rather,ECT was one of the first electroporation-based modalities to progress to clinical trials and is routinely used in Europe for cutaneous malignancies at over 150 centers –67. ECT Expanding on ECT strategies, the use of calcium represents another option to this treatment strategy. Calcium electroporation enhances necrosis in the treatment zone and its application can forgo or reduce the use of chemotherapeutics and avoid some chemotherapy side effects , 80. TheIRE utilizes microsecond pulse electric fields, similar to ECT, but for a higher pulse count. This higher pulse count results in pores and tears forming in the cell membrane that stabilize, leading to loss of cell homeostasis and initiating cell death processes , 88. Thein vitro at comparable electric field magnitudes  utilizes 1–10 μs bipolar bursts applied in a pattern with interpulse delay when switching poles. These parameters are highly effective in non-thermally ablating tissues without causing the muscle contractions and heart dysrhythmia associated with the long-duration monophasic pulses of IRE , 109–112 signals . These din vivo findings provide greater mechanistic insight into the types of cell death induced by nsPEFs (Nanosecond pulse electric fields (nsPEFs) are characterized by PEFs with short nanosecond pulse durations and high electric fields. Originally, nsPEFs were thought not to permeabilize the cell membrane but rather induce cell death by interfering with molecular patterns inside the cell, disrupting processes in the mitochondria, and other intracellular membrane-bound organelles . Howevery nsPEFs –120. Basy nsPEFs –120.As electroporation ablation modalities become more mainstream and progress from preclinical studies to clinical applications, characterization of specific cell death mechanisms associated with treatment will become more relevant. The type of cell death has significant consequences for the patient's treatment outcomes, immune system activation, regeneration and repair processes, and co-therapy applications. Seemingly conflicting reports on cell death mechanisms ranging from apoptosis to necrosis and pyroptosis has led to confusion in the field. However, these data suggest that cell death following electroporation may be dependent on electric field and cell type, and that multiple cell death mechanisms could occur within the treatment zone. While studies investigating the effects of related cell lines with varying morphology suggest that cells with larger nuclei are more likely to be affected by H-FIRE, whether these findings are consistent among different electroporation modalities remains to be seen , 15. It RB, NB-W, RD, and IA contributed to the writing and editing of the manuscript. All authors contributed to the article and approved the submitted version.IA, NB-W, and RD are inventors on pending and issued patents related to the work. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Health workforce governance has been proposed as key to improving health services delivery, yet few studies have examined the conceptualisation of health workforce governance in detail and exploration in literature remains limited.A literature review using PubMed, Google Scholar and grey literature search was conducted to map out the current conceptualisation of health workforce governance. We identified all published literature relating to governance in health workforce since 2000 and analysed them on two fronts: the broad definition of governance, and the operationalisation of broad definition into key dimensions of governance.Existing literature adopts governance concepts established in health literature and does not adapt understanding to the health workforce context. Definitions are largely quoted from health literature whilst dimensions are focused around the sub-functions of governance which emphasise operationalising governance practices over further conceptualisation. Two sub-functions are identified as essential to the governance process: stakeholder participation and strategic direction.Although governance in health systems has gained increasing attention, governance in health workforce remains poorly conceptualised in literature. We propose an improved conceptualisation in the form of a stakeholder-driven network governance model with the national government as a strong steward against vested stakeholder interests. Further research is needed to explore and develop on the conceptual thinking behind health workforce governance. It is well established that key systemic issues in health workforce  stewardship and policymaking in areas such as health workforce assessment, planning and feedback-monitoring . An imprThis review aims to outline the current conceptualisation of governance within health workforce literature. Governance is a process with different implications for different actors; however, considerations towards governance will be focused on the national level due to the stewardship responsibilities bestowed on national entities in advancing global health initiatives . Up to now, no such review is known to have be published in existing literature.definition of governance (an objective description), and the dimensions of governance  as they apply to the health workforce. A discussion will begin with a critique of the current conceptualisation of governance followed by suggestions on possible ways to move forward.Findings are modelled after Barbazza and Tello’s previous work in conceptualising and bringing applicability of governance to a health system setting . As goveA literature review was conducted to rapidly aggregate literature findings up until July 2020. Inclusion criteria were limited to all literature pertaining to health workforce and governance since the year 2000 (when ‘stewardship’ was first established by the WHO). Sources must explicitly discuss governance in reference to health workforce, whilst literature which marginally mentions governance will only be considered more generally. Search terms include a variety of combinations of key terms including ‘governance’, ‘stewardship’ and ‘leadership’ in addition to ‘health workforce’ and ‘human resources for health’. Searches for published literature were conducted through PubMed and Google Scholar, with additional searches for grey literature through Google Search.The main perspective adopted towards governance will be from the national public level; as the state government is bestowed with powers in legislation, financing and leadership, it acts as an ideal point of intervention for further discussion. This does not necessarily restrict literature findings as most literature already present national or supranational perspectives, or derive from international organisations that routinely deal with national governments as primary ‘nodes’ for domestic policymaking.In total, 28 publications were identified. This included 12 case studies referencing domestic or regional governance in health workforce, either by outlining the general landscape and challenges (10) -23, or befforts and processes  for which the system's steward has oversight’  there are games in the rules" ; we cannMeanwhile, an increase in complexity of governing institutions and issues  means thbarrier towards discussing governance issues but rather an opportunity for improving the conceptualisation of governance towards a health workforce context.We believe that a general characterisation of health governance is insufficient when dealing with governance of the health workforce. We also argue against using ad hoc normative descriptors of governance (i.e. a list of characteristics of ‘good’ governance) before a sufficient conceptualisation of governance within health workforce is established that takes into account the specific, intractable challenges unique to the field. The fundamentally political nature of health workforce issues  should nprocesses through which responsibilities are distributed amongst different actors, but also the relationships and connections within a complex web of interlinked stakeholders wishing to influence the processes of governance.Instead of viewing governance at the domestic level as a public policymaking affair effected primarily in a top-down fashion, an improved conceptualisation of health workforce governance sees the governance process as network-based and stakeholder-driven. Teter previously argued for problem-driven collaborative governance in health workforce which emphasises stakeholder engagement and accountability through robust feedback loops . In thisment. We believe these are two distinct concepts and that the government is by virtue no more intrinsic within governance than any other stakeholder. Of course, governments often do (and should) play a stewardship role in directing policymaking to meet global health objectives; however, this is not within the inherent conceptualisation of governance and assumes erroneously that any government has absolute authority in policymaking. Kuhlmann and Larsen have previously noted multi-level governance as an alternative framework eschewing the traditional hierarchical basis of governance for multi-level, content based governance in which a central government has relatively reduced direct authority [This characterisation seeks to clarify the distinction between governance and governuthority ; they noGovernment policymaking which acknowledges the fragmentation of formal and informal power and actively navigates through the stakeholder landscape, instead of reasserting power under a central authority;interconnections between stakeholders as well as the close-knit, complex relationships of vested interests that underpin governance, stewardship and policy-setting;A deep understanding and respect of the complex network of A proactive willingness to collaborate and negotiate policy decisions with stakeholders, instead of top-down unilateral implementation of policies;An emphasis towards bottom-up consensus-building policymaking that encourages buy-in, trust and collaboration between stakeholders and the government;A keen focus towards achieving health system objectives whilst encouraging stakeholder influence and input within the governance process;Stewardship against vested interests through institutional and regulatory reform where necessary should stakeholder consensus be unachievable.If the government should be seen as distinct from (but still highly involved with) the governance process, redefining the government’s role is required. Some salient characteristics of this effort are listed below:interconnections between stakeholders.This conceptualisation simultaneously acknowledges the increasingly crowded stakeholder landscape that dominates the health workforce discussion and empowers the government to seek solutions which include bottom-up stakeholder participation and consensus-building within the policymaking process. One particular model of this approach would be multi-level governance as described by Kuhlmann and Larsen  in whichstakeholders which answer to different constituencies and have different mandates. Therefore, the Ministry of Health must help guide stewardship during the governance process and ensure political commitment from the highest levels of policymaking power.Key stakeholders within the governance process include health professional groups, financiers, regulatory bodies, professional educational institutions and health provider organisations, all with differing interests and requiring strategic stewardship from the government in order to align policymaking focus towards global health objectives. In addition, within government there is also a requirement to collaborate with other intra-governmental ministries, most principally the Ministry of Education  and the Ministry of Finance . These also represent context-specific in governance strategies. This is because stakeholder positions may be similar across countries in the same region, but their powers and roles vary depending on circumstances that are not easily observable [process should instead be the focal point of intervention rather than the specific policy positions. For example, in a country with a self-regulated professional nursing body which controls professional registration, it is necessary to consolidate stakeholder involvement before seeking any policy changes regarding nursing membership; in another country without self-regulated professional groups, deep stakeholder participation may still be highly desirable due to extensive stakeholder influence. In both cases, the objective may be professional licensing reforms; however, the governance process is adaptive and flexible to stakeholder demands. Pushing for universal governance reforms on ‘equity’ or ‘transparency’ is tone-deaf to domestic policymaking that should also be responsive and adaptive to local circumstance, derived after acquiring a deep and thorough understanding of stakeholder dynamics and interests.Emphasis on a stakeholder-driven process should also drive governments to be servable . While tTraditionally, a network governance-based approach has rarely been discussed within health literature and remains a concept developed from business and public policy contexts . We advoIt is important to note that in pursuing a network-based, stakeholder approach, the government must continue to sustain stewardship over the health workforce. Stakeholder involvement in the governance process—if appropriately structured—enables capacity-building towards an integrated health workforce , whilst With key steward functions in legislation, public institutional arrangements, financing , the government is ideally suited to act as a ‘broker’ in providing stewardship towards health objectives. We are not proposing that the government abandon their stewardship role through stakeholder participation; rather, we propose that stakeholder expertise is hugely beneficial in the governance process and thus stewardship should be towards governance practices that involve bottom-up stakeholder input.What would this look like in practice? One possibility could include stakeholder-driven governance deliberately weighted to ‘steward’ against dominant stakeholder influence. Kuhlmann et al. have described a German regional health workforce monitor which counterbalances against the influence of one particularly strong stakeholder group (doctors) by excluding them from the governance process, thus directly connecting smaller diverse stakeholders with policymaking and ‘disrupting a cycle of ineffective health workforce policy’ . AnotherA bottom-up governance approach can only be successfully pursued with the government firmly as a steward to counterbalance unequal stakeholder interests and direct policymaking towards global health objectives. As potentially the only participant whose interests are most aligned with a health-for-all approach, governments are also the only actors capable of utilising institutional arrangements to negotiate the unequal power dynamics between stakeholders. Thus, governments will have the unenviable task of balancing between driving stakeholder consensus and fulfilling a ‘stewardship’ role—a fundamentally political affair.In visualising stakeholder-driven governance, we delineate key implications according to the perspectives of various actors in the governance process. Mitchell and Bossert have previously outlined the relative stakeholder positions and interest clashes in a health workforce reform context  which seLeaders at the highest level of public office drive the political support necessary towards stakeholder-driven governance reforms both internally  and externally (with stakeholder interests). Establishing a strong vision aligned with community interests and global health mandates alongside policymaking which embraces stakeholder involvement is perhaps the most critical link in fostering reform within sectors that may previously be ‘silo-ed’ with little inter-disciplinary collaboration.Health officials at the national level are responsible for formulating policies towards broader health system objectives with the additional emphasis on encouraging stakeholder participation, establishing a conducive environment for communication and consensus-building, and enabling continual feedback-ing such that policymaking is reflective of stakeholder input. They act as a leader both within government and with external stakeholders in coordinating stakeholder concerns and priorities towards national health objectives.Other ministries involved in components of health workforce policy must collaborate widely and actively with the Ministry of Health in identifying common issues and feasible solutions in collaboration. The goal is to develop coherent national policies which do not contradict and antagonise other existing policies and priorities within government.interconnections between different stakeholders and with governmental agencies in an organic and bottom-up manner—connections that are both synergistic and functionally relevant help develop resiliency and support in HRH policymaking.Stakeholders responsible for health service delivery should participate actively in the governance process and communicate across disciplines. The focus is on fostering It is essential to include community stakeholders directly within the governance discourse in order to counterbalance professional self-interests in the policymaking process. Increasing the diversity of the policy discussion will also ease the alignment of objectives towards national policy targets .not been emphasised enough in the HRH crisis [Whilst governance within the context of health systems has gained increasing attention , the infH crisis  which wehealth systems governance, enables the operationalisation of governance policies that improve health workforce performance and ultimately delivers health gains on the path towards universal health coverage and health systems strengthening.We clarify that governance is not simply an ad hoc consideration in improving the implementation of health workforce policies but a distinct process through which networks of conflicting stakeholder interests influence the formation and implementation of policy decisions. Improving the conceptualisation of health workforce governance deepens our understanding of network-based dimension and the stakeholder-driven dimension: network-based places the emphasis of governance on the connections between stakeholders, whilst stakeholder-driven enshrines the bottom-up participatory approach that improves health systems performance and builds consensus. The government still maintains an intractable role in stewardship; however, the focus is on encouraging structures that bring stakeholders together and in fostering bottom-up outputs whilst balancing power dynamics and vested stakeholder interests. We believe this is an improved conceptualisation of governance in health workforce and reflective of how governance can better influence HRH policymaking.The two key elements of this approach involve the We note this review is limited to secondary sources with no primary data collection or first-hand case studies. We therefore suggest further research into case studies of governance practices across regions and reform efforts aligned with stakeholder-driven network governance, and government-stakeholder interactions where particular groups exercise dominant influence. It is also pertinent to explore the health workforce issues exposed by the COVID-19 pandemic and what role governance must play in future health workforce and health systems strengthening. Expanding the literature will ultimately drive improvements in the conceptualisation and operationalisation of governance in health workforce and, in turn, deliver on the essential attributes of a well-functioning health system towards universal health coverage—quality, efficiency, equity, accountability and resilience.


Behavioural economic theories of addiction contend that greater expected value of drug relative to alternative non-drug rewards is the core mechanism underpinning vulnerability to and recovery from addiction. To evaluate this claim, we exhaustively review studies with human drug users that have measured concurrent choice between drugs vs. alternative rewards, and explored individual differences. These studies show that drug choice can be modulated by drug cues, drug devaluation, imposition of costs/punishment and negative mood induction. Regarding individual differences, dependence severity was reliably associated with overall drug preference, and self-reported drug use to cope with negative affect was reliably associated with greater sensitivity to mood induced increases in drug choice. By contrast, there were no reliable individual differences in sensitivity to the effect of drug cues, drug devaluation or punishment on drug choice. These findings provide insight into the mechanisms that underpin vulnerability to dependence: vulnerability is conferred by greater relative value ascribed to drugs, and relative drug value is further augmented by negative affective states in those who report drug use coping motives. However, dependence does not appear to be characterised by abnormal cue-reactivity, habit learning or compulsion. We then briefly review emerging literature which demonstrates that therapeutic interventions and recovery from addiction might be attributed to changes in the expected relative value of drug versus alternative rewards. Finally, we outline a speculative computational account of the distortions in decision-making that precede action selection in addiction, and we explain how this account provides a blueprint for future research on the determinants of drug choice, and mechanisms of treatment and recovery from addiction. We conclude that a unified economic decision-making account of addiction has great promise in reconciling diverse addiction theories, and neuropsychological evaluation of the underlying decision mechanisms is a fruitful area for future research and treatment. Althougequences ,16. Compequences . Finallyequences  and thusequences , includiequences  and impaequences , renderiUnified economic decision making accounts of addiction have attempted to reconcile these competing theories by suggesting that all of the secondary processes might promote drug-seeking via their impact on the expected relative value of the drug compared to competing non-drug alternative rewards, that is, by biasing preferential choice towards drugs ,10,22,23The current article evaluates the unified economic decision model of addiction in three sections, before outlining future directions. First, we consider whether the relative value of drugs vs. alternatives can explain vulnerability to dependence. An exhaustive review is provided of human concurrent choice studies which have tested whether choice between drugs vs. alternative rewards can be modified by experimental manipulations  and whether these effects are associated with self-reported dependence severity and associated risk factors (psychiatric symptoms and drug use to cope with negative affect). This work indicates that dependence severity is reliably associated with greater relative drug value , and drug use to cope with negative affect is reliably associated with greater sensitivity to negative affect induced increases in relative drug value, suggesting at least two risk pathways converging on relative drug value. In the remainder of the paper we offer a brief overview of emerging research findings which demonstrate that recovery from addiction might be explained by changes in the relative value of the drug versus alternative rewards. Finally, we outline a speculative computational account that describes the internal processes that underlie valuation of drug and alternative rewards as a precursor to behavioural choice. Overall, we believe that the unified economic decision-making account has great promise in explaining both vulnerability to and recovery from addiction, and that neuropsychological evaluation of the underlying decision mechanisms would be a fruitful area for future research.2Evidence that addiction is driven by expected relative drug value comes from the finding that dependence severity in humans, assessed by questionnaires or diagnostic criteria, is reliably associated with greater economic demand for drugs. In economic demand tasks, participants report their hypothetical consumption of a drug across a range of prices, indexing the relative value of the drug compared to money (money is exchangeable for most rewards). This index of drug value has been shown to correlate with dependence severity in 41 studies on alcohol demand, 34 studies on nicotine demand and 10 studies on other substance demand, in both clinical and non-clinical samples . AlthougHuman concurrent choice tasks have also indexed the value ascribed to drugs relative to money and other rewards (e.g. food). In the concurrent choice task, participants make a choice between the drug and another reward across a series of trials, and the proportion of drug choices indexes the relative value of the drug versus the alternative reward ,25. Choiinsensitivity to drug devaluation, because drug choice is controlled by an autonomous S-R association established in initial training, rather than by an expectation of current value of the drug [insensitivity to devaluation treatment in more dependent individuals. On the basis of these outcome devaluation studies, human dependence severity does not appear to be associated with a propensity to habit learning . Other studies not included in the drug , such ththe drug , the devFinally, Negative reinforcement theory predicts that substance users who have psychiatric symptoms should ascribe greater relative value to the drug (i.e. show greater baseline drug choice) and should be more sensitive to acute negative mood induced increases in drug choice  . Table 2Negative reinforcement theory predicts that substance users who report using substances to cope with negative affect should ascribe greater relative value to the drug (i.e. show greater baseline drug choice) and should be more sensitive to acute negative mood induced increases in drug choice  . AlthougA key study indicates that negative mood induced drug choice is goal-directed, i.e. driven by an increase in expected drug value . This stThe human concurrent choice findings reviewed above provide insight into the type of unified economic decision theory that might explain vulnerability to addiction. Our observations were that drug choice could be modified by a variety of distinct decision variables, namely drug cues, drug devaluation, costs , and negative mood induction (stress and sadness). Indeed, two of these decision variables – devaluation and negative mood induction – were shown to have opposing effects on drug choice when compounded, demonstrating a convergence of decision variables on behaviour . More woThe second observation is the absence of an association between dependence severity and drug cue priming of drug choice in all seven studies that investigated this. By contrast, mood induced increases in drug choice was more reliably associated with individual differences. Mood induced drug choice was associated with dependence severity in four of the seven studies that investigated this, with psychiatric symptoms in three out of 13 tests of this association, and with self-reported drug use to cope with negative affect in eight out of 10 studies. Examples of these associations are shown in 3Many people recover from addiction, often without any formal treatment  and therIn humans, recovery from addiction occurs when the availability of drug-free rewarding activities increases  and/or wRegarding the mechanisms of action of established treatments for addiction, some studies have implicated changes in behavioural economic demand as important mediators of the effects of a variety of psychological interventions on drug use outcomes. For example, brief motivational interventions and pharmacotherapy prompted changes in behavioural economic demand for the drug, and these changes in turn predicted the likelihood of sustained changes in drug use after receiving the treatment ,103. Anorelative value of drugs. These interventions lead to reductions in drug use that may be mediated by increases in engagement in drug-free activities [The effectiveness of contingency management and related interventions provides more direct evidence that changing the valuation of drugs versus drug-free alternatives plays an important role in the successful treatment of addiction. Contingency management approaches offer financial incentives to people with addiction if they can confirm their abstinence from drugs, which should in principle devalue the drug whilst increasing the value of drug-free activities that the financial incentives can be used to obtain. These approaches lead to reductions in drug use  that maytivities ,111,112.tivities .In this section we have outlined how changes in valuations of drugs and drug-free alternatives may at least partially account for how diverse treatments for addiction exert their therapeutic effects, and how people recover from addiction. We acknowledge that this is speculative, and further work with validated measures of valuation  is needed to confirm and build on these findings. We also acknowledge that our focus on the centrality of valuation processes may appear to overlook other aspects of addiction treatment and recovery such as self-efficacy and the acquisition of coping skills that may play an important role in the valuation processes. These important constructs may be reconciled with a valuation-based account if one considers the internal mechanics of value-based decision-making. We describe computational work on value-based decision-making in the next section.4Concurrent choice tasks in which participants choose between a drug versus alternative reward have contributed important information about the role of decision making in addiction ,114. HowExperimental procedures for assessing value-based decision-making (VBDM) are similar to those used in the concurrent choice tasks described above: Participants must choose between two pictures that depict valued outcomes. However, there are a number of important differences. Firstly, in VBDM procedures participants initially view a battery of images and they are asked to report the degree to which they would most like to consume or experience each one – this is important for rank ordering the images in each category from least to most valued . If VBDMParticipants’ reaction time and ‘error’ data  are then fitted using drift diffusion models ,117. TheAccording to a recent conceptual model ,118 thesApplication of VBDM as a tool to explain vulnerability to addiction and recovery from it can be used to identify novel hypotheses regarding the mechanisms through which some people are particularly vulnerable to addiction, and how they eventually recover. Regarding vulnerability to addiction, prospective studies could investigate if future dependence severity is best predicted by elevated evidence accumulation for the drug, suppressed evidence accumulation for non-drug alternatives, a low response threshold when evaluating drug options, an elevated response threshold when evaluating non-drug options, or if each of these parameters is equally predictive of dependence in the future. We also noted earlier that coping motives are associated with increased sensitivity to negative mood induction raising the expected relative value of the drug, augmenting goal-directed drug choice. It would be interesting to test whether this mood induction effect was due to elevated evidence accumulation for the drug, suppressed evidence accumulation for non-drug alternatives, a low response threshold when evaluating drug options, and / or an elevated response threshold when evaluating non-drug options. Similarly, future work could investigate whether the impact of other experimental manipulations, including the presentation of drug cues in the PIT task, drug devaluation, and the imposition of costs on the drug choice, can be explained by changes in evidence accumulation rates or response thresholds for the drug versus alternative reward.Regarding recovery from addiction, in our recent paper we outlined the changes to VBDM parameters that we would expect to see as people receive treatment for addiction and recovery . For exa5We started with the premise of behavioural economic theory of addiction, that greater expected value of drug relative to alternative non-drug rewards is the core mechanism underpinning vulnerability to and recovery from addiction. We evaluated this claim by reviewing human concurrent choice studies with drug users, which showed that dependence severity was reliably associated with overall drug preference, and self-reported drug use to cope with negative affect was reliably associated with greater sensitivity to mood induced increases in drug choice, suggesting these two risk pathways underpin addiction. By contrast, addiction severity was not consistently associated with sensitivity to the effect of drug cues, drug devaluation or punishment on drug choice, an observation which contradicts cue-reactivity, habit and compulsion theories of addiction. We then described evidence that therapeutic interventions and recovery from addiction might be attributed to changes in the expected relative value of drug versus alternative rewards. In the final section, we outlined a speculative computational model and novel experimental method that could be used to probe accumulation of evidence about drugs and alternative rewards that could drive action selection. Combining the standard concurrent choice paradigm and these new computational approaches will be fruitful areas for future research, improving the understanding and treatment of addiction.10.13039/501100012450Alcohol Change UK grant (RS17/03) to Lee Hogarth, and a Medical Research Council  Confidence in Global Mental Health pump priming award (MC_PC_MR/R019991/1) to Hogarth. Funders had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.The research was supported by an None.


Grimwade Although ‘payment for risk’ would diverge from most current research ethics guidelines, it is noteworthy that the difference in payment to participants that their framework would allow might only be small, at least in the case of currently accepted studies. The absolute difference would likely be small because the risk of currently accepted HCS participation (after risk minimisation strategies) is usually very low.et alHCS participation (in high-income countries) frequently attracts payment of thousands of dollars . Such payments are usually considered to be justified by the burdens of participation .et alAdditional payment for risk might be concerned primarily with fatality risks or potential lasting harms. Although there have been no deaths in modern HCS and lasting harms are rare,et alIf payment for risk is an inadequate solution for harm and results in minimal change to current payment levels, one might question the justification for a change in practice, especially since higher payments  are associated with several potential concerns (discussed further below). Grimwade et al,We reported the findings of a projectMoreover, people from different cultural backgrounds may hold different attitudes towards payment. Our study found that significant payment (even for burdens) is not widely accepted in Latin America and has led to controversy in Kenya, for example.Finally, normalising large payments to participants might result in subtle changes in the relationships between researchers and participants. Whereas HCS investigators, who are frequently clinicians, report a strong sense of responsibility for the welfare of the participants in their studies,


The coronavirus disease pandemic has created opportunities for innovation in diabetes care that were not possible before. From the lens of this “new normal” state, we have an opportunity to rapidly implement, test, and iterate models of diabetes care to achieve the quadruple aim of improving medical outcomes, patient experience, provider satisfaction, and reducing costs. In this perspective, we discuss several innovative diabetes models of care which promote collaborative care models and improve access to high-quality specialty diabetes care. We discuss ongoing threats to diabetes care innovation, and offer practical solutions to foster evolution and sustain current strides made during the pandemic. The “new normal” has been coined as a term to denote the major shift in paradigm that coronavirus disease 2019 (COVID-19) has forced around the globe. In health care, the “new normal” has fostered innovation and allowed for real-world testing of care models in unprecedented ways. In this watershed moment for health care systems around the world, real change may be possible to create a better new normal beyond the pandemic if careful steps are taken to promote advocacy and ensure sustainability.For diabetes, which affects half a billion people worldwide, the thrust toward innovation has long been overdue. Achieving optimal glycemic control on a large scale has major implications for population and economic health, yet less than 50% of people with diabetes meet glycemic targets , 2. BefoIn 2018, the Endocrine Society convened a taskforce to examine and promote innovative models of care in diabetes. In this perspective, the members of the taskforce review several models of care, with which they have experience and which have potential to become standards of care in the new normal. We discuss the current challenges to widespread adoption of new models of care. Last, we provide potential solutions to foster innovation and create pathways for sustainability.We review in detail here models that each of the Taskforce members have had success with. Specifically, these models focus on improving access to high-quality specialty endocrinology care through care coordination and opening lines of communication.Clinically, each of these models is applicable to both type 1 and type 2 diabetes. Although historically, some of these innovations have been more popular to a particular type of diabetes, they are becoming increasingly relevant across the spectrum because there is wider distribution of both types of diabetes across the lifespan and technological treatments traditionally reserved for type 1 diabetes are now being used for type 2 diabetes as well.Telemedicine has become a critical strategy to improve access to diabetes care while simultaneously supporting necessary physical distancing during the pandemic, representing one of the biggest and swiftest care transformations worldwide. There is a large body of evidence for the efficacy of traditional telemedicine in diabetes care , showing parity in outcomes with traditional office visits . The adveConsults are another innovation that greatly increases the collaboration of different service lines, providing access to high-quality endocrinology care, and was particularly useful during the pandemic. eConsults are patient-specific, asynchronous virtual communication between a specialist and referring provider  that occurs within a shared EHR or other secure electronic platform. The benefits of eConsults across specialties are well documented and include increased access to specialty care , provideProject ECHO  is a scawe take care of patients”  lack of generalizable payment models; (2) slow technology integration into health care; (3) real-world implementation challenges; (4) a dearth of rigorous outcomes and cost data; (5) workforce shortages from burnout; and (6) no infrastructure for sustainability of innovative models.Although some countries already had payment models for innovative diabetes care and more have adopted compensation strategies during the pandemic, it remains unclear whether coverage of innovative services will continue. Efforts to innovate care have typically been limited to institutions or practitioners with external funding or to integrated payor-provider systems, leading to a lack of generalizability and sustainability. Of late, health systems and stakeholders have increased their appetite for care strategies that work to improve medical outcomes and cut costs, even if not traditionally implemented. However, sustainability of pay models will rely on rigorous and large-scale outcome and cost data, which so far remains scarce.In addition, lack of a roadmap for sustainability of innovation continues to threaten real change. Features of EHR workflows that facilitate telemedicine and e-Consults require extensive builds or funds to partner with third-party companies. Hardware and software support in addition to training on new technologies requires financial and staff resources that most nonacademic institutions are not able to provide. Lack of interoperability of different EHRs limits communication between care sites that are not part of the same institution. Continually siloed health centers and cultural differences in paradigms of care prevent different provider groups  from working together, even within the same health system. These systems of care, if not altered in more permanent ways, will continue to challenge foundational changes.Moreover, continuing to align with organizational priorities will allow for continual support of strides made in health care. However, making a business case for these innovations is difficult. Many innovations require up-front investment and continued support from health care or governmental organizations. Endocrinologists also often lack the training, vocabulary, and pilot data to effectively advocate for budgets for innovative ideas. Moreover, the success of business cases somewhat relies on the environment in which the care is being practiced, whether fee for service or value-based system. This will continue to be relevant after the pandemic ends.Finally, maintaining an impassioned and highly skilled workforce of endocrinologists to carry innovation forward remains the ultimate challenge. Before the pandemic and even more so now because of cost-limiting measures, both endocrinology teams and operations staff can be overwhelmed with routine work, having little time or resources to pursue innovation, even if the interest is there. Overall, fewer trainees are entering the field of endocrinology, limiting the influx of new ideas that are necessary for innovation. Although diabetes care can attract trainees from multiple disciplines, the increased administrative aspects of outpatient care greatly diminish the joys of work, leading to increased rates of burnout and mental health issues.To promote lasting health care transformation and create a better new normal for the health care community and our patients with diabetes, we must create systems that promote pathways for success and sustainability. Following are recommendations for all levels of stakeholders, which will help to ensure that innovation is sustained beyond the current pandemic. Professional Societies:Create virtual platforms, networks, and in-person meeting opportunities for health care practitioners to share practice transformation ideas and pilot project resultsEnhance training opportunities in quality improvement methodologies and formulation of the business case for innovationLeverage professional society relationships to advocate at the governmental level for alternative reimbursement models that facilitate innovationEncourage collaboration of primary care and specialty care professional societies to foster cross-collaborative networks such as quality improvement learning collaboratives, joint national meetings, and shared practice guidelinesFoster technology-healthcare industry collaboration, and integration of health care redesign approaches into clinical practice settingsHealthcare Institutions and Practices:Encourage health care practitioners to incorporate quality improvement and implementation science methods in routine careAllocate philanthropic funding to promote clinical innovation and obtain pilot outcomes and cost data that can garner longstanding institutional or payor supportProvide time for regular practice meetings to discuss innovative solutions to common clinical challenges supported through data collectionFoster mentorship of clinicians to identify clinical improvementsEnable multidisciplinary collaboration with service lines outside of endocrinology to build and sustain infrastructure for communication and innovationEncourage beta testing and early stage collaboration with health technology companies to introduce nontraditional frameworks of careHealth Care Practitioners:Seek virtual training opportunities in quality improvement methodology and dissemination-implementation scienceSearch for mentorship and collaboration within or outside practice setting to discover best practices and learnings from failed experiencesUnderstand organizational priorities and align initiatives by actively approaching administratorsRecruit multiple team members  to create a unified voice in advocating for changeFaced with an unprecedented public health threat with the arrival of the COVID-19 pandemic, the value of innovative models of diabetes care is clearer than ever before. The pandemic has presented a disruptive force to health care worldwide. The response has been an embrace of innovation in diabetes care. Longstanding challenges were overcome seemingly overnight, showing us the great potential of innovative models. These successes in implementation have yet to be fully scaled, although with each passing month, we get closer to a better new normal. We are on the brink of a complete redesign in health care. Advocacy and community will be tantamount to the continued forward momentum we have gained. We must monopolize on this unique opportunity to reshape our current history into a positive and hopeful future.


Digits develop in the distal part of the embryonic limb primordium as radial prechondrogenic condensations separated by undifferentiated mesoderm. In a short time interval the interdigital mesoderm undergoes massive degeneration to determine the formation of free digits. This fascinating process has often been considered as an altruistic cell suicide that is evolutionarily-regulated in species with different degrees of digit webbing. Initial descriptions of interdigit remodeling considered lysosomes as the primary cause of the degenerative process. However, the functional significance of lysosomes lost interest among researcher and was displaced to a secondary role because the introduction of the term apoptosis. Accumulating evidence in recent decades has revealed that, far from being a unique method of embryonic cell death, apoptosis is only one among several redundant dying mechanisms accounting for the elimination of tissues during embryonic development. Developmental cell senescence has emerged in the last decade as a primary factor implicated in interdigit remodeling. Our review proposes that cell senescence is the biological process identified by vital staining in embryonic models and implicates lysosomes in programmed cell death. We review major structural changes associated with interdigit remodeling that may be driven by cell senescence. Furthermore, the identification of cell senescence lacking tissue degeneration, associated with the maturation of the digit tendons at the same stages of interdigital remodeling, allowed us to distinguish between two functionally distinct types of embryonic cell senescence, “constructive” and “destructive.” C. elegans  characterized by sharing sequence and structural similarities. This gene/protein family comprises pro-apoptotic and pro-survival members  lack the digit phenotype and most of them develop normally . SyndactNTR neurotrophin receptor, TNFR1, FAS (CD95), and TRAIL Receptors 1 and 2  during digit morphogenesis constitutes the most appropriate model to study the biological significance of cell senescence in developing systems . ConsistMolecular compounds, such as tissue transglutaminase (tTG), which has been reported to be a marker of cell senescence , are speA central question about cell senescence in INZ  is whether it is a degenerating event that precedes apoptosis or whether it is concurrent with apoptosis but plays a protective role against local stressors.The pattern of SAβ-gal staining in vibratome sections of the developing autopod reveals two extremely different domains: the interdigits and the core of the differentiating tendon blastemas . As descThe abundance of rounded dark dying cells in histological sections of interdigits during remodeling suggests that apoptosis is the predominant cell degenerative feature of this regressing tissue . HoweverStudies devoted to analyzing the involvement of lysosomes in the areas of embryonic cell death provided compelling evidence for active lysosomal participation in remodeling limb tissues , albeit Although autophagy and even heterophagy are survival mechanisms that supply energy to support the secretory profile of senescent cells , the abo2O2) dying signals supports this interpretation  observed in caspase-deficient mouse Bax/Bak–/–  acting in parallel with caspases , independent of caspases (midgut cell death) and, upstream or downstream caspases in a context depend fashion (ovary maturation) . By contrast, senescence in the developing tendons, is not associated with tissue degeneration and appears to be a constructive process that regulates tendon maturation .The experimental data surveyed here support the occurrence of a unified process of embryonic tissue remodeling involving the activation of two main degenerative routes, namely, the lysosomal pathway-mediated and caspase-dependent cell death. From an historical point of view, the introduction of the term ecrosis”  led to aecrosis” . The destructive , but finJM, CL-D, and JH discussed, reviewed, edited, and wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Net increases  in consumption of unhealthy food  and alcohol  were observed. Net decreases  in visits to the doctor  and other health professionals  were observed. Compared with females living without children, females who lived with children were significantly associated with increased alcohol consumption , decreased visits to the doctor  and decreased visits to other health professionals . Results suggest that public health approaches may be required to support females residing in rural areas to optimise their health behaviours during the pandemic, particularly for those living with children. Policies must be gender responsive to counteract worsening health and social inequities both during and after the pandemic.Women are predicted to be disproportionately impacted by the COVID-19 pandemic due to increased carer responsibilities, loss of income, worry about the virus and a predominantly female healthcare workforce. Whilst there is emerging evidence that negative mental health impacts associated with the COVID-19 pandemic may be more pronounced for women than men, less attention has focussed on changes to health behaviours and health seeking experienced by women. Similarly, the impact of the pandemic in rural areas has not been investigated in detail. Our research questions were ‘ Pandemics and public health responses to control spread of infection can disrupt everyday life and have consequences for health and well-being. Pandemics, including COVID-19, have the capacity to worsen pre-existing inequities in health and social outcomes among vulnerable groups of people . These cIncreased psychological distress associated with the pandemic and widespread restrictions have been reported internationally and appear to be impacting females more than males. Internationally, studies from China , United There is evidence that the COVID-19 pandemic has been associated with changes to people’s health seeking behaviours, prompting concerns of delayed care or late presentations for important health conditions. A large study in the United States reported that 41% of respondents had avoided or delayed medical care during the pandemic, and this was particularly evident among females and adults with carer responsibilities for other adults . A recenThe impact of COVID-19 on the health and well-being of people residing in rural areas has yet to be explored in detail. However, it is important to understand the impact of the pandemic and restrictions to everyday life in rural areas where there may already be less access to health services and higher rates of poor health behaviours compared with metropolitan areas . In addihave females residing in rural areas experienced changes in alcohol consumption, unhealthy food consumption, smoking, exercise or health seeking during the COVID-19 pandemic?’ and ‘are there reported differences in health behaviour changes between rural females living with or without children?’To date, the majority of research into the impact of restrictions on everyday life during the COVID-19 pandemic has focused on the psychological impacts, and limited research has focussed on health behaviour changes , particAn electronic survey link was distributed to the authors’ personal and professional networks via email and social media. The authors’ networks were predominantly located in rural areas, typically in the fields of healthcare and education. Recipients of the link were invited to distribute the link within their own networks, reflecting a snowball recruitment strategy . ResponsDo you live with a long-term physical health condition?’ and ‘Do you live with a long-term mental health condition?’. For further detail see An online survey was developed using the REDCap survey platform hosted at the University of Melbourne . REDCap People were eligible to participate if they resided in Australia, were aged 18 years or older and had volunteered or had been employed at any time during the period December 2019 to July 2020. The survey was accessible from 29 May 2020 to 8 July 2020. In late May, the first Australian COVID-19 infection curve had flattened and some lockdown measures  were starting to ease.The study was approved by the University of Melbourne’s COVID-19 Central Human Ethics Committee (2056921.1). Respondents were unable to enter the survey unless they provided electronic informed consent. Respondents could choose to enter a prize draw for one $100 gift-card and/or register their interest in a follow-up survey, and for these purposes an email address was required. If respondents declined to enter the prize draw or register their interest in a follow-up survey, their responses remained anonymous. Responses received after the 8 July were removed from the dataset. Respondents’ postcodes of residence were recoded into the Modified Monash Model categories of 1–7 and subsequently divided into metropolitan (MMM1) and rural  (MMM2-7) . RespondCategorical variables are presented as number and percentages, while continuous variables are presented as mean, standard deviation (SD) or 95% confidence intervals (95% CI). Comparisons were made between rural females living with or without children using chi square analysis for categorical variables and independent samples t-tests for continuous variables. Net change in behaviours were analysed as 95% confidence intervals after coding decreased behaviours as −1, unchanged as 0 and increased as +1. A series of separate logistic regression analyses were conducted to assess associations between changes in health behaviours (dependent variables) and the independent variables of symptoms of depression, anxiety or stress , living with or without children, age and presence of self-reported chronic disease. The dependent variables were selected as they had shown significant differences between females living with or without children in unadjusted tests, namely increased alcohol consumption and decreased social interaction, personal care activities and visits to doctors or other health professionals. DASS-21 sub-scale scores were compared to normative values for Australian females  using anThe results of the sub-set of rural females are reported. There were 339 valid responses received from females residing in rural areas between 28 May and 8 July 2020. The demographic characteristics and DASS-21 scores of this subset are reported in p = 0.003). There was no significant difference in the percentage of self-reported chronic disease or mental health conditions among rural females living with or without children . The DASS-21 scores for stress, anxiety and depression were not significantly different between rural females living with or without children , as per Further analysis revealed that the average age of females living in rural areas without children was significantly older than females living in rural areas with children . Respondents living with children were significantly more likely to report decreased social interaction and personal care activities than respondents living without children . Respondents living with children were significantly more likely to report decreased visits to the doctor and other health professionals than respondents living without children , as per Respondents living with children were significantly more likely to report increased alcohol consumption than respondents living without children  were further analysed using logistic regression. Significant associations between independent variables (namely living with children) and detrimental health behaviour change (dependent variables) are outlined in The COVID-19 pandemic and restrictions associated with the public health response appear to be associated with changes to several health behaviours among this sample of females residing in rural areas of Australia. Respondents living with children were approximately twice as likely to report increased alcohol consumption, decreased visits to the doctor or other health professional and decreased social interaction or personal care activities compared to respondents not living with children. Net increases in consumption of unhealthy food, alcohol intake and smoking (among respondents who smoked) were observed, along with net decreases in social interaction, personal care activities and visits to the doctor and other health professionals among females residing in rural areas during the pandemic compared with pre-pandemic. It has been proposed that females will be disproportionately impacted by the pandemic due to reduced income and employment opportunities, increased carer responsibilities and worry about the virus . IncreasRespondents reported mixed changes in health behaviours, with substantial proportions of respondents reporting detrimental changes in certain behaviours, while substantial proportions of respondents reporting beneficial changes in the same behaviours. This highlights the importance of asking about bidirectional changes in behaviour, as also noted by others . A similThe increased alcohol consumption reported in our study was higher than reported by Stanton et al. (29%) . Two larIn this study, 37% of respondents reported increased consumption of unhealthy food. Few other studies have assessed consumption of unhealthy food during the COVID-19 pandemic, particularly in Australia, and in rural areas. However, unhealthy changes to diet were reported in a recent study in Scotland and these changes were associated with low mood . In anotDecreased visits to doctors and other health professionals during the pandemic as reported by rural female respondents were particularly pronounced among those living with children. This is a concerning finding, as important health care including women’s health checks may be being delayed. This finding is in agreement with a study from the US that reported 41% of respondents had delayed or avoided medical care during the pandemic, and this was significantly higher among females than males and those with carer responsibilities for other adults . This maMean scores for anxiety, depression and stress symptoms as per the DASS-21 scale were within the normal to mild range  and simiFemales residing in rural areas appear to be experiencing potentially detrimental changes to health behaviours, particularly those living with children. The association between health behaviours and the stress of the pandemic is important to understand as unhealthy behaviour changes can increase the risk of development of chronic disease or exacerbation of pre-existing health conditions, which can be compounded if people are not engaging with healthcare providers at their usual level. Certain groups of people, such as females, those with carer responsibilities and rural people may require additional support during the pandemic to optimise their health and wellbeing and reduce their stress and risk of chronic ill health. This study shows that gender responsive, if not specific, policies are required to address the implications of the COVID-19 pandemic . There hThe results of this study are based on a convenience sample of employees and volunteers recruited online, and the sub-sample of females and residents of rural areas are presented in this paper. The convenience sample from which this sub-sample was drawn was over-represented by females (80%) and people residing in rural areas (78%) and is therefore non-representative of the Australian population  . The medFurther research is required to better understand changes to health behaviours and ways to support people, particularly people in rural areas, women and families, during crises at a systems level. Workplaces play a crucial role in employee health and wellbeing during and after pandemics, as they are pivotal to retaining connection and sense of purpose. It is important that employers ensure that policies support female employees and employees with carer responsibilities during stressful periods. The inclusion of questions related to sleep patterns and screen time would be valuable in future studies. Longitudinal studies or repeat cross sectional studies will be important to better understand the longer-term associations between the restrictions on everyday life that have been necessary to combat the COVID-19 pandemic, stress and health behaviours. We plan to repeat this study after restrictions to everyday life have lifted. The COVID-19 pandemic and restrictions associated with the public health response have been associated with potentially adverse changes in a range of health behaviours, social interaction and health seeking behaviours. Women living with children may be at heightened risk of unhealthy changes and may require additional support during the pandemic. Gender responsive policies are required to avoid worsening health and social inequities associated with the COVID-19 pandemic.