Background: As a fundamental human right, the right to health (RTH) can influence state actors’ behaviour towards health inequities. Human rights advocates have invoked the RTH in a collective demand for improved access to essential medicines in low- and middle-income countries (LMICs). Similarly, scholars have used the RTH as a framework for analysing health problems. However, its utility for addressing skilled health worker (SHW) shortages in LMICs has been understudied. Realising that SHW shortages occur due to existing push-and-pull factors within and between LMICs and high-income countries (HICs), we sought to answer the question: "how, why, and under what circumstance does the RTH offer utility for addressing SHW shortages in LMICs?"Methods: We conducted a realist synthesis of evidence identified through a systematic search of peer-reviewed articles in Embase, Global Health, Medline (Ovid), ProQuest – Health & Medical databases, Scopus (Elsevier), Web of Science (Clarivate), CINAHL (EBSCO), APAIS-Health, Health Systems Evidence and PDQ-EVIDENCE; as well as grey literature from Google Scholar.Results: We found that the RTH offers utility for addressing SHW shortages in LMICs through HIC state actors’ concerns for their countries’ reputational risk, recognition of their obligation to support health workforce strengthening in LMICs, and concerns for the cost implication. State actors in LMICs will respond to adopt programs inspired by the RTH when they are convinced that it offers tangible national benefits and are not overly burdened with ensuring its success. The socio-economic and institutional factors that constrain state actors’ response include financial cost and sustainability of rights’-based options.Conclusion: State and non-state actors can use the RTH as a resource for promoting collective action towards addressing SHW shortages in LMICs. It can also inform negotiations between state actors in LMICs and their HIC counterparts. The United Nations Committee on Economic, Social and Cultural Rights has described core obligations that governments should progressively fulfil to respect, protect and fulfil this right. These core obligations include (1) ensuring access to health facilities, goods and services in a non-discriminatory manner; (2) access to essential medicines; (3) developing and implementing an evidence-based national public health plan that addresses the health needs of its entire population through a transparent and participatory process; (4) the use of RTH indicators in monitoring this strategy; and (5) promoting conditions that improve the social determinants of health . Backman et al described a 72-indicator framework for assessing the RTH features of health systems including four that directly impact maintaining and retaining an optimal skilled health workforce. These include adequate remuneration, sustainable national financing for an essential public health system, international assistance and cooperation, and measures to prevent violation of populations’ RTH.The right to health (RTH) is a fundamental human right. It captures the entitlement of everyone to enjoy the highest attainable standard of physical and mental health. Access to health services, and skilled health workers (SHWs) are essential aspects of realising this right.During the HIV pandemic, human rights advocates mounted pressure on governments worldwide to see the effects of the disease in low- and middle-income countries (LMICs) as a violation of human rights. Seeing that populations in LMICs had limited access to necessary health services, the RTH was used to give normative force to collective demands for improved access to essential medicines. Seeing the role that invoking human rights played in mobilising international solidarity to control the HIV pandemic, experts have applied its framework in studying various health problems. Though access to health workers has come up indirectly within efforts to address the HIV pandemic; there is a knowledge gap on the potential of using the RTH to address SHW shortages in LMICs.At the time, the United States, as a global world power, came under much criticism because its foreign policy did little to address the HIV pandemic in LMICs. Its decision to support measures to improve access to HIV treatment in LMICs was influenced by a combination of international solidarity, social pressure, and concerns for a public health threat from an uncontrolled HIV pandemic in LMICs. For retention of SHWs, state actors in LMICs have favoured restrictive/regulatory mechanisms and incentives. High-income country (HIC) have provided technical and financial aid to support the health systems of LMICs, and enacted measures to end active recruitment of LMIC-trained SHWs.Efforts of LMIC governments to address health workforce deficits in their countries include focusing on improving entry into the workforce, eg, training schemes aimed at increasing the number of appropriate people entering the health workforce. To improve and maintain the current stock of SHWs, LMIC governments have focused on compulsory service requirements, regulating the scope of practice, distribution of personnel, financial incentives, and personal and professional development. This study aimed to generate an understanding of how the RTH influences the response of state actors towards addressing SHW shortages in LMICs and describe the social systems that may enable or constrain its use and effects. Using a realist review, we sought to answer the question: how, why, and under what circumstance does the RTH  offer utility for addressing SHW shortages in LMICs?However, compared to policies focused on entry into the workforce and maintenance of the current stock of health workers, controlling the exit of SHWs has proved far challenging to achieve due to HIC’s reliance on foreign-trained SHWs, and various push factors  in LMICs. These theories or “causal connections” are often expressed using a C-M-O configuration. “C”refers to the context , “M” refers to mechanisms , and “O” refers to outcome patterns. Rather than focus only on intervention types and their outcomes, a realist methodology also argues for the agency of individuals. It links the success/failure of programs/interventions to their reasoning and behaviour . We established a priori that the RTH is a conceptual resource that operates through actors’ reasoning and behaviour. We therefore aimed to design, test, and refine an initial program theory for how its presence or lack thereof yields workforce initiatives/policies aimed at addressing SHW shortages in LMICs. We relied on the World Health Organization (WHO) work lifespan for a definition of desired outcomes – change in (i) enrolments into undergraduate or graduate health training posts (O1), (ii) graduation rates (O2), (iii) recruitments into the health workforce (O3), (iv) total stock of SHWs in a country (O4), and (v) retention/migration rates (O5), and focused not on the workforce intervention types, but on explaining semi-predictable (demi-regularities) patterns of reasoning and behaviour among state-actors in LMICs and HICs.We considered the realist approach for evidence synthesis best suited to the review question and submitted a protocol to the PROSPERO registry (ID number CRD42019139372). A realist review produces program theories  that explain what it is about interventions/programs that work, under what conditions, and why.We conducted an initial non-systematic literature search in Google Scholar and PubMed and held discussions among the authorship team  to understand how the RTH may offer utility for addressing SHW shortages. The findings from our search and discussions informed the development of an initial program theory see , a singuTo derive a refined program theory, we used the terms #1[“Emigration and Immigration”] AND #2[Health Personnel OR Health workers] AND #3[“Recruit” OR “Retention” OR “Regulation”] AND #3[“Developing countries” OR “low- and middle-income countries” OR “LMICs”] and conducted a systematic search of peer-reviewed articles in Embase (Ovid), Medline (Ovid), Global Health (Ovid), ProQuest – Health & Medical databases, Scopus (Elsevier), Web of Science (Clarivate), Embase (Ovid), CINAHL (EBSCO), APAIS-Health: Australian Public Affairs Information Service – Health, Health Systems Evidence and PDQ-EVIDENCE. For grey literature, we included the first 300 documents from Google Scholar. While searching the peer-reviewed literature, we set the date range from the inception of each of the databases to March 2021. We have provided details of the search strategy in  To be included, studies had to report, at minimum, a policy  aimed at addressing SHW migration, their recruitment and retention in a low-income or middle-income country. We defined SHWs as doctors, nurses, midwives, and pharmacists irrespective of their specialisation. We excluded any article that did not mention a specific policy or focused only on describing the problem of SHW shortages. Based on the description of relevance by Pawson, we considered whether each primary study provided helpful information for testing or refining the initial program theory. To establish the rigour of each study, we considered whether the information they provided was plausible. We did this by examining the extent to which the methods and findings align, and whether the authors’ inferences were justifiable based on similar studies, or what we know about the subject matter. To reduce bias, two authors (KY and CB) reviewed each article independently, discussed disagreements, and reached a consensus for all articles.To assess the quality of each primary study in a realist synthesis, it is essential to consider their relevance and rigour. with four RTH indicators adopted from Backman’s framework. The four RTH indicators include adequate remuneration, sustainable national financing for an essential public health system, international assistance/cooperation, and measures to prevent violation of a population’s RTH. See The authors (KY and CB) independently screened the abstracts of articles identified from the search strategy and the full text of the articles that met the eligibility criteria. The two review authors discussed and resolved any disagreement regarding the eligibility of an article at each stage of the review process. After that, we included 68 articles in the review . We pilo 1. Does it mention access to good quality health facilities, products, and services in a non-discriminatory manner, especially for vulnerable or marginalised groups? 2. Does it mention access to the minimum essential food nutritionally adequate and safe to ensure freedom from hunger to everyone? 3. Does it mention access to basic shelter, housing, and sanitation, and an adequate safe and potable water supply? 4. Does it mention the provision of essential drugs from time to time, as defined under the WHO Action Programme on Essential Drugs? 5. Does it mention an equitable distribution of all health facilities, goods, and services? 6. Does it mention the adoption of a national public health strategy and plan of action based on epidemiological evidence, addressing the health concerns of the whole population? 7. As per (6) above, is there a plan to use the RTH indicators in periodic monitoring of this public health strategy; based on transparency, accountability, and participation of the population ? 8. Does it mention a national health workforce strategy ? 9. Does it mention adequate remuneration of skilled health personnel ? 10. Does it mention sustainable national financing for an essential public health system? 11. Is there mention of international assistance and cooperation  to promote and protect population health and strengthen health systems? 12. Are there measures to prevent violations of population health by state and non-state actors, such as private persons , employers and enterprises? Abbreviations: RTH, right to health; WHO, World Health Organization.i) a concrete description of the event, (ii) analytical resolution into its sub-components, (iii) abduction or theoretical redescription of what may have led to the event, (iv) retroduction, (v) comparison between different theories and abstractions, (vi) concretisation and contextualisation. For this review, we adapted these six steps and were informed by Abimbola et al andJagosh. Our adaptation merged Danermark’s steps (iv-vi) and was easier to apply in this study. We have provided a stepwise account of the realist analysis in To arrive at underpinning explanatory mechanisms of an outcome, Danermark et al described six steps ranging from  documented in each article. We considered a piece of information as context if it described peculiar characteristics, socio-economic circumstances, formal or informal rules peculiar to individuals, groups, institutions, and countries that influenced actions, decisions, and relationships among state actors.Step 3: Abduction – For each context-outcome pair, KY studied state actors’ documented decisions and actions, including what led them to consider a policy/workforce option  and the types of policies implemented . These documented decisions and actions were then compared with the list of RTH items ; Iraq, Saudi Arabia (East Mediterranean region); the Caribbean region; Brazil, Cuba (South America); Afghanistan, Australia, Bangladesh, Cambodia, Fiji, India, Indonesia, Kazakhstan, Laos, Nepal, Papua New Guinea, Philippines, Thailand, and Vietnam (Asia-Pacific); Canada and the United States (North America); France, Germany, Norway, the Netherlands, Sweden, and the United Kingdom (Europe). In describing our findings, we mentioned the workforce outcomes and where the workforce initiatives were implemented (whether solely by HIC or LMICs). We also mentioned the associated context  and the mechanisms .The RAMESES publication standards for realist synthesis guided the reporting of our findings see .25 In We did not focus on the mechanisms triggered by the workforce intervention types  but on the program theories that explain how state actors respond to an invocation of the RTH. We have provided a summary of the program theories using CMO configurations in CMO1. If there is a sustained expression of discontent by the international community about the impact of foreign recruitment on access to healthcare services in LMICs, then state actors in HICs will be concerned about the reputational risk of their countries (M) and will take actions leading to a reduction in SHW migration (O5). This action by state actors in HICs is more likely to occur with the involvement of civil society in both LMICs and HICs, and individuals in LMICs who have achieved global recognition for the values they stand for. A change in HIC recruitment behaviour is further enabled when the workforce is centrally managed at the national level (C1) and when the government has access to alternative sources from which to recruit SHWs (C2). HIC governments came under significant pressure to change their recruitment policies (RTH 12) when interactions with LMICs featured civil society organisations in both LMICs and HICs, and elder statesmen that were globally revered. HIC state actors signalled a change in recruiting behaviour by implementing visa restrictions, an ethical code of conduct to guide recruitment practices, and reduced issuance of work permits to LMIC-trained SHWs. This action by HIC state actors eventually led to a reduction in SHW migration from LMICs (RTH 12).The international community has repeatedly expressed concerns about the negative impact of HIC recruitment practices on access to healthcare services in LMICs (RTH 12). Compared to LMICs that had little negotiating power and posed little reputational risk, It was also easier for HICs to reduce recruitment of SHWs from LMICs when a global financial crisis discouraged government spending, domestic production of health professionals in HICs increased, recruitment of SHWs from other sources apart from those with critical shortages was possible, or when other political interests and language requirements made recruitment from LMICs less desirable.A change in recruitment behaviour was enabled when HIC governments operated a centralised health workforce management system  such that it was possible to implement an ethical code of conduct.In the absence of alternative options for meeting the rising demands for health services in their countries, HIC government’s concerns for reputational risk waned, and recruitment from LMICs continued.CMO2. When relevant stakeholders in LMICs and HICs demand improved access to healthcare services in LMICs, then HIC governments may recognise their obligation to achieve this through health workforce strengthening (M1). Such recognition is easier for HICs where a shared understanding of this obligation has been reinforced over time through engagements between relevant actors within and outside their borders (C1). However, if the financial cost of providing this support is high and unsustainable (C2), then they will either avoid commitment to workforce strengthening in LMICs (M2) or provide support that is time-bound and limited in scope (M3). This support by HIC governments may have no impact on SHW shortages in LMICs or lead to an initial (but unsustainable) increase in the number of enrolments into health training programs (O1), recruitments (O3), and their retention in the country (O5). For HICs with a history of recognising an obligation to LMICs, existing expectations from their citizens and the international community has enabled continuity of such supportive behaviour. As a result, HIC governments have provided funds for building more training institutions in LMICs ; scholarships for enrolment into speciality training programs that are a priority to populations in LMICs ; supported recruitment, remuneration and the provision of incentives for SHWs . These efforts have led to increased enrolment into professional health training programs, expansion of the existing health workforce, and retention of SHWs in LMICs.Governments of LMICs, health professional groups, and the news media in both HICs and LMICs have repeatedly argued that HIC governments should do more to protect access to health services in LMICs through health systems strengthening (RTH 11). It was also easy for HIC governments to commit to improving access to health services in LMICs when they identified mutually beneficial arrangements with LMIC governments . Collaborating with HICs often imposed an additional burden on LMIC health staff, who had to add the management of those partnerships to their routine health services.These outcomes were further enabled in LMICs with a centralised workforce management system, acting as the single point of entry and diffusion of HIC technical and financial support. For many LMICs, local training capacity for health workers was limited and required trainees to travel abroad. When present, training programs often led to an overproduction of health workers who either remained in the urban areas or migrated abroad. In other instances, available training staff were overstretched, raising concerns about the quality of training offered. Yet in other LMICs, high rates of HIV among young SHWs constrained efforts to increase the stock of SHWs, resulting in a predominantly ageing workforce. Many LMICs also experienced an economic downturn and had a cap on public employment, such that external funding constituted a significant part of health expenditure. As a result, it was common for HIC support to be time-bound, focused on vertical programs for diseases that were perceived to be public health threats , where outputs linked to inputs could be demonstrated and evaluated.For LMIC governments that relied mainly on HIC support for their infrastructural development, it was difficult to sustain these health workforce outcomes .CMO3: If LMIC state actors are presented with policy options inspired by the RTH and are not overly burdened with negotiating the trade-offs required to ensure its success (M1), then they will be motivated to work with these options. This response by LMIC state actors is possible when SHWs lead multi-stakeholder engagements to reduce the impact of migration on access to healthcare services (C1). Implementation of these policy options leading to a reduction in the rate of SHW migration (O5), increased enrolment into health professional training programs (O1), and an expansion of the current stock of SHWs in LMICs (O4) is easier to achieve when there are existing collaborations between state and non-state actors within and outside their countries (C2), and because these stakeholders are willing to share in the financial cost of achieving a compromise between SHWs’ right to migrate, and citizens’ access to health services (C3). They played a gate-keeping role for colleagues who sought verification for international employment, which reduced the rate of SHW migration to a HIC. Leveraging on existing regional and international networks, they designed initiatives to increase enrollment into training programs for health workers, their retention in LMICs, while ensuring that their countries benefit from SHW migration . Since SHWs provided leadership for communicating the benefits of these rights-based initiatives and were willing to bear the cost of negotiating a compromise between relevant stakeholders, it was easy for state actors to support their recommendations and accept them as part of their programs for achieving health workforce sustainability. Where interactions between multiple stakeholders in LMICs was absent, each pursued its interests, thus weakening existing capacity for monitoring and implementing health workforce initiatives.Following public concerns about availability, safety, and quality of health services in LMICs, SHWs remained committed to promoting their rights to migrate and took a leadership role in promoting initiatives to reduce the impact of SHW migration on access to health services (RTH 12). Even when there was a synergy between state and non-state actors, but the predominant reasoning was to make economic gains from the migration of SHWs to HICs, adopting a holistic approach to SHW shortages was difficult. Hence, where there was political stability and state actors were embedded in a network of stakeholders with a rich uptake of the RTH and a willingness to negotiate competing interests around increasing access to health services; it was easier to achieve increased retention of SHWs.Such interactions between state and non-state actors in LMICs were further constrained in the presence of political instability. During such periods, migration spikes were observed, leading to larger social networks abroad and a constant pull-effect on remaining SHWs.CMO4: Since disruption in the provision of health services will reflect poorly on state actors in LMICs (M1), they are willing to avoid or resolve industrial strike actions in the health system by taking steps that improve work conditions, favour an expansion of the existing workforce (O4), increase enrolments into health training programs (O1) and improve retention (O5). This response by LMIC state actors is made easier with support from other LMICs and constrained in the presence of poor socio-economic conditions (C1). This was easier to achieve in LMICs with health professional groups mobilised towards advocating for improved working conditions. It was constrained by worsening social and health inequities, insecurity, and national economic difficulties that exacerbated existing trends for SHW migration.When SHWs in LMICs strike to protest worsening working conditions, they draw state actors’ attention to a worsening health workforce crisis. Even though the agitations were not primarily concerned with improving access to health services, LMIC governments still sought to resolve the prevailing labour crisis. They responded by increasing remunerations for health workers, providing incentives, improving work conditions and increasing training programs. Without evidence of an implicit or explicit invocation of the RTH or strike action by SHWs in LMICs, some LMIC state actors have shown concerns for improving access to health services in their countries and addressing existing health inequities that arise due to shortages of SHWs (RTH 8).In other instances, external triggers did not precede state actors’ response to worsening SHW shortages in LMICs. This finding may especially be true in countries where commitment to public service and an egalitarian health system are encouraged. and improve service delivery from an existing stock of SHWs . They have also implemented policies to expand their stock of SHWs by increasing remunerations and offering work incentives, extending health workers’ retirement age, and sending SHWs to provide health services in rural areas. In addition, they have offered continuous professional development to existing SHWs and recruited from LMICs with health worker surplus . Where such LMICs were unable to fund their own training program, they leveraged on existing regional collaboration to support and achieve training initiatives .Without external triggers, LMIC state actors have considered options to expand health professional training systems,i) concerns about their reputational risk when their recruitment practices were criticised for impacting access to health services in LMICs, and (ii) a combination of recognising their obligation to support health workforce strengthening in LMICs, and concerns for the cost implication.We found that the RTH influenced the response of HIC state actors to SHW shortages in LMICs through two mechanisms. These include  over those of other countries . This supports other studies where prevailing norms of social justice and reciprocity offered utility for addressing health inequities in the absence of rights-based interventions. Even though the concepts of community, social justice, and human rights are often understood as separate entities, our findings reiterate those from other studies that have demonstrated how a sense of community and social justice can have a synergistic effect on rights-based approaches.Where state actors showed a positive response to SHW shortages in LMICs, we also found that the RTH was not always the motivation. The UN High Commission on Human Rights has described the use of a subjective approach  for examining state actors’ reasoning and behaviour towards the RTH as valid, provided there is transparency in the approach.To our knowledge, this is the first realist review that examined the utility of the RTH for addressing SHW shortages in LMICs. We included studies that implicitly referred to the RTH. This decision to include articles with implicit reference to the RTH is consistent with methods used by other authors where they mapped portions of government interventions to the normative components of the RTH. The RTH items we observed in this review were limited to the health system and included access to an equitable distribution of health facilities, goods, and services . It also includes access to essential medicines (RTH 4), a national public health plan based on epidemiological evidence (RTH 6), a workforce strategy, adequate remuneration/incentives , international cooperation and assistance (RTH 11), and steps taken to prevent violation of a country’s public health (RTH 12). We may have missed broader efforts  that address factors impacting SHW migration. The geographical spread our review represents suggests the reach of our program theories, where it can be tested and further refined.Workforce interventions are dynamic and emergent, and a complete understanding of their content may have been limited by the brief descriptions we provided in each paper. However, our study is consistent with the realist methodology, which seeks to explain analytically derived mechanisms rather than the actual contents of interventions.Our decision to focus on the behaviour of state actors (instead of SHWs) aligns with the United Nations Committee on Economic, Social and Cultural Rights. The United Nations committee places the obligation for the realisation of the RTH on state actors and their collaboration with non-state or foreign actors who can provide support. While our study acknowledges SHW shortage as a global problem, to promote health equity, we have focused on LMICs where a critical shortage of SHWs exist.Seeing that a similar study examined interventions aimed at addressing SHW shortages by focusing on their distribution within countries, our study contributes to the literature by addressing this from a perspective of international migration. Though improving the justiciability of the RTH may improve its utility for addressing SHW shortages in LMICs, our findings suggest that a combination of legal and non-legal mechanisms may be required for promoting accountability in the global governance of the health workforce and health professional migration. Promoting accountability among state and non-state actors worldwide is even more pertinent as the coronavirus disease 2019 (COVID-19) pandemic increases concerns about achieving a sustainable global health workforce.Judicial systems in many LMICs do not yet offer robust mechanisms for protecting the RTH. Furthermore, state and non-state actors in LMICs may need to rely on the RTH as a tool for increasing reputational risk for HICs and negotiating mutually beneficial workforce arrangements. However, the results of such negotiations may be short-lived in LMICs that lack strong public institutions and democratic systems for promoting accountability among relevant stakeholders. Hence, appropriate use of the RTH for addressing SHW shortages in LMICs will require capacity building for strengthening health, social, economic, and political systems in LMICs. Such capacity-building efforts will also need to consider SHWs not just as victims of push and pull migration forces but also as potential leaders in engagements between relevant stakeholders.Since human rights are interdependent and indivisible, the RTH by itself will offer little utility for addressing SHW shortages in LMICs and will require the presence of other socio-economic  and political rights. As a conceptual resource, the RTH (either explicitly or implicitly) can influence the reasoning and behaviour of state actors towards addressing SHW shortages in LMICs. Its utility for addressing these shortages may be realised when state actors in HICs are exposed to reputational risk. Getting the desired response from HIC state actors will require a high capacity for global health diplomacy among relevant stakeholders in LMICs, and their ability to lean on the RTH as a resource for negotiating mutually beneficial workforce initiatives. Realising the utility of the RTH for addressing SHW shortages in LMICs will also require multi-stakeholder engagements. Such engagements should include SHWs not just as victims of the push and pull forces of migration but as relevant stakeholders willing to use the RTH as a resource for promoting collective action within and between LMICs and HICs. It will also require the willingness of LMIC state actors to harness available resources and expertise within and outside their countries for strengthening health, social, economic, and political systems. Simultaneous considerations for reducing the transactional cost of maintaining these engagements, incorporating the RTH into domestic judicial systems, and implementing the policy options they yield, will be needed. It will also require a critical number of state and non-state actors in LMICs and HICs who are committed to the concepts of social justice and an inclusive global community. We would like to thank Drs. Emmanuel Laabes , Joshua Sule (Nigeria), Klaus von Pressentin (South Africa), Innocent Besigye (Uganda), and Murtaza Haiderbhai (Tanzania) for their feedback on the initial program theory for this review. Since this is a review of the existing literature, no ethical approval was required. Authors declare that they have no competing interests. KY and CB conducted the literature search, screening, and extraction of relevant data. KY conducted the realist analysis and received feedback from all the co-authors. KY wrote the first draft of the manuscript, which all co-authors reviewed and made contributions for improving its intellectual content. All authors agreed on the final draft. RJ is the senior author for this study. The authors alone are responsible for the views expressed in this publication and these do not necessarily represent the views, decisions, or policies of The George Institute for Global Health, University of New South Wales (UNSW), Australian National Heart Foundation, or the Australian National Health and Medical Research Council. KY is supported by the Scientia PhD Scholarship at UNSW. RJ is a Scientia Fellow at UNSW and is supported by a Future Leadership Fellowship from the Australian National Heart Foundation (102059). DP is supported by fellowships from the National Health and Medical Research Council of Australia (1143904) and the Heart Foundation of Australia (101890). SA is supported by the Australian National Health and Medical Research Council (NHMRC) through an Overseas Early Career Fellowship (APP1139631).Supplementary file 1. Search Strategy.Click here for additional data file.Supplementary file 2. RAMESES Publication Standards: Realist Syntheses.Click here for additional data file.Supplementary file 3. Studies Included in the Review, and Their Corresponding Right to Health Items.Click here for additional data file.Supplementary file 4. Formal Theoretical Perspectives.Click here for additional data file.


Physician mental health is critical during the recovery of natural and human-made disasters (NHDs), yet the accessibility of mental health resources to physicians has not been characterized. This study examined emergency medicine and trauma physician knowledge of and access to mental health resources in NHD settings.The survey was electronically disseminated to the American College of Emergency Physicians and the American Association of the Surgery of Trauma between February 4, 2020, and March 9, 2020. The 17-question survey assessed physician awareness and access to emergency preparedness resources at their institutions.Of the responders, 86% (n = 229) were aware of written emergency response plans for their facility. While 31% were aware of the hospital’s mental health policies and resources outside of the emergency response plan, only 25% knew how to access these resources during and after NHDs. Finally, 10% reported the incorporation of mental health resources during institutional practice drills.Physicians reported knowledge of emergency preparedness policies; however, significant gaps remain in physician knowledge and access to mental health resources NHD settings. As NHDs increase on a global scale, it is critical for health systems to ensure accessible infrastructure to support the mental well-being of health professionals. NHDs often necessitate that physicians work in areas of devastated health care infrastructure, profoundly limited resources, and surges in acute and chronic care patients. Thus, the mental health of hospital physicians is a key issue during and after NHDs.The treatment of people affected by natural and/or human-made disasters (NHDs) is a critical aspect of emergency management, and physicians are amongst those at the front lines of administering this care.Physicians are exposed to a triple threat as they are victims of the NHD, responsible for providing emergent and ongoing care for their community, and must deal with the complex decision making of staying to deliver care or moving to safe places to protect themselves and their families. A growing body of literature highlights that high stress environments can result in negative mental health outcomes and burnout in physicians, leading to decreased workplace productivity and decreased quality of patient care. Prior to COVID-19, few studies have provided a systematic assessment of physician preparedness for a diverse set of health emergencies, much less the accessibility of mental health resources for physicians surrounding NHDs.Disasters such as the 2011 Fukushima Nuclear Disaster, 2012 Superstorm Sandy, 2015–2022 California wildfires, and the coronavirus disease (COVID-19) pandemic have underscored a critical gap in data on physician mental health following disasters. Strong mental health support systems and system resilience will provide an environment in which physicians can provide essential medical care to affected populations during an NHD.The frequency and severity of global natural disasters have increased threefold since 1975, and the increased global burden of disease as a result of climate change and strained health care infrastructure threatens to compromise workforce mental health.Physician Emergency Preparedness Survey, a 60-question survey that asks physicians about how they view preparedness for emergency situations. Specifically, this survey examined United States physicians’ assessments of their NHD preparedness, training, and perceived support needs. They found that approximately 44% hospital physicians did not know whether their institution had an emergency response plan. The study did not explore the accessibility of mental health resources to physicians in those settings.Researchers at Harvard T. H. Chan School of Public Health developed The This study examined physicians’ knowledge of and access to mental health resources at their institutions surrounding NHDs. While this study was initiated 2 years before the COVID-19 pandemic took hold in the United States, the pandemic has further highlighted the importance of this work. A review of available studies in databases including PubMed and Google Scholar revealed no prior peer-reviewed national studies assessing physician awareness of mental health resources in the setting of NHDs.A 17-question survey collecting information on physician awareness of and access to emergency preparedness resources at their institutions was administered nationally to practicing emergency medicine and trauma surgeon physicians. The survey, which was approved by the American College of Emergency Physicians (ACEP) research team, was distributed electronically to members of ACEP and AAST from February 4, 2020, to March 9, 2020. No incentives were offered for participation. The Institutional Review Board (IRB) granted this study exempt status.Physician Emergency Preparedness Survey. In 2019, the survey was initially validated by Pennsylvania State Health emergency medicine and trauma physicians, and subsequently approved by Emergency Medicine Practice Research Network (EMPRN) at ACEP.Researchers at Penn State College of Medicine developed the survey based on the The survey included 17 questions on details of institution-specific written emergency response plans and physician awareness of and access to mental health resources surrounding NHDs Appendix ppendix ANHDs were defined as (1) natural disasters , (2) chemical, biological, radiological, nuclear, or explosives (CBRNE) incident, (3) mass outbreak, and (4) mass shooting. Mental health resources include, but are not limited to, a mental health professional available to physicians during and after NHD; trainings during and after NHD on how physicians are to deal with the traumatic consequences of the NHD; creation of “safe spaces” for physicians to process NHD consequences; mental health professional monitoring, limiting, and rotating individual physicians when providing care during and after NHD; and mental health screening of physicians during and after NHD.Statistical analysis was performed using SPSS, version 25.0 . Descriptive analysis was used to report frequencies for all items in the questionnaire for ACEP and AAST participants together. In addition, responses of physicians practicing at Level 1 Trauma Centers were compared to physicians practicing at Non-Level 1 using chi-square analysis to explore differences by the Trauma Center Level.Responses were categorized by demographics, knowledge components of written emergency response plan, and physician views on mental health resources. There were no differences in responses by gender, but significant differences were found between Level 1 Trauma Center and Non-Level 1 Trauma Centers.P = 0.000) and to work in urban inner-city settings (P = 0.000).Of those who completed the survey (n = 229), 80% were white, 75% were male, and 80% were > 10 years out of graduate training; 76% reported working at a trauma center, and over 59% were based in urban inner-city environments . RespondOf the respondents, 86% were aware of an emergency response plan for their facility, 72% knew the communication plan to link all providers and administrative staff at home or in the care setting, 70% knew the roles for each staff member, and 49% knew information sources for treating illnesses and injuries related to different kinds of emergencies and triage plans with the names of alternative locations of care. Only 20% of respondents indicated that this written response plan included policies that addressed physician mental health during and after an NHD .P = 0.521).On all items, physicians practicing at Level 1 Trauma Centers were more likely to be aware of the components of the written emergency response plan. However, there was no difference between physicians practicing at Level 1 and Non-Level 1 Trauma Centers in their knowledge of whether the written plan addressed mental health needs during and after an NHD . However, there were no differences in their knowledge of means to access hospital NHD mental health resources, awareness of ACEP and AAST disaster guidelines, and use of these resources in practice drills.Physicians working at Level 1 Trauma Centers were more likely to be aware of NHD mental health policies compared to those working at Non-Level 1 Trauma Centers . Yet, only 13% of physicians have sought treatment to address pandemic-related psychological concerns due to fear of stigma and harming their reputation.A comprehensive review of physician emergency preparedness by SteelFisher et al. (2015) demonstrated continuing barriers to physician preparedness, despite federal investment in physician and health system preparedness. The COVID-19 pandemic exemplifies the stress that frontline workers are under. Hospitals and health care system leaders must seek ways to implement and communicate accessible mental health resources to physicians.Additional examination of changes in the accessibility of mental health resources available to physicians in the setting of NHDs after the COVID-19 pandemic may reveal ways to improve emergency preparedness. However, no study has reported on the accessibility of mental health resources to frontline physicians surrounding NHDs. The COVID-19 pandemic underscores the need for training of public health emergencies, and the recovery provides a critical opportunity for the health systems to prepare their workforce for future crises. As large-scale public health crises like this cripple global supply chains, strain hospital resources, and limit hospital capacity, the increasing strain on personal health care becomes increasingly problematic.Previous studies have reported adverse psychological reactions among frontline workers in the setting of the 9/11 terrorist attacks, wildfires, nuclear incidents, and major infectious disease outbreaks.This is the first study examining physician awareness and accessibility of mental health resources during NHDs in a national sample of Emergency Medicine and Trauma Surgery physicians who were members of ACEP and AAST. This study was conducted prior to the COVID-19 pandemic in the United States and provides a baseline that will allow the comparison of mental health resource accessibility in the post COVID-19 era. It will help assess whether the resources are now being better redirected toward this issue.This study was conducted prior to the COVID-19 pandemic and may not be reflective of current physician attitudes and knowledge. Furthermore, this survey was administered to only Emergency Medicine and Trauma Surgery physicians as a sample of physicians working on the front lines during NHDs and should be expanded to all frontline workers during a diverse array of NHDs. Finally, this survey did not consider participants’ prior exposure to NHDs. However, this study provides a baseline to compare the impact of NHDs, like COVID-19, on physician mental health emergency preparedness. It reinforces the need for easily accessible mental health infrastructure in disaster preparedness protocols.With the increasing frequency and severity of NHDs in the setting of the climate crisis, the findings in this study provide much needed direction for the development of robust, easily accessible mental health resources for physicians on the front lines of emergency response. This study demonstrates that easily accessible mental health resources within emergency response plans are critical in the recovery from the COVID-19 pandemic and provides an opportunity for growth in recovery. This will improve resilience among health systems and physicians, thus improve their personal and professional lives and their patient interactions.An understanding of the extent of mental stress levels among physicians in NHD will help formulate robust health policies to be adopted by hospitals and other agencies .


To compare the medicines for mental disorders included in national essential medicines lists with the World Health Organization (WHO) essential medicines list and assess the extent to which economic status and WHO Region account for the differences.We searched WHO repository and government sites for national essential medicines lists and we abstracted medicines for mental disorders. We calculated the proportion of WHO essential medicines included, the total number of differences (counting both additions and deletions) between national and WHO model list and the proportion of lists including one second-generation oral antipsychotic plus one new-generation antidepressant. Non-parametric statistics was used to investigate whether these indicators were dependent on economic status and WHO Region.p < 0.001) and the number of differences , implying that countries with higher income level included more WHO essential medicines, but also more additional medicines. Significant differences were observed in relation to WHO Region, with the African and Western Pacific Region showing the lowest proportions of WHO essential medicines, and the European Region showing the highest median number of differences. Overall, 88 national lists  included at least one second-generation oral antipsychotic and new-generation antidepressant, with differences by income level and WHO Region.Amongst the 121 identified national lists, the total number of medicines for mental disorders ranged from 2 to 63 . The median proportion of WHO essential medicines for mental disorders included was 86% (IQR: 71–93%), with 16 countries  including all WHO essential medicines, while the median number of differences with the WHO EML was 11 (IQR: 7 to 15). Country economic level was positively associated with both the proportion of WHO essential medicines included (Spearman's rho = 0.417, The degree of alignment of national lists with the WHO model list is substantial, but there are considerable differences in relation to economic status and WHO Region. These findings may help decision-makers to identify opportunities to improve national lists, aiming to increase access to essential medicines for mental disorders. Since 1977 an essential medicines list (EML) has been drawn up by the World Health Organization (WHO) to provide countries with a guide in their own choices for national EMLs , 3. EsseIn the field of mental healthcare, access to evidence-based treatments remains a huge global challenge . More thAgainst this background, the present study compared the medicines for mental disorders included in national EMLs with those included in the WHO EML, aiming to determine the degree of alignment of country choices with WHO recommendations, and whether economic status and WHO Region accounted for the differences.The 21st WHO Model List of Essential Medicines was accessed to identify essential medicines for mental health conditions. Medicines listed in the following categories of the section on mental and behavioral disorders were included: medicines used in psychotic disorders, medicines used in mood disorders (including depressive and bipolar disorders), medicines for anxiety disorders and medicines used for obsessive compulsive disorders. For each mental health condition, the listed essential medicines were extracted, recording whether they were included as individual medicines or as representatives of a specific pharmacological class. In the latter case, the WHO Model List of Essential Medicines includes an accompanying ‘square box’ symbol . For eacNational EMLs were accessed from the WHO repository of National Medicines List/Formulary/Standard Treatment Guidelines. From each national EML, we abstracted all medicines for mental disorders, and we recorded which of these were also included in the WHO Model List of Essential Medicines . OfficiaFor identified countries with national EMLs, we collected information on WHO Region, population size, and gross domestic product (GDP) per capita. Data on WHO Region was obtained from the WHO Global Health Observatory , while dIn order to compare the EMLs of each country with the WHO Model List of Essential Medicines, the following indicators were calculated, in line with the methodology described by Taglione and colleagues and Persaud and colleagues , 15: proFor descriptive data, medians with interquartile ranges (IQRs) were calculated for continuous variables, and proportions with 95% confidence intervals (95% CI) for categorical variables. Spearman's rho was used to determine whether continuous variables were associated with country income level, expressed as GDP per capita. For binary variables, two-sample Wilcoxon rank-sum (Mann–Whitney) test was used to investigate their association with GDP per capita. Kruskal-Wallis test was employed to assess whether continuous variables differed in relation to WHO Region , while Pearson’s chi squared was used to investigate the association between binary variables and WHO Region.p < 0.001) and the number of differences , implying that countries with higher GDP included more WHO essential medicines, but also more additional medicines not included in the WHO Model List of Essential Medicines. However, in low-income countries the median proportion of WHO essential medicines included in national EMLs was 79% (IQR: 71–86%), with only five countries below 70%. Both the proportion of WHO essential medicines included in national EMLs  and the number of differences  differed by WHO Region, with the African and Western Pacific Region showing the lowest proportions of WHO essential medicines, and the European Region showing the highest median number of differences.We identified 121 national EMLs posted on the WHO repository and on government sites. The total number of medicines for mental disorders extracted from the WHO model list of essential medicines was 14: chlorpromazine oral formulation, chlorpromazine injection, fluphenazine injection (decanoate or enantate), haloperidol oral formulation, haloperidol injection, risperidone oral formulation, clozapine, amitriptyline oral formulation, fluoxetine, carbamazepine, lithium carbonate, valproic acid, diazepam, clomipramine. The total number of medicines for mental disorders on each country’s list ranged from 2 to 63 . Table Interestingly, of the 16 countries including all WHO essential medicines for mental disorders, three countries included less than five additional medicines, namely Indonesia , Lebanon (three), and Pakistan (one), resulting those with the highest alignment with the WHO list.p < 0.001). The distribution of countries with at least one second-generation oral antipsychotic and new-generation antidepressant differed by WHO Region , with the African and Western Pacific Region showing the highest rates of counties non including any newer medicines recommended by WHO  included at least one second-generation oral antipsychotic and new-generation antidepressant, with differences by GDP  developed a standardized methodology to conduct such surveys , and regAnother important implication comes from the finding of high alignment with WHO recommendations in geographical areas with limited resources, as it shows that it is possible to follow WHO recommendations with a limited health care expenditure. However, in some countries of the African and Western Pacific Region, alignment was found to be still very low. In these countries decision-makers may want to consider the example of other countries with similar economic development to revise their national selection process, aiming to include and increase access to a very selected number of medicines for mental disorders. Decision-makers should consider that access to psychotropic medicines may be considered a proxy of access to mental healthcare, and increasing access to essential medicines for mental disorders may give the chance for a transformative improvement of the whole mental healthcare system, offering a unique opportunity for re-engagement in society by people suffering from mental disorders. By working at all levels of the health system, it may be possible to offer this essential component of mental health care to all who can benefit.Overall, this study provides evidence on the global relevance of the WHO Model List of Essential Medicines as a reference standard for the pharmacological treatment of mental disorders. This evidence should urge WHO to try to keep this tool regularly updated. Over the last ten years the WHO has made a tremendous effort to produce, and regularly update, a number of evidence-based tools in the area of mental health, including recommendations –26, evid


It is widely known that exercise improves inhibitory control; however, the mechanisms behind the cognitive improvement remain unclear. This study analyzes the extant literature on the neuronal effects of exercise on inhibitory control functions. We searched four online databases  for relevant peer-reviewed studies to identify eligible studies published before September 1, 2021. Among the 4,090 candidate studies identified, 14 meet the inclusion criteria, and the results of 397 participants in these 14 studies are subsequently analyzed. We quantify the neural effects on the entire brain by using GingerALE software and identify 10 clusters of exercise-induced neuronal with either increases/decreases in the superior temporal gyrus (BA 22), precuneus (BA 7), superior frontal gyrus (BA 10), cuneus (BA 19), precuneus (BA 19), caudate, posterior cingulate (BA 19), middle temporal gyrus (B 37), parahippocampal gyrus (BA 30), precentral gyrus (BA 6). Meta-analytic coactivation map (MACM) showed that multiple functional networks overlap with brain regions with activation likelihood estimation (ALE) results. We propose the effect of exercise on neural activity is related to inhibitory control in the extended frontoparietal, default mode network (DMN), visual network, and other pathways. These results provide preliminary evidence of the neural effects of exercise on inhibitory control. Inhibitory control or inhibition is defined as suppressing prepotent responses to goal-irrelevant stimuli and contributes to anticipation, planning, and goal setting. Inhibitory control is one of the three core executive functions of the brain Aron, . People Physical activity has garnered significant attention as a potentially effective method for elevating cognitive function and improving brain health throughout life  is a relatively way to estimate the probability that at least one activation focus from a set of experiments lies at the location of a specific voxel, using Gaussian assumptions of spatial uncertainty . The protocol was registered as trial registration number CRD42021285736 under the International Prospective Register of Systematic Reviews (PROSPERO).Four electronic databases  were searched from their inception to September 1, 2021, to identify all published studies on functional magnetic resonance imaging (fMRI) that investigate the impact of exercise on the activation of different brain areas during inhibitory control tasks. The initial search used three key terms: physical activity or exercise, inhibitory control, and fMRI. We also hand-searched recent systematic reviews and meta-analyses to identify potential studies . For inclusion, retrievable data in standard Talairach or Montreal Neurologic Institute (MNI) space was also required. Finally, the chosen studies included randomized controlled trials (RCTs) and non-randomized controlled trial studies (NRCTs) published in peer-reviewed journals.The screening for relevant studies was conducted in accordance with the PICOS  principles. The participants included individuals of all ages and pathologies. The studies must have investigated the effect of exercise on inhibitory control and examined pre/post-intervention with at least one group assigned to physical activity/exercise intervention. During fMRI scanning, studies must have assessed brain activation patterns Two reviewers independently conducted the multi-step search process based on these selection criteria and screened the studies based on their title and abstract. Full-length texts were eventually used to identify eligible articles. If consensus could not be reached, a third reviewer made the final decision after discussion with the two reviewers.A standardized data extraction form was developed to extract relevant data from each study, including the bibliographic details (author and year), participant characteristics , intervention components (intervention design and duration), fMRI task, software used, and active results/foci.The Physiotherapy Evidence Database (PEDro) scale, a reliable and valid instrument for assessing the methodological quality of studies that focus on the effects of physical activity on cognitive functions, was used to determine the methodological quality  software is used to analyze the data. A statistical threshold of uncorrected p < 0.001 and a minimum cluster size of 100 mm3 were used  software and overlaid on an anatomical template in MNI space for visualization. The effect of exercise on behavioral performance is not examined due to missing data and changes in an inhibitory control task that resulted in the effect magnitude being inestimable.The ALE is a reliable quantitative method for coordinate-based meta-analyses to identify brain activation during cognitive functions after exercise . Namely, a z-score is assigned to each voxel, representing the strength of the association between a given voxel and the seed coordinates.Additionally, to obtain the MACM based on the ALE results, we followed the procedure proposed by Robinson et al.  as impleFour thousand and eighty-eight studies were identified from the four databases, and two studies were identified from other systemic reviews. Included studies were chosen after thoroughly screening the titles, abstracts, and full text. Fourteen studies were identified for the meta-analysis .M = 6.71). Notably, none of the studies reported blinded data due to the difficulties of using blinded subjects, therapists, and assessors in an exercise intervention. The studies that failed to obtain points in other criteria due to their study design include lack of eligibility (n = 1), random allocation (n = 9), and concealed allocation (n = 10).n = 13), scan rejection reason (n = 14), the method for motion correction (n = 7), volume acquired per session (n = 14), and clear descriptions of the first (n = 8) and second level contrasts (n = 7).Among the 14 studies that assessed brain activation during inhibitory control tasks after exercise, the exercise groups (EGs) show increased brain activation compared to the control groups (CGs) in six clusters: (1) superior temporal gyrus (BA 22), (2) precuneus (BA 7 and BA 19), (3) superior frontal gyrus (BA 10), and (4) cuneus (BA 19). Five regions showed reduced brain activation: (1) caudate gray matter, (2) posterior cingulate cortex (BA 31), (3) middle temporal gyrus (BA 37), (4) parahippocampal gyrus, and (5) precentral gyrus (BA 6), as shown in Coactivation maps were plotted after the MACM analysis, as shown the The primary aim of the ALE meta-analysis in this study is to offer the first quantitative summary of the effect of exercise on increased and decreased neural activity of different brain areas during inhibitory control tasks. We identified five clusters of increased neural activity  and five clusters of diminished neural activity  following exercise. MACM analysis suggested that inhibitory control involved multiple functional networks. These findings may help identify the underlying mechanisms of increased inhibitory control that are exercise-induced.Previous work found that the neurophysiological mechanism that controls movement is located in the prefrontal cortex (Niendam et al., The superior frontal gyrus is also part of the prefrontal cortex, which is responsible for cognitive control functions. This is closely connected with high-level cognitive functions such as interference inhibition, conflict solving, and selective attention (Cabeza and Nyberg, Our findings showed one change in brain activity in the parietal lobe is the precuneus. The precuneus region is an essential area for attention selection and response to conflict (Indovina and Macaluso, Besides, the finding showed that three regions' activity changed, including the superior temporal gyrus, middle temporal gyrus, and caudate in the temporal lobe during inhibitory control tasks. It is worthy to note that the superior temporal sulcus typically provides the amygdala with visual information that contributes to identifying the affective or motivational significance of visually perceived objects (Arzimanoglou et al., via the indirect pathway (Jahfari et al., It has been proven that the caudate is one of the primary input nuclei receiving inputs from the prefrontal cortex and transferring information to the basal ganglia (Kunishio and Haber, Finally, we found posterior cingulate gyrus and parahippocampal gyrus have activation changes, and these two regions both belong to the limbic structures. The posterior cingulate gyrus is close to the limbic system and belongs to the cortical region functioning as a gateway between the limbic system and the midbrain and diencephalon (Li et al., The parahippocampal gyrus is an active region in the limbic system, and exercise intervention appears to strengthen their neuronal excitability, increase the volume of white matter/gray matter, and positively change the production of brain-derived neural factors (Li et al., There are some limitations to this study. First, only 14 studies are included, which is a smaller sample size. As a result, a subgroup analysis of the exercise intensity and type of exercise is challenging. Second, this study contains different inhibitory control tasks; although the flanker, go-no-go, and stroop tasks are all standard tasks for measuring inhibitory control, the components are slightly different.Neural mechanisms increase exercise-induced inhibitory control by changing the activation of single and multiple brain regions. We guess that critical areas mediate inhibitory control and are associated with the frontoparietal, visual network, DMN, and other pathways. However, due to the lenient threshold used in the ALE analysis, further research with more rigorous methods is required to link exercise to neuroplasticity changes with respect to inhibitory control.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.JW and ZR were responsible for the conceptualization, investigation, and hypothesis of the research. JW and WX conducted systematic search, data extraction, quality assessment, and data analyses. JY, KZ, LP, OT, and ZR reviewed and edited the initial draft and revisions. All authors contributed to the article and approved the submitted version.The article was supported by Research Foundation for Young Teacher of Shenzhen University [grant number QNJS0274]; High-level Scientific Research Foundation for the Introduction of Talent of Shenzhen University [grant number RC00228]; and Natural Science Featured Innovation Projects in Ordinary Universities in Guangdong Province [grant number 2021KTSCX297].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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This review deals with such futuristic applications of biophotonics like miniature living lasers, wireless remotely controlled implantable and cellular optoelectronics for novel imaging, diagnostic and therapeutic applications. We begin with an overview of the competency and progress in biophotonics as one of the most active frontiers in advanced analytical, diagnostic and therapeutic modalities. This is further followed by comprehensive discussion on recent advances, importance and applications, towards miniaturization size of laser to integrate into live cells as biological lasers, and wearable and implantable optoelectronic devices. Such applications form a novel biocompatible platform for intracellular sensing, cytometry and imaging devices. Further, the opportunities and possible challenges for future research directions to transform this basic research to clinical applications are also discussed.Advancements in light technology, devices and its applications have tremendously changed the facets of biomedical science and engineering to provide powerful diagnostic and therapeutic capabilities ranging from basic research to clinics. Recent novel innovations and concepts in the field of material science, biomedical optics, processing technology and nanotechnology have enabled increasingly sophisticated technologies such as cellular scale, wireless, remotely controlled micro device for  Biophotonics uses innovative and transformative light-based technologies for understanding and manipulating biological systems at the molecular, subcellular, cellular, tissue, and organ levels in a non-invasive manner, which exclusively depends on the interaction of light with biomolecules and tissues at nano, micro and macro scales as represented in Figure The term photonics coined by the French physicist Pierre Aigrain in 1967, is a branch of science and technology that deals with all methodologies and technologies of light and its interaction with any matter in vitro and in vivo imaging. While on the other hand due to widespread applications and advances in endoscopic technique as minimally invasive procedures for treatment and diagnosis has led to surface imaging as the fastest growing segment As per market analysis, the global biophotonics market size is expected to reach $63.1 billion by 2022 from $31.6 billion in 2015 Biophotonics is no longer confined to optical properties of light and simple engineering technology. The introduction of nanotechnology in biophotonics has greatly expanded various novel scope and unique capabilities in diagnostics to therapeutics. The use of nanostructured materials such as robust contrast agents, fluorescent probes, sensing substrates and quantum dots have already revolutionized the field of biophotonics in vivo cellular and implantable levels emphasizing their potential applications as micro and nano-fabricated tools with respect to present and future diagnostics and therapeutics.The field of nano-biophotonics is much broader hence this review tries to create a constructive overview of some of the major advances in certain important selected topics in the field of miniature living lasers, wireless remotely controlled implantable and cellular optoelectronics. Some reviews published in the field of biolasers and integratable optoelectronic microprobes focusing more on their basic concepts, designing strategies, potential multifunctional materials and their potential biological and biomedical applications in bio and/or chemical sensing th anniversary in 2020. The conceptual foundation of Laser technology dates back to 1916, when for the first time Albert Einstein proposed the concept of “Stimulated Emission” stating that the photons could stimulate the emission of identical photons from excited atoms. His concept of “Stimulated Emission” became the foundational principle of all laser operations The LASER (Light Amplification by Stimulated Emission of Radiation) technology celebrated its 602, etc), organic dyes, semiconductors and solid materials  etc. as lasing materials As shown in Figure Along with the invention of Lasers, application of Lasers in medicine shares a history of 60 years. Soon after the invention of first working prototype of ruby laser in 1960, Dr. Leon Goldman reported the first ever application of lasers in medical field in 1962. For which, Dr. Leon Goldman, is regarded as the “father” of lasers in medicine and surgery. He used lasers for dermatology, to treat a variety of pigmented lesions (melanoma) and showed selective destruction of skin pigmented structures by ruby lasers. Following which in 1963, McGuff used ruby laser in cardiovascular surgery for ablation of atherosclerotic plaques. With encounter of difficulties of ruby laser for controlling the power output, like light delivery rate and poor absorption by some types of tissues, necessitated the discovery of new laser types. Later, in 1968, F. L'Esperance, E. Gordon, and E. Labuda successfully used an argon ion laser for the treatment of diabetic retinopathy. The surgical uses of various types of lasers were investigated extensively from 1967 to 1970 by many great pioneers T. Polanyi, G. Jako, V. C. Wright and I. Kaplan in otolaryngology, gynecological and latter for general surgeries. After more advancement in laser technology and longtime of investigations, first clinical applications of lasers were performed by Choy and Ginsburg in 1983 for angioplasty in coronary and peripheral vessel The unique properties of laser light such as monochromaticity, coherence, directionality, high brightness, and generation of a focused narrow beam of light has made the applications of laser radiation in medicine so important. Being faster, less invasive, with better accuracy and a greater intervention effect, lasers have greatly revolutionized the field of medicine ranging from surgery and therapeutics to diagnostics which has been represented in Figure Biological lasers or biolasers make use of biocompatible, biological and/or natural molecule as lasing medium and/or part of its cavity for optical feedback and can also constitute passive optical components that tune the laser output by modulating the system's effective refractive index Although it sounds fascinating investigation of biological lasers started long back in 1970s. Arthur Schawlow's and Theodor Hänsch developed first ever edible laser by adding a dye, sodium fluorescein, to unflavoured gelatin in vivo biological processes at the cellular and molecular level with the advantages of proving visible, quantitative and real time analysis. However, the broad emission spectra of these fluorescent probes limit their applications in high-resolution imaging, spectral multiplexing and ultra-sensitive bio-sensing.The need for investigating various life reactions within the living human body and single cell level has led to the development of molecular biosensing and bioimaging techniques. Such techniques depend on the reliable, sensitive, fast, and reproducible detection of the interactions between various biomolecules which allows understanding of the biological complexities, various disease processes, medical diagnosis, targeted therapeutics, and molecular biology in vivo optical amplification within biological systems have gained great importance for intracellular sensing, cytometry and imaging by overcoming the limitation of optical microscopy or fluorescence imaging modalities due to poor penetration depth of light in biological tissue and also due to better spectral, spatial, and temporal characteristics than fluorescence based imaging or detection as represented in Figure To address this issue, intracellular laser probes, with the advantage of narrow bandwidth, strong coherence, and threshold-gated nonlinear emission were proposed Humar et al., demonstrated the comprehensive design principles of cell lasers using various fluorescent organic dyes as a convenient gain medium, cell types, and laser configurations Figure . ImportaAlthough fluorescent proteins had shown promising results as gaining materials but major issue with these proteins is their probability of eliciting immune response due to their foreignness. In this regard, Yun et al., demonstrated a miniature all-biomaterial laser, using U.S. Food and Drug Administration (FDA) approved biomaterials known as Generally-Recognized-AsSafe (GRAS) substances. They exploited the fluorescence property of intrinsic biomolecule Flavin mononucleotide (FMN) and vitamin B2 as a potential candidate for gain medium which showed high efficiency for permitting low lasing thresholds on the order of tens of nanojoules. Furthermore, vitamin encapsulated glycerol-mixed microspheres acted as a microdroplet-based whispering gallery mode (WGM) resonator in vivo biophysical and biochemical processes. Depending on the applications, optical cavities can vary from planar to circular-shaped microsphere and ring resonators Most of the studies in biological lasers mainly deal with different approaches and advancements in optics and optical devices to generate laser emission within the cell, but more important to this approach is how to couple the laser output with the intracellular or in vitro biological lasers into in situ and in vivo, more like tissue microlasers. However, translational research suffers from several challenges which includes: (a) chemical stability in aqueous biological medium; (b) decreased refractive index contrast between the laser material and its surrounding; and (c) biocompatibility and biodegradability issues of potential lasing material, microresonator and optical pump. Further, the intracellular lasers should operate in the spectral region with minimum tissue absorption and scattering, and can easily be integrated with other in vivo bioimaging techniques and microscopy Q-factor optofluidic ring resonator in human whole blood. ICG lasing was only accomplished when ICG binds to serological components such as albumin, globulins and lipoprotein in vivo temperature sensing Besides designing and applications of biological lasers with the different biological lasing medium it is of great interest to translate +2 channel blocker) on contractility of neonatal cardiomyocytes, real time measurement of complete contractility profiles for the beating heart in live zebrafish. Moreover, this have also been used as a robust contractility sensor at subcellular resolution, in thick living myocardial slices (~ 100s of µm) of rat heart tissue, which is even not achievable with multiphoton microscopes in vitro and in vivo with enhanced contrast for dual-modality tracking and imaging via both OCT and fluorescence microscopy 3+-doped upconversion nanoparticle with energy-looping excitation mechanism coated onto polystyrene microbeads as WGM microresonators was developed by Fernandez-Bravo et al. These microlasers showed their lasing activity when submerged in serum with an emission at 980 nm when excited with 1064 nm light The real time cell tagging and tracking is one of the most reliable techniques for understanding the complexity of biological processes and systems down to single-cell analysis. Many studies have shown the utility of intracellular microlasers with spectral multiplexing capability and improved optical properties for cell tagging and tracking applications. Laser particles made up of silica-coated semiconductor microcavities, generating single narrowband emission peaks have been utilized for large-scale, comprehensive single-cell analysis. These stable and biocompatible Laser particles identified tagged cells at single cell level using Laser pArticle Stimulated Emission (LASE) microscopy in a 3D breast cancer cell tumour spheroid model Further, microlaser based lasing emissions have been used for imaging and mapping, where the light emitted by tiny intracellular laser particles can produce images to provide biomolecular and morphological information about the cells, particularly valuable for deep tissue imaging. For example, LASE microscopy offers the advantage of subdiffraction resolution, low out-of-focus background and 3D optical sectioning, required for imaging of thick biological tissues. LASE microscopy is fundamentally based on the principle of excitation of nano/micro- laser particles by a tightly focused optical pump beam with nonlinear power dependence stimulated emission of narrow spectrum. LASE microscopy offers the advantage of a standalone submicron size laser, where it uses single-photon absorption  to generate stimulated emission only at the focal volume without the need of a pinhole or complex illumination or detection schemes as required in confocal laser scanning microscopy and two-photon microscopy in vitro monitoring of as low as nM concentration of Ca2+ ion dynamics and activities in single neurons and massive neuronal networks. Compared to a conventional fluorescence-based recording, LEM based recording showed about 100 times enhancement in sensitivity to detect intracellular Ca2+ ion fluctuations Other than cancer detection, Chen et al., employed LEM for in vivo optical fluorescence-based mapping, contact/temperature monitoring, pH and electrical impedance sensing, radio frequency ablation and localized photo/chemotherapy Optoelectronics which is often considered as a subdiscipline of photonics, combines both photons and electronics and deals with applying electronic devices to the sourcing, detection and control of light. Optoelectronic devices are transducers that basically rely on light-matter interactions and electronic properties of matter to convert light into an electrical signal or vice versa. Optoelectronic devices are complex systems combining optics, electronics, mechanics and software all in the same system and involved in study of light emission and detection using light sensitive devices and light generating components in vivo biomedical applications Implantable optoelectronic systems that can be easily integrated within the body provides a promising diagnostic and therapeutic potential for basic research and clinical medicine in vivo monitoring of vital biophysical, electrophysiological, biochemical signals and further can be extended for cardiac/brain disorders treatments in situ, real-time evaluation and differentiation between malignant tissues from benign tissues. In this respect, Lee et al., engineered and reported a proof-of-concept miniaturized prototype optoelectronic sensor compatible with a 19-gauge fine-needle aspiration needle for rapid, volumetric, and quantitative multisite tissue optical sensing for pancreatic tissue assessment. This prototype was proposed to a promising step towards overcoming the challenges of accurate pathological diagnosis of suspected pancreatic neoplasm Over the past recent years, the importance of self-powered flexible inorganic optoelectronic systems as next-generation electronics has gained interest as biomedical implantable optoelectronics due to their biocompatible, lightweight, self-sustainable, and thin properties. These self-powered flexible inorganic devices include batteries, LEDs, sensors, high-density memories, energy harvesters, and large-scale integration. The most attractive property of such self-powered optoelectronics that have drawn great interest is the utilization of a flexible energy harvester that can generate electricity by harnessing kinetic and mechanical energy from human muscular movements and can charge a flexible battery. Thus, it is being speculated that these systems can permanently operate in heart, diaphragm, and shoulders using their sustainable muscular movement energy. This will avoid the need for invasive operated replacement of battery and/or use of an external energy supply in implantable electronic systems over time. Such prototypes hold great promise in the future implantable biosensors, self-powered cardiac pacemakers, phototherapeutic or optogenetic tools for wireless remotely controllable Other than conventional light-based imaging, diagnosis and therapies, novel concepts in bio-optics and optoelectronic systems have revolutionized the field of neuroscience with the introduction of optogenetics approach. Broadly, the term “optogenetics” refers to an approach which involves precise control and monitoring of biological functions in cells, tissues, organs and organism by making use of genetic engineering and optical technology Figure . This ap3) implantable wireless optogenetic system with minimal tissue heating upon optogenetic stimulation. Using this system, they demonstrated wireless optogenetic stimulation of central nervous system (brain) as well as peripheral nervous system  in mice model As a foundational work, Kim et al., reported ultrathin multifunctional all-in-one optoelectronic system of single cell dimension which incorporated independent and inorganic μ-LEDs collocated with optical, thermal, and electrophysiological sensors and actuators. These systems were easily mounted on releasable injection needles for insertion in deep tissue of brain in mice model in vivo cell tagging as well as for long term tracking to gather information from biological processes occurring at the molecular to subcellular and cellular level, as well as in small animals. Application of biological microlasers will certainly advance our understanding of important biological processes like cancer metastasis, neuronal network development, wound healing, and immune response. Future designs in the field of optoelectronic applications in optogenetics will allow bioelectric signal-based sensing and power control for simultaneous stimulation of multiple and deep neural targets outside brain, spinal cord and peripheral nerve. Thus, this approach holds great promise in the treatment of several neurodegenerative diseases.In recent years, biophotonics have witnessed tremendous transdisciplinary discoveries in the field of clinical diagnostics to therapeutics. Here we have discussed two advanced and promising areas of biophotonics: intracellular biological laser and cellular scale optoelectronics. Biological microlasers offer the advantages of better performance at deep tissue depth due to their high sensitivity, bright narrowband emission, single-cell specificity, high signal to noise ratio, low background autofluorescence and minimum scattering interferences. Thus, they have shown to be potential in imaging, sensing, in vivo “recognition,” “think,” “analyze,” “decide” and “control” abilities to assist in smart diagnosis, drug transport followed by controlled drug delivery. Fast growing research and advancement in technology will surely increase the integration of these light-based functionalities in patients for early detection and real time diagnosis of several diseases and designing of personalized treatment with better therapeutic outcomes. It's exciting to see how the biophotonics field will evolve in the future as a smart human health monitoring and therapeutic strategy.Both fields are still in their basic research phase, they need to overcome several limitations mainly with the biocompatibility issues, before proceeding with clinical translations. Other than biocompatibility issues few more challenges in the field of biological microlasers need to be addressed such as surface passivation, heat management, lowering the exposure of pumping light to avoid damage to biomolecules/cells, advanced calibration, broadening the range of fluorescence detection limits. Although in the area of optoelectronics, advancement in electronics now allows their easy delivery into any site of body via syringe injection, still the power supply, size and heat generation of optoelectronic implants needs to be taken care off. In near future, it is being envisaged that integration of self-powered and machine learning technology in portable wearable optoelectronic systems will allow