Saudi Arabia is currently passing through a transformational phase. There is a huge demand on the Saudi healthcare system to provide better healthcare facilities to the rapidly increasing Saudi population, as well as the growing elderly population. Lack of trained healthcare professionals and heavy reliance on foreign workers are significant aspects for policymakers to consider and deal with. It is also important to re-examine the healthcare Human Resource Development (HRD) initiatives so as to provide a huge reserve of healthcare professionals with appropriate learning and competence.This paper is a critical review based on secondary data collected from various sources including databases, reports, articles, books, government documents and earlier research undertaken in this regard. The paper is an attempt to document and evaluate the various steps suggested and undertaken by the new strategic plan, Vision 2030, and consequently documented in the National Transformation Program (NTP) adopted in April 2016 in the healthcare HRD sphere in Saudi Arabia.It has been shown that appropriate HRD capacity building needs to be adopted along with the aggressive policy regulation. It is also important to ensure that future health sector investment meets the needs of local healthcare HRD. Saudization and the adoption of the ‘Nitaqat’ program have played an effective role in pushing the Saudization targets in the private sector, and there is a huge scope for the absorption of young trained Saudi boys and girls in the healthcare sector.Vision 2030 adopted in 2016 is a testimony to a revolutionary step undertaken by the government and that the healthcare sector is also passing through a major shift in its approach and execution. Vision 2030 has come out with a very clear sense of direction to the healthcare sector, and the projected shift from the existing one-third to two-third Saudi-to-foreigner workforce ratio by the year 2030 needs to be adopted carefully to turn the healthcare HRD challenges into opportunities. Healthcare facilities have come a long way in the Kingdom of Saudi Arabia (KSA). Starting from the establishment of the first public health department in Mecca by a royal decree in 1925, and Ministry of Health (MOH) in 1950, at present, Saudi Arabia has a total of 487 hospitals providing 72,981 beds, which are around 2.2 beds per 1000 population in the Kingdom . The KSADespite these achievements, there are still enormous challenges in providing better healthcare services to the fastest growing population of the Saudi Kingdom –7. BetweVision 2030 adopted in April 2016 identifies its priorities across all economic sectors and serves as a roadmap for the economic development of the KSA. It sought to identify the general directions, policies, goals and objectives of the Kingdom. Accordingly, ministries, institutions and government entities underwent a restructuring process to align themselves to the requirements of the plan. As part of Vision 2030, the National Transformation Program (NTP) 2020 in the year 2016 was adopted, and strategic objectives, key performance indicators (KPIs) and key performance targets (KPTs) were listed for each ministry . In thisPrior to 1925, healthcare resources in Saudi Arabia were scarce and the infrastructure was relatively weak. In the early 1900s, only three small-sized private hospitals, the Al-Juad Hospital, Al-Kaban Hospital and Al-Shareef Hospital existed in Mecca . The preAlthough relatively few models for public healthcare systems can be identified, the ways in which these models are applied vary considerably, with each having its own unique features. However, within this uniqueness, a constant issue exists as to how to raise the standards of healthcare without imposing prohibitive costs on the tax or insurance paying population. One approach is to develop the level of private healthcare effectively so that those who can afford it will opt for it as opposed to public healthcare . Such a According to the annual statistical book released by the MOH in Saudi Arabia, there has been a significant progress in the key health indicators. Between 1983 and 2017, life expectancy increased from 66 years to 74.9 years. The infant mortality rate (per 1000 live births) declined from 52 to 6.3. The mortality rate for children under 5 years of age also declined from 63 to 8.9. The maternal mortality rate dropped from 3.2 to 1.2. The infection rate for polio was brought to zero in the year 2009. Moreover, there has been a significant improvement in the availability of health resources. At present, Saudi Arabia has 487 hospitals providing 72,981 healthcare beds, which are around 2.2 beds per 1000 population [Nonetheless, it has been noticed that there is a sharp rise in chronic diseases such as obesity, diabetes, hypertension and coronary heart diseases . Saudi AIn the present health scenario, with an increasing population growth, which is the highest in the region, there is a huge need for restructuring the health sector, and the McKinsey Global Institute (MGI) report in 2015 also advocated the transformation of the Saudi economy [The MGI report suggested that the Saudi government has to move away from the government-led economic model currently used to a more market-based approach. It envisaged that for better household income, Saudi men and women should jointly participate in workforce. Besides, stakeholders such as households, the private sector and foreign investors need to be involved in the process as well, and the government should adopt a new delivery philosophy while businesses adjust themselves to a more competitive setting and Saudi individuals take more responsibility for themselves . This wiThis paper is a critical review based on the secondary data collected from various sources including databases, specialist organisations’ reports, articles, books, workshop reports, government documents and earlier research done on the Saudi healthcare reforms. This paper attempts to document and evaluate the various steps suggested and undertaken by the new strategic plan initiated in the healthcare HRD sphere in the KSA in recent past. This paper will strive to discuss, analyse and evaluate these initiatives with an emphasis on evaluating the restructuring of the health sector in facilitating the localisation (Saudization) of the workforce employed in this sector.The documentation and evaluation of the healthcare HRD initiative under the new economic scenario will add to the scarcely existing literature on the healthcare HRD reform in the KSA. This paper can serve as a baseline evaluation of the existing healthcare HRD imperatives in the context of Vision 2030 and can form part of a longitudinal study, which can be carried out after few years. Vision 2030 provides a considerable number of challenges as well as opportunities for the development of human resource policies for the healthcare sector, and an attempt will be made to identify those challenges and opportunities in this regard.According to MGI report, the healthcare sector was employing 600,000 employees in Saudi Arabia which constituted about 350,000 healthcare professionals and about 250,000 management and support staff by the end of the year 2014 . In the In addition, in order to fulfil the objectives of Vision 2030 and the NTP 2020, a huge number of Saudi nationals will need to be recruited in the sector of healthcare. The localisation of the workforce, referred to as Saudization, is an important aspect of Vision 2030. At present, only 1 out of 3 healthcare professionals is in fact a Saudi citizen. Currently, the number of healthcare graduates who are Saudis may not be adequate enough to replace professionals who retire or simply quit (regardless of filling vacant positions too). Elderly Saudis are expected to have an increasing demand. Thus, the Kingdom is required to have filled no less than a hundred thousand nursing positions by the year 2030. This makes up a net average of 6000 to 7000 new nurses to join the workforce annually. Yet, only 812 nurses who are Saudi citizens graduated in the KSA in the year 2014. Similarly, overspecialization of physicians exists with serious scarcity of family medical practitioners too. In other words, only 5% of the workforce of physicians actually practices the family medicine .Moreover, currently, the private healthcare sector owns 24% of the hospital beds  and 32% of the hospitals (158 out of 487), and there is a need to expand the private sector participation in the health sector . The detGenerally, with regard to the challenges of the transformational change adopted in the KSA, the MGI report encourages increased labour participation, especially from Saudi women and young people. It advocates developing the skills of Saudi workers by providing proper education and needed vocational training, as well as improving the mobility and flexibility of labour market for both Saudi and non-Saudi workers, hindering growth in regard to the workforce of the public sector, and increasing the cost of recruiting foreign workforce .In this regard, it highlights two significant challenges. The first is the availability of skilled workforce, which can raise the KSA’s economy to a new level of productivity and efficiency. Indeed, the statistics referred to above in terms of numbers of Saudi workers required in the healthcare sector and necessary increases in the infrastructure and support system as the population increases as well as ages, meaning that there must be significant improvements in the productivity and efficiency of the healthcare system. This also refers to a combination of improved outputs relative to inputs and more cost-effective uses of existing resources. If this is not achieved, the choice will be a deteriorating level of healthcare provision or a health budget that is untenable.In order to improve and raise the standards of household income and also absorb the demographic youth bulge, both women and men in Saudi Arabia will be required to be fully and equally involved in the workforce. Furthermore, the KSA will have to find ways to counteract the alarming discrepancy between Saudi people’s skills and what the labour market actually requires. The benefits and incentives involving work in the KSA are in conflict with having a truly productive labour force. For instance, workers in the public sector earn, on average, around 70% more than those working in the private sector. Moreover, the benefits of unemployment as well as welfare transfers are reasonably higher than wages. Besides, a good number of employers opt to recruit expatriates lacking adequate skills as opposed to Saudi citizens who naturally demand double or triple the rate demanded by non-Saudis .The second challenge for the KSA economy in general and in providing a better healthcare facilities is creating an economic and controlling setting encouraging business through both transparency and unambiguity. This should warrant the need for building upon the progress achieved in the KSA during the last 15 years, with regard to releasing the economy to foster competition and encourage foreign investors. Furthermore, this involves making multifaceted, controlling environments less complicated, less bureaucratic and easier to manage, through expediting procedures, removing red-tapism, and overcoming the obstacles and opening the road towards a broader, more productive and self-managed private-sector environment.Vision 2030 declares to enhance and appropriately employ the capacity of medical centres and hospitals as well as improve the standards of healthcare services (e.g. therapeutic and preventive). This also indicates that the main focus of the public sector should be on prevention-related care and controlling infection besides urging individuals to first start with primary care. Vision 2030 intends to offer healthcare via public organisations so as to raise its standards and also get ready for the advantages of privatisation in the long run. The vision aims to implement a plan to enhance private medical insurance so individuals can better access needed medical services swiftly without having to wait for long until they could meet the medical professionals and doctors. Furthermore, the vision discusses better training of healthcare professionals to improve treatment for chronic diseases such as heart disease, diabetes and cancer, which all threaten people’s health. Seeing beyond oil, it advocates the diversification of the economy to unleash the capabilities of promising economic sectors and privatise some of the government services in the KSA; one of which is health sector .Among other goals, Vision 2030 envisages to increase the competitiveness (current 25th position to the top 10) on the Global Competitiveness Index and enhance the Foreign Direct Investments flow to 5.7% from 3.8% of GDP. It prescribes to have increased the private sector’s contribution from current 40 to 65% of GDP by 2030. The vision also aims to lower the rate of unemployment in the KSA from existing 11.6 to 7% and raise women’s participation in the workforce from 22 to 30% [These KPIs and KPTs serve as the dashboard to evaluate the efficacy of the implementation of the NTP. The important strategic objectives of NTP which have a direct and indirect impact on the HRD of the healthcare are as follows: 1) to increase private sector share of spending through alternative financing methods and service provision; (2) to increase the efficient utilisation of available resources; (3) to improve the efficiency and effectiveness of the healthcare sector through the use of information technology and digital transformation; (4) to increase training and development on both a national and international level; (5) to increase the attractiveness of nursing and medical support staff as a preferred career path; (6) to improve the infrastructure, facility management and safety standards in healthcare facilities; (7) to attain acceptable waiting times across all stages of service delivery; (8) to improve governance in the health system in order to enhance accountability with regard to quality issues and patient safety; (9) to improve the quality of life and healthcare service provided to patients outside hospitals; 10) to improve quality and safety principles as well as skills of the service providers [ to impro to increThere is also a need to emphasise and link ‘affluence’ diseases to an appropriate HRD capacity building along with the aggressive policy regulation rather than only increasing funding or number of hospital beds, technology, and medicine. An optimal shift from the existing one-third to a projected two-third Saudi-to-expatriate workforce ratio is likely to have occurred by 2030 through sustained policy approaches—converting challenges into opportunities as envisaged in the NTP 2020. Moreover, there is a scope for ensuring that future healthcare sector investment matches the need for local HRD requirements vis-à-vis job opportunities, especially for nurses, doctors and allied professionals and equally disengaging from costly consultant-level specialisation for hospitals to specialist-level primary healthcare. A launching of public-private partnership models in selection of upcoming institutions for resource sharing including human resources is therefore essential . There iIn this regard, the KSA faces three critical healthcare reform challenges that can be converted into opportunities by undertaking appropriate investment in this sector: (i) tackling the present under par financing and productivity that the private sector can cover, (ii) having a healthcare labour force not designed to handle the increasing prevalence of non-communicable diseases and (iii) an increasing need for skilled professionals both in the clinical medicine area and healthcare management . If the It was estimated that if the KSA could make the rate of Saudization, i.e. making workforce more local, double for health specialists (e.g. two thirds), this should generate around 400,000 posts by 2030. Furthermore, around 50,000 management and support posts can also be created. Raising the number of Saudi nationals who become health practitioners needs a declining trend to be reversed. It is similar to exerting a great effort so as to enhance the way well-talented Saudi young people view healthcare posts and also cultivate a positive educational environment at faculties, universities and adequately prepared teaching hospitals.At present, a huge restriction, besides the limited teaching capacity, lies in the lack of on-the-job on-going training provided for medical assistants in public hospitals. Today, overspecialization of medical practitioners exists with serious scarcity of family medical professionals. With the ageing Saudi population and the heavy load of serious chronic diseases, the Kingdom is bound to move its medical workforce towards primary care. Innovative and creative solutions are also required in terms of the actual obstacles facing medical professionals such as flexible work hours and shift-based schedules. Moreover, the stereotypical perception of healthcare institutions, which are usually seen as being ‘hierarchical’ and not taking nurses into consideration with regard to more advanced or specialised tasks, will indeed need improvement as well. Besides training and staffing, the private sector does have a greatly significant role in the country’s healthcare evolvement . The NTPAt present, private healthcare sector makes up to 24% of hospital beds which is around 17,622 out of 72,981, as well as 32% of the hospitals which is around 158 out of 487. If healthcare private sector needs to develop itself, a clear strategy will be needed as to the provisioning areas which could be available for growth. For instance, operators of private sector can play a great role in appropriately developing service provision in certain aspects such as long-term care, day surgery units, rehabilitation and secondary care hospitals characterised by the limited nature of the care delivered. Also, the state could expand privatising specific other areas such as making the manufacturing of pharmaceuticals as well as healthcare education local. The NTP 2020 proposes to have reached 40% share of pharmaceutical manufacturing in Saudi Arabia from the existing 20% by the year 2020. As a short-term goal, the government has assigned certain selected new facilities scheduled for opening in the coming years to operators of private sector and will also assess the effectiveness of the partnership models of public and private sectors together. It will also be beneficial to guarantee cost neutrality and/or savings for the government spending. From a law-enforced point of view, the state will have to tackle the barriers in terms of the participation of private sector, including legal requirements of ownership by Saudi physicians. Besides, the existing investment barriers would also need to be removed .The increase of foreign workers in Saudi Arabia and the shortage of job opportunities for the Saudi citizens have forced the Saudi government to take swift measures to deal with the challenges of the widespread unemployment and employing locals in place of the expatriate workforce. This awareness has triggered the coining of a new technical term ‘Saudization’, which signifies a revolutionary strategy aiming to properly train Saudi nationals to replace foreign or expatriate workers. The word was created by the government of the KSA in the 1970s, but it only became active within the Saudi economic sphere in 1994. The KSA government implemented the Saudization programme intensively through the sixth development plan (1995–1999), and private sector companies employing more than 20 employees were told, by a royal decree in 1995, to reduce the number of non-Saudis by 5% annually .The Saudization program focussing on the private sector, referred to as Nitaqat Program, was firstly launched in Saudi Arabia in June 2011, and consequently, the Saudization level went from 10% in 2011 to 13% in private sector by the end of 2012. In addition, in the past, the private sector had passively reacted to Saudization, and the actual enforcement of localisation was non-active until the late 1990s . In the The MGI report provides the employment levels of all Saudi citizens and an estimated growth in Saudization, i.e. the share of total employment calculated in the private and the public sectors held by the Saudi nationals. Currently, a positive relationship between wages and Saudization exists, where Saudi citizens take over high-income sectors and expatriate workers control low-income sectors. It is expected that the possible impact of the efforts exerted by the government and the changes of policy can swiftly expedite the process of higher level of Saudization . SimilarThe ‘Nitaqat’ Program was launched to replace the previous Saudization program. Nitaqat (which translates to ‘zones’ or ‘bands’) defines Saudization targets for each firm in the private sector with more than five employees. The present Nitaqat Program divides organisations into six categories namely Platinum, Green , Yellow and Red, depending on their size and the percentage of Saudization level achieved. Platinum and Green categories represent the highest ratios of Saudi nationals in their organisations, whereas Yellow and Red indicate the lowest ratios of Saudi nationals employed. Thus, based on their performance, it classifies them according to a colour scheme: Red or Yellow refers to non-compliant companies, while compliant companies are referred to as Green, and finally outperforming organisations are referred to using Platinum. Nitaqat was quite different than the previous program to a significant degree. Firstly, the program could be effortlessly supervised by the state. The information and data in terms of the number of Saudi national workers and expatriate workers recruited by a company were collected regularly and systematically using the state’s integrated system of social insurance and foreign visa records. Also, the program of Nitaqat was primarily implemented to set attainable goals and objectives. Nitaqat divided companies into more than 50 different types of business. Moreover, it classified them based on 5 different segments with fixed objectives in each according to the level of Saudization which was already reached by the companies in the given segment. For instance, if the number of employees in a given firm is between 6 and 49, the Saudization requirement could be between 5 and 34% of the total labour force .Unlike previous efforts, it has been noted by the policymakers that ‘Nitaqat has real teeth’. Those companies referred to as being red are successfully stopped from growing due to the restrictions put on them in terms of reissuing more visas for the expatriate workers they are recruiting. However, fewer limitations are imposed on the Yellow companies, and the Platinum ones are compensated with swift and real-time access to expedited government services including smooth visa processing and/or flexible grace periods given after expiration.There has been a major shift in the policy direction in Saudi Arabia in the recent past, and the government has taken a very rigorous initiative to balance its expenditure and fiscal deficit. The new Vision 2030 adopted in 2016 is a testimony to revolutionary steps that the government has started to take in all sectors. The healthcare sector is also passing through a major shift in its approach and assumptions. In the healthcare HRD initiatives, the government has chalked out many plans, policies and benchmarks to ascertain the effectiveness of all stakeholders. It has come out with strategic objectives, KPIs and KPTs, which provide a very clear sense of direction to the healthcare sector.The government is aiming to generate SAR 4 billion from the utilisation of its services by the private sector in the coming 4 years (2016–2020). It plans to have increased the participation of private sector in healthcare expenditure by 10% (25 to 35%) by 2020. There are a number of steps taken by the government, which will surely enhance the larger participation of Saudi workforce in the healthcare sector. The NPT 2020 clearly identifies the training and development, career planning and talent management areas for the healthcare professionals. Saudization of workforce, which for long felt the need to counter the rising unemployment level of Saudi youth, will surely find an answer through these plans. Secondly, an optimal shift from the existing one-third to a projected two-third Saudi-to-foreigner workforce ratio by 2030 through sustained policy approaches has to be adopted carefully, thus converting challenges into opportunities. There is a huge scope for the absorption of young trained Saudi boys and girls in the healthcare sector.The private sector role in the creation of more medical, nursing and dental colleges and other specialised learning institutions is a challenge as well as an opportunity for the first movers in this sector. There is going to be a huge demand of healthcare professionals, and government and private sector partnership needs to expedite this process by providing more learning and development facilities to counter the rising demand of healthcare professionals. Consequently, the role of private sector in human resource training also needs to be enhanced and redefined in the new context especially for long-term care, rehabilitation services, day surgery units and secondary care hospitals where the complexity of care delivery is limited.There is a need to adopt appropriate HRD capacity building along with the aggressive policy regulation rather than increased funding or number of hospital beds, technology and medicine. It is also important to ensure that the future health sector investment matches the need for the local healthcare HRD needs. Launching the public-private partnership models in selection of upcoming institutions for resource sharing including human resources will be a real test. However, the policy direction given in the new plan envisages for creating a synergy between all stakeholders and facilitates to give the required push to realise the larger objective of diversification of economy and empowering private sector to play bigger role. In regard to the question as to how far this role happens to be credible and coherent with the new initiative, only time will tell.The paper is a critical review of the Healthcare HRD reform adopted in Saudi Arabia in the recent past, specifically Vision 2030 and NTP 2020, which were both adopted in 2016 based on the findings of the MGI report. Saudization  of the workforce in healthcare sector and their learning and development form an important part of the government policy in Saudi Arabia, and earlier research and insights available on the Saudi healthcare reform were also referred to in that regard. There is a limitation of data to evaluate the efficacy of these provisions adopted under the NPTs in the form of KPIs and KPTs, but an attempt has been made to document and evaluate these provisions from the available resource as of today.


Provision of high-level healthcare is a challenge for all low- to middle-income countries (LMICs) since healthcare systems are heterogeneous, face many challenges such as inadequate funding, inequitable distribution of resources and services and usually are not adequately equipped to deal with a huge problem such as breast cancer. The development of anti-HER2 therapies can be considered one of the most important examples of the translation of molecular biology knowledge into clinical benefits for cancer patients. While a variety of novel therapeutic strategies are emerging, current treatment regimens remain focussed on targeted therapy with monoclonal antibodies, mainly trastuzumab, the first agent developed in this field. While these results have revolutionised the outcome of HER2+ patients in clinical trials and in high-income countries where they are widely available, results have not impacted the natural history of this aggressive disease in most of the world. Unfortunately, the availability of these drugs is far from universal in many LMICs, and in Latin America, in particular, patients with HER2+ breast cancer are treated exclusively with standard chemotherapy, a more toxic and less efficient therapy. While the complexity of the situation and the multiple factors that have an impact in this scenario are recognised, we need to map the future and develop feasible strategies to address possible solutions to the problem of drug access. A clear and unbiased diagnosis of the situation is a good starting point. Defining healthcare priorities and a clear strategy for the allocation of resources is difficult but mandatory. In this article, we will discuss current and future challenges regarding access (and lack of access) to high-cost cancer drugs in Latin America, with a focus on anti-HER2 therapies. Cancer represents a significant and growing global concern. With the progressive control of other causes of mortality and the increase in life expectancy, cancer is a truly major universal health challenge. It is projected that new cases of cancer will increase from about 14 million in 2012 to 22 million in 2030, with most cases in low- to middle-income countries (LMICs) located in Africa, Asia and Latin America [According to the GLOBOCAN database, breast cancer is the most frequent cancer among women in the world, the most frequent cause of cancer death in women in less developed regions and the second most frequent cause of cancer death in more developed regions . It is nRecently reported data from the United States indicates a 26% decrease in overall cancer mortality over the past two decades with breast cancer deaths reducing an impressive 39% from 1991 to 2015 .Currently, provision of high-level healthcare is a challenge for every country in Latin America, since health ministry’s policies and healthcare systems are heterogeneous, face many challenges and usually are not adequately equipped and unprepared to deal with problems such as cancer. Within this context, our objective in this paper is to explore the issue of access to high-cost cancer medications in Latin America, with special focus in HER2-positive (HER2+) breast cancer and access to anti-HER2 therapies.Breast cancer is the most common cancer in Latin American women, and, in most cases, it is diagnosed at later stages. Due to demographic transition, the breast cancer rate will approach epidemic proportions with great social and economic consequences . TherefoLatin America and the Caribbean have a heterogeneous population with distinct cultural, ethnic and socioeconomic backgrounds and provision of adequate care for breast cancer patients remains a major challenge. The incidence of cancer is 63/100.000 in the region, much lower than that seen in the US (300/100.000) and Europe (264/100.000). However, a patient that develops cancer in Latin America and the Caribbean has a much greater chance of dying from the disease. More advanced stages at presentation and difficulties in accessing optimal treatment care are the main reasons for this disparity. While in the US more than 60% of patients are detected in earlier stages of the disease, with much higher curative possibilities, data from Brazil and Mexico indicate that more than 60%–70% of cases are diagnosed in more advanced stages requiring more complex management with lower chances of cure .The rising cancer incidence is closely linked to the increasing economic burden of cancer, alongside with the growing investment needed for disease prevention, diagnosis and treatment. While it is estimated that new cancer drugs have accounted for 50–60% of the increase in cancer survival rates since 1975, at the same time, they are also associated with a significant increase in costs . In EuroTaking into consideration where new drugs are consumed globally, we identify an awkward discrepancy that clearly helps to pinpoint some of the challenges we will face ahead. One of the most important aspects in reducing cancer mortality is the availability and health system uptake of innovations and life-saving cancer drugs . AnalysiUniversal healthcare coverage is not the rule in Latin American countries, and even in those regions where the entitlement to oncology services is guaranteed by law, it is not accompanied by the necessary resources. Vast disparities in access to breast cancer care in Latin American countries, and even within the same country, exist and lead to unequal outcomes. All these factors are compounded by the fact that in Latin America and the Caribbean each country has unique healthcare system issues. In the region, we identify inconsistent or absent health care planning addressing cancer control associated with lack of resources to finance public healthcare. As a result, fragmented systems with significant discrepancies in care in different regions within the same country are frequently the case with unplanned and unfair distribution of the scarce resources generally spent in the absence of a clear or strategically defined plan. Infrastructure needed for cancer care and processes of care suffer accordingly, leading to worse outcomes and poor or highly inadequate outcomes. While in most countries we can recognise inequitable healthcare systems, some initiatives of universal healthcare systems have been launched such as in Mexico or Brazil .Further challenges include a clearly unbalanced distribution of healthcare specialists and facilities, generally concentrated in urban centres and most populated areas. While having availability where most of the population lives is appropriate, this still leaves a large proportion of the rural population unassisted . These hThe significant achievements that led to the reduction in breast cancer mortality observed in developed societies clearly demonstrate that it is possible to curb the devastating impact of this disease. Recent reports from Canada indicate that important improvements have been made in the management of early stage breast cancer with a clear decrease in the initial peak of recurrence when comparing results from the past two decades. These benefits were seen in all sub-types of the disease and especially in HER2+ and triple-negative tumours . FurtherBreast cancer is a heterogeneous disease with many distinct biological sub-types. Approximately 15–25% of breast cancers are classified as HER2+, a sub-group of tumours with a more aggressive clinical phenotype and worse prognosis due to unregulated cell growth mediated by overexpression of the HER2 protein . HoweverThe development of anti-HER2 therapies can be considered one of the most important examples of the translation of molecular biology knowledge into clinical benefits for cancer patients. A variety of novel therapeutic strategies are emerging, but current treatment regimens remain focussed on targeted therapy with monoclonal antibodies, particularly trastuzumab, the first agent developed in this field.Trastuzumab was approved in 1998 in the USA and a couple of years later in the European Union for patients with metastatic disease. A pivotal study demonstrated a significant prolongation in overall survival when added to standard chemotherapy agents in patients with metastatic disease . This eaDemonstrating benefits in the advanced and early disease settings, trastuzumab was also shown to improve pathological complete response rates when used in the neo-adjuvant setting, covering as expected, the whole spectrum of presentations of the disease . CurrentIt is important to point out that after trastuzumab, other efforts led to important advances in anti-HER2 therapy and other innovative medications became available, adding to the results in the management of these groups of patients . The comWhile these results have revolutionised the outcome of metastatic HER2+ patients in clinical trials and in HIC where they are widely available, results have not impacted the natural history of this aggressive disease in most of the world. Unfortunately, the availability of these drugs is far from universal and today, in many regions and in Latin America in particular, patients with HER2+ disease are still treated exclusively with chemotherapy. We will address some of the data available in this regard in our region.As reported in different regions, barriers to optimal access to trastuzumab are multi-factorial and include issues related to drug cost and high overall treatment expenses for patients in ill-equipped health systems , 27. WitMoreover, one of the most challenging aspects of drug development is the translation of the results obtained in clinical trials to the clinical practise scenario. While a clinical trial is a coordinated experiment that has very tightly controlled inclusion and exclusion criteria and precise pre-defined procedures for most if not all predicted situations, clinical practise does not fit and does not follow the same setup. Reproduction of any observed benefit in a real-world patient scenario is arguably the most important step in the impact of any new development. If a result cannot be reproduced in a real population care situation it becomes of questionable value. Generation of RWD is, therefore, an important endeavour that has been progressively singled out by the Food and Drug Administration (FDA) as key in the incorporation of new treatment alternatives, emphasising the fact that having an impact on the whole population remains the foremost objective .Taking the example of anti-HER2 therapy development and trastuzumab, in particular, unquestionably we observe major improvements in patient care with categorical and reproducible consequences in outcomes. While trastuzumab is approved in most countries in the Latin American region, access to the drug is far from universal. While this may be considered a problem of LMICs, in reality, limitations in access have been documented in HICs as well , 28. HowBrazilian regulatory authorities approved trastuzumab following the demonstration of its benefits in the metastatic and the adjuvant settings . However, this regulatory approval does not guarantee universal access to the drug and mainly applies to the privately insured patients that represent approximately 20% of the country’s patient population. Women in the public health system, representing 80% of the population, remained with no access to trastuzumab in the adjuvant situation until early 2013 and until 2017 for metastatic disease. Access to anti-HER therapy is historically very restricted in the Brazilian public health system. In 2006, only 5.6% of patients with HER2+ tumours received trastuzumab in the public healthcare system compared with 56% in the private sector . With thA similar analysis was performed by our group addressing the potential consequences of the lack of access to the combination of double blockade with trastuzumab and pertuzumab as utilised in the CLEOPATRA trial. We projected more than 700 early deaths of patients with metastatic HER2-positive metastatic breast cancer due to lack of access to optimal treatment . Not surIn some countries, the increasing economic burden is compromising access to new developments. At the same time, this places physicians under significant pressure to balance the cost of cancer care during each testing and/or prescribing decision. This can lead to patients being denied access to effective treatments. As discussed in Brazil, trastuzumab is not generally available in public settings for the treatment of metastatic disease. It is estimated that of 2,008 women diagnosed with advanced HER2-positive breast cancer in 2016, only 808 would be alive by 2018 if they receive only chemotherapy . Having access to the combination of chemotherapy and anti-HER2 therapy, an estimated 1,408 women would be alive in the same period instead .Breast cancer health disparities also exist at a worldwide level, and the discrepancies between socioeconomic status, breast cancer presentation and outcomes have been well established. There is lack of RWD to provide decision makers with a credible information to confirm whether the results of randomised clinical trials are applicable to real-world clinical practise, or to understand how and why they differ .Several studies demonstrate that not all patients with HER2+ breast cancer are treated with anti-HER2 therapy. In some cases, this reflects patient comorbidities and treatment preference. However, physicians worldwide encounter various barriers to prescribing biologic agents that may also contribute to underuse of anti-HER2 therapy  Age, socp < 0.05) [Similar disparities are also seen in LMICs in different parts of the world. In a RWD study from China, patients with early stage breast cancer in resource-abundant regions were more likely to receive trastuzumab than those in resource-limited regions  . Similar < 0.05) .An international physician survey showed that 94% of responders from low-income countries and 63% from middle-income countries cited drug costs as a barrier to prescribing adjuvant trastuzumab . In a sup = 0.005) and most often cited by physicians from Africa (100%), Asia (89%) and Latin America (80%) [In a 2011 international physician survey, the vast majority (92%) of respondents indicated that they routinely recommend 1 year of adjuvant trastuzumab; however, 47% reported having at least one case within the prior year in which anti-HER2 therapy was recommended but could not be started. Failure to begin the recommended treatment with trastuzumab was more frequently reported in LMICs (75%) than HICs  . ArguablUnquestionably, the economic impact on the health system is one of the main reasons for the lack of access to trastuzumab. Despite being considered an essential medicine by WHO and the established clinical benefit in early breast cancer, some studies have not found adjuvant trastuzumab to be cost effective in several Latin American countries . In ColoIn LMICs, the cost of cancer treatment frequently exceeds the average per capita income by many multiples. For example, the cost of a typical trastuzumab course, prescribed during the treatment of advanced breast cancer, is approximately 15 times the per capita monthly income of an average Indian . SimilarA number of added issues should be taken into consideration. Regulatory aspects of drug approval are one of them. As an example, the Brazilian healthcare system is complex and harbours severe inequity issues leading to disparities in access to novel expensive therapeutic agents, especially in the public health system that, despite their scientifically confirmed clinical benefits, are not available to the vast majority of the population . KeepingIn the Brazilian public health system, access to innovative and high-cost drugs is low and, in general, is lagging many years behind in relation to the date of drug approval in developed countries. In addition, there is usually a similarly long timeframe from the drug approval and availability of new agents in the private setting until its availability in the public health system. It is important to mention that in reality huge disparities exist, even within public hospitals and probably the majority of patients treated for breast cancer outside major urban centres do not receive trastuzumab in the same proportion as patients treated in reference centres located in the major cities. Recently, expanding on this discrepancy, the Brazilian Clinical Oncology Society reported that there were 37 therapeutic indications there were available on private but not on the public health system .Delays in drug approvals have been significant and this has measurable impacts in the outcomes of patients that are unlucky enough to face the diagnosis in between periods when the scientific evidence is already available but the drug is yet to receive regulatory approval. Submission requirements, lack of transparency on the evaluation process and delays in the submission of regulatory documentation by the pharmaceutical companies have also been cited as contributing elements for the delay in access.While the complexity of the situation and the multiple factors that have an impact in this scenario are recognised, we need to map the future and develop feasible strategies to address possible solutions to the problem of drug access. A clear and unbiased diagnosis of the situation is a good starting point. Defining healthcare priorities and a clear strategy for allocation of resources is difficult but mandatory. The hard decision of who will get what and when is the most important one. Well-designed comprehensive cancer plans adjusted to each country’s reality are mandatory and clearly the initial point in this discussion.Better control and more appropriate strategic regulation of the drug development process is critical as the costs and time associated with the current model do not fit with the urgent needs our patient have for better results. This would be one of the many aspects that could introduce more pressure and transparency in the drug pricing process. More discussion of the price of drugs is obviously not the only one but one of the many elephants in the room.Biosimilars could improve patient access to anti-HER2 therapies worldwide . BiosimiPatents for several biologic drugs, including trastuzumab, have recently expired or will soon expire, which has stimulated the development of biosimilars . SeveralIn 2013, the trastuzumab biosimilar Hertraz (MYL-14010) was approved in India. In 2014, the trastuzumab biosimilar CT-P6 was approved in Korea for the treatment of early and metastatic HER2-positive breast cancer. A variety of other trastuzumab biosimilars are in various stages of development with phase III trials publication expected for the near future . RecentlIn addition, modern and more transparent processes of regulatory drug evaluation and approval will certainly bring to light many of the local issues that generally play a significant role but remain hidden in bureaucracy. Often, undisclosed restrictions with questionable interpretations of scientific data conceal lack of resources, ill-designed allocation policies or other commercial issues that end up protecting individuals or committee’s decisions with negative consequences for cancer outcomes. More transparency would certainly help in the process and would identify the real problems easing the process of reaching a solution. At the end of the day, putting a price on how much each society is willing to invest or can invest in a particular disease scenario or patient is the main question we keep dancing around.Clinical research initiatives represent a particularly important aspect of the discussion. While not a solution for the central problem, research participation, with all its different caveats, is a very easy and practical solution to access and at the same time helps to speed development, access possibilities and lower the cost of drug development. Short and rapidly recruiting trials are clearly less expensive than those with long and slow accrual. Tailoring research questions to the main problems faced by different populations and regions is certainly one major strategy to increase physician and patient participation in the process. Physicians and patients in LMICs may choose to participate in clinical trials as a means of accessing medications that would otherwise not be covered in health systems with limited resources. Ten years ago, 94% of oncologists practicing in Latin America reported that there was insufficient clinical and epidemiological research on breast cancer in their countries . ImportaAddressing the development and stimulating clinical research in LMICs will certainly result in a very positive impact in cancer care. Latin American countries should develop strategies to foster local research aimed at the specific health problems of its population. Tailored research has the potential to develop more effective medicines adapted to local problems and to reduce production costs. Consequently, all these strategies could enhance the effectiveness of a health system while maintaining its affordability .It is of paramount importance to note that, while this article has focussed on access to trastuzumab for advanced breast cancer, effective cancer control strategies have to be culturally appropriate and are context dependent. Comprehensive efforts should be able to involve data gathering, health education, prevention, screening, early detection, multidisciplinary care strategies and surgical and radiotherapeutic treatments in addition to access to anticancer drugs .Breast cancer is the most common cancer and it kills more women than any other tumour type in Latin America. Important disparities in the access of anti-HER2 therapies for breast cancer have been demonstrated in LMICs and are linked to inferior cancer outcomes. Consequently, every year thousands of women die as a consequence of lack of access to standard of care treatment. As expected, there is not a single generalizable solution. The likely answers to increase access to anti-HER2 therapies for Latin American patients and decrease the existing disparities are usually complex, context dependent and depend on an intense interaction and active participation of different players requiring a passionate involvement of engaged local experts.None.Honorarium, consulting/advisory role, research funding and meeting support from Novartis, Roche/Genentech, Pfizer, AstraZeneca, MSD and GlaxoSmithKline.Honoraria and research funding from Sanofi.Honoraria, consulting/advisory role and research funding from Boehringer Ingelheim.Honorarium, consulting/advisory role and meeting support from Eisai.Research funding from Amgen, Lilly, Taiho Pharmaceutical, Mylan, Merrimack, Merck, Abbvie, Astellas Pharma, Biomarin, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, inVentiv Health Clinical, Celgene, Covance, Janssen, Atlantis Clinical, INC Research and Halozyme.Research funding, consulting/advisory role and meeting support from Bristol-Myers Squibb.Consulting/advisory role and meeting support from LibbsSteering committee member for the IMpassion130 trial. He did not receive travel support or reimbursement as part of the activities for the IMpassion 130 steering committee.Dr Barrios´ disclosures:Research funding from AstraZeneca.Speaker honoraria from AstraZeneca, Lilly, Novartis, Pierre Fabre, Pfizer.Dr Reinert’s disclosures:Dr Werutsky has no disclosures of conflicts of interest.


Toxin weapon research, development, production and the ban on its uses is an integral part of international law, with particular attention paid to the protection against these weapons. In spite of this, hazards associated with toxins cannot be completely excluded. Some of these hazards are also pointed out in the present review. The article deals with the characteristics and properties of natural toxins and synthetic analogs potentially constituting the basis of toxin weapons. It briefly describes the history of military research and the use of toxins from distant history up to the present age. With respect to effective disarmament conventions, it mentions certain contemporary concepts of possible toxin applications for military purposes and the protection of public order (suppression of riots); it also briefly refers to the question of terrorism. In addition, it deals with certain traditional as well as modern technologies of the research, synthesis, and use of toxins, which can affect the continuing development of toxin weapons. These are, for example, cases of new toxins from natural sources, their chemical synthesis, production of synthetic analogs, the possibility of using methods of genetic engineering and modern biotechnologies or the possible applications of nanotechnology and certain pharmaceutical methods for the effective transfer of toxins into the organism. The authors evaluate the military importance of toxins based on their comparison with traditional chemical warfare agents. They appeal to the ethics of the scientific work as a principal condition for the prevention of toxin abuse in wars, military conflicts, as well as in non-military attacks. The term toxin is rather more complicated. It came up only at the end of the 19th century, after the discovery of diphtheric toxin . In accootoxins) . These aetc. Since time immemorial, people have also used natural toxins to commit suicide, murder, and also to wage war. They invented different methods for the propagation of natural poisons for military purposes, but only the development of munitions and carriers made it possible to efficiently use them in the form of toxic aerosols.One of the important characteristics of toxins is that they serve living organisms as a protection from predators or as a tool for hunting and killing prey. Their use in wildlife is part of the passive or active struggle for survival in certain species. As soon as people became acquainted with the special effects of natural poisons on living organisms (without understanding their principle), they started using them for their own purposes. They employed them to treat different diseases, to increase resistance to mental and physical fatigue, to reduce feelings of hunger, for magic and religious rituals, for hunting animals, for protection from troublesome insects and from dangerous animals, The present article is focused on selected problems associated with the possible military use of toxins and appropriate protection against them. It is based on the fact that the research, development, production and use of toxins for military purposes are strictly prohibited by international conventions and legislation in a vast majority of countries. The authors, however, believe that even under these beneficial conditions, it is desirable and purposeful to acquaint the scientific community and professionals with basic facts concerning the history of the military development of weapons based on toxins (toxin weapons) as well as with the state of art and possible risks resulting from the dynamic development of science and modern technologies, particularly biotechnologies. The authors are convinced that the consequent implementation of international conventions and qualified, sufficiently effective defense and protection against risks of the possible use of toxins in wars, military conflicts, or non-military attacks at any time in the future cannot be provided without the knowledge of history and a deep study of contemporary scientific and technical trends. In other words, the problems will not be solved by avoiding a relevant discussion. Deep knowledge free of myths and speculation, together with the ethics of the scientific work, are a basis of preventing any abuse of toxins and also enhance the trust in the sufficient efficacy of provisions adopted for the protection against any possible use of toxins.Derris elliptica roots, containing rotenone, was used. North-American Indians from the Californian area used extracts from plants of the genus Croton containing phorbol for fishing [Euphorbia [Strategemata) and Pausanias (Hellados Periegesis) describe the poisoning of the river Pleistos, the source of drinking water for the city Kirrha, by military troops of the League of Delphi with extracts from the hellebore (Helleborus spp.), which contains a number of toxins with cardioactive and spastic effects . Florence chronicler Giovanni Villani (Nuova Cronica) reports the poisoning of a drinking water source with hemlock (Conium maculatum) in a war of Florence and allies against Verona in the 14th century. Similar events accompanied our history for centuries.Indigeneous tribes living essentially on all continents developed a technique of fishing by poisoning water with the use of plant extracts exerting dazing effects. For example, in Asia, the juice of  fishing . This suuphorbia . CertainAtropa belladonna containing tropane alkaloids [Food was also subjected to deliberate contamination with toxins for military purposes. The origin of this technique can be found in indigenous tribes, for protection from wild animals by using poisoned baits. Numerous cases of poisoning food have been described as a stratagem since antiquity. A case from the Middle Age (11th century) is known, where Scottish troops poisoned food in the encampment of the invading Norwegian army with the juice from lkaloids .Observation of the nature and possible attacks of snakes or other actively poisonous animals led people to the discovery of arrow poisons as early as the Paleolithic era, used for soaking the tips of arrows and spears to enhance their efficacy ,7. This Strategemata) reports that the Carthaginian military leader Hannibal recommended throwing vessels with poisonous snakes against the enemy´s boats in the second century BC. According to the Greek historian Herodian (History of the Empire from the Death of Marcus), at the end of the 2nd century, defenders of the Mesopotamian city Hatra threw clay vessels filled with scorpions and other poisonous animals against the Roman army. The same technique was also employed by warriors in the Middle Ages  as well as in the Modern Age (for example during the Thirty Years’ War) [In historical military literature, it has been proposed that in the area of the Tigris and Euphrates rivers, “living grenades” were used in wars in the pre-historical period in the form of beehives and hornet nests . Frontinrs’ War) ,10.Arthashastra) (3rd to 4th centuries BC) gives instructions for the military use of toxic smokes obtained by burning poisonous plants, insects, snakes, and other animals. In the list of recommended substances, there are also the seeds of Ricinus communis or Abrus precatorius containing ricin or abrin, respectively. The burning mixtures were thrown either by hand or with the help of catapults. In the period of the Dong Dynasty (9th to 11th centuries), Chinese soldiers used toxic smoking balls of hemp fibres and dried toxic plants , possibly enriched with snake venoms [Atropa belladonna) or producing toxic smokes were encountered [Capsicum spp., Piper niger or Veratrum spp., designed for the artillery or for dropping from balloons, were implemented in the course of the American Civil War [Old-Indian strategist Kautilya , veratrine (Veratrum spp.), and capsaicin (Capsicum spp.), and based on these alkaloids, they also proposed experimental ammunition [World War I brought a dramatic development of CWA and their mass use in the battlefield. Chemical programmes of warring countries included not only synthetic CWA, but also natural toxins. As early as at the beginning of the war, British scientists carried out research into the military use of nicotine  filled into four-pound aircraft bombs, but the inhalation effects were poor; most experimental animals were poisoned due to injuries with contaminated fragments [R. communis under pilot plant conditions in the USA did not exceed 1.7 tons [In the course of World War II, research on toxins was implemented within the framework of biological programmes. The USA tested botulinum toxin  were proposed that could comprise a suspension of ricin in tetrachloromethane  or certaNaja atra, insect poisons, toxins of certain species of sea fish, and ricin on humans [In the course of World War II, in the German concentration camps Sachsenhausen and Buchenwald, experiments with pistol projectiles poisoned with nicotine or aconitine were performed , which wn humans . The Miln humans . It is an humans .For military purposes, protein as well as non-protein toxins, occurring essentially at all levels of living organisms, can be used. As already mentioned, some of them found their use in the past during the development of experimental toxin weapons. Numerous toxins have been described, but only a small proportion of them can be effectively used for military purposes. In general, the main limitation results from a relatively tedious production process when it comes to industrial scale, in spite of the fact that some toxins can be produced in a simpler manner compared to classic CWA and that the availability of toxins is ever-increasing. The second key moment is their difficult application under battle conditions, which would make it possible to induce mass poisoning in the battlefield. For an outline of certain interesting military toxins and their comparison with the most important CWA, see Physostigma venenosum, served as a comparative standard in the development of synthetic inhibitors of acetylcholinesterase (AChE) or possibly in the development of protecting means against them. A less numerous but important group of metabolites in terms of their military use are toxic proteins. The top attention is focused on ricin or possibly abrin, modeccin (Adenia digitata), viscumin  or volkensin (Adenia volkensii), which have a similar structure, similar mechanism of toxic action (inhibition of protein synthesis), and almost identical clinical course of intoxication.The vegetable kingdom offers a great variety of substances with considerable biological activities, which are typically produced as final products of the metabolism. Secondary metabolites with considerable toxic effects include terpenes, glycosides, alkaloids, amines, phenols, and other organic compounds. Plant toxins, as we have seen, serve as a basis of arrow poisons and they have long been used as parts of different tactical warfare mixtures. Some of them were recently subjected to military research. For example, the alkaloid physostigmine, isolated from the species 50 values  for ricin are lower by a factor of five compared to VX and lower by a factor of more than 30 compared to sarin. In spite of the fact that the inhalation lethal dose of ricin for humans is at the level of sarin, the protection from ricin aerosol in the form of powder or solutions does not pose special difficulties. Pure ricin is readily soluble in water only, which is frozen at low temperatures. The suspension of ricin in tetrachloromethane  is unstable and affects the ballistic parameters of the ammunition. All forms of ricin are very sensitive to ultraviolet radiation, and thus its use in combat is problematic in periods of high solar activity. A certain handicap of ricin is also its slow action (toxic effect occurs after 8 to 72 h), which excludes operational-tactical use under the conditions of modern mobile combats. These disadvantages of ricin are not outweighed even by its easy preparation [LDparation .Oxyuranus scutallatus), bungarotoxin (Bungarus multicinctus), and α-cobratoxin (Naja siamensis), spider toxins, for example α-latrotoxin isolated from the species Latrodectus mactans, and other toxins of terrestrial animals.An important source of protein as well as non-protein toxins exerting a variety of toxic effects is also the animal kingdom. Certain poisonous animals have a special organ (gland) producing toxins , some others do not have such an organ and their toxins are products of their metabolism or possibly parts of the biochemical structure of certain body parts. A proportion of animals acquire toxins from their environment (for example from their food) and the toxins are subsequently accumulated in their bodies. The military use of animal toxins is limited compared to plant toxins due to the fact that there are usually problems with their manufacture on a large scale . HoweverAn interesting group of toxins are those of marine origin produced by toxicogenic algae, cyanobacteria, and bacteria, which are common food of marine animals , in which they are deposited . These are non-protein substances, inducing alimentary poisoning in man and animals with different syndromes: paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), amnesic shellfish poisoning (ASP), diarrheic shellfish poisoning (DSP), ciguatera fish poisoning (CFP) and azaspiracid shellfish poisoning (ASP) . The hig50) of saxitoxin for man is about 5 mg·min/m3; i.e., twice as low as for the substance VX and 15 times lower than for sarin. The saxitoxin aerosol is, however, very instable. It degrades at a rate of about 17% per minute. Saxitoxin  is also able to overcome the dermal barrier, but it does not reach the efficacy of organophosphate CWA. The value of the percutaneous lethal dose of saxitoxin for man is unknown, but the analogue brevetoxin can be considered to act similarly. Experiments demonstrated that even a percutaneous dose of brevetoxin higher than its lethal parenteral dose by a factor of 20 does not cause any lethal poisoning [Marine toxins also have a high inhalation efficacy and thus their filling into ammunition producing toxic aerosols was considered. As early as the late 1980s it was found that the inhalation administration of saxitoxin (STX) to mice is about 10 times more efficient compared to intravenous administration. This is explained by the fact that in inhalation, the toxin effect is focused on a particular organ (lungs) and not on the organism as a whole, which is the case in intravenous administration. The inhalation lethal concentration , enzymatic activity, as well as effects on cells of the nervous system.Protein toxins produced by microorganisms induce a number of bacterial diseases . Their biochemical structure is considerably diverse; they can be in the form of simple chains or substances comprising several units. Based on the chemical composition, thermostability, and method of release as a pathogen, bacterial toxins can be divided into two groups: exotoxin  and endotoxins (toxic lipopolysaccharides) . Exotoxi50 of botulinum toxin through inhalation is 0.02–0.1 mg·min/m3), however, it is less suitable for combat use. The basic problem results from the aerosol’s stability. The most effective fractions  are dispersed in the upper layers of the atmosphere. The fractions reaching the Earth’s surface are then too large and do not have the efficacy required. Under comparable conditions, the area hit by aerosol of the substance VX is at least three times larger compared to the area hit by botulinum toxin. In general, in a long-distance transfer of aerosol through the atmosphere, an active portion of the toxin is degraded by the action of the surrounding environment. A disadvantage of botulinum toxin is also its poor capability to penetrate through the skin, and the possibly long latent period of the effect [The highest risk of abuse is particularly associated with toxic exotoxins, such as botulinum toxins, staphylococcal enterotoxins, diphtheric toxin, tetanus toxin, and shiga toxin. Some of them can be employed for poisoning water and food, or for producing fragment ammunition (poisoned weapons). Certain toxins can also act in the form of aerosols for inducing mass inhalation intoxications on larger areas, but their use is restricted. For example, botulinum toxin or its type A toxin, which is most interesting in terms of the military use (e effect .etc.) [Toxins are also produced by microscopic and macroscopic fungi. Particularly mycotoxins, low-molecular weight secondary metabolites of microscopic fungi that are responsible for various mass food poisonings (mycotoxicoses) can also be of importance from the viewpoint of military applications. The advantage of mycotoxins is the ease of their production on a large scale (by cultivation techniques or by synthetic methods) and their generally high stability (they are resistant to boiling). However, the existing military experience with several mycotoxins cannot be directly applied to the whole group of mycotoxins, since they have different chemical structures, biological characteristics, and effects  .Claviceps purpurea), aflatoxins (Aspergillus spp.), and over the last decades, to trichothecenes (Fusarium spp.), particularly a group including T-2 toxins  is at least 20 times higher than for the substance VX, and its action is much slower [Enhanced attention of military specialists was given to ergot alkaloids  of 1972 and Chemical Weapons Convention (CWC) of 1993. These conventions (particularly the BTWC and CWC) belong to the historically most important disarmament actions, which considerably contributed to a reduction in the probability of using chemical, biological, and toxin weapons. They also established appropriate conditions for the enhancement of the protection against these weapons in moderation or in certain cases, even elimination of their destructive effects. Specific problems are nevertheless still persisting.inter alia) refers to weapons containing any toxic chemicals, which can cause death, temporary incapacitation, or permanent harm to humans or animals due to its chemical action on life processes. It includes toxic chemicals independent of their origin or method of production, i.e., toxins as well. For purposes of the CWC implementation, the Schedules of Chemicals (Schedule 1) contains ricin and saxitoxin, i.e., representatives of both basic types of toxins: protein and non-protein. However, the CWC is aimed at the use rather than at the chemicals , and thus it also covers substances which have not yet been discovered and synthesized and can emerge in the future with the aim of using them as chemical weapons. On the other hand, even the most toxic toxins can be manufactured in defined amounts and under international control (including toxins specified in Schedules) for purposes not prohibited by the convention, i.e., for industrial, agricultural, research, medical, pharmaceutical (or other peaceful purposes), protection purposes, military purposes not connected with the use of chemical weapons and law enforcement including domestic riot control purposes.For example, the main drawback of BTWC is the persisting absence of control mechanisms. The convention also applies to toxins, but does not comprise their definition. Only at the second conference evaluating the BTWC in 1986 was it demonstrated that it concerns toxins (protein as well as non-protein ones) of microbiological, animal, or plant origin, and their synthetically-produced analogs. For purposes of the CWC, the term “chemical weapon” (Aloe vera) or in the form of dry aerosol in 1991 [The scientific and technological progress and the availability of information about technologies of product synthesis suggest that there may be an enhanced likelihood of the non-military use of toxins and an increased awareness of their psychological effects. This can be referred to as the problem of chemical  terrorism, which is part of a wider set of concepts called superterrorism or ultraterrorism. As far as toxins are concerned, this concerns their use (including attacks against facilities in which toxins occur) by individuals, non-state groups, or state-supported subjects against a particular social group to induce fear or terror. In the past, there were a number of planned or implemented attacks of such kind. For example, in 1980, the West-German terrorist group Red Army Faction was suspected to have planned using botulinum toxin, which was prepared in a private laboratory in Paris . This ki in 1991 . In the  in 1991 .The use of toxins for terrorist purposes is less probable than the use of industrial harmful substances or classic CWA, but the probability is higher than for military use. There are questions about their actual effects. Ricin as well as other known toxins are relatively easily accessible to any qualified specialist, but their use in terrorist attacks with the aim of inducing mass intoxications through inhalation is difficult. This reduces the probability of inhalation attacks. Terrorist attacks focused on drinking water and food sources, and particularly on the destruction of a particular person or group are more realistic. At the time of modern information, technologies and propagation of the fear of a global threat by weapons of mass destruction, toxins can serve as an efficient psychological weapon, even if they are not actually used.There are a number of definitions of non-lethal chemical weapons. For example, in accordance with the NATO definition, these are “Weapons which are explicitly designed and developed to incapacitate or repel personnel, with a low probability of fatality or permanent injury, or to disable equipment with minimum undesired damage to or impact on the environment” . Non-letThe active components of non-lethal chemical weapons are traditionally incapacitating agents with very diverse biological effects on the human or animal organism. They can cause physical incapacitation , but also psychological incapacitation (sympatomimetics or anticholinergics). Many of these incapacitating agents were studied in the past as potential CWA , and some of them were even introduced into the standard military armament . In association with these agents, one can speak about non-lethal chemical weapons, but many of them belong to natural toxins or have chemical structures which are analogs of naturally-occurring substances. Natural alkaloid capsaicin or its synthetic analogs, e.g., vanillylamide of pelargonic acid (PAVA) or morpholide of pelargonic acid, can serve as examples of this relationship. Hallucinogen LSD-25, intensively studied in military laboratories fifty years ago, is a synthetic analog (diethylamide) of lysergic acid, which belongs to the ergot alkaloids. The structure and toxic (anticholinergic) effect of the synthetic psychoactive agent BZ are similar to those of tropane alkaloids, for example scopolamine .50) of 0.1 to 1 µg/kg (depending on the route of administration). In certain experiments, staphylococcal enterotoxin serves as a standard for the comparison of synthetic emetics developed as possible candidates for incapacitating agents.Protein toxins, particularly staphylococcal enterotoxin B (SEB), an activator of immune response, were studied in the past as incapacitating agents . This toxin induces strong vomiting, and so it can be compared with the strongest modern emetics already at effective doses  [The military potential of toxins is not necessarily associated with their lethal effects. Many toxins have unique biological effects, which can affect cognitive functions or intellectual capacities in humans. Domoic acid, a relatively simple compound close in structure to glutamic acid occurring in molluscs, can serve as an example of this. It is only moderately toxic (LD0 µg/kg) , but dueThe convention on CWC categories does not define “non-lethal chemical weapons” or “incapacitating agents”, in contrast to other relevant organizations . HoweverEuphorbia resinifera or E. poissonii  [50) of 2.4 × 10−7–2.4 × 10−9 mg/cm2. This can have an important impact on their military use. The protection from aerosols of toxins and their analogs important in terms of their military use typically does not pose serious problems for appropriately-trained and technically-equipped military units. Isolation of the body surface completely eliminates effects of toxic aerosols and the currently used protective masks are designed in such a way that the concentration of aerosol penetrating into the space under the mask is lower by a factor of 100,000 to one million compared to the aerosol concentration in the external environment. A different situation can be encountered in using modern super-effective irritating toxins . With certain new methods, under field conditions, it is possible to maintain concentrations of solid aerosols at a level of 1–10 mg/m3 for sufficiently long periods of time. In this case, super-effective toxins can cause lacrimation, cough, respiratory problems, and other undesirable effects, thus forcing the exposed individual to remove the mask and expose themselves to life-endangering concentrations [In practice, these are  the already-mentioned irritating agents. However, experience shows that there is a risk that this category can factually include not only irritating agents but also mentally and physically incapacitating agents with diverse characteristics and effects. For example, during the Moscow anti-terrorist intervention in 2002, synthetic opioids (non-toxins) derived from fentanyl  were used , which hin 1997)  effectivtrations . These cThe development of incapacitating agents (including RCA) is in many respects analogous to the development of medical products with high therapeutic effects. There is a problem, also demonstrated by the experience from Moscow, that the use of agents incapacitating wide groups of persons having different degrees of the susceptibility  without endangering their health is technically enormously difficult, if not impossible. Based on this experience, many specialists consider that there is a low probability of finding substances with sufficient safety coefficients . This aletc. They are characterized by being active already in extremely low doses, their effects being very rapid. Bioregulators formally do not belong to the group of toxins, but they share a similar potential for military use [Atractapis). Drawbacks of bioregulators as potential new-generation chemical or biological weapons  is their low resistance to ferments present in the human organism, for example, in the skin. The advantage of this fact can be taken in the protection against bioregulators and moderation of their toxic effects. Weapons based on bioregulators are sometimes referred to as hormonal weapons, and together with toxins, as biochemical weapons.Together with toxins, bioregulators are studied, which are naturally occurring substances, usually peptides, participating in physiological and neurological processes in the body. They affect for example blood pressure, myocardium activity, breathing, muscle contractions, body temperature, sleep, mood, emotions, immune reactions, tary use . CertainAtelopus zeteki [Research on natural sources brings ever new discoveries of sometimes very effective toxins. In this respect, interesting knowledge is encountered in the field of marine pharmacology and marine toxicology. Hundreds of substances are found in the seas every year, which open new views of life processes in the still scarcely studied sea environment and offer applications in medicine and other fields beneficial to the human being . Some ofs zeteki .in vitro screening , and so, they need not reflect the actual toxicity.The research of toxins is usually a part of the development of new medicinal products in biomedical and pharmaceutical laboratories. New medicinal products are traditionally discovered by the verification of biologically-active substances (including toxins or bioregulators) produced by living organisms. Once discovered, a substance can be modified chemically in different ways with a realistic hope that its biological activity will be enhanced. New pharmaceuticals are also currently prepared by methods of combinatory chemistry, which makes it possible to systematically combine different structural blocks and thus to obtain great sets (libraries) of structurally closely related low-molecular compounds and peptides. These libraries can be then used by ”high-throughput screening” for the identification of specific compounds, depending on the effect required ,58. TherBacillus thuringiensis [An interesting trend in the development of protein engineering is represented by hybrid or modified protein toxins produced by a combination of binding and catalytic domains of two different toxins. The result of this is a toxin with programmed characteristics suitable for use in different fields. In agriculture, hybrid insecticide toxins are promising; for example, based on delta-endotoxin produced by the bacterium ngiensis . In oncongiensis . In termngiensis .50 lower by more than an order of magnitude compared to botulinum toxin should reach values of about 1500 kDa (only few proteins with this molecular mass are known). If the toxins should be more toxic than botulinum toxin by two orders of magnitude, then they should have their molecular mass as large as 15,000 kDa, but such proteins have not yet been described. This means that the botulinum toxin toxicity is limiting not only for bacterial toxins but for natural toxins in general. The modification of any toxin will probably result only in a change in the spectrum of its effects [In certain groups of natural substances (including toxins interesting for military use) as well as synthetic compounds (including CWA), a certain increase in the biological activity was observed with increasing molecular mass. By modification of the chemical structure (introducing substituents), a certain increase in the toxicity can be actually achieved, which was also implemented in the past within the framework of the CWA development. However, this modification has its limits. In the case of a substantial increase in the toxicity (at least by an order of magnitude), structural changes in a certain type of the compound are insufficient and it is necessary to use a compound having a much higher molecular mass and a much more complicated structure. Presently, the biologically most active substance is botulinum toxin, the molecular mass of which (150 kDa) approaches the upper limit of possible molecular masses of proteins. Based on a theoretical analysis, it is possible to suggest that molecular masses of toxins with LD effects ,62. On tetc. are known and have been successfully used for thousands of years ; some others, for example biotechnological procedures, were relatively recently proposed and were supplemented by modern methods of isolation and purification. A proportion of toxins can also be obtained from natural sources in amounts sufficient for military use, as is the case for example with ricin, botulinum toxin, SEB, or capsaicin. The industrial production of certain toxins in this way can be, however, for economic, ecological and other reasons  non-effective, if not impossible.The basic method of toxin preparation is production directly from natural sources. Some procedures, such as the extraction of toxins from natural materials, fermentation, Many low-molecular weight toxins became attractive for military purposes only after it was possible to determine their chemical structure and develop a procedure of the total chemical synthesis. This knowledge reduces the dependence on natural sources  and makes possible the production of toxins even on an industrial scale. As an example, it is possible to mention saxitoxin (STX) or a group of chemically related compounds referred to as saxitoxins  . SaxitoxConsiderable progress in the production technology of pure chemical and pharmaceutical compounds was achieved by using methods of chemical microtechnology . The useIn the late 1970s, there was a rapid development of gene technology, which now makes it possible to produce certain natural substances more easily than any time before. The fact that by methods of gene and metabolic engineering, used for example in the pharmaceutical or food industries, it is also possible to produce toxins more effectively, resulting in a new increase in the danger of their use as chemical or biological weapons. By genetic manipulation, specific genes important for toxin weapons can be put to a different place within the framework of the genome of a certain cell to achieve a higher gene expression. It should be taken into account that these genes can also be introduced into a cell of another  organism to provide toxin production or to establish conditions for its mass biotechnological production. In the far future, the biosynthesis of toxins interesting for military purposes can also occur in “artificial” (yet unknown) organisms produced by synthetic biology.Microencapsulation is a technique of pharmaceutical administration in the form of microdroplets with a biologically degradable polymeric shell. The purpose of microencapsulation is the protection of the active substance from its degradation, the possibility of the control of its release into the organism, and simpler handling . This teThe development of nanotechnology involved fears that it can also be used for the development of chemical or biological weapons including toxins ,68,69. TMilitary applications of toxins in the form of tactical mixtures offer other possibilities of the military application of toxins. This technique was commonly used in the past for the adjustment of physical and chemical properties of CWA. Suitable admixtures increased the CWA stability, improved ballistic characteristics of the ammunition and provided more effective transfer of the agents to the warfare condition. Certain components added (as for example dimethyl sulfoxide) improved the absorption of CWA by the skin and thus increased their percutaneous effects. In military laboratories, CWA mixtures were also proposed which exerted unusual toxic effects and increased requirements for the chemical analysis, use of protective means, decontamination and therapy. Certain proposals of mixtures also included classic CWA in combination with toxins, for example mustard gas with aflatoxins. Enhanced effects can also be achieved by dissolving ricin in liquid CWA . A conceToday, perhaps more than any time before, it is of importance to study historical texts, military handbooks, and notes on the military use of natural toxic substances. Even the oldest information on sources of toxins, methods of their application, and destructive effects could inspire contemporary as well as future scientists dealing with the research of toxin weapons. Toxins important for military purposes  belong to the so called “mid-spectrum agents”. They are found in chemical and biological weapons, which have been subjected to several international disarmament conventions and thus, their military use to a considerable extent is not currently taken into account. In spite of the fact that in the past the development of toxin weapons was not successful compared to classic chemical weapons, and that it is currently forbidden by disarmament conventions, the research and use of toxins  for activities which are not forbidden is further in progress. There is a problem that certain new trends in the development of chemical, biochemical, and biological technologies can undermine the intention of these conventions, because they may establish conditions for upgrading toxin weapons to a level which possibly enables their effective mass use. The development of toxin weapons  can be more easily concealed compared to the development of classic chemical weapons or biological weapons based on pathogens causing infectious diseases. It seems that classic chemical weapons have reached their zenith and possible risks of their further development can be at least anticipated. However, potential possibilities of the development of weapons based on toxins and their synthetic analogs pose quite new problems in the field of the protection and healthcare, including the detection, means of chemical protection, decontamination, first aid, diagnosis, and qualified therapy. A certain period of time is necessary for the development of any weapon, which also holds for toxin weapons. If we consider the development of toxins for military use to be similar to the development of any other biologically active product , then it would take a period of 5 to 10 years. However, it can be expected to be carried out under conditions of concealment. This fact gives rise to fears that the world could implement appropriate countermeasures by developing effective methods and means of protection or legislative tools only after experiencing the consequences of their application.


Bone-health issues may arise for oncology patients as a side effect of their treatments. One of these may be the development of an atypical femoral fracture. Advanced practitioners should be aware of the risk factors for atypical femoral fractures, and be able to promptly recognize signs, provide patient education, and manage them competently.  Advanced practitioners in oncology (APs) frequently encounter bone-health issues in oncology. A significant number of oncology patients are at risk for accelerated bone loss due to treatment sequelae. Many of those patients may also have preexisting osteoporosis. Reports of atypical femoral fractures (AFFs) have created uncertainty about the duration of bisphosphonate or receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor therapy for bone health in both patients with cancer and osteoporosis, despite the fact that they are uncommon consequences of treatment for osteoporosis, osteopenia, and bony metastasis. The AP should be aware of the risk factors for AFF, be able to provide patient education, promptly recognize signs of an AFF, and manage it competently .Initially, AFFs were thought to be related to bone-turnover suppression and were likened to stress fractures. In researching the history of AFF, however, it was found that this type of fracture was recognized prior to the introduction of bisphosphonates.There are many mechanisms behind AFF, and they are well documented in the biomechanics literature. A review in the Journal of Biomechanics stated that the mechanisms that lead to AFF have not been definitively identified, so a causal relationship between bisphosphonates and AFF has yet to be established . Other rA small study of 25 patients who had taken bisphosphonates for a mean duration of 9.84 years suggested suboptimal vitamin D levels may be a risk factor for development of AFF in addition to prolonged bisphosphonate use. AFFs are heralded by prodromal thigh pain in about 75% of cases .The term "atypical femur fracture" was first described in 1978 and reported in publication in 2005. To settle ongoing confusion about what constituted an AFF, the American Society for Bone and Mineral Research Task Force published a position paper in 2010 to clarify what type of fractures were included, and this report was updated in 2014. Prior to that time, available research did not differentiate between subtrochanteric and femoral shaft fractures .To be defined as an AFF, a fracture must meet the major criteria listed in Although there have been reports of AFF for more than 10 years, it is still not well understood, and the reports of its incidence vary greatly. The majority of accounts of AFF in the cancer population have been primarily in postmenopausal women treated for a prolonged period with a bisphosphonate. There are conflicting reports of AFF occurrence in patients taking denosumab (Xgeva).The denosumab FREEDOM trial reported no incidence of AFF in the first 3 years of therapy. According to the American Society for Bone and Mineral Research , the relThe National Comprehensive Cancer Network (NCCN) summarized the risk factors for AFF in a 2014 report , and addApproximately two-thirds of all women with breast cancer are postmenopausal with hormone-sensitive tumors. For many years, aromatase inhibitors (AIs) have been part of the standard of care for the estrogen receptor–positive breast cancer patient, because they reduce breast cancer mortality in postmenopausal women. However, AIs promote more rapid bone loss. Bisphosphonates have been a mainstay of osteoporosis treatment and prevention, and along with the RANKL inhibitor, denosumab, have been utilized to reduce the bone loss induced by AIs. Therefore, this group of patients, who are seen frequently in the oncology setting, is at increased risk for AFF.Male patients with reduced testosterone production, such as those treated with androgen-deprivation therapy or orchiectomy, have an increased risk for osteoporosis and are likely to have been treated with bisphosphonates or a RANKL inhibitor to prevent bone loss. Other patient populations with potential bone-health issues and an increased risk for osteoporosis and AFF would include those who have received radiation , those taking high doses of steroids, survivors of childhood cancer, and those who have had stem cell transplant .What does this information mean to the AP and to patients being treated with bisphosphonates or RANKL inhibitors? First, the patient must be managed according to standard guidelines for osteoporosis or bony metastasis. Regardless of the type of treatment initiated, the patient’s education must include information about atypical fracture and the associated symptom of mid-thigh pain, with instructions to report this problem to the health-care provider. Patients should be reassured that the risk of AFF is very low, generally < 1%. Close surveillance of patients and assessment for prodromal complaints of thigh pain are essential at every visit, particularly if they have been on therapy for several years.If a patient presents with groin pain or complains of mid-thigh pain, an x-ray of the affected femur should be performed, with a notation to the reading radiologist regarding concern for development of an AFF in a patient on bisphosphonates or RANKL inhibitors. If abnormalities are present on the x-ray of the affected leg, it is appropriate to order an x-ray of the opposite femur, since 30% of patients with an AFF have bilateral involvement. If the patient has no obvious AFF but does have continued pain, a computed tomography or magnetic resonance image may be needed to establish the presence of an AFF .Minimally symptomatic patients with incomplete fractures or severe comorbidities precluding surgery can be given conservative treatment with a 3-month trial of no-weight bearing, but there is little evidence of the success of this approach. Several case reports have shown teriparatide (Forteo) to be beneficial, with reduced healing time and an increased union rate. However, the health-care provider should be mindful that teriparatide is contraindicated in patients with skeletal malignancy, bony metastasis, and metabolic bone disease .The presence of a complete AFF generally calls for surgical repair, with intramedullary nailing as the surgical treatment of choice. When referring to surgery, APs should request that microscopic bone pathology and an assessment of fracture pattern be obtained at the time of surgery .With every patient who experiences an AFF, evaluate/reevaluate the history for potential association with bisphosphonates and/or RANKL inhibitors. Treatment with these agents should be discontinued regardless if the fracture is incomplete or complete. Patients should be evaluated for adequate calcium and vitamin D intake, as well as the presence of any underlying and previously undiagnosed disease process .Oncology clinicians are utilizing bisphosphonates and denosumab to improve the bone health of patients; however, reports of AFFs have created uncertainty about the duration of bisphosphonate therapy for bone health in both the cancer and osteoporosis patient. The American Society for Bone and Mineral Research Task Force offers the following recommendations:After 5 years of oral bisphosphonate or 3 years of intravenous bisphosphonates, reassess risk.Consider continuing oral therapy for 10 years and intravenous therapy for 6 years if the fracture risk is high or the patient has had a fracture while on therapy.Consider a drug holiday with reassessment after 2 years, with resumption of therapy if indicated.Consider dose modification in patients who are continuing on daily corticosteroids, as risk may outweigh benefit.For patients taking denosumab, the oncology provider should assess regularly for prodromal complaints of thigh pain. Unlike bisphosphonates, denosumab does not have a recommended limit on the duration of treatment. The FREEDOM extension trial, in which patients had up to 10 years of treatment, showed long-term safety with no increased incidence of an AFF over time .Decision-making in these cases can be difficult, but with a clear understanding of AFFs, the AP can confidently assess and care for patients on bone therapy should an AFF occur.