case study of malaria

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• Published: 13 September 2021

Malaria: a problem to be solved and a time to be bold

• Pedro L. Alonso 1  

Nature Medicine volume  27 ,  pages 1506–1509 ( 2021 ) Cite this article

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Vaccines alone will not be sufficient for the eradication of malaria, which will also require investment in health professionals, better use of data, and universal access to quality health services.

COVID-19 has provided a wake-up call that infectious diseases can have huge health, economic and social costs and require investments that protect the wellbeing of people across the world. By threatening the health and economies of all countries, unprecedented financial efforts and incentives were deployed in a very short period of time to develop and implement new tools against COVID-19, especially vaccines.

This unprecedented investment has revealed the extraordinary power of science, delivering several safe and effective vaccines within months of the sequence of SARS-CoV-2 being determined and shared. The investment and benefits from science, coupled with global solidarity and a focus on equity, should ensure sufficient supply and the equitable distribution of vaccines. It should also be extended to other diseases, such as malaria, that currently threaten the lives of millions of people around the world.

A golden era

History demonstrates that such an investment in malaria can reap remarkable benefits. At the start of the twenty-first century, the transmission of malaria was taking place in 107 countries across five continents, where more than 80% of the world’s population lived 1 . Sub-Saharan Africa carried the brunt of the disease, where a child probably died of malaria every 45 seconds and efforts to control the disease were very limited. Yet this desperate situation had not gone unnoticed.

Towards the end of the last century, there was a growing political and scientific momentum that would lead to a golden era in the fight against this ancient killer of humankind. Insecticide-treated bed nets, artemisinin-based combination therapies, rapid diagnostic tests, new approaches to chemoprevention of target groups with drugs (such as intermittent preventive treatment in pregnancy or in infants, and seasonal malaria chemoprevention) were the extraordinary outputs of a small and underfunded research community.

On the political front, the Abuja Declaration by African Heads of State, followed by the inclusion of malaria in the United Nations Millennium Development Goals, was accompanied by the creation of new funding mechanisms such as The Global Fund to Fight AIDS, Tuberculosis and Malaria, and the US President’s Malaria Initiative 2 , 3 , 4 , 5 . For the first time, substantial financial resources ensured that antimalarial tools could be procured and delivered at scale. The effect has been staggering: 7.6 million deaths and 1.5 billion cases averted in the first 20 years of this century 1 .

These gains have also occurred at a time when many malaria endemic countries have experienced considerable economic growth and social development, both of which are important contributors to decreasing malaria burden. In sub-Saharan Africa, GDP has grown by an average of 4% per annum in the period from 2000 to 2019 6 . During the same time, access to electricity has increased threefold 7 and the percentage of the African population in urban settings has increased from 31% to 41% (ref. 8 ). It is the combined efforts from the scientific community, leadership across the world and socioeconomic development that have contributed to a public health success story and a great return on global health investment.

However, the past five years have shown both the success and the limitations of this effort 1 . More than half (46) of the 87 malaria endemic countries in 2019 are within reach of eliminating the transmission of malaria within their borders. These countries, mostly outside Africa, now account for less than 0.2% of all malaria cases globally, and some, such as El Salvador and China, have recently been certified malaria free 1 , 9 , 10 .

However, for a considerable proportion of the remaining countries with ongoing malaria transmission, reductions in disease incidence and mortality rates have slowed down, particularly in sub-Saharan Africa, where 94% of global malaria cases and deaths occur.

Funding, from both international partners and the endemic countries themselves, has stalled. In the face of a doubling of the population over the past 20 years in sub-Saharan Africa alone, the stark reality is that after US$26 billion of investment to tackle malaria in this region, the estimated number of malaria cases are slightly higher in 2019 (215 million) than in 2000 (204 million) 1 .

The world is therefore likely to continue to see success as a good number of countries become malaria free. However, we are not on track to achieve the agreed targets for reductions in morbidity and mortality by 2030 as set out in the WHO Global Technical Strategy 11 , and malaria eradication is not within sight. In 2017, the WHO raised the alarm on the stalling of progress by declaring that the world was at a crossroads in the fight against malaria 12 , 13 .

Sustaining the gains

First, more financial resources are required. Financing mechanisms and governance also need to acknowledge and enable the leadership of malaria endemic countries, who in turn need to take greater financial responsibility.

Second, plans and activities to control malaria have to be imbedded in the Universal Health Coverage and Primary Health Care agenda 14 , 15 . Robust, resilient, quality health systems are essential to tackle malaria.

Third, data can also support subnational operations, inspired by a problem-solving mindset, to move away from a one-size fits all approach. Countries must invest in quality health-management information systems. The scale up of point-of-care malaria diagnosis, the gradual switch to electronic databases and the investment in malariometric surveys in recent years, which determine the level of malaria in specific locations, have led to increasing availability of reasonable quality data 1 .

Geospatial and mathematical modeling approaches can take into account the inherent heterogeneity of malaria transmission as well as contextual elements, such as access to health facilities, urbanization, important social determinants and other factors. This allows stratification at a national and subnational level, empowering governments to reliably define the optimal mix of malaria interventions that will achieve maximum effect within a given resource envelope.

This sub-nationally tailored approach must extend beyond what is delivered to include local decisions of how to efficiently and equitably deliver to those in need. A sub-national approach will also require further investments in improving surveillance systems, establishment of dynamic integrated national repositories to systematically curate relevant data and national capacity to analyze and make use of the data for locally tailored responses.

Fourth, the malaria community needs to acknowledge the strength and limitations of the tools and strategies available today. We should be able to diagnose and treat all malaria cases. Affordable and easy to use point-of-care diagnostics allow a parasitological confirmatory test. Similarly, safe and highly effective antimalarial medicines exist and can be used to treat all infections. Consequently, no one should be dying of malaria. However, more than 400,000 malaria deaths continue to take place every year owing to a lack of access to prompt quality care.

Preventable deaths

Prevention relies on both tools against the anopheline vector, such as insecticide-treated mosquito nets, and the use of medicines to prevent infections in key target groups. When properly implemented, prevention with medicine results in a substantial reduction in disease and malaria deaths.

However, a lack of prioritization in research and development means that there is a lack of optimal drugs, regimes and formulations for prevention, which represent a barrier to adoption and impact. Furthermore, both drugs and diagnostics will remain challenged by the emergence and spread of drug resistance or parasite gene deletions, a threat towards which the malaria community has so far responded effectively.

In most of sub-Saharan Africa, long-lasting insecticide-treated nets (LLINs) represent the cornerstone of efforts to control the malaria vector. The efficacy of LLINs in the prevention of disease is modest—around 45% in children under the age of five 16 —and the nets need to be replaced every three years. Part of the efficacy of LLINs relies on impregnation with insecticide, against which Anopheline mosquitoes can develop resistance, and they also rely on quality and integrity, which may represent an even greater challenge 17 .

New prevention tools are needed, including against the mosquito vector and antimalarial medicines. Monoclonal antibodies may also provide opportunities to prevent infection for several months during the periods of highest risk for the key target populations.

Various vaccines

COVID-19 reminds us that vaccines remain the most important tool to prevent communicable diseases. The quest for a malaria vaccine started more than a century ago. Today, there is a first-generation malaria vaccine (RTS,S produced by GSK) based on a recombinant protein that targets the circumsporozoite protein, the predominant sporozoite surface protein of Plasmodium falciparum . RTS,S has completed its clinical development and received a positive scientific opinion by the European Medicines Agency 18 . The efficacy of RTS,S is modest — around 40% reduction of disease.

RTS,S is currently undergoing large-scale pilot implementation that involves several hundreds of thousands of children in three African countries, and will be considered for a potential WHO recommendation for broader scale use before the end of the year. If this historic decision is reached, it would represent the first time that a vaccine against a human malaria parasite is recommended for public-heath use and a first vaccine incorporated to the antimalarial armamentarium toolbox, with the potential to avert millions of cases and hundreds of thousands of deaths. More importantly, this first-generation vaccine will show that the 30-year-long development effort has yielded a safe and effective vaccine against a complex parasite.

A limited number of other vaccine candidates are being tested. One of the most advanced is the R21/MM vaccine candidate. This is based on a similar circumsporozoite antigen to RTS,S and has been developed using the Matrix-M adjuvant platform. In a phase 2b trial, R21/MM showed 77% protection over a one-year follow up, among 450 children living in an area of intensely seasonal malaria transmission in Burkina Faso 19 . The results of the phase 2b trial are encouraging, and has increased anticipation for phase 3 trials that, crucially, need to include areas where malaria occurs all year round, as well as long-term follow up to allow adequate comparison with RTS,S.

In recent years, the use of whole parasite immunization strategies has been tried. Whole-cell P. falciparum sporozoite ( Pf SPZ)-based vaccines are a promising way to evoke immunity, as a broad antigenic repertoire of the parasite is present in the pre-erythrocytic development stages, especially in the liver phase. Sporozoites either attenuated by radiation, or with their development arrested via antimalarial medicines, have been reported to induce 100% protection against heterologous challenge in a small number of volunteers 20 .

BioNTech has recently announced its intention to develop a malaria vaccine using its mRNA technology, which has been used so effectively against COVID-19 21 . The goal is to yield a tool that will enable eradication, with a high efficacy in preventing infection and with a long duration of protection. This declaration represents a U-turn in the decades-long trend of major vaccine developers abandoning or scaling down their efforts in the field of malaria. This announcement also represents the potential of new visions and approaches from the field of oncology being applied to address the challenges and complexities of inducing immunity against complex parasites.

Malaria has plagued humans for millennia and has led to an unimaginable loss of life. Malaria has also had an important role in the geopolitics and evolutionary history of humans. The malaria problem is evolving, dynamic and diverse, but it is now concentrated in some of the poorest communities in the world. The lessons of the past two decades show that success in malaria is possible when the world pulls together. However, enormous biological, political, governance, socioeconomic, data and financial challenges remain. These challenges require the world to be bold again.

New tools, including vaccines, could represent game changers, and demand a collective effort that builds on scientific learning and collaboration. But vaccines by themselves will not be a solution to the problem of malaria. No progress will be made without a well-trained and empowered cadre of health workers. Better use of data to plan, implement and track progress, even within a single country, will allow resources to be used more efficiently.

Finally, national decision-making processes must be at the core of public health governance. Governments must identify and serve those communities that are consistently not reached with quality malaria services, especially those delivered through the public health system. Only then can we move again toward global eradication.

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Acknowledgements

This manuscript has benefitted from several discussions with partners and colleagues within the Global Malaria Programme, particularly A. Noor, D. Schellenberg and A. Robb.

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Alonso, P.L. Malaria: a problem to be solved and a time to be bold. Nat Med 27 , 1506–1509 (2021). https://doi.org/10.1038/s41591-021-01492-6

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Case Report

Two cases of plasmodium falciparum malaria in the netherlands without recent travel to a malaria-endemic country.

Recently, two patients of African origin were given a diagnosis of Plasmodium falciparum malaria without recent travel to a malaria-endemic country. This observation highlights the importance for clinicians to consider tropical malaria in patients with fever. Possible transmission routes of P. falciparum to these patients will be discussed. From a public health perspective, international collaboration is crucial when potential cases of European autochthonous P. falciparum malaria in Europe re considered.

Plasmodium falciparum malaria is an important cause of morbidity and mortality worldwide. 1 It is not endemic to Europe, and reported cases in Europe are almost exclusively in travelers returning from malaria-endemic areas. 2 Imported infections with P. falciparum ( P. falciparum malaria) account for most malaria-related morbidity and mortality in Europe. 3 The Netherlands was declared malaria free by the World Health Organization in 1970.

The incubation period of P. falciparum malaria is 12–14 days, but longer incubation periods can occur in semi-immune persons and persons taking ineffective malaria prophylaxis, but is typically less than one month. 4 , 5 Importantly, diagnosis of P. falciparum malaria may be missed or delayed in patients who have malaria years after leaving a malaria-endemic area or who do not report recent visits to malaria-endemic countries. 6 However, early detection of apparently non-imported cases of P. falciparum malaria in Europe is of major public health importance because it enables effective response activities to prevent outbreaks. We describe two patients who had not been in malaria-endemic areas for years, but had P. falciparum malaria shortly after returning from countries in southern Europe. Informed consent was obtained from the patients for publication of this report.

Case-Patient 1

A 23-year-old man from Liberia was seen at an emergency department in the Netherlands because of abdominal pain for three days and a fever of 40°C. Besides an episode of malaria in the past (before 2008), he had no medical history. His travel history indicated a visit to a malaria-endemic country, Liberia, in 2008. Nine days before admission to our hospital, he returned from a four-week holiday in Barcelona, Spain and Treviso, Italy, where he traveled by car. During his travel, he stayed with immigrants who recently returned from Africa, some of whom were sick and had fevers. The patient reported that in both places the living conditions were poor, and many indoor insects, including mosquitoes, were present. No other risk factors for transmission of malaria (e.g., intravenous drug use, blood transfusion, surgical interventions, airport visit) were reported.

At a physical examination, he did not appear acutely ill. His blood pressure was 108/55 mm of Hg, his pulse rate was 84 beats/minute and his temperature was 40 °C. He had abdominal tenderness. There were no other abnormalities. Laboratory test results showed hemoglobin level of 8.3 mmol/L, a thrombocyte count of 56 × 10 9 /L, a leukocyte count of 4.5 × 10 9 cells/L and a normal differentiation pattern, a C-reactive protein level of 127 mg/L, and a lactate dehydrogenase level of 278 U/L. Surprisingly, examination of a peripheral blood smear showed P. falciparum- infected erythrocytes with a parasitemia index of 2.3%. A rapid immunographic test (Binax NOW Malaria Test; Binax, Portland, OR) result for P. falciparum was positive.

The patient was initially treated with intravenous quinine and improved after one day. After an initial increase of his parasitemia to 4.6% it decreased to < 0.1% after 3 days, after which he was treated with four tablets of atovaquone/proguanil a day for three days. He fully recovered and at follow-up visits at the outpatients department, no malaria parasites were seen on a thick blood smear. Although the patient denied making any recent visits to tropical areas, his blood count revealed 17 × 10 9 eosinophils/L and his feces contained Schistosoma mansoni eggs. He was then successfully treated with praziquantel.

Case-Patient 2

A 34-year-old woman from Sierra Leone was seen at an emergency department in the Netherlands because of periodic spiking fever that lasted for two weeks. Her medical history was unremarkable, except for uterine fibroids and an episode of malaria several years ago. She used no medications. Besides the fever, she had abdominal pain and arthralgia since that time. She noticed that her symptoms felt like malaria, which she experienced in the past in her home country. Her travel history showed that her last visit to a malaria-endemic country, Sierra Leone, was in 2003. In recent years, her travel was limited to Belgium and France. On the first day she experienced symptoms, she had returned from a four-week stay in the Bourgogne area in central France, where she spent time in an apartment block with family and friends. According to the patient, several persons who recently returned from Africa to the apartment block, came down with malaria-like symptoms in the same period. The patient also reported a one-day visit to Charles de Gaulle International Airport. No other risk factors for the recent infection (e.g., intravenous drug use, blood transfusion, surgical interventions) were reported.

At a physical examination, she did not appear sick or anemic. Her blood pressure was 150/90 mm of Hg, her pulse rate was 85 beats/minute and her temperature was 36°C. Peripheral oxygen saturation was 98% at room temperature, and her respiratory frequency was normal. Abdominal examination showed uterine fibroids, which were known to be present, but no hepatosplenomegaly. Several small wounds, possibly caused by insect bites, were seen around her ankles.

At laboratory test examination, the most striking findings were an anemia with an hemoglobin level of 7.1 mmol/L (11.4 g/dL), thrombocytopenia (80 × 10 9 cells/), and slight leukocytopenia (3.7 × 10 9 /L) and a normal differentiation. Lactate dehydrogenase (501 U/L) and C-reactive protein (109 mg/L) levels increased. A chest radiograph showed no abnormalities.

Despite absence of recent travel to malaria-endemic areas in her travel history, but given the patient's remark about her symptoms resembling malaria, microscopy of a thick blood smear and malaria antigen test (Binax NOW malaria test; Binax) were performed and showed an infection with P. falciparum with a parasitemia of 0.18% and gametocytes. She received a 3-day course of atovaquon/proguanil (4 tablets/day) and was sent home. She fully recovered and in follow-up visits at the outpatients department, no malaria parasites were seen on a thick blood smear.

We describe two residents of the Netherlands, both originating from Africa, who came to two hospitals in the Netherlands with P. falciparum infections. Thorough reviews of their travel histories did not show visits to a malaria-endemic area in recent years, but visits to different areas in Europe: Italy, Spain (patient 1), and France (patient 2). Other patients with a P. falciparum infection without a designated source have been reported in Germany. 7

These observations are important because of their relevance for public health and clinical practice. Regarding clinical practice, P. falciparum infections are rarely considered in the differential diagnosis of patients with fever returning from these parts of Europe. For clinicians in the Netherlands, malaria is a traveler's disease and often only considered when patients return from malaria-endemic (i.e., tropical) countries. A delay in the diagnosis and treatment of P. falciparum malaria can lead to increased morbidity and mortality. 8 Therefore, a thorough review of the travel history is important in establishing the origin of the infection.

Discrepancies between reported and actual travel history may occur, giving rise to uncertainties and unexplained symptoms, such as signs of schistosomiasis despite absence of recent travel to tropical areas in the travel history reported by case-patient 1. 9 There are no formal barriers against accessing emergency health care for anyone in the Netherlands. However, it is known from anecdotal evidence reported by clinicians that immigrants unjustly fear the existence of formal barriers, including payments and connections between immigrant regulations and health care and public health authorities. These barriers can potentially influence the reporting of their travel history, limiting thorough analysis of the transmission routes, including on-site entomologic investigations.

In accordance with the Public Health Act, both patients were reported to the Municipal Health Services and subsequently to the Dutch National Institute for Public Health and the Environment. Reporting of these patients in a short time interval without reported travel history to a malaria-endemic country was considered remarkable. European autochthonous malaria was considered as a diagnosis ( Table 1 ). The Dutch National Institute for Public Health and the Environment informed the French, Spanish and Italian Public Health Authorities in France, Spain, and Italy through the European selective exchange Early Warning and Response System.

Possible routes of Plasmodium falciparum transmission for the two case-patients described, the Netherlands

During the past few years, outbreaks of P. vivax malaria have occurred in parts of southeastern Europe, but P. falciparum malaria outbreaks have not been reported. 10 Historically, P. vivax in Europe has been transmitted predominantly by five Anopheles species. 11 However, these mosquito species have been shown to be incompetent for transmitting P. falciparum malaria. 12 The only two mosquito species in Europe known to be competent for transmitting P. falciparum are Anopheles algeriensis and An. plumbeus . 13

Theoretically, with the presence of P. falciparum -competent mosquito species, local malaria transmission is possible when gametocyte-carrying persons that are infected in malaria-endemic areas reside in Europe. 14 This hypothesis of local household transmission in France is supported by the fact that insect bite wounds on the lower extremities were reported by the second patient, whereas the indoor presence of mosquitoes, as well as other persons with malaria-like symptoms at the visiting location, were reported by both patients. However, no autochthonous transmission of P. falciparum has been reported in Italy, Spain, France, or any other country in Europe in 2012 ( http://data.euro.who.int/cisid/?TabID=303151 ). Unfortunately, neither patient was willing to reveal their exact locations of stay, making any follow-up in France, Italy, or Spain impossible.

Local transmission in the Netherlands was also considered but seems unlikely. If one considers that the duration between infection and development of gametocytes was at least 14 days, symptoms developed in both patients within 1 and 9 days, respectively, after returning from travel, and gametocytes in blood smears in relation to reported recent travel of the patients, these three factors probably exclude infection acquired in the Netherlands. Anopheles plumbeus is endemic in the Netherlands. However, in the current circumstances, the vector capacity is considered to be low. There are no indications of autochthonous transmission. 15

The latest reported cases of locally acquired tropical malaria in the Netherlands could be explained by airport malaria in patients staying near Schiphol Airport. 16 , 17 This so-called airport malaria could be another possible route of transmission in our patients. Mosquitoes can hide in freight or passengers area of the planes, or can be transported in the wheel bays and released when the bays open during the approach for landing. 18 – 21 Neither of the patients lived near an airport in the Netherlands, but airport malaria could have been a mode of infection for the second patient because she mentioned that she paid a one-day visit to Charles de Gaulle International Airport during her visit to France. Luggage malaria could also be a route of transmission because both patients visited friends who recently came from malaria-endemic countries. Mosquitoes could have been imported in their suitcases.

Plasmodium falciparum transmission by direct inoculation of infected blood is considered a route of transmission. However, neither of the two patients had received blood or undergone recent medical procedures before infection, reported use of intravenous drugs, or had scars at the physical examination. 22 – 24

Finally, late recrudescence or relapse has been described for different forms of malaria, mostly associated with P. malariae , P. vivax , 25 – 29 or P. ovale . 30 , 31 Interestingly, our patients were originally from malaria-endemic countries, but they reported that they had not returned to their countries of origin for four and nine years, respectively. Late recrudescence of tropical malaria has been described in immunocompromized patients or pregnant women, although these findings are extremely uncommon. 32 – 35

Several cases have been attributed to infected Anopheles spp. mosquitoes traveling in luggage or at least associated with pre-existing partial immunity from repeated prior exposures. 33 Late recrudescence caused by pregnancy or immunosuppression in our patients was considered unlikely.

In conclusion, we report two P. falciparum malaria patients without reported recent travel to a malaria-endemic area. Physicians should be aware of the possibility of P. falciparum infections in patients who have been in contact with travelers who recently returned from malaria-endemic area (luggage, airport, local transmission). Rapid communication between physicians and public health authorities in Europe is needed to effectively respond to signs of possible autochthonous transmission.

ACKNOWLEDGMENTS

We thank our colleagues in France, Italy, and Spain with whom we communicated through the Early Warning and Response System and our colleagues at the Municipal Health Service Utrecht and the Municipal Health Service Midden Nederland for their work and expertise. We also Dr. Marieta Braks (National Institute for Public Health and the Environment) for her contributions to the manuscript. Joop E. Arends and Jan Jelrik Oosterheert managed patients and wrote and edited the manuscript; Marleen M. Kraaij-Dirkzwager and Ewout B. Fanoy were responsible for possible outbreak investigation and edited the manuscript; Jan A. Kaan performed microbiologic diagnosis and edited the manuscript; Pieter-Jan Haas performed microbiologic diagnosis; Ernst-Jan Scholte and Laetitia M. Kortbeek performed vector analysis; and S. Sankatsing managed patients and edited the manuscript. The American Committee on Clinical Tropical Medicine and Travelers' Health (ACCTMTH) assisted with publication expenses.

Authors' addresses: Joop E. Arends, Jan Jelrik Oosterheert, and Pieter-Jan Haas, Department of Internal Medicine and Infectious Diseases and Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands, E-mails: [email protected] , [email protected] , and [email protected] . Marleen M. Kraaij-Dirkzwager, Department of Infectious Diseases, National Institute for Public Health and the Environment, Bilthoven, The Netherlands, E-mail: [email protected] . Jan A. Kaan, Department of Medical Microbiology and Immunology, Diakonessenhuis Utrecht, Utrecht, The Netherlands, E-mail: ln.siuhkaid@naakj . Ewout B. Fanoy, Infectieziekten, Municipal Health, Midden-Nederland, Zeist, The Netherlands, E-mail: ln.nmdgg@yonafe . Ernst-Jan Scholte, Laboratory of Entomology, Wageningen University, Binnenhaven 7, Wageningen 6700 EH, The Netherlands, E-mail: [email protected] . Laetitia M. Kortbeek, Department of Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute of Public Health and the Environment, Bilthoven 3720BA, The Netherlands, E-mail: [email protected] . Sanjay U. C. Sankatsing, Department of Internal Medicine and Infectious Diseases, Diakonessenhuis Utrecht, Utrecht, The Netherlands, E-mail: ln.siuhkaid@gnistaknass .

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This should state clearly the main conclusions and provide an explanation of the importance and relevance of the case, data, opinion, database or software reported.

List of abbreviations

If abbreviations are used in the text they should be defined in the text at first use, and a list of abbreviations should be provided.

Declarations

All manuscripts must contain the following sections under the heading 'Declarations':

Ethics approval and consent to participate

Consent for publication, availability of data and materials, competing interests, authors' contributions, acknowledgements.

• Authors' information (optional)

Please see below for details on the information to be included in these sections.

If any of the sections are not relevant to your manuscript, please include the heading and write 'Not applicable' for that section. 

Manuscripts reporting studies involving human participants, human data or human tissue must:

• include a statement on ethics approval and consent (even where the need for approval was waived)
• include the name of the ethics committee that approved the study and the committee’s reference number if appropriate

Studies involving animals must include a statement on ethics approval and for experimental studies involving client-owned animals, authors must also include a statement on informed consent from the client or owner.

See our editorial policies for more information.

If your manuscript does not report on or involve the use of any animal or human data or tissue, please state “Not applicable” in this section.

If your manuscript contains any individual person’s data in any form (including any individual details, images or videos), consent for publication must be obtained from that person, or in the case of children, their parent or legal guardian. All presentations of case reports must have consent for publication.

You can use your institutional consent form or our consent form if you prefer. You should not send the form to us on submission, but we may request to see a copy at any stage (including after publication).

See our editorial policies for more information on consent for publication.

If your manuscript does not contain data from any individual person, please state “Not applicable” in this section.

All manuscripts must include an ‘Availability of data and materials’ statement. Data availability statements should include information on where data supporting the results reported in the article can be found including, where applicable, hyperlinks to publicly archived datasets analysed or generated during the study. By data we mean the minimal dataset that would be necessary to interpret, replicate and build upon the findings reported in the article. We recognise it is not always possible to share research data publicly, for instance when individual privacy could be compromised, and in such instances data availability should still be stated in the manuscript along with any conditions for access.

Authors are also encouraged to preserve search strings on searchRxiv https://searchrxiv.org/ , an archive to support researchers to report, store and share their searches consistently and to enable them to review and re-use existing searches. searchRxiv enables researchers to obtain a digital object identifier (DOI) for their search, allowing it to be cited. 

Data availability statements can take one of the following forms (or a combination of more than one if required for multiple datasets):

• The datasets generated and/or analysed during the current study are available in the [NAME] repository, [PERSISTENT WEB LINK TO DATASETS]
• The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
• All data generated or analysed during this study are included in this published article [and its supplementary information files].
• The datasets generated and/or analysed during the current study are not publicly available due [REASON WHY DATA ARE NOT PUBLIC] but are available from the corresponding author on reasonable request.
• Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
• The data that support the findings of this study are available from [third party name] but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of [third party name].
• Not applicable. If your manuscript does not contain any data, please state 'Not applicable' in this section.

More examples of template data availability statements, which include examples of openly available and restricted access datasets, are available here .

BioMed Central strongly encourages the citation of any publicly available data on which the conclusions of the paper rely in the manuscript. Data citations should include a persistent identifier (such as a DOI) and should ideally be included in the reference list. Citations of datasets, when they appear in the reference list, should include the minimum information recommended by DataCite and follow journal style. Dataset identifiers including DOIs should be expressed as full URLs. For example:

Hao Z, AghaKouchak A, Nakhjiri N, Farahmand A. Global integrated drought monitoring and prediction system (GIDMaPS) data sets. figshare. 2014. http://dx.doi.org/10.6084/m9.figshare.853801

With the corresponding text in the Availability of data and materials statement:

The datasets generated during and/or analysed during the current study are available in the [NAME] repository, [PERSISTENT WEB LINK TO DATASETS]. [Reference number]  

If you wish to co-submit a data note describing your data to be published in BMC Research Notes , you can do so by visiting our submission portal . Data notes support open data and help authors to comply with funder policies on data sharing. Co-published data notes will be linked to the research article the data support ( example ).

All financial and non-financial competing interests must be declared in this section.

See our editorial policies for a full explanation of competing interests. If you are unsure whether you or any of your co-authors have a competing interest please contact the editorial office.

Please use the authors initials to refer to each authors' competing interests in this section.

If you do not have any competing interests, please state "The authors declare that they have no competing interests" in this section.

All sources of funding for the research reported should be declared. If the funder has a specific role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript, this should be declared.

The individual contributions of authors to the manuscript should be specified in this section. Guidance and criteria for authorship can be found in our editorial policies .

Please use initials to refer to each author's contribution in this section, for example: "FC analyzed and interpreted the patient data regarding the hematological disease and the transplant. RH performed the histological examination of the kidney, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript."

Please acknowledge anyone who contributed towards the article who does not meet the criteria for authorship including anyone who provided professional writing services or materials.

Authors should obtain permission to acknowledge from all those mentioned in the Acknowledgements section.

See our editorial policies for a full explanation of acknowledgements and authorship criteria.

If you do not have anyone to acknowledge, please write "Not applicable" in this section.

Group authorship (for manuscripts involving a collaboration group): if you would like the names of the individual members of a collaboration Group to be searchable through their individual PubMed records, please ensure that the title of the collaboration Group is included on the title page and in the submission system and also include collaborating author names as the last paragraph of the “Acknowledgements” section. Please add authors in the format First Name, Middle initial(s) (optional), Last Name. You can add institution or country information for each author if you wish, but this should be consistent across all authors.

Please note that individual names may not be present in the PubMed record at the time a published article is initially included in PubMed as it takes PubMed additional time to code this information.

Authors' information

This section is optional.

You may choose to use this section to include any relevant information about the author(s) that may aid the reader's interpretation of the article, and understand the standpoint of the author(s). This may include details about the authors' qualifications, current positions they hold at institutions or societies, or any other relevant background information. Please refer to authors using their initials. Note this section should not be used to describe any competing interests.

Footnotes can be used to give additional information, which may include the citation of a reference included in the reference list. They should not consist solely of a reference citation, and they should never include the bibliographic details of a reference. They should also not contain any figures or tables.

Footnotes to the text are numbered consecutively; those to tables should be indicated by superscript lower-case letters (or asterisks for significance values and other statistical data). Footnotes to the title or the authors of the article are not given reference symbols.

Always use footnotes instead of endnotes.

Examples of the Vancouver reference style are shown below.

See our editorial policies for author guidance on good citation practice

Web links and URLs: All web links and URLs, including links to the authors' own websites, should be given a reference number and included in the reference list rather than within the text of the manuscript. They should be provided in full, including both the title of the site and the URL, as well as the date the site was accessed, in the following format: The Mouse Tumor Biology Database. http://tumor.informatics.jax.org/mtbwi/index.do . Accessed 20 May 2013. If an author or group of authors can clearly be associated with a web link, such as for weblogs, then they should be included in the reference.

Example reference style:

Article within a journal

Smith JJ. The world of science. Am J Sci. 1999;36:234-5.

Article within a journal (no page numbers)

Rohrmann S, Overvad K, Bueno-de-Mesquita HB, Jakobsen MU, Egeberg R, Tjønneland A, et al. Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition. BMC Medicine. 2013;11:63.

Article within a journal by DOI

Slifka MK, Whitton JL. Clinical implications of dysregulated cytokine production. Dig J Mol Med. 2000; doi:10.1007/s801090000086.

Article within a journal supplement

Frumin AM, Nussbaum J, Esposito M. Functional asplenia: demonstration of splenic activity by bone marrow scan. Blood 1979;59 Suppl 1:26-32.

Book chapter, or an article within a book

Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. In: Bourne GH, Danielli JF, Jeon KW, editors. International review of cytology. London: Academic; 1980. p. 251-306.

OnlineFirst chapter in a series (without a volume designation but with a DOI)

Saito Y, Hyuga H. Rate equation approaches to amplification of enantiomeric excess and chiral symmetry breaking. Top Curr Chem. 2007. doi:10.1007/128_2006_108.

Complete book, authored

Blenkinsopp A, Paxton P. Symptoms in the pharmacy: a guide to the management of common illness. 3rd ed. Oxford: Blackwell Science; 1998.

Online document

Doe J. Title of subordinate document. In: The dictionary of substances and their effects. Royal Society of Chemistry. 1999. http://www.rsc.org/dose/title of subordinate document. Accessed 15 Jan 1999.

Online database

Healthwise Knowledgebase. US Pharmacopeia, Rockville. 1998. http://www.healthwise.org. Accessed 21 Sept 1998.

Supplementary material/private homepage

Doe J. Title of supplementary material. 2000. http://www.privatehomepage.com. Accessed 22 Feb 2000.

University site

Doe, J: Title of preprint. http://www.uni-heidelberg.de/mydata.html (1999). Accessed 25 Dec 1999.

Doe, J: Trivial HTTP, RFC2169. ftp://ftp.isi.edu/in-notes/rfc2169.txt (1999). Accessed 12 Nov 1999.

Organization site

ISSN International Centre: The ISSN register. http://www.issn.org (2006). Accessed 20 Feb 2007.

Dataset with persistent identifier

Zheng L-Y, Guo X-S, He B, Sun L-J, Peng Y, Dong S-S, et al. Genome data from sweet and grain sorghum (Sorghum bicolor). GigaScience Database. 2011. http://dx.doi.org/10.5524/100012 .

Special reference instructions for .Tex submissions

For .Tex submissions, authors are advised to follow the below instructions for reference formatting:

• Before they compile any version of the manuscript, the should switch the line the bmc_article.tex file which reads "\bibliographystyle{bmc-mathphys} % Style BST file (bmc-mathphys, vancouver, spbasic)" to read "\bibliographystyle{vancouver}"

 In the .zip file which is uploaded authors should include only (with limited exceptions) figures, and files with the .tex, .bib and .bst file endings. Authors should not include the temporary or intermediate files created when a TeX document is compiled into a PDF

Figures, tables and additional files

See  General formatting guidelines  for information on how to format figures, tables and additional files.

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