The International Working Group on the Diabetic Foot (IWGDF) recently published updated definitions for the diabetic foot field. However, the suggested definitions of lower limb amputations differ from the definitions of the International Organization of Standardization (ISO), which may create problems when implementing the definitions. This paper compares and discusses the amputation definitions of IWGDF and ISO.Despite many similarities, the IWGDF and ISO systems have some important differences. First, the IWGDF uses the term “minor amputation” which is value‐laden, arbitrary and has been defined in several different ways in the literature. Second, the IWGDF system lacks descriptions of amputations distal or through the ankle, which may increase the risk for misclassification. Third, hip disarticulations and transpelvic amputations are not included in the IWGDF system.It is suggested that future updates of the IWGDF definitions should be aligned with those of ISO, to meet the goal of global consensus on terminology related to lower limb amputation. The International Working Group on the Diabetic Foot (IWGDF) recently published an update of definitions for the diabetic foot field. However, the suggested definitions of lower limb amputations differ from the definitions of the International Organization of Standardization (ISO), which may create problems when implementing the definitions. This paper compares and discusses the definitions of IWGDF and ISO and suggests that future updates of the IWGDF definitions should be aligned with those of ISO, to meet the goal of global consensus on terminology related to lower limb amputation. The latest update2The IWGDF and ISO systems have many similarities, for example the general definitions of amputation are very similar, with IWGDF defining it as ‘resection of a segment of a limb through a bone or through a joint’, and ISO defining it as ‘surgical removal of the whole or part of a limb’. Additionally, most lower limb amputation levels can be found in both classification systems Table . Despite3The IWGDF definitions are a valuable source for clinicians and researchers working with diabetic foot disease, bringing clarity to the diverse terminology of this multidisciplinary field. However, as different international initiatives to standardize may overlap, it is important to compare suggested definitions with those already existing in the field and, when appropriate, harmonize definitions across standardization systems. For example, for diagnosis of foot infection, the IWGDF is aligned with the Infectious Diseases Society of America (IDSA).GJ is a consultant for Novo Nordisk and AJ is an employee of Össur Clinics Scandinavia. DFR has no conflicts of interest to disclose.GJ wrote the first draft. All authors have contributed to writing, discussions of the content, and have read and approved the final manuscript.Not applicable.


Zimbabwe has a high burden of HIV . In 2017, the country developed and implemented a pilot of HIV case surveillance (CS) based on the 2017 World Health Organisation (WHO) person-centred HIV patient monitoring (PM) and case surveillance guidelines. At the end of the pilot phase an evaluation was conducted to inform further steps. The pilot was conducted in two districts  from August 2017 to December 2018. A mixed-methods cross-sectional study of stakeholders and health facility staff was used to assess the design and operations, performance, usefulness, sustainability, and scalability of the CS system. A total of 13 stakeholders responded to an online questionnaire, while 33 health facility respondents were interviewed in 11 health facilities in the two districts. The HIV CS system was adequately designed for Zimbabwe’s context, integrated within existing health information systems at the facility level. However, the training was minimal, and an opportunity to train the data entry clerks in data analysis was missed. The system performed well in terms of surveillance and informatics attributes. However, viral load test results return was a significant problem. The HIV CS system was found useful at the health facility level and should be rolled out in a phased manner, beginning in Manicaland and Matabeleland South provinces. An electronic link needs to be made between the health facilities and the laboratory to reduce viral load test results delays. The World Health Organisation (WHO) released the first HIV patient monitoring (PM) guidelines in 2006, providing technical recommendations on the collection and use of individual-level data for patient care and tracking . In 2015By 2019, HIV CS had not been widely implemented in sub-Saharan Africa, where the burden of the disease has been highest. In fact, among low-income countries with large, generalised epidemics, only Haiti has implemented case surveillance at a national scale ,5. Yet, Setting: at the time of the evaluation, there were 1574 facilities offering HIV services in Zimbabwe; of these, 624 (40%) high volume sites have an electronic patient monitoring system (ePMS) while the remaining sites use paper-based tools. The ePMS system was rolled out since 2013, as a complement to the paper-based patient monitoring system that uses a client intake form for all patients and a facility held OI/ART Care Booklet (green book) for clients testing HIV positive. Data from paper forms are entered into the ePMS retrospectively. Data from ePMS sites is then pushed manually monthly to the national level for analysis and report sharing quarterly. MOHCC, through support from Global Fund, is in the process of establishing a macro  database in the national data centre which will connect all ePMS sites thereby providing inter-facility linkages and facilitate de-duplication of records. The unique identification code used (OI/ART number) is only available to HIV positive clients. The OI/ART number is viewed as unstable because it uses data points that change , and patient names may change or be misspelt. With the possibility of re-testers and self-transferring patients, it has been challenging to have an accurate record of the actual numbers of people living with HIV and accessing services in Zimbabwe. There is a plan to extract and upload deduplicated ePMS data to the DHIS2 database monthly. For sites without ePMS, data on monthly return forms are abstracted from the paper-based registers and the green-book and uploaded into DHIS 2 which produces district-level aggregate data. It is not possible to detect duplicate records in the aggregate DHIS2 data.Evaluation approach: the evaluation was implemented in September 2019 and conducted by a team comprising Zimbabwe MOHCC and WHO staff; and led by an external consultant. We performed a cross-sectional study using mixed methods  and based on published public health surveillance evaluation methods [ methods . We deveDesign and operations: health information system components of the HIV CS model, including digital and paper tools, data flow and resource requirements.Performance: system attributes, including simplicity, timeliness, acceptability, sensitivity, representativeness, data quality, stability, and informatics attributes, such as information quality, system quality, user experience and service quality.Usefulness: use of CS data, achievements, implementation challenges and lessons learned.Sustainability and scalability: views on the scalability and sustainability of the HIV CS system in Zimbabwe.Evaluation questions: the following evaluation questions were used to guide the assessment: a) what is the design of the HIV CS pilot? b) what is the performance of the HIV CS pilot? c) has the HIV CS pilot been useful for HIV programming? d) if Yes to question 3, how can the MOHCC and its partners sustain and scale up the HIV CS?The health facilities visited in the two pilot districts were selected based on the number of new HIV cases reported in 2018, starting with those that had the most substantial client volumes and could be visited within the evaluation period . At the A total of 13 (52%) stakeholders out 25 to whom the questionnaire was sent responded to the online survey. A total of 33 health facility respondents were interviewed at 11 health facilities, four from Mutare district and seven from Umzingwane .Design of HIV CS: respondents reported that the HIV CS system was adequately designed for Zimbabwe´s context, leveraging existing system capacity and operations at the facility level, using the patient flow that was designed for ePMS. However, the training was minimal, only the health facility in-charges were trained for the most part, and an opportunity to train the data entry clerks to become data entry and analysis clerks was missed. District and provincial responsibilities were not clearly defined. The nurses and counsellors were also not trained adequately on the system; they relied on being trained by the facility in charge. The system also lacked geocoordinates, and a mapping module, to enable mapping of hotspot locations of new HIV diagnoses, high ART attrition, and viral load non-suppression. The respondents reported that the numerous forms and registers increased the burden of work on staff as the CS system added new forms on top of existing ePMS forms. Solar power backup was not available to all data entry sites; in some cases, it just needed a cable to be provided. Not all the data entry was linked to the MOHCC local area network.Data flow in the HIV CS system: the HIV CS system had a paper-based and an electronic component (omponent . The papPerformance of the HIV CS: the system (both paper-based and ePMS) performed relatively well in terms of the surveillance attributes and informatics attributes  health facilities believed that the system should be scaled up to the rest of the country. They reported that the country would lose the ability to track HIV clients and identify double testers if there was not a national linked system. They also said that a national system would also identify hotspots. They also reported that a national system would help in ordering the right number of antiretroviral drugs. The health workers believed that a national system would reduce the paperwork and forms.Stakeholders´ views on scale-up: a total of 10/13 (77%) stakeholders thought that the system was an efficient option for Zimbabwe since it leverages existing digital platforms. A majority of 11/13 (85%) stakeholders thought the country would be able to roll out CS to all facilities with targeted partner support given the current funding challenges. The stakeholders believed that the country would lose the ability to conduct longitudinal tracking of HIV patients and individualised care if the system was not rolled out. The CS system allowed patient-level tracking of cases.Principal results: this is the first report of findings from an evaluation of HIV case surveillance implementation in sub-Saharan Africa. In our evaluation of the HIV CS pilot in two districts in Zimbabwe, we found that the HIV CS system was adequately designed for Zimbabwe´s context, leveraging existing health information platforms and operations at the health facility level. We also found that the system (both paper-based and ePMS) performed well in terms of both surveillance informatics attributes, and that the data are used at the health facility level to ensure linkage from testing to treatment and track PLHIV on ART in their catchment area. All facilities that were visited were using these data to conduct essential cascade analyses, including both new and old clients. Almost all respondents reported that, with partner technical and financial support, the country can rollout the HIV CS system to all health facilities. Whereas the system was adequately designed, the training to staff was minimal, and an opportunity to train the DECs into DEACs  was missed. The nurses and counsellors were also not trained adequately on the system, and staff turnover led to a reduction in those who had primary training on the system. The system needs to include geocoordinates and related data analysis module should enable mapping of “hotspots” of new cases, ART retention and loss to follow up (LTFU), and viral load suppression/non-suppression based on granular health administrative units which facilitate programme response.At the time of this evaluation, Zimbabwe was in the process of implementing electronic health records (EHR) system ; more efThe usefulness of the HIV CS was evident at the health facility level, where the system enabled them to order the exact number of antiretroviral drugs needed for their clients and thus minimise wastage. However, use in programme management at higher administrative levels - another important data use case-was not apparent. The small scale of the pilot likely limited utility at the provincial level, however, one would have anticipated data use at the district level, and this was not seen; it is possible that this was still viewed as a study, hence hampering system utility. We also believe that the relatively positive experience that Zimbabwe has had can inform and strengthen planned or similar efforts by other African countries given the low level of implementation CS in Africa to date . We beliLimitations: interpretation and generalisation of the findings of this pilot are subject to some limitations. First, health facility respondents were also participants in the pilot and could have views that were influenced by their role in the program. There may also have been a natural bias to focus on program successes, although we tried to tease out other critical points to the questions, and we performed some observations. Secondly, although several attempts were made to obtain answers from all relevant stakeholders; some did not respond, and their answers could have been different from those who responded. Third, the evaluation was limited in time, and we could not look at every facet of the performance of HIV CS and PM system, and could have missed vital information. Finally, the evaluation questions required the respondents to have adequate recall of events that occurred in the past, and this could have had a bearing on the results. The team tried to triangulate several sources of information to limit the effect of recall bias. Finally, this was a primarily qualitative assessment with limited direct assessment of CS data.We recommended the following to the MOHCC based on the findings of our evaluation. First, the HIV CS system is useful at the health facility level and should be rolled out in a phased manner, beginning with all facilities in Manicaland and Matabeleland South. Lessons learned from the provincial rollout can be used for a nationwide scale-up. Secondly, training modules and courses should be developed for all the DECs to enable them to conduct data analysis  and data use to inform health facility-level interventions to monitor local response to care and treatment and HIV prevention. Consideration should be made to change the name from Data Entry Clerks to Data Entry and Analysis Clerks. Third, standard operating procedures, training, and regular support supervision and mentorship should be provided to the health facility teams in the operation of HIV CS. Fourth, regular feedback on the data collected should be provided from all levels back to the health facility, and resources  should be regularly provided. Solar power backup and link to MOHCC local area network should be strengthened for all health facilities where HIV CS is implemented.et al. [We also recommended that an electronic link needs to be made between the laboratory information system (LIMS) and ePMS to facilitate the rapid turnaround of viral load test results to MOHCC local area network- linked health facilities, and ePMS should include geocoordinates and a mapping module. Finally, a workflow analysis should be conducted to reduce duplicative and redundant paperwork and registers at health facilities. Efforts should also be undertaken to utilise innovations in public health surveillance, including careful piloting and use of electronic systems given the electricity uncertainties in Zimbabwe, and other innovations as described by Groseclose et al. . We beli


Background: Lymphedema is a condition in which excessive fluid accumulates in soft tissues. It is a common complication of breast cancer treatments. It can lead to serious consequences and interfere with the activity of daily living. This study aimed to determine the level of awareness of breast-cancer-related lymphedema (BCRL) among women with breast cancer in the Kingdom of Saudi Arabia. This was a descriptive quantitative cross-sectional design that included a convenience sample of women diagnosed with breast cancer in the Kingdom of Saudi Arabia. Data were collected by distributing a self-administrated online questionnaire consisting of four parts, including demographic data (five items), the status of education about BCRL (three items), basic medical history of breast cancer (six items), and BCRL level of awareness of risk factors and management (nine items). Results: In total, 95 out of 135 of participants did not know about lymphedema, 119 of the participants (88.1%) did not receive any explanation about the possibility of lymphedema from their medical team before surgery, and 121 of them (89.6%) did not receive it after surgery. The most significant factor affecting participants’ level of awareness regarding BCRL was the lack of information about the possibility of BCRL occurrence, which was not provided to them by the medical team. Recommendation: Early and continuous education for future management is essential to prevent problems related to BCRL and improve quality of life. Breast cancer is a type of cancer in which breast cells grow out of control. It is considered to be one of the most common cancers affecting women worldwide, with an incidence of 23%  and 28.7Lymphedema has different causes, and it commonly occurs as a result of breast cancer treatment such as radiotherapy, chemotherapy, and lymph node dissection . LymphedIt can be managed by multiple treatments, including compression therapy, therapeutic exercises, and pharmacotherapy , but theBCRL can lead to serious consequences and have a negative impact on the quality of life of women with breast cancer in many aspects, such as psychological problems that can disturb body image, anxiety, depression, social isolation, and sexual problems ,19,20,21This study aimed to determine the level of awareness of breast-cancer-related lymphedema (BCRL) among women with BC in the Kingdom of Saudi Arabia, as well as provide the basic data needed to initiate proper education.The research question was, “What is the level of lymphedema awareness among women with breast cancer in the Kingdom of Saudi Arabia?” Therefore, our study was done to determine the level of awareness of BCRL among women with breast cancer in the Kingdom of Saudi Arabia and to determine the gap of knowledge so as to provide basic data needed to initiate an early and proper educational program about BCRL for women with breast cancer.There are 10 studies that discuss the awareness of lymphedema among women with breast cancer. For example, one study aimed to explore the evidence for cancer-related lymphedema. The results show that physical activity and sentinel lymph node biopsy can minimize the risk of lymphedema (LE), while chemotherapy and obesity are considered as risk factors for increasing LE. Lymphoscintigraphy may increase awareness regarding LE, which can reduce the development of LE .A literature review was done in the United States in 2016 to review the knowledge of public health care providers on BCRL. It was found that the long-lasting risk factors for BCRL include the following: axillary node involvement, the type of breast surgery, and radiotherapy . AnotherIn addition, a study was conducted to explore the prevalence of lymphedema occurrence in women undergoing breast cancer treatment. It showed that the prevalence of lymphedema among 250 women undergoing breast cancer treatment was 44.8%, and this is considered to be relevant because it is a disease that affects many aspects of a patient’s overall health  . A totalFurthermore, another study was published in Business at Kaiser Permanente Northern California (2012). The results show that lymphedema awareness varied depending on the age of the breast cancer patients .Likewise, a qualitative systematic review was published in Clonmel. The participants expressed their inability to engage in daily activities, thus leading to a decrease in their quality of life. The results show that the participants lacked information regarding BCRL . A similFurther, a cross-sectional study was done in New York, United Sates, which aimed to investigate cognitive and symptomatic outcomes when providing information about BCRL. The results were as follows: 57% of participants said that they had received information on BCRL, 18% of the participants did not have symptoms of BCRL, and the participants who received information about BCRL had fewer symptoms than the participants who did not receive information regarding BCRL .The researchers had to use old studies as a reference in the literature review to reach the necessary numbers of studies, and there was no adequate recent research about BCRL in general and BCRL level of awareness in particular.A descriptive quantitative cross-sectional design was used among females with breast cancer in Saudi Arabia.This study was conducted in Saudi Arabia.A convenience sample of 135 voluntary participants involved in the study included adult women with breast cancer or women who were breast cancer survivors. Their ages were 18 years and above, and they lived in the Kingdom of Saudi Arabia. We excluded males who have breast cancer, women with breast cancer under 18 years old, and persons outside the Kingdom of Saudi Arabia. A convenience sample of women with breast cancer was conducted through an electronic questionnaire. The researchers introduced the study aim, objectives, and the significance of the study to the participants, and the consent form was obtained from the participants at the beginning of the questionnaire as follows: Your answer to the questionnaire questions means that you agree to participate in this study. The questionnaire took approximately 5–7 min.The data were collected using a descriptive cross-sectional electronic online questionnaire, which can reach a large number of participants. The participants can answer with complete privacy and anonymity, and it can cover every aspect of a topic. It is considered to be more reliable and offers a quick, practical, and cost-effective way to obtain the desired results and save data collectors’ time. On the other hand, electronic online questionnaires do not include open-ended questions. Therefore, participants cannot convey their feelings or emotions, some participant may not answer all the questions with credibility, and there is no chance for explanation or clarification of questions from the researchers when participants fill out the questionnaire. In this study, we used an adopted questionnaire from a previous study done in Korea to determine the level of awareness regarding BCRL .The electronic online questionnaire consisted of a total of 23 questions in two languages; the participants could choose either Arabic or English. It consisted of four parts. The first part included demographic data (five items) such as age, body weight, height, region, and dominant hand. The second part concerned status of education about BCRL (three items), including the following: did they know about lymphedema, did they receive any explanation about lymphedema from health care providers before surgery, and did they receive any explanation about lymphedema from health care providers after surgery. The third part was the basic medical history of breast cancer (six items), including disease duration, lymphedema treatment, lymph node dissection, lymphedema diagnosis, if they received chemotherapy after surgery, and if they received radiotherapy after surgery. The fourth part covered BCRL level of awareness of risk factors and management (nine items), including upper limb hygiene, mild trauma to the upper limb, tight clothing or wearing bracelets, excessive use of upper extremities, weight gain, is lymphedema a disease that should be treated, is lymphedema completely curable, which activities help lymphedema occurrence, and which department can manage lymphedema. The participants’ responses were measured by answering multiple choice and yes or no questions.We obtained ethical approval from the Faculty of Nursing at King Abdul-Aziz University, Jeddah, Kingdom of Saudi Arabia. Ethical approval included the purpose of conducting this study, the questionnaire, and sampling method. We obtained the data from participants who were selected according to the following inclusion and exclusion criteria: adult women with breast cancer or women who are breast cancer survivors, their ages were 18 years and above, and they live in the Kingdom of Saudi Arabia. The exclusion criteria were males who have breast cancer, women with breast cancer under the age of 18 years old, and persons outside the Kingdom of Saudi Arabia.An electronic online questionnaire was used that included informed consent, which was distributed through social media applications such as WhatsApp, Twitter, and Instagram.Descriptive analysis was performed after data collection using Statistical Package for Social Sciences (SPSS software)  version 26 in the form of means, percentages, frequencies, and standard deviations.Of the study sample, 52.6% were between the ages of 18 and 35 years, 18.5% were between 36 and 45 years, 26.7% were between 46 and 65 years, and 2.2% were 65 years or above. Regarding weight, 47.4% of the participants weighed less than 60 kg, 47.4% weighed between 60 and 100 kg, and 3% weighed more than 100 kg. Regarding height, 71.1% of participants were less than 160 cm, 25.2% were between 160 and 170 cm, and 3.7% were more than 170 cm. Regarding region, 9.6% of participants lived in the Central Region, 71.9% of them lived in the Western Region, 6.7% of them lived in the Eastern Region, and 5.2% of them lived in the Southern Region. Of the study sample, 92.6% were right-hand dominant and 7.4% were left-hand dominant. .The study was done to investigate the level of lymphedema awareness among women with breast cancer in the Kingdom of Saudi Arabia, as it is considered to be a common complication among women with breast cancer. It was found that the majority of the participants in this study did not know about lymphedema (70.4%) . A similFurthermore, a study on a total of 103 women with breast cancer stated that knowledge of lymphedema was remarkably related to adherence of women with breast cancer to the recommended strategies of the treatment plan, and women who recognized lymphedema risk management showed greater adherence to the recommended strategies . LikewisAnalysis of the questionnaire used in this study shows that the most significant factor affecting participants’ level of awareness regarding BCRL is the lack of information about the possibility of BCRL occurrence, which was not provided by the medical team . A previous study suggested that an early educational program regarding BCRL awareness for women with breast cancer could be a major factor in preventing the development of lymphedema, and detecting the signs and symptoms of BCRL, early diagnosis, and proper treatment will lead to improving patients’ quality of life . In addiThis study revealed the emerging need for medical teams to provide women with breast cancer the necessary information regarding BCRL. Moreover, the findings of our study highlight the need for providing early education programs for women with breast cancer carried out by the nursing staff, who are considered to be important members of the health care team involved in the care plan and who are most in contact with the patients. The nursing staff must also have adequate knowledge regarding BCRL signs and symptoms, risk factors, and how to prevent it when caring for women with breast cancer in order to help and educate women with breast cancer to be more knowledgeable and to decrease the likelihood of developing BCRL.This was the first study to investigate the level of awareness of BCRL among women with breast cancer in the Kingdom of Saudi Arabia. The study showed an extremely low level of awareness regarding BCRL among the women with breast cancer who participated in this study from different regions of the Kingdom of Saudi Arabia in comparison with another study in another country . The mosThe limitations of this study include the small number of participants. Moreover, this study was conducted during the Coronavirus Disease 2019 (COVID-19) pandemic, which forced us to change the number of the target population and the method for data collection from face-to-face interviews  to an electronic online questionnaire distributed through social media applications such as WhatsApp, Twitter, and Instagram. Therefore, the time required to conduct this study was limited, which was considered to be the most significant factor for us in our study. In addition to these limitations, there were limited numbers of recent studies about the level of awareness of BCRL globally. So, we were forced to use old studies as a reference in this research. Further, no studies had been conducted regarding the level of awareness of BCRL among women with breast cancer in the Kingdom of Saudi Arabia.The study results indicate that there is an intense need for developing an early educational program regarding the possibility of BCRL occurrence for women with breast cancer, especially women who have undergone breast cancer surgery and have received chemotherapy or radiotherapy, as these are considered to be major risk factors for developing BCRL. This educational program should be provided during the early course of treatment by the medical team, as such information plays a significant role in preventing problems related to BCRL for women with breast cancer and will increase their awareness about signs, symptoms, and risk factors. Therefore, early detection and proper treatment should be provided to improve patients’ quality of life and to ensure a better outcome for women with breast cancer. We advise that medical teams should have a continuous educational program emphasizing especially the importance of the awareness of BCRL to educate and increase the knowledge of women with breast cancer and their caregivers.In addition, as there is serious relationship between the level of awareness of BCRL and improving the quality of life of women with breast cancer, this study revealed that there is an emerging need for more studies to be conducted regarding the level of awareness of women with breast cancer about BCRL in the Kingdom of Saudi Arabia.We recommend that future studies investigate the relationship between the level of lymphedema awareness and improving the quality of life of women with breast cancer and engage a greater number of participants.


Mitochondrial diseases (MD) are rare disorders caused by deficiency of the mitochondrial respiratory chain, which provides energy in each cell. They are characterized by a high clinical and genetic heterogeneity and in most patients, the responsible gene is unknown. Diagnosis is based on the identification of the causative gene that allows genetic counseling, prenatal diagnosis, understanding of pathological mechanisms, and personalized therapeutic approaches. Despite the emergence of Next Generation Sequencing (NGS), to date, more than one out of two patients has no diagnosis in the absence of identification of the responsible gene. Technologies currently used for detecting causal variants  is far from complete, leading many variants of unknown significance (VUS) and mainly based on the use of whole exome sequencing thus neglecting the identification of non-coding variants. The complexity of human genome and its regulation at multiple levels has led biologists to develop several assays to interrogate the different aspects of biological processes. While one-dimension single omics investigation offers a peek of this complex system, the combination of different omics data allows the discovery of coherent signatures. The community of computational biologists and bioinformaticians, in order to integrate data from different omics, has developed several approaches and tools. However, it is difficult to understand which suits the best to predict diverse phenotypic outcome. First attempts to use multi-omics approaches showed an improvement of the diagnostic power. However, we are far from a complete understanding of MD and their diagnosis. After reviewing multi-omics algorithms developed in the latest years, we are proposing here a novel data-driven classification and we will discuss how multi-omics will change and improve the diagnosis of MD. Due to the growing use of multi-omics approaches in MD, we foresee that this work will contribute to set up good practices to perform multi-omics data integration to improve the prediction of phenotypic outcomes and the diagnostic power of MD. Mitochondrial diseases (MD) are rare disorders caused by a deficiency of the mitochondrial respiratory chain, which provides energy to individual cells through oxidative phosphorylation . These dGenome regulation encompasses all facets of gene expression, from biochemical modifications of DNA to the physical arrangement of chromosomes and the activity of transcription mechanisms. To understand how the different layers of gene regulation act together in pathophysiological contexts, multiple types of data are needed. Lately, several techniques have developed to interrogate this complex process in multiple dimensions , known as “omics.” While these approaches can reveal physiopathological mechanisms in the sample, only the joint use of several omics on the same sample is the key toward the understanding of the associated phenotype. However, there is the need to develop integrative computational approaches to enable the integration of this type of data. The main challenges are to identify models that allow efficient selection of important characteristics and to analyze high-dimensional, scattered and heterogeneous data. To meet these challenges, several algorithms and mathematical structures have been used . However, no reference method has been identified yet. Omics data analyzed independently often prove unable to identify genes responsible for MD and explain the complexity of all the molecular phenomena leading to these diseases on their own, thus methods of integrating multiple omics represent a real hope for reducing the diagnostic deadlock for patients with MD.In this review we will discuss why multi-omics will improve the diagnosis of MD, the few approaches used in the literature on these diseases and their limitations. We will present an up-to-date list of multi-omics algorithms developed in the latest years and we will discuss why these are not employable for MD. A new nomenclature to summarize the different approaches and a data driven interpretation of recent benchmarks will be presented. Finally, we will provide guidelines to develop multi-omics approaches to be used to improve the diagnostic power of mitochondrial diseases.De novo occurrence is also possible.Mitochondria are present in all the cells of the body, in variable quantities depending on the energy needs of the organs. MD are due to an energy deficit caused by a dysfunction of the mitochondrial respiratory chain and ATP synthase, which supplies energy to the cells in the form of ATP. MD are a group of rare diseases that are extremely heterogeneous both clinically and genetically. Prevalence is estimated at 1/5,000 births, i.e., about 150 new cases per year in France. MD begin at any age with neonatal forms that are generally more severe than those beginning in adulthood. These diseases therefore affect all organs in isolation or in combination and are generally evolutive. This clinical heterogeneity makes the diagnosis of MD challenging. In addition, many pathological situations and other genetic diseases can lead to a secondary respiratory chain deficiency and there is no single reliable biomarker for MD. The proper functioning of the respiratory chain is dependent on mitochondrial biogenesis and it is estimated that more than 1,500 mitochondrial proteins are involved (MitoCarta2.0). The majority of these proteins are encoded by nuclear DNA (nDNA) but 13 are encoded by mtDNA. Each cell contains 2–10 copies of mitochondrial genome which also codes for 22 transfer RNAs and 2 ribosomal RNAs. As a result, mitochondria are under the control of two genomes, and each clinical presentation results from mutations either in nuclear genes or in mtDNA. In mtDNA encoded disease, a correlation between mutational heteroplasmy level and disease severity is usually observed with a “threshold effect” for disease expression. Heteroplasmy (coexistence of wild-type and mutated mtDNA molecules) is an additional difficulty in the diagnostic process because it requires looking for enzyme deficiency in the affected tissue. This double genetic control also explains why all modes of transmission are observed in these diseases: maternal for mtDNA variants, autosomal dominant, autosomal recessive or X-linked for nuclear genes. The diagnosis of MD is based on the identification of the responsible gene which allows genetic counseling, prenatal diagnosis and sometimes directs treatment choices. Furthermore, it is the first step toward understanding of the disease mechanisms. Today, more than 400 nuclear genes are known to be responsible for MD and the list of candidate genes continues to grow . AlthougThe twenty-first century has been marked by the arrival of HTS, such as NGS, which have revolutionized the world of biology. Omics appeared at that time and represent a different strategy, i.e., they study not a single molecule but a set of molecules from the same biological domain, making possible to study biological mechanisms in the globality of living organisms and in the complexity of their interactions.There are several types of omics ,1 launched by the NIH, offers platforms such as the Model Organisms Screening Center (MOSC) that uses genetics and biology of Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio to help in the diagnostic of rare diseases. In addition, WGS is used to detect coding and non-coding variants of the genome. However, the number of variants to be interpreted by WGS is very high  and makes difficult its usage in routine diagnosis.The search for genes involved in MD is done by NGS and based on the identification of pathogenic nucleotide variants through two techniques: WES (Whole Exome Sequencing) and WGS (Whole Genome Sequencing). WES allows the sequencing of all exons, and exon-intron boundaries that represent 2% of the genome. On average, it allows us to find 20,000 coding variants per individual, of which only 9,000 concern the modification of an amino acid . This teOmics have thus progressed thanks to technological advances, which have enabled high-powered analysis of biological molecules, with a reduction in cost-effectiveness. Nevertheless, simple omics allow understanding the functioning of biological and pathological processes at a single level, as the different methodologies assess different parts of the complex physiopathology of disease development and progression. However, it is essential to understand the relationships between different molecular entities and their interactions, as well as their role in regulating gene expression .Despite the wide range of data that can be generated to characterize differences between healthy and diseased cells or tissues, the analysis of a single subset therefore provides an incomplete picture of the underlying biology. More importantly, how do we select the most meaningful types of omics data to be generated, considering the costs and tissue availability?Whether WES or WGS, they do not allow for the understanding of transcript expression levels or tissue-specific expression that reflects the functionality of a gene and the effect of a variant on it. Thus, the study of the transcriptome by RNA-sequencing (RNA-seq) is a major complement to the WES. Recent studies have shown that the joint use of RNA-seq and WES increases the diagnostic yield of MD by 10% . In tranAnother omics tool that can be used to determine the impact of these variants is proteomics. This omics technique provides a functional validation of variants and completes the outliers detected in transcriptomics. A significantly reduced protein level in a sample compared to other samples or controls is a strong evidence of the presence of a variant that is responsible for this decrease . This woSince their first employ, omics techniques have generated a significant amount of complex and voluminous data. These data are available on online databases. There are many mitochondrion-specific ones such as MitoCarta , MITOMAPHowever, the volume of data creates considerable challenges to enable meaningful conclusions to be drawn. To date, MITOMAP contains 14,431 mtDNA variants, MitoMiner and MitoCarta contain approximately 1,157 human and mouse genes encoding mitochondrial proteins. There are also databases associating clinical data or pathologies with genetic variants such as OMIM , ClinVarMulti-omics data broadly cover the domains of “-omes” and can provide useful biological information at several levels and thus help to understand the mechanisms of pathologies, contribute to diagnosis, prognosis and potential therapeutic interventions . There aFinding an appropriate method for data integration and interpretation is often complicated because the data are heterogeneous, large and composed of several variables. Although there are several methods for multi-omics analysis, choosing the most appropriate method for each dataset is quite difficult. To meet these needs, the development of a new classification of multi-omics analytical methods is fundamental.Multi-omics methods are emerging as valuable tools for understanding the functioning of the mitochondria. Data integration is defined as a process by which data from different sources are combined statistically to make large-scale conclusions about a disease and to obtain a comprehensive view of biological processes. Omics integrative approaches increase the reliability of a biological discovery if it can be validated by concordant omics signatures  .The classification of methods for multi-omics integration is currently quite complex because each article proposes its own classification, making the choice of their use complicated. All these classifications are mainly based on the type of algorithm, making difficult to choose which method to use depending on the characteristics of the dataset. For this purpose, we propose a new classification with three categories based on the way the methods analyze the data: “feature selection,” “clustering,” and “fusion” .In the next paragraphs, the main multi-omics integration techniques existing in the literature will be presented according to our new classification with examples of the most commonly used algorithms.Feature selection methods take the results of simple omics data, concatenate them, and perform variable selection using different techniques . The mosClustering methods use clustering techniques to identify clusters on single omics data . In clasFusion methods directly take all available single omics data and merge them . This prHow can the performances of these methods be evaluated? To answer this question, the researchers conducted studies on several data sets to show the performance and limitations of the different methods. Here we will discuss the main findings of these valuable benchmarks.The paper by Rappoport et al. demonstrated that in most of the cases the rMKL-LPP , featureOverall, in case of complex biological data , it is recommended to choose a method from the feature selection category that performs a feature selection step to attenuate the noise.To date, algorithms for multi-omics data integration, have very little application to MD because they are developed to be used on a large number of patients and which are not applicable on rare disorders as MD.The limited number of patients is not the only difficulty in applying existing algorithms for multi-omics integration to MD. MD are rare and heterogeneous and the causative variant(s) are usually unique or “private” for each patient (or family). They require a methodology that identifies unique signatures making difficult to apply most of multi-omics methods available because they are more suitable to identify common signatures.The specificity of MD has led scientists to reinvent new approaches to integrate multi-omics data from MD patients to improve their diagnosis. In this paragraph, the first studies that have demonstrated the feasibility and usefulness of multi-omics approaches for MD will be described.ad hoc, they found one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed variants. This approach resulted in the diagnosis of 5 patients from the 48-patient cohort with undiagnosed MD and the identification of a candidate gene for 36 other patients.Kremer et al. decided to integrate WES data with RNA-seq data to identify variants responsible for MD for a cohort of 48 patients . They haTo improve the results and design a tool that can be used on other datasets, most of the same authors as this pioneer work, developed the OUTRIDER (OUTlier in RNA-seq fInDER) method that identifies “outlier” genes that are aberrantly expressed in the entire cohort . OUTRIDEad hoc bioinformatics approach. They analyzed the inconclusive cases in the WES samples by running transcriptomics and proteomics analyses in parallel. They tracked the impact of a variant on the abundance of transcripts and their sequences during translation and vice versa by tracing the aberrant expression and splicing back to the responsible protein.ad hoc approaches in order to standardize the analysis of multi-omics data for MD. For example, the WeiGhted Correlation Network Analysis (WGCNA)   method tBioinformatics tools particularly useful in MD include SAVNet (Splicing-Associated Variant detection by NETwork modeling) . It alloAlthough many data are public, they cannot be integrated simply or directly into a mathematical framework or statistical model. The integration of these data to obtain a global understanding of biological processes and diseases presents particular challenges: the underlying heterogeneity of the omics data, the large size of the data leading to intensive analysis of the calculations, and the lack of studies to prioritize the various tools . One of In addition to these challenges, one of the major obstacles is the non-standardization of data formats in different technologies. Most multi-omics integrative analysis tools require the data to be in specific formats , so indiThe availability of methods that are not specific to a type of omics will allow the extension of integration applications to approaches that are still little addressed by specific methods  . A cruciFinally, the main key to any integrative analysis is the right choice of method to answer the question of biological or medical interest. There are many studies that provide a comparative analysis of integration tools (as discussed in the paragraph “Comparisons between integration methods”), but they are not comprehensive enough in terms of the choice of tools and the biological context. Further studies of this type are needed to guide the community in gaining a better understanding of the wide range of tools.A new era of personalized medicine has arrived, offering a project of individualized care with treatment and medical management targeted and adapted to each patient. The continuous improvement of broadband technologies facilitates this process by transmitting detailed information about the human body . The intThe personalized approach in omics catalyzes precision medicine on two levels. For diseases and biological processes whose mechanisms are still unclear, it will facilitate research that would greatly advance our understanding; and when mechanisms are clarified, individualized care can be provided through health surveillance, preventive medicine and personalized treatment. This approach also facilitates the development of other important health-related fields, such as nutritional systems biology, which studies personalized diet and its relationship to health from a systems perspective .With the rapidly declining costs of omics technologies, we expect an increasing number of applications in the development of personalized medicine and in many aspects of health care. This will considerably improve the price charged to patients and reduce the cost of care for the general public. Scientists, governments, pharmaceutical companies and patients should work closely together to ensure the success of this transformation. As part of health surveillance, the iPOP  tool  is used Progress in the NGS has reduced the number of patients in diagnostic impasse, but it is still not enough. Multi-omics approaches are very promising for improving diagnostic performances, but several problems remain to be solved. They are generally developed for cancer research where large numbers of samples are available, which is not the case for MD. Therefore, there is a need to develop multi-omics approaches applicable to small cohorts. Moreover, in oncology, these methods look for common signatures, whereas for MD, there are mainly “private” signatures for one patient or one family, i.e., an altered gene for a patient. However, it could be possible to identify common signatures for small groups of patient, e.g., deficiency of a specific complex of the respiratory chain.Another challenge is to develop databases specific to MD. For rare diseases, very few patients are affected, so few data are available and especially very few patients share the same pathogenic variant. Data from a single hospital are not sufficient and the establishment of interoperable national and European clinical-biological databases would allow us to expand the available cohorts and accelerate the knowledge of these diseases. Several initiatives have been set up, including the RD-Connect project. Funded by the European Union since 2012, RD-Connect is developing data sharing mechanisms and tools for omics and bioinformatics analysis that are incorporated into an integrated platform linking patient registries, biobanks and clinical bioinformatics data into a central resource for rare disease research .In the future, international and interdisciplinary collaborations are essential to develop more effective tools and share data to fight the diagnostic impasse and improve patient management.This review has therefore enabled us to develop a new classification by summarizing the main methods of multi-omics integrations, which will benefit the entire scientific community by simplifying their choice of a method adapted to each type of data set.In conclusion, multi-omics is nowadays evolving in bioinformatics and will soon go beyond the use of single omics in biological and medical research to obtain a better understanding of human diseases, to develop approaches for predicting outcomes, biomarker discoveries and molecular signatures .Nevertheless, in the future several points remain to be developed. First, more comparative analyses will be needed to assess the performance of tools in contexts other than cancer, as this will allow the selection of the right tool based on the dataset, even if one tool may not always be preferred. Reference data sets should also be developed using simulation tools, which will allow for more accurate estimation of false positives and false negatives. Two other points need to be developed. On one hand, the development of tools that can be used on small cohorts and capable of managing more variables than patients. On the other hand, the development of databases for healthy individuals that will be used as a control to calibrate the tools.Collaboration between scientists from different fields is also essential for the integration of multiple layers of information. This superimposition of information is very useful for elucidating how pathological processes occur, as well as for the development of new therapeutic interventions.JL and MF performed bibliographic research, wrote the manuscript, and prepared figures and tables. SiB and VP-F conceived the review and wrote the manuscript. SA-E-M and SyB contributed to the manuscript and critical interpretation. All the authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The worldwide increase in unnecessary caesarean sections (CSs) is a major global health issue. Mass media campaigns have been used in several countries to reduce this trend. The objectives of this systematic review were to identify, critically appraise and synthesise the findings, including the barriers and enablers, of mass media campaigns directed at lay people to reduce unnecessary CS.We included any study design that reported health communication mass media campaigns directed at lay people with the specific objective of reducing unnecessary CS, created by any agent, in any format. We searched seven electronic databases without language restrictions, from inception to February 2019. Experts in the field were contacted.The search yielded 14 320 citations; 50 were selected for full-text reading; and one was included. Six other reports were included. The seven campaigns were conducted in 2009–2017, mostly in Latin America. Most campaigns were independent efforts by non-governmental or activist organisations. Only one campaign conducted formative research and pretested the intervention. All campaigns used indirect communication, mostly through internet channels; two campaigns also used direct communication with the public. None assessed their effects on CS rates. Only two campaigns measured their impacts on participants’ knowledge, attitudes and birth preferences but only in the short term. The main barriers were lack of financial and human resources. The main enablers were the enthusiasm of volunteers, the participation of famous persons/celebrities and the involvement of communication professionals.There are few mass media campaigns directed at lay people to reduce CS. Most campaigns did not use key principles recommended for the creation and implementation of health communication interventions, and none assessed their effects in reducing CS rates. If media campaigns can play a role in modifying population views towards CS, there is a need for more rigorous studies including impact assessment.CRD42019120314. Scientific evidence does not support caesarean sections (CSs) for non-medical reasons, and numerous studies report increased maternal and perinatal risks associated with this type of delivery.The worldwide overuse of CS is a major global health issue that has led to considerable international debate.Mass media campaigns are recommended to change population health behaviours, but there are no systematic reviews on campaigns to reduce CS rates.We found four campaigns in Latin America, two in Europe and one in Asia directed at lay people with the specific objective of reducing unnecessary CS.Most campaigns were independent efforts by non-governmental or activist organisations, and did not use key principles recommended for the creation and implementation of health communication interventions.None assessed their effects on CS rates.There is a paucity of publications and data about mass media campaigns to reduce unnecessary CS.If mass media campaigns can play a role in modifying population views towards CS, there is a need for more rigorous studies including impact assessment.During the last decade, there has been a steady worldwide increase in the rate of caesarean sections (CSs). In 2014, the global CS rate reached 19.1%, a threefold increase from 1990, with large variations between and within countries. Currently, Latin America and the Caribbean have the highest CS rates (40.5%), followed by North America (32.3%), Oceania (31.1%), Europe (25%), Asia (19.2%) and Africa (7.3%).3–8Maternal request, motivated by convenience, fear, misconceptions or cultural trends, is often mentioned as one of the key contributors to the increase in CS rates.21 28–36Over the last decade, there have been some campaigns targeted at the general population to reduce unnecessary CS. In view of the increasing concern about the worldwide rise in caesarean deliveries, potential negative consequences of CS for the health of mothers and infants, and the limited effectiveness of strategies tested to date to revert this trend,The objectives of this review were to identify, critically appraise and synthesise the information available on mass media campaigns directed at lay people to reduce unnecessary CSs. We assessed the main characteristics, the effectiveness, and the barriers and enablers to the creation and implementation of these campaigns.This review followed Cochrane methods and the MOOSE reporting recommendations.We included any type of report on mass media campaigns directed at lay people to reduce unnecessary CS or to increase vaginal delivery (VD). This included articles published in scientific journals or presented in events, as well as written, audio or video material available on the internet (including YouTube) or on social media channels . We included randomised, quasi-randomised, cluster randomised or non-randomised trials, as well as controlled before–after studies or interrupted time series studies or case reports. The reports had to describe the main components of the campaign in sufficient detail so that they could be understood and eventually adapted/replicated in other settings. We included only reports that stated that the main objective (or primary outcomes) of the campaign was to reduce unnecessary CS or to increase VD.We defined a mass media campaign as an intervention that uses a set of organised communication activities to produce specific results or effects in a relatively large number of individuals, usually within a specific period of time.We included campaigns that used either direct or indirect communication strategies. Direct communication strategies involve the transmission of messages through face-to-face interventions such as presentations, performances and group discussion sessions in clinics, schools or other public areas. Indirect communication campaigns use mass media instruments such as radio, TV, movies, newspapers or magazines to transmit their message to the general public during a specific period of time. This mode of communication is indirect because the consumer was not expecting this information, and it is presented to him/her in the context of another experience of his/her interest.42–44We included campaigns of any cost, size, duration or catchment area conducted as a stand-alone intervention or as part of a broader, multicomponent, intervention. We included campaigns with or without formative research to inform the creation and development of the campaign, as well as campaigns with or without previous research to assess the baseline and/or postintervention (before and after the campaign) outcomes of interest.We included studies that described campaigns targeted at healthy pregnant women , non-pregnant women of reproductive age or the general lay public (men and women of any age). We included campaigns targeted at laypersons of any nationality, gender, social class or educational level. We excluded campaigns aimed at specific high-risk groups, such as people with HIV, as well as campaigns targeted exclusively at health professionals or institutions.We included reports with or without quantitative assessments of the impact of the campaign on hard or soft outcomes. Hard outcomes were changes in the rates of CS or VD after the campaign, or in the exposed versus non-exposed groups. Soft outcomes were changes in knowledge, attitudes, beliefs or preferences for route of delivery on a sample or all participants after the campaign or in exposed versus non-exposed groups.We collected and present the main barriers and enablers described by authors for the creation and implementation of their campaigns as part of the outcomes of this review.https://ccp.jhu.edu/). We screened the reference lists of all studies selected for full-text reading and contacted experts in the field to identify additional potentially relevant campaigns.The search strategy used the following general search words, adapted to each specific database: ‘campaigns’, ‘birth’ and ‘preferences’ . After the exclusion of duplicates, two investigators independently screened the titles and abstracts of all citations to select potentially relevant studies. The full texts of these studies were retrieved and read; those that fulfilled the aforementioned selection criteria were included in the review. Discrepancies between reviewers were discussed until consensus was reached; if needed, a third reviewer was invited to arbitrate.Two review authors extracted the data from each included report using a standard form created for this review . Discrep10.1136/bmjgh-2019-001935.supp2Supplementary dataWe presented the main characteristics, barriers and enablers of the campaigns descriptively. If data were available, we planned to assess the effectiveness of each campaign by calculating the mean absolute and relative reduction in CS rate and 95% CIs. We planned to combine the results of similar studies and to calculate pooled mean differences or mean standardised differences and 95% CIs. Due to lack of data, this was not possible.It was not appropriate or possible to involve patients or the public in the design, conduct, reporting or dissemination of our research.et al, ‘No to Unnecessary Caesarean Section': Evaluation of a Mass Media Campaign on Women's Knowledge, Attitude and Intention for Mode of Delivery, in press), Italy  and Puerto Rico   . Six of 10.1136/bmjgh-2019-001935.supp3Supplementary data10.1136/bmjgh-2019-001935.supp4Supplementary dataDetails of the objectives and the creation and implementation of the campaigns are presented in The majority of the campaigns were independent efforts of NGOs, activist organisations or associations strongly engaged in this topic. Only two (Brazil and Cyprus) had the the involvement of the ministry of health, and three  had the involvement of professional associations. Three of the campaigns  were stand-alone interventions. Only one of the campaigns (Iran) conducted formative research, and two campaigns (Brazil and Iran) used theories of behavioural change in the development of the campaign. Five of the campaigns  had communication specialists in their creation teams, and four  used authority figures/celebrities to disseminate the campaign messages. All campaigns used indirect communication: five disseminated messages through internet channels ; three used TV spots ; and four used pamphlets or posters . Two of the Latin American campaigns also used direct communication with the target audience. The Argentinean campaign held group discussions with women. The Brazilian campaignDue to lack of data, we could not pool the results from individual studies into a combined estimate to assess the effectiveness of the campaigns. We therefore present a narrative description of the most important characteristics and findings of each campaign, as well as the barriers and facilitators reported by the authors.There is no publication of this campaign. We obtained information through its website and interviews with the main coordinator. The campaign occurred in May 2009, during the ‘International Week for Respecting Childbirth’. It was created by the Argentinean chapter of the international NGO network Red Latinoamericana y del Caribe para la Humanización del Parto y el Nacimiento (RELACAHUPAN) as part of a multicomponent intervention that took place during the week in the country. RELACAHUPAN is a Latin American network of NGOs that spans 20 countries.The campaign occurred between 2015 and 2017 (34 months) in five cities in Brazil. It was created by health professionals and involved experts in communication and museum exhibits. The campaign was part of a long-term multisectorial initiative led by the municipal health department to increase VD in the city of Belo Horizonte , which started in 2007 and lasted 10 years. The campaign consisted of an interactive exhibition that combined digital art with theatrical techniques, videos, photos, scenarios and panels to promote an emotional experience, engage the visitors and encourage them to think critically. The free exhibition consisted of a 40 min guided interactive circuit that took place inside five containers parked on outdoor spaces in different locations . Immediately after going through the experience, visitors were invited to participate in group chats. This itinerant exhibit remained in each site for several weeks and was then packed up and transported to other locations by truck. The campaign also involved indirect communication through a website, Facebook, Instagram pages and a YouTube channel. The campaign cost approximately US$350 000 per year to cover 12 exhibits in the five cities. It was funded by national scientific agencies, the Brazilian Ministry of Health, the Bill and Melinda Gates Foundation and the Pan-American Health Organisation.45A total of 42 170 persons of all ages visited the exhibits in the five cities. There were 8204 followers on Facebook, 4505 on Instagram and 2900 on YouTube. The authors used written questionnaires to measure changes in visitors’ preferences for route of delivery, knowledge about risks of CS and opinion on VD. There were significant changes in these three measures . The invThere are no publications of this campaign. Data were obtained through interviews with one of its creators, who also provided the web content of the campaign. This national, internet-based campaign lasted 6 months (November 2013–May 2014). It was created by the Chilean chapter of the international NGO network RELACAHUPAN.This report was presented only as an oral communication in an international meeting. Additional details were obtained by contacting the presenter. This national campaign took place in Cyprus between 2014 and 2015 (12 months). It was designed as a stand-alone intervention by the Council of Midwives Committee and the Ministry of Health. Communication experts from TV channels volunteered to help create the campaign’s video clip. The campaign was supported by the country’s first lady, national specialist societies, religious authorities, several NGOs and civil trade unions. The messages were delivered through indirect communication, including posters, banners and pamphlets in local hospitals, and press releases that were sent through emails and mass media posts. The central piece of the campaign was a short video clip, with local female celebrities, that was disseminated in local open TV channels during 12 months. There is no information on the frequency of the campaign messages. The cost of the campaign was approximately €5000, and it was funded by the Cyprus Nurses and Midwives Association, trade unions and the Nursing and Midwives Council. There is no information on the estimated number of persons exposed to the campaign. No outcomes were measured or reported. The effectiveness of the campaign was not assessed.This prepublication manuscript (obtained from the authors) describes a national campaign conducted in Iran during 10 days in April 2016. The campaign was created by an expert panel of nine persons . There is no information on the cost of the campaign. The campaign consisted of a short video clip that was broadcast on four of the country’s eight open TV channels during 10 consecutive days and in antenatal care clinics (on closed-circuit TV). There is no information on the estimated number of persons exposed to the TV campaign. The authors measured changes in knowledge, attitude and preferred route of delivery of 466 pregnant women without a previous CS and living in Teheran for at least 6 months, who were managed in public and private antenatal care clinics in that city. The authors used written questionnaires to assess all participants before and after the campaign. Most of the participants  stated they had not seen the TV spots when they answered the second questionnaire. The 194 exposed women had a significant increase in knowledge and attitude scores towards VD and a significant decrease in the proportion of pregnant women who intended to have a CS, but no significant changes in attitude towards CS .A manuscript describing this campaign is in press and was shared by the authors. Additional information was obtained by contacting representatives of various partners involved in this initiative. The nationwide campaign took place between January 2010 and September 2011 (21 months). The campaign was created by ONDa , an NGO focused on women’s health, with the participation of the World Health Organization (WHO), the Italian Society of Gynaecologists and Obstetricians and a group of Italian female bipartisan parliamentarians. The campaign was part of a multicomponent intervention that included technical meetings at WHO to increase the awareness of Italian parliamentarians about the overuse of CS and to foster political action at national and regional levels to promote vaginal births and to reduce CS. The main elements of this campaign were a TV spot , an online survey disseminated by a national women’s magazine and an educational brochure about indications and risks of CS. A short TV spot was initially broadcast on open and paid TV channels three to four times/day for up to 2 weeks and then posted on YouTube and campaign websites. The largest Italian women’s magazine featured a text about CS in Italy and invited readers to answer an online anonymous survey about their preferences for and knowledge about the risks of CS versus VD. The magazine also distributed a special brochure with information on CS, including indications and risks. This brochure was also available in hospitals and clinics. There is no information on the estimated number of persons exposed to the campaign. No outcomes were measured, and the effectiveness of the campaign was not assessed.There are no publications of this campaign. Data were obtained through personal contact with the campaign coordinator. This national campaign was created by the Maternal and Child Health Student Association of Puerto Rico’s University School of Public Health. The messages were delivered using indirect communication through a hip-hop video posted on the campaign webpage and internet channels . Celebrities  acted as spokespersons pro bono. No outcomes were measured, and there is no information on the number of persons exposed to the campaign or its effectiveness.This review identified seven mass media campaigns directed at lay people with the specific objective of reducing unnecessary CS, only one of which was published in a scientific journal. In their creation phase, only one of the campaigns used formative research to inform the design and implementation of the intervention and obtained input from the target population (through pilot testing) before being launched. The involvement of health authorities was not frequent. None of the campaigns assessed its effects on CS rates. Only two campaigns measured their impacts on participants’ knowledge, attitudes and birth preferences, but only in the short term. The main barriers to the creation and implementation of the campaigns were lack of financial and human resources. The main enablers were the enthusiasm of the volunteers, the participation of famous persons/celebrities and the involvement of communication professionals.The lack of formative research and testing in six of the seven campaigns was surprising. Formative research is essential to assess knowledge, awareness and beliefs of the population, to understand local cultural norms, to ensure that the content and format of the campaign are appropriate and acceptable, and to identify the most credible and most persuasive channels and spokespersons.29 30 41–43 47Several campaigns depicted messages about the value of VD. Overall, in the material produced with the aim of reducing CS, the benefits of VD are often lost in the midst of messages focused on the potential adverse consequences of CS. We believe this perspective is important and should be included in future campaigns since women welcome this information and value what is best for their babies and themselves.48The specific types of communication used by the campaigns varied, but they were mostly indirect, that is, did not involve personal contact with the target audience. Traditionally, most mass media campaigns rely on the use of posters, handouts, public service announcements and presentations, along with information disseminated in newspapers, magazines, radio and TV.We could not assess the effectiveness of the campaigns in reducing the rates of CS because none of the included studies measured this outcome. Soft outcomes  were assessed in two campaigns (Brazil and Iran) but only immediately after exposure to the campaign. The duration of mass media effects, that is, the persistence of the positive effects of mass media on knowledge, attitude, behaviour or preferences over time, is considered an important element in assessing the effectiveness of mass media interventions.27Our review has several strong points. To our knowledge, this is the first review on this topic. We designed a broad and sensitive search strategy and used rigorous methodology to reduce bias. Extensive efforts were undertaken to contact experts in the field to identify campaigns not identified through electronic searches. Six of the seven included campaigns were uncovered using this strategy. We acknowledge that, despite our extensive search, we may have missed relevant reports. An additional limitation of this review is that many reports were incomplete and did not provide all relevant details, which can be an obstacle to the replication of similar campaigns in other settings. Due to the lack of details and outcome assessments, we are not able to infer what elements of a mass media campaign on this topic could be most associated with success.Mass media campaigns have been recommended as a key component of comprehensive strategies aiming at behavioural change.Importantly, the success of any campaign to reduce unnecessary CS will depend on the existence of facilities that offer women safe and adequately resourced environments to encourage and support them during labour and vaginal birth. Suboptimal quality of care, disrespect and abuse, insufficient communication or perverse relationships between women and providers must be addressed for women to prefer VD.37 55This review found seven mass media campaigns directed at laypersons to reduce CS, only one of which was published. Most campaigns did not use key principles recommended for the creation and implementation of health communication interventions, and none assessed the effects of the campaigns in reducing CS rates. There is a need for more well-designed and well-reported studies in this area, including rigorous research to assess impact.


Owing to an increase in digital technologies in health care, recently leveraged by the COVID-19 pandemic, physicians are required to use these technologies appropriately and to be familiar with their implications on patient care, the health system, and society. Therefore, medical students should be confronted with digital health during their medical education. However, corresponding teaching formats and concepts are still largely lacking in the medical curricula.This study aims to introduce digital health as a curricular module at a German medical school and to identify undergraduate medical competencies in digital health and their suitable teaching methods.We developed a 3-week curricular module on digital health for third-year medical students at a large German medical school, taking place for the first time in January 2020. Semistructured interviews with 5 digital health experts were recorded, transcribed, and analyzed using an abductive approach. We obtained feedback from the participating students and lecturers of the module through a 17-item survey questionnaire.The module received overall positive feedback from both students and lecturers who expressed the need for further digital health education and stated that the field is very important for clinical care and is underrepresented in the current medical curriculum. We extracted a detailed overview of digital health competencies, skills, and knowledge to teach the students from the expert interviews. They also contained suggestions for teaching methods and statements supporting the urgency of the implementation of digital health education in the mandatory curriculum.An elective class seems to be a suitable format for the timely introduction of digital health education. However, a longitudinal implementation in the mandatory curriculum should be the goal. Beyond training future physicians in digital skills and teaching them digital health’s ethical, legal, and social implications, the experience-based development of a critical digital health mindset with openness to innovation and the ability to assess ever-changing health technologies through a broad transdisciplinary approach to translate research into clinical routine seem more important. Therefore, the teaching of digital health should be as practice-based as possible and involve the educational cooperation of different institutions and academic disciplines. With the progress in the introduction of digital solutions in patient care, such as electronic health records -3, artifAlthough the introduction of new technologies in medicine is accompanied by public hope for better and more efficient patient care ,12, expeTraining physicians and nurses in the practical use of digital technologies at an early stage of their career is overdue to prepare them for their future challenges ,13,16. IThe relevance of implementing digital health education in medical curricula is evident . VariousAccording to a Europe-wide survey, medical students felt lacking digital literacy and demanded a wider implementation of digital health topics in their curricula ,24. AlonWe intended to deliver a proof of concept of teaching digital health at a medical school, describing the development, introduction, and evaluation of a 3-week elective module. We further aimed to identify undergraduate medical competencies in digital health and their suitable teaching methods.Ethical approval for this study was granted by the ethics committee of the Charité—Universitätsmedizin Berlin (EA1/236/19). Participation in the study was voluntary. Before the study, all participants provided their consent.Approbationsordnung für Ärzte) since 1989, medical informatics is only marginally taught in the German medical curriculum. The terms digital or digital health are still not mentioned in the Medical Licensure Act in Germany. By the end of the third year of the undergraduate modular medical track, students at the Charité have to choose an elective module from a variety of 3-week course programs covering different medical fields that are usually not covered by the mandatory curriculum. The modules are in direct competition for the students’ interest and comprise 60 teaching hours (45 min each). Only the modules selected the most often by the students take place.This mixed methods study took place at the medical school of a large German university hospital, the Charité—Universitätsmedizin Berlin, in the context of the development and deployment of a pioneer teaching module for digital health, which was realized in January 2020. At the time of the study, approximately 7500 students were enrolled at the medical school . AlthougOver the course of 2 years, we developed a teaching module for digital health based on qualitative results of semistructured interviews with experts described below and by reviewing similar existing projects. The module was designed to change over time, flexibly reacting to the feedback received and to new scientific findings. In multiple face-to-face meetings, calls, and emails with potentially interested parties, we identified 32 lecturers from 16 departments of our university hospital as well as from 6 academic and nonacademic partner organizations who were willing to participate.The cooperation with the lecturers led to a high variety of digital health topics, such as lessons on law, ethics, and economics as well as on digital pharmacology or AI and big data in research. In addition to the theoretical teaching in seminars, our main focus was to provide hands-on experience with digital health technologies. Practice units on smart implants and wearables, symptom checker apps, telecardiology, mixed reality-assisted surgery, and video consultations were included with the help of experts and developers of the corresponding technologies. To enable the students to play the roles of different health system stakeholders, we encouraged them to compete in groups during a mini-hackathon. During the course of the whole module, each student group invented and eventually pitched a new product for a specific problem in health care. Further details and lessons can be found in the module timetable .We chose a mixed methods approach consisting of an abductive, qualitative study based on semistructured interviews and a cross-sectional survey study using a web-based questionnaire. Qualitative data included the interview transcripts and results from the open-ended questions of the questionnaire. Items from the questionnaire with a five-point Likert-type scale as a response format were considered quantitative data.Between October and December 2019, DG conducted semistructured interviews with 5 experts in digital health and medical education. Purposive sampling was deployed on the research team’s professional external networks to select experts with complementary backgrounds in Europe.We developed the interview guideline according to the research question  and testFurthermore, we collected feedback on the module and further digital health topics from the participating lecturers and via corresponding surveys. Survey items were generated through a literature review and informal research meetings . We grouPretests within the research team did not alter the questionnaire. Through pilot tests with associated research colleagues, clarity, relevance, and arrangement of the questionnaire items were improved.The survey questionnaire was given to the participated students on the last day of the module as a paper version and slightly modified for participating lecturers of the module. For the latter, we sent an email invitation with multiple reminders to participate in the survey to all 32 lecturers. This web-based survey data were collected and managed using REDCap (Research Electronic Data Capture) tools hosted at Charité—Universitätsmedizin Berlin ,28. No iWhat is your relation to digital health and what are you currently dedicating to professionally?How do you think will digitalization affect doctors' work in the future, and what are the biggest challenges?What topics of digital health would you recommend to teach at German medical schools?Which teaching methods would you imagine or consider to be the most effective for teaching digital health?How can awareness for the challenges of digital health be maximized among medical students?Based on your own experience, do you have further advice on what factors should be considered when teaching digital health?We performed an abductive analysis of the interview transcripts and the results of the open-ended questions of the questionnaire from the lecturers and students to identify the predominant themes . PredefiDescriptive data analysis of questionnaire items was conducted using Microsoft Excel 2020 (version 16.35).We constructed this mixed methods study based on 5 interviews with digital health experts and a questionnaire involving lecturers and students. The sunburst diagram  visualizThe quantitative data were represented by the questionnaires, where the response rate was 91% (10/11) for the students and 100% (32/32) for the lecturers.According to the respondents, the positive effects of digital health on the health care system were clearly visible in areas such as communication, documentation, and patient empowerment. Digital health technologies would be already integrated into physicians’ everyday lives and were indispensable, as younger patients, in particular, would explicitly demand for them.It was stated that the health care system of the future would be highly digitalized. It would, therefore, be necessary to prepare medical students accordingly as early as possible. Digital health would already be part of today’s clinical practice, and concerns were expressed that a lack of knowledge in this field would lead to individual failure. Medical students would have to lose their initial reservations and become critical experts of digital health as much as their analog counterparts.Respondents emphasized that training with digital technologies from various perspectives, such as engineering, law, data protection, and ethics as well as statistical knowledge in the context of evidence-based medicine, should be part of the curriculum. The digital literacy acquired in this way would include an understanding of the meaningfulness and application areas of AI, robotics, big data, and telemedicine and thus help in one's own clinical work and in cooperation with other professional groups. Increasingly, patients would use digital services and apps, but convincing doctors to use them would remain to be a major challenge. As health apps are already being used in practice, their medical, legal, ethical, and economic implications should be a part of medical education and training.Digital literacy would describe the sensitivity, confidence, and understanding with which physicians could apply new digital applications to promote health. Respondents pointed out that by gaining practical experiences with digital health, medical school graduates should be able to use a wide variety of digital health technologies. Interpersonal skills such as intuition and sensory experience in patient contact would gain importance, especially regarding diagnostics. Health care staff would have to be able to communicate in various novel ways . Therefore, expertise in a variety of communication methods with a special emphasis on remote care should be acquired in medical schools.Adapting to the constantly changing professional environment would require physicians to have their own inventive spirit and a lifelong willingness to progress and rethink. Physicians would be responsible for proactively shaping the transformation of medicine. This role could only be fulfilled by the corresponding conviction to be innovative. Innovation methods such as design thinking could be helpful to act visionary in this context.Future medical school graduates should be trained to apply entrepreneurial skills in a digitalized and data-rich health care system to promote health care, according to the respondents. They should be able to think entrepreneurially and act innovatively, searching for new ways to sustainably integrate innovation into clinical workflows.Problems could be approached and solved confidently in transdisciplinary cooperation. The respondents stated that this should also be taken into account in the teaching concept for digital medicine. Cooperation with other disciplines, such as computer science, nursing, administration, user experience design, industry, law, data protection, and ethics, should be trained at an early stage because mutual understanding of the roles would facilitate communication.In our health care system, including medical schools, much more cooperation and sharing of knowledge is needed. E-learning should ideally be publicly available.Physicians should be given the freedom to focus on patients rather than on technology. For this purpose, their focus should be on human interaction. For physicians, digital health would be about the ability to advise mature, proactive patients sensibly and to accompany them through the health care system appropriately through direct communication using digital health wherever appropriate.Lack of awareness and experience in using digital technologies would fuel reservations in health care workers, according to the respondents. Actors, especially in leading positions, would feel that their professional authority or seniority was being questioned. Trying out and getting to know new possibilities in a relaxed manner could reduce fears, even among older generations and up to executive levels, and lead to successful clinical implementation.Clinical decisions were increasingly based on complex data. Identifying the relevant data and deriving good decisions from it would require a high degree of data competence from future physicians. Statistics would remain an important basis for scientific action in this context. It was stated that the responsible and sensible use of systems based on AI is an important medical skill and should become a compulsory learning objective for medical students.Medicine in its current form would be unethical according to the respondents. Digitalization and modern data science could improve this by analyzing patient data to make clinical care more based on objective evidence. Often, issues in digital health would lead to ethical questions, which should be discussed by experts and students using exemplary situations. Legal aspects, in particular regarding the regulation of medical practice and medical devices, should be taught by experts during the course of studies. The culture of societal change in the context of digitalization should be a central component of the curriculum.According to the interviewees, data protection, data security, and privacy were one of the greatest challenges for physicians in the course of digitalization, for example, in the case of mobile health apps. They should be taught transparently and according to clear guidelines by appropriate experts. As most patients care about the privacy of their health data, medical students should learn to ensure that their actions are in accordance with the correct data protection regulations.Basic economic knowledge and health economic aspects such as financing and resource optimization were missing in medical schools’ curricula and should be taught specifically for digital health.Learning by doing would be the preferred form to learn about technical applications because it creates experiences, helps to shape interests, and ensures a view beyond the end of one’s own nose (interview quote). The goal of teaching digital health would be its successful clinical implementation. Therefore, existing technologies should be included in the medical curriculum and demonstrated by experienced lecturers. Students should be trained practically involving direct contact with patients and technologies to handle unexpected new situations in relation to digital health and encouraged to be creative and culturally reflective by creating their own content, for example, in the course of a hackathon.The direct handling of new technologies would reduce fears and promote enthusiasm for digital technologies. Short impulse lectures would be a useful teaching method, especially for large groups. Frontal lectures could be more effective for deepening a topic or as a supplement to practical training, especially if they do not last longer than 10 min.An open-ended discourse on the values, visions, and competencies of medical students among themselves and with various stakeholders in digital health  would lead to a high degree of reflection and heightened awareness of the relevance of the topic. Thus, critics and enthusiasts would be simultaneously involved.Small group lessons in (carefully selected) groups of up to 10 students would ensure more enthusiasm for the course content, stated the respondents. Peer teaching would be very effective and bring individual experience into the curriculum. The creation of independent work is recommended as a teaching format. E-learning would be a suitable format, especially for theoretical content, and could be used in a scalable manner. In general, digital medicine teaching should be integrated longitudinally into the curriculum.Digital health could be taught as a study component of various study programs, such as medicine, economics, or sociology. According to respondents, transdisciplinary teaching was more attractive and stimulating. Interuniversity exchange would be profitable, and joint courses would be useful for students and lecturers.In the teaching of digital health, lecturers, students, scientists, alumni, and experts from all participating study programs as well as external experts would be partners. It would also be advisable for the lecturers to consult with each other to ensure continuity and interlocking of the teaching content.The respondents believe that integration of different actors from industry and business into the teaching of digital health at medical schools would help both students and companies to benefit and learn from each other.All participating students agreed that digital health should be part of the mandatory curriculum at medical schools (8 strongly agree and 2 agree) and taught early in their careers (8 strongly agree and 2 agree) and that competencies are more relevant than knowledge for medical graduates , that the teaching format helped them in the study process , and that interdisciplinary teaching formats would be an enhancement to the module  and that medical students should be taught digital health early in their career  clinical practice and applications, including the ability to integrate digital health into clinical routine; (3) data analysis and knowledge creation, including the ability to apply basic data analytics to unstructured digital data sets; and (4) and system and technology implementation, suggesting that medical professionals should participate in the development and implementation of digital health. The latter aspect is also stressed by our results and a recent publication that demands physicians with dual competencies in clinical and data science expertise [The future-proof physician must be able to apply digital health in the clinical routine. Our results emphasize that physicians should be open toward innovation and transdisciplinary cooperation throughout their careers and include the ability to recognize entrepreneurial potentials. Brunner et al  classifixpertise . A medicAnother main finding of our study is that teaching digital health should be about teaching a mindset that allows flexibility and suitability for an unknown and rapidly evolving future of our health care sector, rather than teaching the use of individual technologies or the right approach only for specific situations. This mindset includes openness to change, curiosity, and collaboration across functions, roles, professions, institutions, and hierarchical gradients. It also requires the willingness to actively anticipate and form the future of health care through reflection and innovation. Eventually, a strong awareness of changing patients’ and health care workers’ needs and for new ELSIs should result from this mindset. It may be acquired by confrontation with a broad variety of different digital health aspects in terms of patient treatment, medical technologies, and the structure of health systems, as we did in our module.Our results emphasize that passive knowledge transfer in the form of lectures is outdated, although it is the most used teaching method in medical schools . A focusThis mixed methods study provided novel insights into undergraduate medical competencies in light of digital transformation in health care and the development and deployment of a digital health module at a German medical school. However, a number of limitations apply.First, the results are based on a limited number of participants. As a descriptive approach, quantification or generalization of the results is not possible but may still provide important impulses for further research and development in the field. Second, due to the selection bias of students and lecturers, the results of the questionnaire might only reflect the opinion of digital health advocates and are not representative. Third, the described undergraduate competencies in digital health are an additional source of information; therefore, there is no guarantee of completeness.Digital health competencies are key competencies for future-proof physicians and should therefore be included in the core curriculum at medical schools. For a first curricular implementation and to gain early local experiences, elective modules such as ours are suitable and can provide important information for existing didactic strengths in teaching this topic. The exchange of best teaching practices and institutional collaborations will further leverage the reach of this intent.digital health mindset, rather than passively transferring knowledge of technology specifics. Active teaching methods such as practice units, discussions with experts, and hackathons should be used to teach a broad variety of subjects. Interprofessional learning and teaching with nonmedical disciplines is recommended to add to the diversity of perspectives and to prepare for increasingly interprofessional patient care.Digital health education should focus on building and sharpening a critical and experience-based