Management of bone fractures must achieve both reduction and stability. However, dermatological conditions such as dystrophic epidermolysis bullosa can lead to catastrophic events when operating on the patient’s bone fracture, possibly leading to wound infections and fracture nonunion.Here, we report the case of a 20-year-old female with dystrophic epidermolysis bullosa who had suffered from a femur fracture after a fall from the bed. The fracture management was challenging due to the severe condition; however, the use of the Nancy nail was efficient.Due to the rarity of the disease, modifications due to the challenges faced during the patient care approach were accomplished to prevent any harm to the patient. Even though the management was challenging, the outcome was good. Children who suffer from epidermolysis bullosa are often referred to as “Butterfly children” as their skin is as vulnerable as the wings of a butterfly . EpidermA 20-year-old female with a history of DEB presented to the emergency room due to a fall from the bed. On initial examination, the patient was conscious with a Glasgow Coma Scale score of 15/15, pale, and cachectic. The patient’s appearance was not suitable for her current chronological age. She was vitally hypotensive in a third-grade hypovolemic shock. The Advanced Trauma Life Support protocol was initiated and 2 L of Ringer lactate was administered along with morphine even though intravenous access was difficult. Afterward, the patient moved to a state of transient normotensive shock. Severe pain and an obvious deformity of the right femur were notable with observable wounds or new skin blisters.Her medical history was positive for DEB that was followed up by a dermatologist. Dilated cardiomyopathy, anal fissures, severe malnutrition, and iron deficiency anemia were present. Additionally, the patient complained of abdominal cramps, constipation, epistaxis, difficulty swallowing, adhesive tight tongue, unexplained shortness of breath, and dental caries. Although surgical and trauma history was unremarkable, a hospital admission 10 years ago due to shortness of breath was reported. At that time, three units of blood were administered due to a hemoglobin level of 5 g/dL.The family history was positive for DEB in two siblings. On examination, scoliosis was evident along with right thigh deformity and flexion contracture of both hip joints of approximately 20 degrees. Both knees showed flexion contracture of approximately 40 degrees, with both feet being equinus and displaying a “mitten” appearance. The right thigh had scattered healed wounds due to the skin condition from all proximolateral aspects up to the middle region of the thigh. The distal thigh skin had several unhealed wounds all over the limb aspects. The range of motion in both lower limbs was normal up to the contractures. On an examination of the hands, flexed syndactyly due to the old skin blisters, wounds, and mitten appearance were noted. The distal pulses were intact, and the neurological examination was unremarkable.Anteroposterior and lateral views of the pelvis and right hip X-rays were obtained demonstrating a femur spiral mid-diaphyseal fracture Figures -4.Routine complete blood count showed iron deficiency anemia with a hemoglobin level of 2.5 g/dL and albumin of 7 g/L. Due to the medical history of dilated cardiomyopathy and in preparation for the management, an echocardiogram was obtained which showed an ejection fraction of 48% along with a systolic murmur.The patient was admitted to the in-patient ward where she received three units of whole blood and albumin. Due to the lack of information available regarding the treatment of femur fracture in a case complicated by DEB, the team discussed the case thoroughly to approach the patient using a method that does not harm the skin and save the patient at any cost. However, the team found that the most suitable surgical treatment in this setting is the use of Nancy nail, which is a flexible intramedullary nail with the aid of a Steinmann pin in the closed versus open reduction and internal fixation for the femur fracture. The open reduction was not a possible treatment option due to DEB. We selected this treatment approach to avoid traumatizing the skin with countertraction, decrease the potential of infection, and reduce the risk of skin sloughing. The team discussed the plan with the patient and her family listing all the pros and cons as well as the possible complications. Consent was given to conduct the operation along with an agreement to hospitalize the patient three days prior to the day of the surgery for preparation.The patient had a Mallampati score of 4 and was at risk for esophageal perforation and difficult general intubation. The team agreed to perform spinal anesthesia and admit the patient to the postoperative intensive care unit. After prepping and draping, we made two 3 cm longitudinal incisions in the distal medial and lateral right distal thigh. Subsequently, 2.5 mm and 3 mm Nancy nails were introduced along with a Steinmann pin during the closed reduction procedure. The layers were closed with Vicryl sutures followed by wet dressing. The team faced the challenge of dealing with fragile bone during the operation as all the steps had to be performed very delicately. However, with the option of Nancy nail, the team could manage the fracture. The patient was admitted to the intensive care unit for close monitoring for one day followed by two days in the burn unit. Along with skin dressing, antibiotics, analgesics, and parenteral feeding with electrolytes and albumin correction were done. The patient was discharged home without any complications, and the family was informed about all the needed considerations to care for the patient. The wound healed with no ulcers, sinus tracts, or infection around the surgical wound Figures .Two months postoperatively, the patient was seen for follow-up; an X-ray was done that showed an ingoing healing femur that was incomplete, with complete healing established only after 18 weeks Figures , 8.Although the rehabilitation program was implemented, the patient did not gain a weight-bearing status until after eight months of rehabilitation, including range of motion, stretching, and strengthening exercises. She was incapable of weight-bearing because of the pain and contracture of the knee and Achilles tendon. The patient started walking with walking aids approximately four months postoperatively, but she did not gain complete weight-bearing due to a decrease in the range of motion compared to her previous state. The patient may need another operation to correct her femur mechanical axis because she gained a deformity that affected her ability to walk. This deformity occurred because of the fracture pattern and the deforming force of the thigh muscle. The aim was to regain the length, correct the rotation, and prevent sagittal and coronal deformity as much as possible. However, we did not achieve the anatomical reduction because the team wanted to prevent further traumatic injuries to the soft tissue in the form of sloughing to the skin as mechanical trauma or causing an iatrogenic fracture. Factors such as the physis not being completely fused, body weight, and skin condition affected the decision of the surgery type and the instruments chosen. A plate and screw with closed reduction could not be used due to the open approach in the lateral thigh in the presence of scars and blisters increasing the risk of infection and delayed wound healing. The diameter of the canal was very narrow justifying the use of the Nancy nail. In choosing the best treatment modality, we considered that we need an acceptable reduction and initiate rapid rehabilitation. During the preoperative, operative, and postoperative phases of treatment, the team handled the case carefully. The soft tissue in the area of the fracture was well taken care of despite the critical skin condition.The patterns of inheritance associated with DEB are autosomal dominant and recessive. The dominant type often manifests at birth or during early childhood and is characterized by generalized blistering that becomes more localized with age. The recessive type ranges in severity from mild to the severe form. Feet and hands pseudosyndactyly, referred to as “boxing glove hands,” deformed nails and affected teeth, flexural contractures, and iron deficiency anemia are all manifestations of the condition . Scar tiA femur fracture in the setting of DEB is challenging to manage. However, with proper decisions taken based on the patient condition and a thorough literature review, optimum management can be sought. In our case, the use of Nancy nail was efficient, and the overall management led to good outcomes.


This study aimed to identify the most frequent reasons for orthopedic medical malpractice, gain insight into the related patient demographics and clinical characteristics, and identify the independent factors associated with it.We collected and analyzed the demographic and injury characteristics, hospital levels and treatments, medical errors, and orthopedist’s degree of responsibility for the patients who were subject to orthopedic medical malpractice at our institution. Univariate and multivariate analyses were performed to identify the factors associated with the orthopedist’s degree of responsibility in the medical malpractice cases.We included 1922 cases of medical malpractice in the final analysis. There were 1195 and 727 men and women, respectively . Of the total patients, 1810, 1038, 1558, 1441, and 414 patients  were inpatients, had closed injuries, underwent surgery, were trauma cases, and had preoperative comorbidities, respectively. Most medical malpractice cases were in patients with fractures and spinal degenerative disease , and occurred in city-level hospitals , which were located in the eastern part of china , including Jiangsu and Zhejiang . Between 2016 and 2017, the orthopedist’s degree of responsibility in medical malpractice claims were deemed as full, primary, equal, secondary, and minor in 135, 654, 77, 716, and 340 orthopedists . Most medical errors made by orthopedists in cases of medical malpractice were related to failure to supervise or monitor cases, improper performance of procedures, and failure to instruct or communicate with the patient . The multivariate analysis found that patients with preoperative comorbidities, who sustained humerus injuries, who were aged ≥65 years, who were treated by doctors who failed to supervise or monitor them, and who were treated at the provincial and city level hospitals were more likely to claim that the orthopedist bore a serious degree of responsibility in the medical malpractice case.Our results provide detailed information on the plaintiff demographics, clinical characteristics, and factors associated with medical malpractice. Medical malpractice is related to poor treatment outcomes. The first preventative measure that is required is a comprehensive improvement in the medical staff quality, mainly through medical ethics cultivation, and professional ability and technique training. Additionally, failure to supervise or monitor cases was the leading cause of medical malpractice and one of the factors that led to orthopedists bearing an equal and higher responsibility for medical malpractice. Orthopedists should improve patient supervision, especially when treating older patients and those with preoperative comorbidities and humerus injuries. As the incidence of fractures and degenerative musculoskeletal disease has increased, so has the incidence of orthopedic surgeries , 2. Due In China, the medicolegal system is the same in each province, municipality, and autonomous region, and all medical disputes and incidences of malpractice should be handled according to the Medical Malpractice Management Regulation and Regulations on the Prevention and Handling of Medical Disputes. When medical disputes occur in China, the patients and physicians can reach a consensus through the following routes: mutual voluntary negotiation, application to the people’s committee for mediation, application for administrative mediation, and appeals to the people’s court, etc. If the physicians and the patients cannot reach a consensus via mutual voluntary negotiation, the physician’s degree of responsibility regarding the medical malpractice, which can be divided into 5 levels, must be judged before the disputes are handled using the afore-mentioned routes.The keys to reducing or preventing errors and accidents are acquiring ongoing information on the factors associated with medical malpractice and adopting preventative strategies. Therefore, we performed a cross-sectional, descriptive survey in China on the characteristics relating to medical malpractice cases against orthopedists from 2016 to 2017. We aimed to investigate the medical errors associated with medical malpractice that are made by orthopedists, identify the factors associated with a large degree of responsibility in medical malpractice, and examine the principles that will foster improvement in the quality of patient care and reduce the incidence of orthopedic medical malpractice cases in future.To examine the professional liability risk among orthopedists, we collected data from the Hygiene Administrative Department of the Medical Accident Appraisal Center of the Chinese Medical Association from August 2018. Participants’ identities were not required during or after data collection. Records from which any basic information was missing and non-orthopedic cases were excluded . If 1 caThe medical malpractice identification process was as follows. First, both doctors and patients submitted appraisal materials, and the Provincial Medical Association composed and stipulated the number of people in the identification team according to the specific medical accident dispute case and each side’s point of view. After performing the necessary avoidance procedures, the Medical Association staff used a computer to randomly select the expert and alternate expert numbers to form the expert identification group. The medical accident technical appraisal meeting was presided over by the expert appraisal group leader. First the patient, then the doctor, stated their opinion and reasons within the prescribed time and answered the expert group’s questions. After an on-the-spot physical examination, the expert group formed the appraisal conclusion according to the consensus of the expert appraisal group members, and the team leader issued the medical accident technical appraisal certificate.This study was approved by the Institutional Review Board of the Third Hospital of Hebei Medical University in compliance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study. This study was authorized by the Chinese Medical Association.Participants were classified by age into 4 major groups: children (≤14 years), young adults (15–44 years), middle-aged adults (45–64 years), and the elderly (65 years and over).The following information was collected: hospital level , region , province , inpatient or outpatient status, interval between the admission and the time of the incident and the seeking of medical expertise .The following information regarding the injury was collected. The injury mechanisms . This classification system is used commonly in the field of traumatology and orthopedics. The pathological type , injury number (representing the number of injured parts), injury type , injury site  were also noted.We collected information on the following aspects of the patient treatment: hospitalization and operation durations, operative type , and elective or traumatic cases. We also noted the patients’ preoperative comorbidities (2 categories: none or yes) including diabetes; hypertension; cardiovascular, cerebrovascular, respiratory, liver, and renal disease; lower extremity venous thrombosis, and others.Failure to supervise or monitor a case meant the doctors did not carefully and comprehensively observe the changes in the disease; thus, they failed to provide timely symptomatic treatment measures.Improper procedure performance meant the surgery did not conform to certain specifications, such as aseptic operation specification violations.Failure to instruct or communicate with the patient meant the medical party did not fulfill the obligation of informed disclosure, or that the information was not made available and there was insufficient communication.An escape diagnosis meant that 1 patient had different diseases simultaneously, and the doctor omitted the diagnosis of a certain disease.Incorrect selection of the surgical method meant the wrong surgical method was used, such as improper selection of the internal fixation steel plate, steel nail, or external fixation support.Failure to recognize a treatment complication meant the doctors did not find the complications in time and did not take timely and effective treatment measures.Improper supervision of the residents or other staff; for example, an unqualified doctor operating on the patient.Postoperative anticoagulation and anti-infection measures were not standardized; for example, anticoagulants were not given promptly for patients with thromboembolism, or antibiotics were not used to prevent infection in patients with infection risk.Non-standard medical records meant the medical department did not adequately document the medical records or did not comply with the relevant provisions of the basic standard for writing medical records.Misdiagnosis referred to an incorrect conclusion on the disease.Medication errors meant incorrect drug use, such as administering anticoagulants to patients at risk of bleeding or stopping anticoagulants prematurely after surgery.Hospitals without the relevant surgical qualifications; for example, when a hip replacement was performed at an unqualified hospital.Procedure was performed when it was not indicated or contraindicated included indications that were not strictly controlled, improper timing of the operation, or not ruling out contraindications.Anesthesia problems included an improper choice of anesthetic method, or nonstandard use of narcotic drugs and anesthetic management.The physician’s degree of responsibility regarding the medical negligence was divided into 5 levels: 1. The physician was fully responsible, which meant that the damage to the patient from the medical malpractice was completely caused by the physician or surgeon, who bore full responsibility. 2. Primary responsibility of the physician meant that the damage to the patient due to the medical malpractice was mainly caused by the physician or surgeon, and other factors played a secondary role. 3. The physician bore equal responsibility referred to the combined action of medical negligence and other factors, and the physician or surgeon was approximately 50% responsible for the damages that the patient suffered. 4. Secondary responsibility of the physicians meant that the physician or surgeon was partially responsible for the damages that the patient suffered and medical negligence played a secondary role in the impairment. 5. Minor responsibility of the physician meant that the majority of the consequences related to the medical negligence were caused by other factors than the physician. The patients were divided into 2 groups: Group A, including minor and secondary responsibility, and Group B, including equal, primary, and full responsibility. Logistic regression analysis was used to compare the relevant information such as the patient demographics, hospital level, injury, treatment, and orthopedists’ skill level between the 2 groups.χ2 test was used to compare the differences between Groups A and B in the nominal variable categories, such as sex; inpatient/outpatient status; preoperative comorbidities; interval between hospital stay and request for medical expertise; hospital level, region, and province; injury cause; pathological type; injury site and type; operation type; and medical error. Multiple classification logistic regression models were constructed to explore how the potential factors for medical malpractice related to the degree of responsibility. Variables for which the P-value was ≤0.20 in the univariate analysis were included as candidate variables in the multivariate models. All statistical analyses were performed using SPSS version 25.0 .The During the study period, a total of 1922 medical malpractice cases met the inclusion criteria, of which 1195 and 727  were men and women, respectively. The average patient age was 48.5±15.2 years old. Every patient had poor outcomes after treatment, such as amputation, joint dysfunction, paralysis, and death. The proportions of the different age groups from high to low were 62.5%, 21.1%, 12.5%, and 3.9%  for middle-aged adults, young adults, the elderly, and children, respectively .Among the 1922 medical malpractice cases, there were 1006 that occurred at a city level hospital that accounted for 52.3% of the cases, followed by county and provincial level cases . The majority of cases involved inpatients with a 1-year interval between symptom onset and the request for medical expertise . There were 1001 cases that occurred in the eastern region, accounting for 52.1% of all cases, followed by the western and central regions  of low energy injuries, followed by no injuries and traffic accidents . There were 1229 cases of fractures/dislocations, accounting for 63.9%, followed by spinal degenerative disease and skeletal tuberculosis . Most patients had 1 injury . Among the injury types, closed injuries  were the most common . Among tMost of the patients were treated with surgery , most of which were open reduction and internal fixation . Most were trauma cases, hospitalized twice, and underwent 2 surgeries . There were 414 patients (21.5%) who had preoperative comorbidities .Most medical errors that were made by orthopedists in the medical malpractice cases involved failure to supervise or monitor the case . There were fewer cases of medical error that involved improper performance of procedures and failure to instruct or communicate with the patient . There were fewer cases that involved the following degrees of responsibility: full, primary, equal and minor responsibility .There were 866 orthopedic surgeons who had an equal or higher degree of responsibility in the medical malpractice case, and 1056 who had a secondary or lower degree of responsibility. Univariate analysis showed that there were significant differences in the degrees of liability that the orthopedist bore in the medical malpractice case depending on the patient characteristics, such as the sex; age; injury type; preoperative comorbidities; cause of injury; operation type; hospital level; pathological type; number of injuries; fracture of the tibia and fibula, humerus, and head; and the medical errors of failure to supervise or monitor a case and recognize a treatment complication . Patients with preoperative comorbidities were more likely to claim that the orthopedic doctor bore a serious degree of responsibility for the medical malpractice than those who did not have preoperative comorbidities . Compared with conservative treatment, undergoing surgical treatment without internal fixation had a protective effect against the orthopedic doctor bearing a serious degree of responsibility for the medical malpractice . Using county level hospitals as a reference, being treated at the provincial or city level increased the likelihood of the orthopedic doctor bearing a serious degree of responsibility for the medical malpractice . Patients with humerus injuries and those treated by doctors who failed to supervise or monitor them  were prone to claim that the orthopedic doctor bore a serious degree of responsibility for the medical malpractice , including Jiangsu and Zhejiang . Medical malpractice is very susceptible to the policy. The medical malpractice system in Western countries differs from that in China. The medical malpractice systems in the United States and United Kingdom are based on British common law. Each state in the United States has its own medical malpractice laws that differ between the states. The malpractice rates can vary greatly depending on the differing interstate laws. Contrastingly, in China, the medicolegal system is the same in each province, municipality, and autonomous region, and all medical disputes and malpractice claims are handled according to the Interim Measures for Medical Accident Technical Appraisal , RegulatThis study found that the number of medical malpractice cases were higher in inpatients and traumatic cases than those for outpatients and elective cases because they are more complex, urgent, or difficult to treat. This study also found that most medical malpractice cases occurred in patients with closed injuries and those who underwent open reduction and internal fixation. This is because closed injuries are easy to misdiagnose, and patients who undergo open reduction and internal fixation are more likely to have greater trauma, more comorbidities, and longer hospitalizations. In this study, the most common degree of responsibility in medical malpractice claims against orthopedists was secondary, which was consistent with the findings from other studies .This comprehensive study of medical malpractice in the field of orthopedics between 2016 and 2017 found that most orthopedists’ medical errors involved failure to supervise or monitor a case, improper performance of procedures, and failure to instruct or communicate with the patient. These findings are similar to those from many previous studies , 19. ThiAnother issue elucidated in this study was that we explored the potential factors associated with a serious degree of responsibility for orthopedic doctors in medical malpractice cases. When compared with participants aged 0–14 years, those aged ≥65 years were more likely to claim that the physician bore a serious degree of responsibility. These findings are similar to those of some previous studies that showed that older patients had multiple preoperative comorbidities and poor outcomes after orthopedic surgery –28.Preoperative comorbidities were associated with claims that the orthopedic doctor bore a serious degree of responsibility, which may be due to their association with more complex conditions and treatments. Our data suggested that, when compared with conservative treatment, undergoing surgical treatment without internal fixation had a protective effect against claims that the orthopedic doctor bore a serious degree of responsibility for the medical malpractice. This was consistent with what we observed clinically. Patients who underwent conservative fracture treatment were prone to displacement at later stages, which increased the medical malpractice risk. When county level hospitals were used as a reference, another issue that this study noted was that being treated at a provincial or city level hospital increased the likelihood of claims that the orthopedic doctor bore a serious degree of responsibility for the medical malpractice. This may be because provincial and city level hospitals are both more likely to receive and manage seriously injured patients. Other factors associated with a serious degree of responsibility in medical malpractice were humerus injuries and failure to supervise or monitor a case. These findings were consistent with those of other studies , 29, 30.Although this study is the first clinically verified, comprehensive, nationwide investigation of medical malpractice cases against orthopedists performed in China, there are some limitations that should be considered. First, it was retrospective with a limited number of cases. This may have led to less accurate information. We reduced this bias by conducting our study on data that was checked repeatedly by the Hygiene Administrative department of the Medical Accident Appraisal Center of the Chinese Medical Association. Second, detailed information regarding the healthcare providers (surgeons and/or nurses) was not available. Third, the cases that underwent judicial authentication and that involved private negotiating on a voluntary basis between healthcare providers and patients without any official medical fault identification procedures were not included in this study. Fourth, without a denominator many data were difficult to interpret.Our results provide detailed information on the plaintiff demographics, clinical characteristics, and the factors associated with medical malpractice that can now be used as an up-to-date clinical evidence base for national healthcare planning and preventive efforts in China and elsewhere. Medical malpractice is related to the effects of poor treatment; however, it is not a sufficient condition for medical malpractice. The first measure to prevent medical malpractice is to comprehensively improve the quality of medical personnel, mainly through medical ethics cultivation, professional ability training, and improvement of treatment techniques, which are the key to the prevention and control of the occurrence of errors and accidents. Failure to supervise or monitor a case was the most common cause of medical malpractice, as well as one factor for orthopedists to bear a higher degree of responsibility for the medical malpractice. Orthopedists should enhance the amount of supervision, especially in the treatment of older patients, those with more preoperative comorbidities, and those with humerus injuries.S1 Data(XLSX)Click here for additional data file.


However, their application to the risk assessment of nanomaterials is still limited, also due to the scarcity of large and curated experimental datasets. Despite a great amount of nanosafety data having been produced over the last decade in international collaborative initiatives, their interpretation, integration and reuse has been hampered by several obstacles, such as poorly described (meta)data, non-standard terminology, lack of harmonized reporting formats and criteria.in vitro Comet genotoxicity data, focusing on the issues and challenges encountered in their FAIRification through the eNanoMapper data model. The case study is part of an iterative process in which the FAIRification of data supports the understanding of the phenomena underlying their generation and, ultimately, improves their reusability.Recently, the FAIR  principles have been established to guide the scientific community in good data management and stewardship. The EU H2020 Gov4Nano project, together with other international projects and initiatives, is addressing the challenge of improving nanosafety data FAIRness, for maximizing their availability, understanding, exchange and ultimately their reuse. These efforts are largely supported by the creation of a common Nanosafety Data Interface, which connects a row of project-specific databases applying the eNanoMapper data model. A wide variety of experimental data relating to characterization and effects of nanomaterials are stored in the database; however, the methods, protocols and parameters driving their generation are not fully mature. This article reports the progress of an ongoing case study in the Gov4nano project on the reuse of  One of the pillars in this work is the reusability of existing nanosafety data. A harmonized workflow is applied for a number of diverse case-studies to demonstrate the reusability of nanosafety data, progressing from data quality assessment and curation, to translation of data into formats suitable for specific purposes SAR based approaches and/or in user-friendly risk assessment tools). These efforts are largely supported by the eNanoMapper data model i.e., data on NM physicochemical characteristics, release and exposure, toxicity and functionality).In recent years, significant investments have been made to contribute to the generation of data, information and tools to enable nano- environmental and health assessment in vitro Comet test data, for their reuse in (Q)SAR based predictive methods.In this paper, we illustrate a Gov4nano case study on the FAIRificationin vitro Comet data hosted in the eNanoMapper database increases the potential of their reuse and supports the understanding of the phenomena that led to their generation.The challenges encountered in data FAIRification and those relating to the specific reuse scenario are reported. The growing FAIRness of The reported work can serve as a concrete example of data FAIRification needs, addressing a specific endpoint and reuse scenario.The FAIR principles  [28] aree.g., supporting discovery of complex interrelations, such as structure–activity relationships, or as weight of evidence for decision-making), and finally it needs to be easily Reusable by others, and thus linked to clear licenses for reuse in order to avoid legal issues The FAIR principles have emerged in response to the realization that research data is not reused to its full potential in vitro Comet assay is one of the most commonly used for a wide variety of NMs, making it attractive for predictive methods. To this endpoint, the Joint Research Centre (JRC) recently successfully applied the workflow for grouping and read-across proposed in the ECHA REACH guidance which was updated for NMs In this paper, we investigate the challenges in reusing genotoxicity data in the perspective of the FAIR principles, to highlight the most important needs in the FAIRification process. This exercise builds on the experience of the Horizon 2020 NanoReg2 project Genotoxicity evaluation is a key element in the safety assessment of chemicals enabling the identification of potential mutagens and/or human carcinogens through the detection of primary DNA lesions and chromosomal damage.e.g., of a consumer product), it is often tested only at the final stages of product innovation when scale-up becomes relevant Data on genotoxicity is crucial in risk assessment and bears heavy weight for whether a material is accepted or not for the market. However, even if knowledge of a materials’ potential for genotoxicity is a “no-go” for marketing , is a rapid and informative method to detect DNA damage at single cell level used on many different cell types. The assay detects single and double strand breaks present in the DNA as a consequence of a direct damage or as intermediate of DNA repair processes and it is successfully applied both in et al. In 1988, Singh in vitro and in vivo genetic toxicology testing in vivo comet assay, until the publication of OECD guideline TG 489: In Vivo Mammalian Alkaline Comet Assay in vivo genotoxicity testing.At the beginning of 2000 the expert’s meetings at the International Workshop on Genotoxicity Test Procedures established the first guidelines for in vitro Comet assay, fostering the use of non-animal tests in compliance with the 3R principles  et al. Although there is no OECD guideline for the in vivo in cells from many different organs; ease of application; the possibility to conduct studies using relatively small amounts of test samples; the relatively short time period (a few days) needed to complete an experiment in vitro Comet assay was recently anchored to a putative AOP for assessment of lung carcinogenicity by nanoparticles together with a number of other assays useful in integrated approaches to testing and assessment The Comet assay has several advantages: its demonstrated sensitivity to detect low levels of DNA damage; the requirement for small numbers of cells per sample; the possibility to apply it in vitro has been widely used for genotoxicity assessment of NMs present on the market. A lot of scientific papers have been published regarding the genotoxicity evaluation of the most widely used NMs and a great amount of in vitro Comet assay results is available from recent international collaborative initiatives.As a matter of fact, in the last years, Comet assay i.e., FP7 NANoREG in vitro Comet results for different NMs and nanoforms under different experimental conditions. In particular, we focused on experiments selected in NanoReg2 for grouping purposes: in vitro Comet experiments performed by various laboratories for different nanoforms of TiO2, ZnO and SiO2 , in three cell lines  and in different conditions  [The data available for the case study were retrieved from the Nanoreg2 instance in the Nanosafety Data Interface. They originate from experiments performed in several EU-funded projects (in vitro Comet assay) and downloading the results in MS Excel format.The Comet data were searched through the eNanoMapper database, filtering with respect to the nanoforms and the endpoint of interest  In the present case study, three templates for in vitro Comet data were generated.The following are the general principles of the protocols by which the in vitro Comet assays were performed in three different cell lines  following the international validated protocols and literature for standard e.g., 0, 1, 10, 50 and 100 µg/ml), following the protocol for NM suspension preparation used in NanoReg project 2O2, were used for the positive control.The e.g., FP7 NANoREG, FP7 NanoTEST, FP7 MARINA, ENPRA, NanoGenoTox, caLIBRAte, H2020 GRACIOUS, H2020 NanoReg2) e.g., SOPs from NanoGenoTox and NANoREG) in vitro Comet test data for modelling purposes. In what follows, the problems hampering the reuse of existing data are analysed from a FAIR perspective. Similarly to the challenges recently reported by Jeliazkova et al. on the reuse of nanosafety data in vitro Comet assay data , mainly related to the interpretation and integration of the experimental results, are highlighted.Since the establishment of the eNanoMapper data model, numerous EU projects have adopted it . In some experiments imported in the database, the term “COMET” was adopted to describe the “Method” used, whilst in others the same term described the “Protocol” applied. This difference in classification is an example of lack of harmonization in terminology that makes findability of available Comet assays laborious, even in the presence of a searchable repository. Since available Comet in vitro data have been generated in the last decade by different laboratories within different research initiatives, and reported in diverse formats and without the use of controlled vocabularies, many inconsistencies in the terminology exist  Findability issues are largely overcome by the use of the Nanosafety Data Interface, where persistent IDs are assigned to the materials from the beginning , F1, so in vitro Comet assay data” e.g., Excel files) onto the eNanoMapper data model, through ontology lookups on several layers Interoperability between different experimental studies carried out on the same endpoint, in the same experimental conditions, on set of diverse NMs, is an essential pre-requisite to obtain suitable datasets for (Q)SAR modelling purposes in vitro Comet assay specific case, the comparison of the ‘Results’ section of NanoReg2 and NanoGenoTox templates (see Methods), is reported in The need to easily compare experiments from different sources also implies that (meta)data are described by means of harmonized terminology , I2. As in vitro Comet assays, monitoring of critical physical–chemical parameters during the experiment is crucial. For instance, knowledge of dispersion state in vitro experiments and associated cytotoxicity data should be available for control to be able to evaluate the outcome of a genotoxicity assay e.g., in projects specific data repositories). This aspect limits the interoperability of data and negatively affects their reusability  and scoring method, whereas the duration of lysis treatment is considered less important for the variability of results so that the OECD in vitro Comet reporting templates to be used by data providers, are ongoing in the Gov4nano and NMBP-13–2018 projects.Although the MIRCA list is not explicitly designed for NMs testing, it can be used as a starting point for creating harmonized templates and for assessing the completeness of existing ones. Efforts to implement these recent community-defined standards in the Another extremely valuable aspect, allowing data reusability in different reuse scenario, is the possibility to access the details, in terms of dose/response results, of each experiment , R1. Fori.e., presence / absence of genotoxic outcome) is a major issue for the modelers, who often have to manage an  large number of complex data, without having the appropriate expertise to go into the technical details of the experiments. Furthermore, difficulties in interpretation arise when contradictory results for the same assay  are available, or in presence of contradictory results for the same assay (on the same NM) under different experimental conditions .The need for a yes-or-no statement  was assigned when the majority of test results were positive, and an absence of genotoxic effect  when the majority were negative In the JRC’s grouping and read-across experiment Moreover, in different frameworks, such as Safe by Design approaches in pre-regulatory settings, a yes-or-no evaluation on the genotoxicity concern posed by the material is often requested.Therefore, the reporting, for instance in the eNanoMapper database, of different levels of detail and processing of genotoxicity tests results on the one hand is recommended , R1, to In this paper, the genotoxicity case study served as an example to illustrate the needs and benefits of FAIRification of nanosafety data.i.e., a domain-specific ontology) and mapping procedures [FAIRness of a large variety of genotoxicity data for NMs is increasingly guaranteed by the use of a FAIR infrastructure, such as the eNanoMapper data model, where the problems encountered in managing and harmonizing test data from different sources have been solved with the implementation of community-developed standards (ocedures . Moreovein vitro test data for (Q)SAR based approaches derive from lack of agreement on the minimum set of parameters to be reported to univocally characterize an experiment and ensure its reproducibility and comparability with other similar experiments. In this context, the recently established MIRCA list will serve as a basis to refine and harmonise existing templates [Furthermore, difficulties in obtaining suitable datasets of Comet emplates .in vitro experiments, thus accelerating the standardization of methods and protocols. In an iterative process, increasingly FAIR data support the understanding of phenomena which in turn increases the reusability of the data.The analysis of existing FAIRified experimental results can help shed light on nano-specific critical parameters whose variation can affect the result of Comet in vitro Comet data reusability, thanks to numerous collaborative initiatives and the development of a FAIR repository to host nanosafety data. However, the process is constantly evolving as is the knowledge of the nano-specific determinants influencing toxicity and the understanding of the hazard posed by nanomaterials to health and environment. To accelerate the FAIRification process, the figure of the data steward prove to be valuable In conclusion, great progress has recently been made towards The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Recall by genotype (RbG) studies aim to better understand the phenotypes that correspond to genetic variants of interest, by recruiting carriers of such variants for further phenotyping. RbG approaches pose major ethical and legal challenges related to the disclosure of possibly unwanted genetic information. The Cooperative Health Research in South Tyrol (CHRIS) study is a longitudinal cohort study based in South Tyrol, Italy. Demand has grown for CHRIS study participants to be enrolled in RbG studies, thus making the design of a suitable ethical framework a pressing need. We here report upon the design of a pilot RbG study conducted with CHRIS study participants. By reviewing the literature and by consulting relevant stakeholders , we identified key ethical issues in RbG approaches . The design of the pilot was based on a feasibility assessment, the selection of a suitable test case within the ProtectMove Research Unit on reduced penetrance of hereditary movement disorders, and the development of appropriate recruitment and communication strategies. An empirical study was embedded in the pilot study with the aim of understanding participants’ views on RbG. Our experience with the pilot study in CHRIS allowed us to contribute to the development of best practices and policies for RbG studies by drawing recommendations: addressing the possibility of RbG in the original consent, implementing tailored communication strategies, engaging stakeholders, designing embedded empirical studies, and sharing research experiences and methodology. The unprecedented amount of human genomic data generated by next-generation sequencing (NGS) in different research settings, including population biobank projects, is an important resource to advance our understanding of both health and disease. However, the richness of the genetic data now attainable through NGS calls for similar levels of detail in terms of the accompanying phenotype(s). In this context, re-inviting or recruiting research participants for deeper phenotyping, based upon the presence or absence of certain genetic variants in an approach termed “recall by genotype” (RbG) or “genotype-driven research recruitment”, is gaining increasing importance. The rationale for RbG is that drawing upon the potential biological impact of the variants in question already at recruitment can render the subsequent phenotyping process more specific and cost-effective .The process of re-inviting individuals who already participated in a research project may seem unproblematic at first glance, but it nevertheless poses a challenge to established ethical, legal, and practical research frameworks, and therefore warrants further consideration , 3. In fDesigning an RbG process requires several decisions to be made upfront . First, The number of studies relying upon RbG can be expected to increase considerably in the near future, and several ad hoc cohorts (e.g. the Oxford biobank ) have beThe Cooperative Health Research in South Tyrol (CHRIS) study is a longitudinal cohort study targeting the general population of Val Venosta in South Tyrol, Italy. CHRIS was launched in 2011 to investigate the molecular basis of common chronic diseases associated with human ageing and to analyse the interaction of genetic factors with life-style and environmental factors . BaselinWhen designing the pilot RbG study, we decided to also embed within it an empirical study, including qualitative and quantitative parts. The empirical study was designed to collect direct feedback from participants who were involved in an RbG study. This was important not only for understanding participants’ experience while participating in our pilot RbG study (feedback on the recruitment and communication strategy) but also for understanding their views on RbG-designed studies in general . The pilot RbG study and the embedded empirical study were conducted in August 2018 at the CHRIS centre in Silandro/Schlanders, Italy. The studies are a joint effort by Eurac Research, Institute for Biomedicine, Bolzano, Italy, and the University of Lübeck, Germany, made as part of a wider scientific project on reduced penetrance in movement disorders (ProtectMove). The pilot study comprised a clinical examination , whereas the empirical study consisted of two questionnaires  and an interview . The whole study  was performed in accordance with the Declaration of Helsinki and was approved by the ethics committee of the Azienda Sanitaria dell’Alto Adige. All participants provided written consent to participate in the study. Here, we describe the design of the pilot study and the policy building process, drawing on some preliminary observations made in the empirical study which shed light on the RbG process. The methodological details and the results of the empirical study will be published elsewhere.The stepwise strategy we took in order to conduct a pilot RbG study in the frame of the CHRIS study is shown in Fig. In the narrative literature review, papers focused on the ethical aspects related to RbG  and papers focused on the biomedical and clinical aspects of RbG-designed studies, aiming at understanding the phenotypic effect of specific genetic variants  were reviewed. We sought to understand how to balance scientific interests and participants’ rights. We expected to find, in the biomedical RbG papers, the translation into practice of the ethical issues discussed in the ethical papers, and approaches to the challenges that an RbG-designed study poses.The ethical papers were mostly focused on the perspective of participants to RbG: authors investigated participants’ understanding of the rationale of RbG-designed studies , the expThe participant’s relationship with the researchers involved , 24.The modality of re-contact, i.e. in which way and by whom the re-contact is made .The nature of the target participants population  –23.The possible involvement of other family members .The focus of the RbG study compared to that of the original study .For participants from a disease-specific cohort or for parents of minors with a disease: disease status, type and nature of the condition being studied, current knowledge about the condition, possible expectations and meanings associated with research results , time, oImportantly, they highlighted that the “context” may influence the steps to be taken while designing RbG studies, especially in the process of re-contact and the communication (or not) of genetic research results. The discussed contextual factors included:The perspective of other stakeholders, like institutional review board chairs, has been addressed as well by Beskow et al. . The autRbG studies are often conducted as sub-studies within the framework of a larger-scale research study, which can be longitudinal, long term, biobank based, and with broad aims. The most recently published RbG studies included in our literature review were conducted in Europe, mostly in the frame of population studies such as the Cambridge BioResource , 26, theIn both RbG studies and the return of research results to study participants, the disclosure of potentially unwanted or distressing information during re-contact might occur, necessitating a reflection on how best to handle the communication with participants In view of this commonality, we drew upon the findings obtained from a previously conducted qualitative study with CHRIS participants on the return of results (own unpublished observation). In order to tackle the issue of disclosure in a nuanced way and to meet the expectations of participants, data from the return of results interviews were used as a basis to develop the questionnaire for the empirical study embedded in the pilot RbG study.To enrich the key ethical issues identified in the literature with the clinical experience of experts, we engaged in a discussion on RbG with nine clinical geneticists, working at the hospitals in Bolzano, Verona, and Bologna. We sought their view because it is of relevance for the medical and ethical implications of reporting genetic information to study participants. Specifically, D.M. and M.K. discussed possible strategies for communicating genetic findings with members of the Clinical Genetics Unit in Bolzano, which will play a vital role in future RbG studies in CHRIS because it is assigned the task of providing necessary genetic counselling within an RbG framework, under specific conditions. Together with the Bolzano Clinical Genetics Unit, we identified four scenarios of inherited genetic disease , Huntington’s disease, and malignant hyperthermia), to serve as a simplified representation of the complexities of interpretation for a genotyping result in terms of associated pathology. The four diseases differed by mode of inheritance, genotype-associated disease risk, age at onset, prevention, treatment, and clinical severity, thereby providing an acceptable typology model of genotyping results. This model has been used in a return of research results study to facilitate the discussion on the views on the return of individual genetic results, by showing a panel of results which will have a very different impact on health: for example, participants were asked whether they would like to receive their genetic results about diseases such as Huntington’s disease, where being carrier of the responsible gene variant results in 100% risk of developing the disease, 50% risk of transmitting the disease to their children, and for which there is no cure and no prevention. Each disease served to represent a different scenario (own unpublished observations). The model was occasionally used during the interviews conducted in the empirical study reported here, if the conversation raised the opportunity. In this case, it served as a summary of the variables that participants might find relevant in their decision in participating in research about genetic diseases, and to stimulate reflection on the impact that the information received during recruitment and participation may have . The description of the diseases in this model has been integrated into the information provided for the CHRIS study informed consent, revised for the first follow-up phase (commenced October 2019) .The option for re-contact for further research inserted into the informed consent .To address the return of individual research results in the informed consent where individuals make an autonomous specific choice addressing the willingness to receive information on their genetic data, explicitly addressing the right to know and not to know.The availability of information about the genetic basis of re-contact for RbG studies that addresses the right to be informed and provides the basis for an informed choice.A clear communication on the rationale for returning (or not) research results for transparency, and again to ensure that individuals are aware of the process.Through the steps described above, we identified several key points to be addressed both in the design of our pilot RbG study and also in a potential general RbG policy:For an RbG study to be acceptable in the first place, any re-contact must be covered by the consent given at the time of recruitment. In the original CHRIS informed consent form, which is a dynamic-based consent , particiWe concluded that legally and ethically the concomitant choice of the options “agree to re-contact for communication and further studies” and “agree to re-contact for incidental genetic findings” is in fact tantamount to approving re-contact by genotype and, hence, meets eligibility requirements for invitation to an RbG study.Through a discussion with the ethics committee of the Azienda Sanitaria dell’ Alto Adige and with local GPs, we agreed on the feasibility and upon additional measures to safeguard participants in the pilot study. First, the pilot study should be focused on genetic variants with moderate to low disease penetrance. Second, participants should be provided further clarifications, if they so wished, in a timely and easily accessible way.PRKN) variants usually disease-causing when inherited recessively. Such biallelic disease-causing PRKN variants (in a homozygous or compound heterozygous state) are causative of PD through a recessive inheritance pattern, with highly variable age of onset. Moreover, recessively inherited heterozygous disease-causing variants in genes for one disease may present as risk factors for PD. Such is the case for biallelic variants in the glucocerebrosidase gene (GBA) which cause Gaucher disease, whereas heterozygosity at the same position strongly predisposes to PD. This and other examples provide support for the notion that disease-causing variants with reduced penetrance and genetic risk factors are sometimes different expressions on a continuum of effect sizes rather than representing a clearly dichotomous situation. Notably, penetrance of GBA variants was estimated as 7.6, 13.7, 21.4, and 29.7% at 50, 60, 70, and 80 years, respectively [PRKN pathogenic variants cause recessively inherited PD with high penetrance and typically earlier onset, whereas heterozygosity only leads to a modestly increased risk for PD [PRKN variant carriers can develop disease, the age of onset of carriers of heterozygous PRKN variants has been shown to fall in between that of biallelic variant carriers (earlier AAO) and sporadic PD patients (later AAO), and imaging and neurophysiological studies have revealed alterations in unaffected carriers of heterozygous variants , which is much higher than the prevalence of PD [Recent major sequencing efforts have revealed a surprisingly large number of carriers of genetic variants reported to cause disease under different modes of inheritance, who do not exhibit overt symptoms of disease . With inectively . Biallelk for PD , 42. Givease see ), these ce of PD .PRKN variants that can cause disease when inherited recessively, or potentially dominantly with very low penetrance, was chosen as a test case for the pilot RbG study.Following the incorporation of additional measures established with the ethics board and local GPs for participant safety as detailed earlier, heterozygosity for PRKN variant carriers and matched non-carriers. Each pair was chosen to be closely related, of the same sex, and of similar age where possible. This approach was taken for two main reasons, satisfying both the measures to safeguards participants and the clinical aim of the pilot. Inviting carriers and non-carriers at the same time without telling them their individual status potentially reduces psychological strain. A matched recruitment design reduces the risk of ascertainment bias due to possible pre- or sub-clinical effects of PRKN gene variants.Our pilot RbG study followed a matched recruitment design with 25 pairs of PRKN” and preferred “Parkin gene” instead. For the same reason we avoided scientific jargon, e.g. we used “standard” instead of “wild-type” when describing the gene. The brochure was structured in the same way as the letter but included more details relative to each section. In the letter, we reminded the invitees of their participation in the CHRIS study and of their expressed interest in participating in further research (by previously agreeing to that in the CHRIS informed consent). Both the letter and the brochure illustrated the following points:The aim of the study, namely to carry out a deep neurological examination to investigate protective mechanisms against neurological diseases, with a focus on PD.PRKN genotype.The concept of reduced penetrance and the need for investigating the phenotype associated with a particular PRKN gene and members of the other group carrying variants of the gene.The study design, i.e. two groups of participants were invited, with members of one group carrying the wild-type PRKN carrier status would not be disclosed as no clinical benefits nor direct individual consequences are currently known.That only results relevant for the participant’s health would be communicated. Their German was used for study communication, as it is the preferred language among CHRIS participants . InviteeWe concluded the letter by announcing an upcoming phone call from the CHRIS study assistants to fix an appointment and the contact details (phone number) of the CHRIS study for further questions and clarifications.PRKN gene heterozygosity are mostly unknown, we disclosed only the type of genetic variant under study, but not the carrier status of the addressee. We decided that the communication of the individual carrier status, with the uncertainty regarding clinical implications, would potentially cause distress to participants. In the information material, we clarified that current findings suggest that PRKN heterozygosity may increase the risk of neurological symptoms. We highlighted the possibility that the addressee could be carrier of either status. To comply with the additional measures to safeguard participants described above, a direct telephone number for answering further questions and for formal enrolment was made available from the date the invitation letters were sent out. Consent was obtained at the study centre, where explanatory material was also available alongside the information provided verbally by study nurses and doctors. If participants wished to ask questions or requested further clarification during the medical examination, a specialist medical doctor was available to respond. If specific outcomes of the clinical examination required medical follow-up, the participant was referred to suitable specialists.Since the consequences of Out of the 58 CHRIS participants invited by mail to participate in our RbG study, 50 (86%) agreed. The main reasons for non-participation were availability during the week of the pilot study. An additional relative of one carrier, interested in undergoing the clinical examination, asked also to be included, to which we agreed, but did not include their data in the subsequent analysis because of the self-referral.As a preliminary finding within the empirical study, most participants reported to be at ease with the recruitment process and with the non-disclosure of their carrier status. They were satisfied that they had the chance to have their concerns duly addressed. Only one person experienced anxiety when receiving the invitation to participate, but was reassured in a phone conversation with a study assistant.The literature review revealed that when designing an RbG study, it is key to consider the context of the study. The dynamic consent model adopted by CHRIS facilitates the ongoing communication between researchers and participants, and offers an easy way of informing CHRIS participants about new study approaches, such as RbG. In our experience, CHRIS participants demonstrate a general positive attitude towards research and participation and trust towards the study (own unpublished results). The focus of the pilot RbG study (research into the mechanisms of PD) fits well into the main scope of the CHRIS study, i.e. the study of cardiovascular, neurological, psychiatric, oncologic, and metabolic conditions. These aspects combined might have played a role on the very high participation rate in the pilot and on the generally positive attitude towards participation. The participation rate of the RbG pilot study was slightly higher than that of other sub-studies conducted in the frame of the CHRIS study (own unpublished observation).The framework of re-contact very much depends on whether re-contact was envisaged during the consent process of the original study. Based on the experience from our pilot study, we think that the possibility of future RbG studies should be addressed in the consent of original cohort studies as standard because RbG studies might entail disclosure of sensitive data and individuals have the right to refuse this information or to express the willingness to be informed. Along with appropriate information, this would provide cohort members an introduction to the concept, and an early chance to decide whether or not they want to be involved in such studies in general. At the time of the pilot study, the informed consent of the CHRIS study addressed the return of research results with several options, and did not specifically refer to RbG. We concluded, however, that the concomitant choice of accepting to be re-contacted for communication and further research and agreeing to be re-contacted with research results  by the participant was acceptable as a condition for invitation to an RbG study also in terms of legal requirements. When the first follow-up phase of the CHRIS study started in 2019, the information material of the informed consent was enriched with specific examples for the typology of genetic diseases that may form the basis of such further RbG studies, developed together with genetic counsellors, in order to offer participants a more nuanced perspective on the meaning and implications of carrying particular genetic variants.PRKN variants under study in our pilot RbG study are usually highly penetrant in a recessive inheritance mode and that we were studying heterozygous carriers with much reduced, or negligible penetrance, we did not set up any professional genetic counselling, which would be required as part of a study for variants with dominant inheritance and severe pathogenic implications. All participants in our pilot reported to be at ease with the recruitment strategy used. We also recommend including, as part of the setup of an RbG study, a point of direct contact (preferably by telephone) for potential participants, in order to collect and respond to potential queries and worries immediately. One invitee in our pilot study made use of this opportunity after receiving the invitation, and their concerns were sufficiently addressed.The ideal framework of the information process, in a general consent setting, should aim to balance between the practicability of the consent procedure and the amount of provided information. We recommend that the communication strategy be adjusted to the significance of the variant(s) in question, e.g. while the carrier status for a variant of unknown significance may be communicated by mail, professional genetic counselling is required for variants with severe pathogenic implications. In Italy, the communication of individual genetic results, especially in the case of disease-causing implications, is usually done through genetic counselling. In this context, the role of informed consent is to pre-assess the willingness of people to be involved in an informational procedure by genetic counsellors, in case variants are found for RbG. This means that, in some cases, individuals should be contacted for proper disclosure/non-disclosure by genetic counsellors, according to clinical severity and actionability. Considering that the PRKN variants), variant-based re-contact generates less anxiety than when being confronted with information of variants with a demonstrated major impact on health. The expected low clinical impact of these variants is also a likely explanation of why most participants deemed the non-disclosure of their carrier status acceptable. However, this does not preclude that, with an RbG study involving variants that cause disease recessively, re-contact can create tensions and anxiety in potential study participants.As yet, no clear guidelines exist regarding the type of genetic variants that may be reasonably disclosed to participants in RbG studies. In our pilot study, we disclosed the genetic variant under investigation to invitees, but not their individual carrier status. This approach was met with ease by the participants. It may be possible that with the specific test case chosen for our pilot study , such an embedded empirical study design would be a valuable strategy for shaping policy, because findings will be useful for understanding the specific context of the study, while designing and implementing an appropriate dynamic adjustment of the RbG policy. In addition, an embedded study design necessitates a close collaboration between researchers with different professional expertise , thus having also a bidirectional educational impact. By increasing awareness of the challenges posed by the re-contact of participants and the disclosure of individual genetic information, scientists be better able to reflect productively upon their own study design. The sharing of experiences, solutions, and tools from RbG studies should be widely encouraged. It is in this spirit we report in our pilot study and the steps we took in the process of a CHRIS RbG policy and offer the tools and insights gained therein.An RbG policy should balance the duty to provide information on the scientific rationale for recruitment with the right of the study participants to not to know sensitive information, while also trying to minimize the risk of deceiving participants by not informing them properly. Here, we outline the steps that we undertook in the policy building process for the CHRIS study. The difficulties in developing an acceptable and practicable RbG policy are to be found in those aspects of disclosing genetic information . By reporting on our experience in designing the workflow for the RbG pilot study, we aim to contribute to the design of best practices and tailored policy, and to participate in the reflection on research methodology in the field of RbG studies.Our approach in understanding how best to design and conduct RbG studies in an ethically acceptable way and potentially draft policy and guidelines for best practices in RbG, included different steps and addressed the main ethical issues from different perspectives, which included reviewing the literature, consulting stakeholders, and collecting feedback from participants through an empirical study. The research on RbG best practices and policy we conducted and described here aimed to respond to different interests at stake: those of scientists, interested in conducting genetic studies to functionally understand the effects of genetic variants in health and disease, and those of participants, interested in having their rights respected and their wishes and expectations addressed, while participating in research. Based upon the insights gained through this policy-development process, we are currently working on a draft for a comprehensive RbG policy for future use and additional testing in CHRIS-based RbG studies.Supplementary information 1


Musculoskeletal physiotherapy provides conservative management for a range of conditions. Currently, there is a lack of engagement with exercise programs because of the lack of supervision and low self-efficacy. The use of mobile health  interventions could be a possible solution to this problem, helping promote self-management at home. However, there is little evidence for musculoskeletal physiotherapy on the most effective forms of mHealth.The aim of this review is to investigate the literature focusing on the use of mHealth in musculoskeletal physiotherapy and summarize the evidence.A scoping review of 6 peer-reviewed databases was conducted in March 2021. No date limits were applied, and only articles written in the English language were selected. A reviewer screened all the articles, followed by 2 additional researchers screening a random sample before data extraction.Of the 1393 studies, 28 (2.01%) were identified. Intervention characteristics comprised stretching and strengthening exercises, primarily for degenerative joint pain and spinal conditions . The most reported use of mHealth included telephone and videoconferencing calls to provide a home exercise program or being used as an adjunct to physiotherapy musculoskeletal assessment . Although patient satisfaction with mHealth was reported to be high, reasons for disengagement included a lack of high-quality information and poor internet speeds. Barriers to clinical uptake included insufficient training with the intervention and a lack of time to become familiar.mHealth has some benefits regarding treatment adherence and can potentially be as effective as normal physiotherapy care while being more cost-effective. The current use of mHealth is most effective when ongoing feedback from a health care professional is available. Musculoskeletal conditions can have a major impact on people’s quality of life, leading them to seek medical care in the form of nonsteroidal anti-inflammatory drugs or surgery , with people aged 55 to 65 years being the most common age group experiencing these conditions . MusculoeHealth is an umbrella term that refers to the use of modern information and communication technology to deliver health care . A brancThis innovative branch of health care has increased accessibility and affordability for patients , providiAnother factor contributing to the rapid development of mHealth apps is the COVID-19 pandemic . Owing tWith the rise in smartphone availability, there has been a concomitant increase in research involving mobile device apps  for the management of chronic pain . The mHeLittle evidence underpins which aspects of mHealth are most effective and allow for the greatest level of engagement regarding musculoskeletal conditions . A recenThe aim of this review is to explore and chart the evidence on the use of mHealth within musculoskeletal physiotherapy, with a view to identifying relevant gaps in the literature by conducting a structured, systematic scoping review and developing relevant themes of the topic in question to address the feasibility of mHealth interventions.This scoping review was conducted in accordance with a standardized framework . This reThe primary objective was to analyze the use of mHealth and the outcomes it had produced in musculoskeletal physiotherapy . The secondary objectives were to determine the following: how mHealth has previously been applied, the types of conditions mHealth has been used for, interventions that have been proposed and implemented using mHealth, the reasons for barriers to and facilitators of mHealth, and the barriers to clinical uptake.Studies were assessed against the inclusion and exclusion criteria described in Inclusion criteriaEnglish language articlesPeer-reviewed articles published in journals where full text was availableFocus on the use and application of mobile health in musculoskeletal physiotherapy, including in patients and therapistsApplication of mobile health could be in an outpatient or home-based settingStudies in which mobile health was used as a whole or partial aspect of treatment combined with or without other modalitiesExclusion criteriaStudies focusing on mobile health in other areas of health care Peer-reviewed articles were identified using key databases, including MEDLINE, Embase, ProQuest Health and Medical Complete, CINAHL Plus, AMED, and IEEE Xplore. These databases were chosen as they include a large collection of literature related to physiotherapy research alongside literature on health technology. Gray literature was also searched to allow for the inclusion of further relevant studies that were not identified through database searches. The search was conducted in March 2021.mHealth, eHealth, or Telemedicine to identify articles related to the application of mHealth within physiotherapy. The reference lists of the appropriate articles were also snowball searched to identify any further literature.The search strategy  used theThe database searches were undertaken by three researchers  to identify all relevant literature, with no date limitations being applied to capture as much relevant literature as possible.All relevant references were imported into RefWorks (ProQuest), and duplicates were removed. One of the researchers (JMRA) applied the eligibility criteria for both the title and abstract review and full-text review stages. To allow for consensus on the eligibility criteria, 10% of the selected studies were reviewed by two additional researchers (DK and CH). This was followed by an assessment of the full texts of the included articles for the final inclusion stage by three researchers .A data-charting form was developed to steer the collection of data from the included studies. This form included general data such as author and publication year, as well as more specific information relevant to this review. The data-charting form was piloted using a random selection from the database search results. This informed us of any changes needed before charting the data from the remaining studies. One of the researchers (JMRA) subsequently charted the data from all remaining studies, with 3 additional researchers reviewing a selection of these studies to ensure extra rigor.A quantitative overview of the included studies was summarized in a series of tables and diagrams to aid in the synthesis of the literature related to the use of mHealth in physiotherapy. This included aspects such as which countries were applying mHealth, the nature of the intervention, and the common conditions for which mHealth was used. The final extracted data were also presented in a narrative account in the literature. The research team developed themes and categories that emerged with aid from both the research question and data produced using an iterative process.The initial database search  of the mThe study characteristics and findings are outlined in Overall, there were more quantitative studies  than qualitative studies , Europe , Asia , and Oceania . The North American locations were divided into Canada  and the United States . The continent of Europe included the largest number of locations, including the Netherlands , Sweden , Spain , Portugal , the United Kingdom , Italy , and Denmark . Asia contained the next most locations, comprising Nepal , Iran , Taiwan , Malaysia , and India . Oceania included only Australia .an exercise program delivered to the patient’s home; however, the exact nature of these protocols was not described in sufficient detail. Those studies that provided enough detail described the elements of strengthening [Despite all studies stating mHealth as part of the intervention, a significant number of studies failed to adequately describe the input of mHealth to the extent that it would be reproducible. Several studies reported the intervention as being gthening ,57,59,73gthening ,56. One gthening . Other sgthening ,60,68,70Of the 28 included studies, 4 (28%) systematic reviews ,61,63,71Only 7% (2/28) of the studies ,61 descrAlthough studies have reported the type of musculoskeletal condition for which mHealth was being used, some studies described a broader term covering a range of conditions within the same area  or videoconferencing . The current articles suggest mHealth is best implemented as an adjunct to  therapy . A numbe therapy ,59. For  therapy ,66 and w therapy ,57,62,73 therapy  involvedclunky design of some of the apps [Approximately 64% (18/28) of articles stated the reasons for engagement or disengagement from the intervention. Overall, these reasons were not described in sufficient detail. In general, patient satisfaction was very high as participants valued the interactive features and readily available support as very important. Studies involving preoperative protocols reported that interest in surgery decreased as knowledge of their condition increased because of the constant engagement with their clinician . It was the apps ,55. Howethe apps . It was Only 4% (1/28) of the studies specifically explored the experience of clinicians in using mHealth . This stThis study represents a mapping of the breadth of evidence for the use of mHealth within musculoskeletal physiotherapy and identifies 5 themes of mHealth implementation, including facilitators of and barriers to uptake. The main aim of this scoping review was to analyze the evidence surrounding the use of mHealth in musculoskeletal physiotherapy and the outcomes it produced. The main findings from this review suggest that videoconferencing or phone calls are the most popular among patients as they provide ongoing feedback with a clinician, potentially leading to a higher adherence rate to rehabilitation programs. Another finding has shown a lack of adequate training in mHealth use among clinicians, leading to poor uptake.This review demonstrates that there is potential in the future for mHealth to be a viable component of musculoskeletal physiotherapy care. Recent studies have proposed that mHealth interventions have the potential to be more effective than usual physiotherapy care, as the increased use of smartphones enables patients to source information and take control of their rehabilitation . HoweverThere is limited evidence suggesting that mHealth can be effectively used for physiotherapy musculoskeletal assessments as an alternative to face-to-face assessments. Of the 28 studies, 2 (7%) studies ,61 suggeA range of conditions was analyzed in this review, suggesting a lack of research on mHealth use for particular musculoskeletal conditions. Postoperative rehabilitation after total knee replacement was the most researched condition for mHealth use. Only 11% (3/28) of studies investigated mHealth for the treatment of chronic low back pain ,60,66, aan exercise program delivered to the home, with follow-up telephone calls from a participating clinician, with the assumption that this is a form of treatment rather than an umbrella term encompassing a range of interventions. This suggests that there is insufficient evidence to guide physiotherapists on how to effectively deliver an mHealth intervention, as supported by 4% (1/28) of the studies in this review [Very few studies described the mHealth intervention in detail in a way that would be reproducible. As this review was conducted in the context of musculoskeletal physiotherapy, it can be assumed that physiotherapy care would be within the context of the intervention. Most authors failed to describe the physiotherapy component in detail, simply describing the intervention as s review .This review highlights a lack of qualitative research on mHealth interventions as most evidence was quantitative in nature. The importance of understanding the experiences of those delivering and receiving these interventions is not to be understated and can be a vital part of enhancing the delivery of future interventions . This caAlthough most evidence within this review was conducted within the past 10 years, we excluded articles that were non-English articles, implying the possibility of excluding relevant articles from non–English-speaking countries , where technology is well-advanced . In addiWith the onset of the COVID-19 pandemic, alternatives to face-to-face musculoskeletal physiotherapy have become a priority. Future smart device–based mHealth interventions should focus on implementing evidence-based strategies in research design and using more innovative health care technologies to help enhance and expand the practice of mHealth. To aid in the development of the rapidly expanding market of mHealth, future research should look to develop evidence-based rehabilitation programs for acute and chronic conditions using the latest technologies and provide adequate training for clinicians.It appears that mHealth has some beneficial effects on treatment adherence and can be as effective as the usual physiotherapy care and potentially more cost-effective. Currently, communication with a clinician via telephone or videoconferencing appears to be the most widely accepted among patients, as this helps maintain confidence in their rehabilitation because of ongoing feedback. This feedback loop between the clinician and the patient potentially leads to positive outcomes regarding pain and self-management because of increased adherence to the rehabilitation program.The limitations identified in this review provide an outline for future studies. This review has shown the main limitations to mHealth uptake from clinicians, primarily as a lack of knowledge and confidence in their judgment when using mHealth interventions and a preference toward an evidence-based clinical technique . Researc


Vitis vinifera (L.) is of great economic importance as Chile is one of the main wine-producing countries, reaching a vineyard area of 145,000 ha. This vine crop is usually very sensitive to local condition changes and agronomic practices; therefore, strategies to counteract the expected future decrease in water level for agricultural irrigation, temperature increase, extreme water stress (abiotic stress), as well as increase in pathogenic diseases (biotic stress) related to climate change will be of vital importance for this crop. Studies carried out in recent years have suggested that arbuscular mycorrhizal fungi (AMF) can provide key ecosystem services to host plants, such as water uptake implementation and enhanced absorption of nutrients such as P and N, which are key factors for improving the nutritional status of the vine. AMF use in viticulture will contribute also to sustainable agronomic management and bioprotection against pathogens. Here we will present (1) the current status of grapevines in Chile, (2) the main problems in grapevines related to water stress and associated with climate change, (3) the importance of AMF to face water stress and pathogens, and (4) the application of AMF as a biotechnological and sustainable tool in vineyards.The crop  Vitis vinifera (L.) is a crop of economic importance, whose value depends largely on the quality of the fruit . The use of biostimulants has been proposed to mitigate stresses associated with climate change , elevated temperature , and partial irrigation (at 40% of field capacity) decreased the berry malic acid and total anthocyanin concentrations, while anthocyanin extractability was facilitated.Because increases in air COincrease , with noincrease . In contperature . Under sperature . The effThough it has been shown that the effects sought with deficit irrigation are attenuated by very high temperatures , in ChilCurrently, the decrease in water level is beginning to be noticed in Chile. In total, 95% of the vineyards have problems with water supply. It is estimated that rainfall in the Maipo Valley will decrease by approximately 20% by 2050 . This wiTherefore, long periods of drought will interfere negatively with wine production. Since the decrease in water triggers a series of effects, such as a decrease in nutrient uptake, the absorption of water and nutrients are closely related to their flow from the roots to the shoots of vine plants . Plant gUnder drought stress, the water potential of the xylem decreases, limiting the amount of water and nutrients that can be used in plant growth —thus genPhaeomoniella chlamydospora, Diplodia seriata, and Inocutis sp. , causing the same symptoms such as necrosis, delayed development, chlorotic leaves, and plant death. Within the most common pathogenic fungi are utis sp.  as well diseases  and whicdiseases . Anotherdiseases . In Chilauvignon .Additionally, in the central area of Chile, a large part of the vineyards shows infestation by nematodes, which represent another aspect of the serious problems affecting Chilean wine production. Nematodes cause damage to the roots, which allows the entry of other phytopathogens such as bacteria, viruses, and fungi . In addi2 generated in the atmosphere, it could affect the response of the transcriptional system in grapevines. In this sense, differences have been found in the expression level of a subset of herbivory-responsive genes when an RT-qPCR evaluation was performed  form a symbiotic association with 78% of vascular plants, representing the most common mycorrhizal symbiosis on earth . Specifi2 to a significant increase in AMF colonization, which can be justified with increased plant nutrient requirement due to increased C fixation  to counteract the action of fungi causing black foot on grapevines. The mechanism of action is not available, but it has been suggested that AMF reduce the infection sites for the pathogens or generate an increase in the absorption of nutrients such as P, N, K+, Ca+, , which originated an increase in the transcription of the VCH3 gene coding for chitinase, activating the defense responses against the nematode  . MIR hasLV virus . R. intrematodes . As to tnematode .Arbuscular mycorrhizal fungi promote and improve defenses already established by plants. One of the best-known mechanisms is the increased concentration of jasmonic acid (JA) in plant roots, which occurs when AMF infection begins in cortical cells because JA is a hormone that facilitates colonization and is closely related to induced systemic resistance (ISR) . When AMDespite the benefits granted by these symbiotic fungi, the application of diverse AMF species and isolates should be justified and carefully studied before inoculation since some studies showed that AMF inoculation has increased fungal pathogen infections. Such data may be due to the synergistic effect of the AMF species used and the pathogen . HoweverV. vinifera in field conditions is normally colonized by AMF. However, there are differences in the biodiversity of these microorganisms, depending on the properties of the soil (Glomus regularly occurred in vine crops (ex vitro survival rate in micropropagated plants (Like most terrestrial plants, the soil  and the ne crops . As a cone crops . Such std plants  and gread plants . The AMFd plants .Another aspect that is important to consider in using AMF as a biotechnological tool is to decide which AMF species should be considered as inoculum. The industry of AMF inoculum has grown at a high speed , and in Given the key role that AMFs are likely to play with regard to alleviating abiotic and biotic stress in grapevine plants, it is important to conduct further research in laboratory experiments and in the field in the coming years. In fact, AMF inoculants will make a significant contribution to sustainable grapevine production systems in the face of climate change. In grapevine, only a few inoculants were used. Studies that focus on the identification of the diversity of AMF present in the grapevine in different edaphoclimatic conditions are required, and there may be dominant species that can effectively contribute to grapevine symbiosis in the grapevines. Upon recognizing areas most affected by climate change, through the knowledge of different species of AMF and the evaluation of their isolates, it will be possible to evaluate the effects of AMF selected in different stress conditions at the greenhouse level for their ability to alleviate both abiotic and biotic stresses in grapevine plants. Such isolates should be tested in subsequent field studies to assess the maintenance of their beneficial activities and could eventually be reproduced for use as biostimulants in more resistant and sustainable grapevine production systems. Finally and as mentioned at the beginning, although this bibliography does not establish the relationship between AMF and Chilean grapevine crop, it does allow us to extrapolate data and open the doors for research on this tool with our national variables.PA, NO, NB, and AT contributed to the initial writing. FG-C and PS-F contributed from their experience from the agricultural and scientific sector. AA-P, JR, EJ-F, MM, and FB reviewed the writing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.