The workplace is a major contributor to excessive sitting in office workers. There are a wide array of adverse effects of high volumes of sitting time, including an increased risk of type 2 diabetes and depression. Active workstations can be used in effective interventions to decrease workplace sitting. However, there are a lack of interventions that have been developed using a systematic process that is informed by participant needs and a framework for identifying the most appropriate content for the intervention. Applying these methods could increase adherence and potential effectiveness of the intervention. Therefore, the purpose of this pilot study is to examine the feasibility, acceptability, and efficacy of a tailored workplace intervention to reduce and break up sitting in office workers that has been developed using the Behavior Change Wheel and the APEASE  criteria. This article reports the protocol for this study that is currently ongoing. Participants will be cluster-randomized (by offices) to control and intervention groups. The evaluation of the intervention includes determining feasibility by assessing participant recruitment, retention and data completion rates. Adherence to the intervention will be assessed based on daily sitting and standing time relative to guidelines provided to participants as part of the intervention. Outcome measures also include productivity measured using Ecological Momentary Assessment, absenteeism, presenteeism, cardiometabolic risk markers, and wellbeing. The findings of this study will inform the effective design and implementation of interventions for reducing and breaking up sitting in office workers. Sedentary behavior has been described as any waking behavior in a sitting, reclining or lying posture that has an energy expenditure of ≤ 1.5 metabolic equivalents (METs) . StudiesIndividuals who spend prolonged periods being sedentary have an increased risk of adverse health outcomes, including type 2 diabetes, cardiovascular disease, some cancers, and mental health problems such as depression and anxiety –9. This There is a growing body of evidence that suggests height-adjustable workstations  could be effective for decreasing sitting in the workplace . When heThis article describes the protocol for a pilot cluster-randomized controlled trial (RCT) to evaluate the feasibility and efficacy of a multi-component intervention to reduce and break up workplace sitting, including the systematic process for identifying the content of the intervention using the BCW. The effects of the intervention on a range of sitting, activity, health, wellbeing and work-related outcomes (including EMA assessment) will be evaluated.The study adopts an 8-week, two-arm cluster RCT design that is planned to be conducted during Spring and Summer months see . ParticiClinicalTrials.gov (NCT03560544). Ethical approval for the procedures detailed below was obtained from the University of Bedfordshire Institute for Health Research Ethics Committee (lHREC836). Participants will provide written informed consent prior to any testing procedures and the study is being conducted in accordance with the Declaration of Helsinki.The study is registered on The study will be conducted with office workers employed across a university campus and a local council, both located in the East of England region, UK. Participants were recruited from one campus at the university and employees at the council worked within offices at a single site. Clusters of participants will be recruited from both organizations who will be randomly allocated to the intervention or control group i.e., there will be intervention and control clusters located at each organization.Management approval will be sought and obtained for the recruitment of the employees, changes to the workplace environment, and for study testing and communications to take place during work time. The project will be advertised to staff as part of a workplace wellbeing programme via internal mail, staff meetings, information fliers in offices and other strategic places within the participating organizations.Participants will be full-time desk-based office employees between the ages of 18 and 60 years employed in any job type and from any ethnic background. Individuals will be excluded from the study if they are pregnant, have a history of musculoskeletal complaints, non-ambulatory, or have a planned holiday that would mean they would not be at work for more than 2 weeks during the 8-week intervention period.There is no standard procedure for determining the sample size for pilot studies as their main purpose is to obtain an estimate of the standard deviation that could be used to determine the likely effect size to inform a full trial . Thus, thttps://www.randomlists.com/team-generator) by an independent researcher , Action planning, Problem solving, Instruction on how to perform the behavior, Credible source, Information about health consequences, Information about emotional consequences, Prompts/cues, Social support [unspecified], Restructuring the physical environment, Restructuring the social environment, Adding objects to the environment, Behavioral practice/rehearsal, Behavior substitution, Habit formation, Habit reversal and Demonstration of the behavior; see In deciding which intervention functions, policy categories and BCTs were most appropriate or have the highest possibility of success in delivering the desired change in this context, the Acceptability, Practicability, Effectiveness/cost-effectiveness, Affordability, Safety/side-effects, Equity (APEASE) criteria was applied. This is line with recommendations for using the BCW in practice , 37. IniThe control group will continue to work as normal with no changes in their routine or environment. They will complete the same measurements as the intervention group.All measures for both intervention and control groups will be performed at baseline and during the final week of the 8-week study period. Questionnaires will be completed online using Qualtrics survey software  with physical measures taking place at participant's workplaces in a private room.The primary outcome measure is sitting time at work, which will be measured using an activPAL3 activity monitor . The activPAL is a portable lightweight device, which is usually worn on the front of the mid-thigh to take measurement of postural information by recognizing periods of lying down/sitting, standing, and stepping based on the inclination of the thigh , 40. TheIn addition to workplace sitting, the activPAL will be used to measure total daily sitting time and the following variables for working hours and across the waking day: time spent in sitting bouts <30 min and ≥30 min, the number of sitting bouts <30 min and ≥30 min, standing time, number of sit-to-upright transitions, number steps and stepping time. Processing PAL  will be used to process the data. A validated algorithm  will be Adherence to the intervention will be assessed using activPAL data for the working day. Participants will be classified into one of three groups at baseline and follow-up in line with recommendations from an expert statement on reducing sedentary time in the workplace : (1) meeFeasibility will be assessed based on recruitment response rate  and eligibility rate . Retention rate will be calculated as number of participants who complete 8-week measures / number of participants enrolled into the study x 100. Data completion rates will be calculated as the number of complete datasets for each outcome measure / number of participants enrolled ×100.Acceptability of the intervention will be assessed using semi-structured interviews with intervention participants. Data will be analyzed using thematic analysis as well as deductive charting using the APEASE  criteria .Work productivity will be assessed using measures of absenteeism, presenteeism, and ecological momentary assessment (EMA) at baseline and during week eight of the study. Absenteeism will be measured using self-report at baseline and at the end of the eighth week. Three questions to assess unsanctioned absences will be used from a previous study . This inThe final measure of productivity is EMA, which has been used previously in a variety of different contexts to measure physical activity and sedentary behavior –50. PromAll cardiometabolic risk biomarker measures will be taken at baseline and within 5 days post-intervention. This includes the following:Blood samples taken after an overnight fast of at least 10 h using a finger prick method with a lancet . Blood sBlood Pressure. Resting systolic and diastolic blood pressure will be measured on the right arm after resting for at least 10 min in a seated position using an automated blood pressure monitor  validated by the European Society of Hypertension , which is a 20-item self-report measure of positive affect and negative affect  bootstrap method will be used to produce unbiased estimates of the confidence limits for all data . Data will be assessed for normality using the Shapiro-Wilk test owing to the relatively small sample size. Linear mixed models will be used with arm and time as fixed effects, participant ID and cluster ID as random effects, and the baseline value of each variable as a covariate. An additional linear mixed model will be used to compare the effect of standing vs. sitting posture for the EMA variables at follow-up with posture and arm as fixed effects, participant ID and cluster ID as random effects, and the baseline value of each variable as a covariate. The Sidak all data . Data wiect size . The magect size . Adherenect size , which cof Cohen  and Hopkof Cohen .This pilot cluster-randomized controlled trial will evaluate the efficacy of a tailored workplace intervention for reducing and breaking up sitting, productivity, wellbeing and cardiometabolic risk biomarkers. The multi-component intervention protocol was designed using a participatory approach informed by the BCW and identification of intervention functions, policy categories and BCTs using the APEASE criteria to enhance the intervention's adherence and effectiveness. In addition to employing this systematic and evidence-based process for developing the intervention, further strengths of this study include the cluster-randomized design to minimize contamination between groups that are located within the same organization. The study will also be conducted within an ecologically valid office environment, thus enhancing its real-world application. Ecological momentary assessment will be used to assess temporal effects of the intervention on productivity during specific postures and work activities; this may provide important evidence to encourage changes in workplace policy and practice. Potential limitations include sample representativeness of the general office worker population as the study is being conducted only within two organizations. It will also not be possible to determine the effects of each individual strategy used as part of the intervention, which could help in determining their suitability for inclusion in occupational health promotion programmes. Furthermore, physical activity levels prior to taking blood samples will not be standardized. This may be a limitation as there is the potential for carryover effects of prior exercise on glucose and lipid levels.In conclusion, this study will provide important evidence regarding the efficacy of a systematically developed tailored workplace intervention. This will include evaluating the effects of the intervention on a range of health and work-related outcomes, including an ecological momentary assessment of productivity that has been seldom employed in office workplace studies; this may be key in promoting the adoption and implementation of such interventions in workplace practice and policies. The findings of this study can be used to inform a future fully powered RCT to determine the effectiveness of this multi-component intervention for reducing sitting and improving health in office workers.The studies involving human participants were reviewed and approved by the University of Bedfordshire Institute for Health Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.SO contributed to the concept, development of intervention, and drafting the manuscript. DB, DH, and AC contributed to the concept, development of intervention, and manuscript review. All authors reviewed 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.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.


Background: Over the past 20 years, there have been many innovations in orthodontic diagnosis and therapy. Among the innovations, there is the taking of dental impressions (DIs). Dental impressions are the negative imprint of hard and soft tissues of one or both arches, and they allow a plaster model to be formed, i.e., a positive reproduction. Traditional dental impressions can be made of different materials, such as alginate, while digital impression is captured by an intra-oral scanner. Digital impression, despite the evident advantages, has not yet replaced the conventional impression. The aim of this study is to evaluate which dental impressions are the most used by dentists. For this purpose, we considered 120 questionnaires sent electronically to patients of different dental private practices from different countries, where the dentists can use both techniques. The results highlighted that the kind of impression adopted is very much influenced by the type of therapy and orthodontic devices used in the treatment. We can conclude that, despite the advent of digital technology, conventional impressions are still used for fixed devices, while digital impressions are more adopted for orthodontic customized devices and therapies with clear aligners, that are very widespread among adult patients. Conventional impression techniques allow an imprint of dental arches to be obtained to form a plaster model. Depending on the impression to be taken, traditional techniques involve the use of one or more impression materials with metal or plastic trays. Clinicians can use different materials with different properties: some materials, such as polyethers and polyvinyl siloxanes, can reproduce the anatomical details of the oral cavity more precisely than others. In the conventional impression method, the tray is filled with a soft paste and inserted into the patient’s mouth, where it is then held in that position until the paste itself has completely hardened, which takes a few minutes .Nowadays, thanks to the improvement in dental materials and the advent of technology, new techniques, such as digital impression, have also been developed.The digital dental impression (DI) occurs thanks to the new scanner technology. The intraoral scanner is a three-dimensional 3D) device capable of detecting dental impressions, first through the acquisition of a large number of images and, then, subsequent processing using dedicated software ,3. One oD device Digital dental impression is detected thanks to the use of scanners. Scanners are digital intraoral imaging devices and consist of data acquisition systems of the tooth surface in three dimensions. They enable an almost completely digital workflow and, in many cases, have replaced the need to take impressions with alginate and then develop the plaster models . All theThe purpose of this study is to evaluate how much digital impressions are used in orthodontics and for which types of appliances.An anonymous questionnaire available in two languages, English and Italian, was diffused between patients of different dental practices and from different countries electronically; 120 answers were considered. The survey was composed of questions made originally for this study using a Google form  and proposed to patients. All collected data were anonymous; all participants provided informed consent and accepted the privacy policy for the protection of personal data before completing the survey. The questionnaire was administered by an online form service . There were no reminders sent to patients, to let them feel free to answer. It was specified that the purpose of the questionnaire was to find ways for clinicians to improve their methods of curing patients [-Demographic data;-Level of education;-If they had an orthodontic therapy in the last two years and if it is finished;-The kind of treatment, if fixed or clear aligners;-The type of DI they had;-The times of DI taking;-The level of annoyance determined by the two types of techniques;-The grade of satisfaction determined by the orthodontic therapy;-The perception of the costs.The questions concerned:We performed chi-square and Fisher Test for dichotomous variables; age was tested for normality, and Kruskal–Wallis, for multiple groups, was performed to analyze aligner therapies and age groups. Clear aligners were approached using the Student t test for independent samples.We enrolled 120 responders, whose demographic characteristics are summarized in p < 0.001 OR: 2.44 IC:1.5–3.9)The choice of impression is correlated with the type of oral device: excluding those who did not take any impression or those who took an impression both ways, those who underwent traditional impression were more prone to use fixed devices, while digital impressions were more correlated with clear aligners  followed by those who underwent none (8.5), only digital (7.8) or only traditional (6.9).p < 0.05), while aligners were more used in older patients (34.0 ± 7.2) and fixed therapy in the younger ones , while kind of impression chosen seems not to be relevant , developed over 30 years ago at the University of Zurich. Subsequently, various intraoral scanning systems were developed, such as the iTero , the True Definition , the PlanScan , the CS 3500 , the TRIOS  and CEREC AC Omnicam .Despite the fact that nowadays dentistry is increasingly digitized and avant-garde, still the use of DI is not widespread and many dentists are still reluctant to replace the conventional impression technique with the new digital technology. The reasons for this are the high cost of the device and the need to learn how to use it, the operator must acquire a certain manual ability because the tongue, the saliva and hypertonic frenula can hinder impression taking . For theOur study underlines that although technology is now present in many aspects of orthodontics, not all dentists use digital impressions. The DI is widespread mainly in the field of invisible orthodontics, that is, among the orthodontic branches, the one that now needs the scanner and digital impressions, considering the companies that produce aligners promote the use of DI, unlike dental technicians that do not have laboratories that are able to acquire digital data . The useMoreover, it is evident that aligners are more requested by adult patients for aesthetic reasons . In thisOne of the main problems with the digital impression is the high cost which, as the results of this study highlight, determines a major expense for both the clinician and the patient. However, different scientific articles have demonstrated the efficacy of the intraoral scanner in other branches of dentistry, as well: according to Takeuchi et al., the direct and indirect restorations produced using a DI exhibited an acceptable marginal adaptation . The difLimitations of the study: All the limits of an anonymous questionnaire were taken into consideration. The questionnaire was compiled specifically for this study and, because of the contingency of the COVID-19 pandemic waves, pre-testing was not a viable option. One of the problems of the study is the possibility of misunderstanding the questions and, consequently, giving wrong answers. Moreover, another limit of this study is the major prevalence of females over males in the sample. Another limitation of the study is the relative small sample size, which limits the study’s power to adequately assess the several confounding factors involved, such as the geographical area or the occupational field, and their potential interactions. Moreover, the distribution of the cases within the various subgroups is not even, resulting in several subgroups with very limited representation. Therefore, the current findings regarding the contribution of these factors to the outcomes need to be treated with caution. Furthermore, most of the sample is composed of patients with a high level of education.It is right to say that, despite the fact that technology has long since entered into dentistry, and even more so in the last two years, the digital impression has not replaced the traditional one. This could be caused by several factors: first, the high cost of the intraoral scanner and, second, the learning curve required to be capable of using it, in particular for elder dentists. This study confirms that, in the orthodontic field, this new way takeoff taking impressions is mainly used in aligner therapy, considering the advantages of a digital workflow for dental technicians and companies producing these devices. More studies are certainly needed to compare the accuracy of traditional and digital impression so that the latter can also become much more widespread in the field of fixed orthodontics and prosthodontics.


During the pandemic, restrictive measures were implemented at Portuguese residential care facilities (PRCF), such as isolating residents and ceasing collective activities. It is important to understand how PRCF are implementing activities that allow residents to occupy their time and fight isolation. As such, we aim to analyze whether: 1. new activities were implemented for residents (identifying which were carried out); 2. occupation activities were provided to isolated residents in their rooms (identifying which were carried out); 3. the implementation of activities is associated with variables like the amount of staff. This is an exploratory, quantitative, and cross-sectional study. An online questionnaire was sent by email to 2325 PRCF and entities were asked to share it with their workers. The study was also divulged on social networks. Data collection occurred between July 8th and October 18th, 2020. The study had 784 staff members participating and 90.8% reported that new activities were implemented at their facilities, predominantly videocalls. Concerning isolated residents most respondents (64.4%) stated that providing activities was impossible. Results showed that those PRCF that expanded teams had a higher percentage of new activities and activities with residents isolated in bedrooms. These results are alarming because while residents should have had more resources to cope with the pandemic, higher risks of unoccupied time and isolation existed, a dramatic situation for its potentially harmful consequences. Focusing on sanitary issues (and less on older adults) may reinforce traditional care models that had shown negative impacts before the pandemic. This highlights the need to evolve the care paradigm during and beyond the pandemic at PRCF: with Person-Centered Care as an option. Portugal is the third country with the highest aging rate in Europe PORDATA,  and therLudic/occupational activities consist of diversified dynamic processes  of participation, which should be significant to the person, maintain a certain structure and infer the stimulation of various dimensions. The participation of OA in ludic/occupation activities promoted at residential care facilities has proven benefits as it allows them to occupy and structure their time where they live, allows them to fight isolation, facilitates personal development, and optimizes physical, cognitive, emotional and social functionality —declared in March 2020 by the World Health Organization , with their daily activities being reorganized and their collective ludic activities terminated. These factors lead to the risk of changing daily routines, limiting daily experiences, reducing the opportunity to enjoy the benefits of participating in activities, a lack of stimulation and personal interaction, which can enhance isolation and unoccupied time. Several studies report on the negative effects that the mitigation measures had on OA, on a physical and mental health level  with an addendum authorized on July 21st, 2020 for the study “Pandemia Covid-19 e cuidados em Estruturas Residenciais para Pessoas Idosas”.The study addressed the staff members employed at Portuguese residential care facilities. Participants’ inclusion criteria included having worked at the organization during the first lockdown (March/April 2020), having worked at the organization since at least January 2020 (3 months before the pandemic), and accepting the commitment to participate in the study. No exclusion criteria were considered.N = 2250) and the Islands (N = 75) were contacted. The contact database included: all contacts present in the Carta Social  and all contacts obtained through the Social Security Institutes (for the Azores and Madeira) and/or through the official online pages of social institutions (available in Google Maps listing). This process comprised sending 2325 emails. In addition, the researchers used the social networks pages (namely Facebook) of their universities, research units, and personal, to disseminate the study and involve more participants. The contact with residential care facilities included a description of the project, objectives, the link to access the questionnaire in Google Forms, and a request to share the link with the institutions’ staff members . The link contained an informed consent with the context of the study, objectives, voluntariness, guarantee of confidentiality and the availability of an investigation team member for contact and clarification.In order to promote a global data collection, all of the residential care facilities in mainland Portugal  and dispersion (standard deviation [sd] or interquartile range [IQR]) or absolute and relative frequencies. Additionally, the frequencies of new activities and also activities with residents isolated in their bedrooms were obtained. Chi-Square tests were performed to evaluate the association between activities (i.e. new activities and occupation activities for residents isolated in their bedrooms) and the existence of Covid-19 cases in the institution, the type of residential care facilities and the number of staff members. Statistical analysis was performed using IBM SPSS Statistics 26 and a significance level of 0.05 was considered.n = 727). In terms of educational level, 82.1% (n = 644) of the sample had more than 13 years of formal education. The main respondents of the questionnaire were technical directors , direct care providers  and nurses  and the median time of work in the area of OA care was 108.00 months (IQR = 129.00 months). The majority of staff members  reported working in Private Institutions of Social Solidarity (non-profit organizations formed exclusively through the initiative of entities), and the number of users ranged between 4 and 154 users. Responses were obtained from staff members working at institutions from all health regions of mainland Portugal and the islands (according to the division adopted by the DGS).The characteristics of the study sample (N = 784) are shown in Table n = 403) of the sample indicated that this number was maintained, 28.4% (n = 223) of the sample reported that there were fewer staff members providing direct care during the pandemic and 19.8% (n = 155) reported that the number of staff members increased.Comparing the number of staff members providing direct care before and during the pandemic at the institutions where participants worked, 51.4% (n = 712) of respondents reported that new activities were implemented for residents, mostly videocalls  (Table Approximately 91% n = 71 of respon = 149) than those that decreased  or maintained  the number of staff members  reported that it was not possible to provide activities that allowed them to occupy their time. In cases where it was possible , the most dynamic activities were entertainment  and cognitive stimulation   than the Private Social Solidarity Institutions . There is also a statistically significant association between the implementation of activities with residents isolated in their bedrooms and the number of staff members providing care during the pandemic. The residential care facilities that increased the number of staff members had a higher percentage of activities with these residents  than those that decreased  or maintained  the number of staff members , this practice seems to have been a panacea, that is, a transversal solution that residential care facilities found to fill the gap left by the isolation and a lack of visitation. These results are coherent with the study by Naudé et al. , which stitution .Recommendations from several authors and entities emphasize the importance of preventing any regression of abilities, as well as physical and mental health problems in OA during the pandemic crisis  in which they were collected. The asymmetrical development of the pandemic in the country means that residential care facilities had to manage the pandemic at different stages, which can influence the results. It is likely that staff members who volunteered to participate in this study were the least overburdened at the time of the research. Collecting data online may have made it difficult for more staff members to participate, especially those with low digital literacy/use, which could indicate that the sample is not representative. However, given the strict standards of infection control that prevented a one-to-one data collection and the use of printed questionnaires at residential care facilities, a remote online data collection was the only viable option.There’s still plenty to study concerning this pandemic context, and considering that videocalls were the main response presented by residential care facilities to this pandemic crisis in terms of implementing activities, it is important to further study the impact of videocalls on OA, their benefits and downsides. It is equally essential to understand how to enhance the effectiveness of this practice , as well as how it should be performed  in order to adapt to the characteristics, needs and rights of OA. Taking into account the alarming result obtained concerning the lack of activities for residents isolated in their bedrooms, future studies are necessary to understand how to fight their isolation and lack of activities, and how to promote the well-being and quality of life of residents at residential care facilities in fruitful ways during and beyond critical situations, such as the current one.In Portugal, residential care facilities assume a central role in providing formal care and support to OA. The promotion of ludic/occupation activities should be highlighted for its benefits and relevance in structuring time. The role of residential care facilities became even more prominent during the pandemic since residents depended mainly on what was provided by the facilities as they found themselves confined in their institutions, limited from free circulation, without ludic collective activities and without visitation (or severely adapted). The current pandemic crisis is an unprecedented situation that must be dealt with concomitantly and, considering that the Portuguese residential care facilities were already showing some pre-existing vulnerabilities, it became crucial to produce literature describing the way residential care facilities are dealing/have dealt with such demanding circumstances. Only then is it possible to gather information that may serve as the basis for informed decision-making, to support technical, political and scientific advancements, and to prepare recovery plans and care management models that are sustainable and protect the well-being, the quality of life and the dignity of residents.The results of this study are deeply alarming. Although the results point to the implementation of new activities for residents, these were mainly videocalls, which tend to occupy very little time, are not likely to be applied efficiently and privately with all OA, and have the potential to promote exclusion and expose the OA to the risk of rights violation. The results also indicate that in the majority of cases it was not possible to provide activities for residents isolated in their bedrooms, who required a reinforcement of options for occupying time and fighting isolation. While a better structure of time and access to strategies and resources to deal with the pandemic should have been provided, it is concluded that they were at risk of greater isolation and a lack of occupation activities, a dramatic situation due to its potentially harmful consequences.The overall results of this study, within the Portuguese context, lead to reflections concerning the negative impact of the pandemic on OA living at residential care facilities, about the emphasis onquantity of life , about loneliness, about digital illiteracy, social segmentation as well as the exposure to the risks of human rights violation. These are potential silent threats that can trigger a hidden pandemic with serious long-term effects. With pandemic-related measures, namely those related to ceasing/adapting activities, the maintenance of basic physical, mental and social abilities, which directly affect the quality of life and dignity of residents, is at risk. Therefore, similarly to the infection control measures, urgent measures are needed to promote meaningful, pleasant and rewarding activities at residential care facilities, allowing its residents to structure their time and fight isolation. The results of this study, related to the association between the amount of human resources and performing activities suggests the relevance of promoting resources at residential care facilities, namely by increasing the number of staff members and by developing their training on infectious-related issues and on promoting the mental health of the people they care for.Overall, the results seem to reflect the worsening of pre-pandemic vulnerabilities at the Portuguese residential care facilities, namely concerning the practice of a traditional care approach. The traditional care approach tends to focus on the illness and the service, and sees OA as a homogeneous group that passively receives care. This perspective fosters paternalism, standardized procedures, and task efficiency. With the pandemic, the focus on Covid-19 prevention (and less on OA as a whole) accentuates and legitimizes more standardized care practices that may reinforce the traditional care model that had shown signs of exhaustion and negative impacts on OA prior to the pandemic. Therefore, this study emphasizes the urgent need for an evolution of the care paradigm at Portuguese residential care facilities. Person-Centered Care is consequently proposed as an option for being currently recognized as the highest standard of quality in the care of OA (with positive repercussions on the well-being of both residents and caregivers).Person-Centered Care is based on respect for the rights and dignity of people in need of care, placing them at the center of attention. This approach privileges the person's role as an active decision-maker on the matters of their daily lives, respecting their psychosocial needs and potentialities. This also includes the opportunity to participate in meaningful activities that respect self-determination, individual risk acceptance, depends on the interests/desires of OA, and promotes their personal autonomy. Considering these principles, the pandemic crisis shows an even higher need for person-centered care in order to balance the risks and weigh the need for infection management against the respect for the rights, physical health, needs and well-being of OA, to overcome this crisis with the least possible impact while preserving their dignity and quality of life.While the pandemic context represents a threat due to the very serious (and long-term) consequences it causes to OA living at residential care facilities, it also forces these organizations to adapt. Therefore, the current crisis is an opportunity for change, as it creates a chance to reflect on quality care and the living conditions of residents at residential care facilities. It is therefore necessary to profoundly redefine priorities and scientifically and politically invest in Person-Centered Care during – and beyond – the pandemic.


New generation wearable devices allow for the development of interactive environments tailored for Virtual Reality (VR)– and Augmented Reality (AR)–based treatment of Autism Spectrum Disorders (ASD). Experts agree on their potential; however, there is lack of consensus on how to perform trials and the need arises for evaluation frameworks, methods, and techniques appropriate for the ASD population. In this paper, we report on a study conducted with high-functioning ASD people in the 21–23 age range, with the objectives of (1) evaluating the engagement of two headsets offering distinct immersive experiences, (2) reasoning on the interpretation of engagement factors in the case of ASD people, and (3) translating results into general guidelines for the development of VR/AR-based ASD treatment. To this aim, we (1) designed two engagement evaluation frameworks based on behavioral observation measures, (2) set up two packages of reference immersive scenarios, (3) defined the association between metrics and scenarios, and (4) administered the scenarios in distinct sessions for the investigated headsets. Results show that the immersive experiences are engaging and that the apparent lack of success of some evaluation factors can become potential advantages within the framework of VR/AR-based ASD treatment design. Autism Spectrum Disorders (ASDs) are characterized by fixated and repetitive patterns of behaviors, restricted interests, and social/communication deficit ,2, severThough the causes of autism remain largely unknown, there is consolidated evidenc on the involvement of genetic, neurodevelopmental, and environmental factors. In particular, deficit in social cognition and its components such as Theory of Mind  is specifically reported in persons with autism ,8,9. GivNotwithstanding the difficulty in predicting which particular intervention approach works best with which ASD individual , startinThe continuous advances in computer graphics and input devices , as well as the ample variety of (affordable) devices offering “synthetic experiences” at various levels of immersion, visual and interactive fidelity, and refresh rates have been fostering the investigation on the use of Virtual Reality (VR), Mixed Reality (MR), and Augmented Reality (AR) tools in a variety of ASD applications, such as neurocognitive assessment, psychotherapy, rehabilitation, prevention and treatment of eating disorder, pain management, social skills training, vocational readiness training, and communication training . ComputBlascovich  defines augmented-reality (when “see-through” displays augment the world surrounding the observer with simulated cues) or based on virtual-reality , which in turn can be either monitor-based or (at some degree) immersive (thanks to Head-Mounted Displays (HMD) or CAVE environments). It must be said that most proposals are conventional monitor-based applications: the survey in , Medium = v ∈ [34–66%], High = v ∈ [67–100%], where the meaning of v depends on the particular metrics of the evaluation framework. Specifically, for the autonomy in managing the devices group, we determined the number of times an ASD student asked for support with respect to the mean of this measure on Typical Development (TD) people and the time spent for mounting the HMD with respect to the mean of this measure on TD people (the control group included five graduated and undergraduate students from Psychology and Computer Science courses in the same age range of study participants); for metrics in the comprehension group, v is the number of recognized elements with respect to the total requested by the activity; for metrics in the interaction ability group, v is the number of correct actions with respect to the total requested by the activity. The Low, Medium, and High values were then mapped onto a classical F (Failure), P  and S (Success) triad values (using an inverted philosophy in those cases where the fewer the better) and the success rate calculated as /Otot, where Stot is the number of occurrences of S, Ptot is the number of occurrences of P, and Otot is the total number of occurrences. Results are summarized in As to comprehension of VE features  is coherent with the need of initial training experienced also by typically developing people attending the lab; further investigation and studies on the medium or long term are needed to evaluate to what extent and with which learning rate practice may improve this scores; anyhow, the slight improvement from the first to the second session—despite the greater complexity of the Oculus interactive environments and the lower directness of the associated interaction modality—seems encouraging in this sense. The successful scores in autonomy in managing the device (particularly for the HoloLens) and in interaction ability open interesting opportunities and research lines for innovative interventions, as we will discuss further on.Possible fears on the cumbersomeness of HMDs seem to be overcome by our results both on acceptability and on the autonomy in managing the device. The partial success of Quantitative and qualitative data relating to behavioral observation were extracted from collected materials (notes and audio/video recording), according to the metrics/activity association defined in Factors in EF_I have been evaluated according to a customary [ustomary ,2,3,4,5 suspension of disbelief, below average for the HoloLens (0.58) and slightly above average for the Oculus (0.64), confirmed also by qualitative findings during the sessions, with participants reporting the perception of the distinction between the real and the virtual world. Consolidated studies on immersive environments would suggest it be regarded as a not so positive result . The average score of body participation  suggests that practice is needed to feel free to physically move during an immersive experience. We recall that in this case we evaluated the degree of coherent body reactions to what they were experiencing within the virtual environment . The difference between the scores in HoloLens (0.68) and Oculus (0.44) suggests that the cable connecting the Oculus Rift headset to the computer may have had an impeding role; we expect that better results would be achieved with the more recent cordless version of the Oculus . The average score of exploration  suggests that practice is needed also to feel free to virtually move. The lower score of the HoloLens (0.65) might be due to the fact that the HoloLens session took place in an unfamiliar setting with two unfamiliar persons from Microsoft giving support, which, for ASD people, might be intimidating . Additional experiments would be appropriate also to evaluate a possible interdependency between body participation and IVE voluntary exploration: to what extent the movement constraints in the physical world affected the sense of agency and control in the virtual world? , P  and S (Success) triad values and the success rate calculated as /Otot, where Stot is the number of occurrences of S, Ptot is the number of occurrences of P, and Otot is the total number of occurrences. These overall mean scores along with standard deviation are depicted in verbal reaction in the HoloLens session; again, this might be explained by the somewhat intimidating interaction with unfamiliar people from Microsoft. In addition, in the case of facial expression, the HoloLens score (0.7) is lower than in the Oculus session (0.9), while level of attention and emotional participation are not so different. As to facial expression, it has also to be observed that changes in the expression may be minimal in ASD persons: several studies demonstrate reduced facial expressiveness, or “flat affect” in ASD, compared to spontaneous expressiveness that occurs during natural interaction [eraction . Hence, Overall, according to EF_II, the engagement is to be judged high for both HMDs. This result appears to be in slight contrast with figures related to EF_I, that, for both HMDs, seem to rather suggest a medium degree of engagement  even when IVE-specific evaluation metrics seem to suggest a not optimal level of engagement?”) and stimulates reflections about the interpretation we must give to the scores of EF_I metrics in case of ASD people. Is the higher still the better? Or, as asked by RQ2: can the lack of success in any IVE-specific evaluation metrics turn out to be potentially useful within the framework of IVE-based ASD treatment design? We analyze this issue in the Discussion.This disagreement between the overall scores of two sets of engagement factors, consistent in both HMDs, provides a positive answer to RQ1  in a group of five young adults with high-functioning ASD, as well as the efficacy of the selected metrics for the measurement of the engagement. In a broader perspective, the aim of our study is to provide indications on the potential use of IVE-based treatment in ASD. In recent years, there has been a growing interest in the use of VR/MR technologies in clinical and educational contexts for autism, demonstrating how the use of ICT-based devices are more engaging, attractive and motivating for people with ASD ,119,120.autonomy in device management, understanding of IVE characteristics and interaction abilities, we note differences between the two devices. Specifically, the HoloLens session seems to have favored greater autonomy in device handling than the Oculus session. On the other hand, the interaction ability seems to be better during the Oculus session. In any case, an initial training session seems to be necessary to ensure greater autonomy, as demonstrated by the partial success in understanding the features and functionality of IVEs.Our results support the accessibility of both devices experimented by all participants. These findings are in line with recent literature suggesting that VR tools are widely accepted and appreciated among individuals with ASD ,121,122.Emotional participation in images and suspension of disbelief are maybe the most interesting results, somewhat deviating from what is expected in TD people, but for this reason providing useful suggestions, as to content issues, nature of applications, and ASD-specific interventions, as discussed in the following.Interesting results come from the analysis of engagement factors. Since according to EF_II the engagement is evaluated as definitely high, one would expect to detect high values also in the IVE specific evaluation factors, for which, in TD people, “the higher the better”. Conversely, values achieved in both HMDs show a clear discrepancy, reaching a medium level. photorealism is generally suggested to play a critical role in the achievement of engagement , the high flexibility of the two investigated HMDs and their high degree of “reproduction fidelity” . Indeed, we achieved almost the same score for emotional participation in photorealistic and non-photorealistic scenarios in the Oculus session (which offered both cases). This result may be due to the fact that ASD people become easily distracted by irrelevant details of a scene and feel more comfortable in facing simplified reality and/or to the fact that, due to their perceptual difficulties, they do not perceive the scene in the same way as TD people, as observed also by . The comIt has been suggested that the main feature of electronic screen media which renders them ideal for the delivery of information to ASD people is the relatively constrained screen viewing area limiting the attentional frame and helping those with ASD to focus their attention on relevant stimuli while ignoring irrelevant ones ,125,126.Regarding the suspension of disbelief, generally considered a key aspect in interacting with IVEs , the parVirtual reality environments can be a powerful training tool, as they provide safe and controlled environments in which scenarios that the person in real-life experiences as anxiety-provoking are proposed. One of the fundamental advantages of using of VR in treatments is that of being able to include objects and/or situations that are difficult to find/use in the real environment and to control the complexity of the required social interaction so to make the simulation gradually evolve towards its real-life counterpart. For example, researchers ,42,131 hAugmented reality as well may be beneficial as to anxiety reduction: we believe that the low scores obtained during the Hololens session with regard to the suspension of disbelief, combined with more autonomy in managing the device and good score in the exploration and action aspects is an advantage for its potential use as a prosthetic tool capable of enriching the real world with familiar objects and making it less scaryIn our study, we also considered more qualitative involvement factors (EF_II) that can be interpreted as indicators of both cognitive and emotional involvement. Our results show that the activities proposed in the IVEs are able to capture the participants’ interest in the specific activity, especially during the Oculus session, showing positive scores in terms of facial expressiveness, focused attention, emotional participation, and verbal reactions. It is worth emphasizing that the factors analyzed represent aspects that are often impaired in autism compared to individuals with typical development; therefore, the results obtained provide further confirmation of the effective engagement capacity of immersive experiences in ASD. A prerequisite for effective learning is to capture attention and motivate the individual to continue the activity. During the experiments, our participants demonstrated active engagement, indicated by verbal reactions with frequent questions about the frameworks and technical specifications of the activities, both during and after the sessions. This result also suggests that the proposed activities aroused a certain degree of curiosity associated with cognitive engagement, with good levels of focused attention to processing and understanding of the proposed activities. Promising results also seem to be those related to emotional engagement, with positive affective attitudes before and during the experimental sessions suggesting pleasure, enthusiasm and excitement for the activities. This may be regarded a surprising result considering that ASD persons may present resistance to change or to facing new situations .While results of this study reveal interesting findings and suggest promising research lines, some limitations are to be underlined . The first one is related to the length of the study and the consequent limited amount of exposure to HMDs and IVEs that the participants received; additional study is necessary to evaluate whether a longer exposure might yield different results. Another limitation is due to the possible bias deriving from the fact that all participants had been previously involved in TetaLab activities (though not related to immersive experiences); additional experiments with different high-functioning users in the same age range would be appropriate for a better generalization of results. Finally, an obvious limitation is given by the small size of the user sample; however, as observed in , even ifIn this paper, we presented the results of a study aimed at evaluating the engagement capability and the potential appropriateness of two HMDs with respect to technology-enhanced ASD treatment, as well as at investigating the indication provided by engagement evaluation metrics and their translation into guidelines for VR/AR-based ASD treatment design. We tried to pave the way towards the definition of methods and techniques overcoming recognized limitations of existing proposals as to assessment aspects in the ASD population: evaluation is typically based on self-reporting, no real consensus on which metrics to use does exist, generally adopted metrics are the ones conceived for typical development people, study participants are generally quite heterogenous, and most of the study are focused in children, leaving other ASD people under considered. All these weaknesses make the evaluation of VR/AR-based ASD treatment still an open problem. Differently from other studies, our study contributes to such open problem by: (1) considering a homogeneous users’ sample, (2) specifically focusing on a specific users’ population under considered in the literature while potentially highly open to the utilization of VR/AR technology, (3) conducting the evaluation according to behavioral observation, (4) reasoning on the contribution that metrics of a different nature may give to the evaluation in the case of ASD population, (5) reasoning on how partial failures of some metrics may be actually positively taken into account for the definition of the treatment. In particular, as to the last two points, engagement was investigated according to two sets of metrics (respectively focused on (1) factors specifically associated with the evaluation of IVE and (2) factors typically associated with the evaluation of engagement in generic situations, in order to determine whether—in the case of ASD people—the immersive experience can be anyhow engaging even when some IVE-specific evaluation metrics seem to suggest differently (RQ1) and whether the lack of success of some IVE-specific evaluation factor can actually become an advantage from the perspective of a treatment (RQ2). Throughout the paper, the working hypothesis, findings, and implications have been discussed, taking always into account related studies .The study provided positive answers to both research questions and our results suggest that the use of IVEs in ASD intervention settings is a promising approach that can increase the effectiveness of learning processes, eliminate environmental distractions, and promote the maintenance of concentration, in part through the structuring of predictable and simple environments experienced as less stressful, thus confirming the results of previous studies ,121. In We are currently working on these two complementary directions within the framework of a project financed with public funds. VR/AR-based interventions and treatment are being defined as bridges to the real world, according to design choices taking into account ASD people’s strong visual memory , visuospAs a final consideration, we observe that ASD impacts an individual’s development and adaptation across their lifespan, and the typical symptomatology of the condition causes significant distress in daily life, even in the presence of adequate cognitive functioning. VR/AR-based interventions can have a strong social and economic impact by improving activities necessary for independent living, such as communication and social skills, as well as community and adaptive skills  and employability. Complete autonomy and integration into the community often remain a challenge even for people with high-functioning ASD (such as in the case of the users’ population considered in our study); providing effective solutions can really improve the quality of life for people with autism and their families.


Metastatic melanoma (MM) is a pathological entity with a very poor prognosis that, until a few decades ago, had a low response rate to systemic treatments. Fortunately, in the last few years, new therapies for metastatic melanoma have emerged. Currently, targeted therapy and immunotherapy are the mainstays of the therapeutic arsenal available for patients with unresectable or metastatic melanoma. However, both clinical evolution and drug efficacy in melanoma patients are very different depending on the stage at which it is diagnosed. In fact, the aggressiveness of melanoma is different depending on whether it debuts directly as metastatic disease or if what occurs is a relapse after a first diagnosis at an early stage, although the biological determinants are largely unknown. Another key aspect in the clinical management of metastatic melanoma at first diagnosis strives in the different prognosis of melanoma of unknown primary (MUP) compared to melanoma of known primary (MPK). Understanding the mechanisms behind this, and the repercussion of implementing targeted and immune therapies in this specific form is crucial for designing diagnosis and treatment decision algorithms that optimize the current strategies. In this review article, we recapitulate the information available thus far regarding the epidemiology and response to immunotherapy treatments or targeted therapy in patients diagnosed with metastatic melanoma as a first diagnosis, with especial emphasis on the emerging specific information of the subpopulation formed by MUP patients. Despite representing 1% of skin tumors, melanoma represents 80% of skin cancer deaths , with diPreviously, many efforts have been made to understand patterns of disease progression, providing information on risks that have helped improve monitoring and the efficacy of new adjuvant treatments ,5,6,7,8.In the following review article, we have reviewed the epidemiology and molecular biology of MM as an initial diagnosis and have analyzed how it is currently managed in clinical trials and in the real world. This presentation of melanoma could have a special importance for the impact of current treatments. Therefore, we believe that this study holds particular utility for the delineation of effective therapeutic approaches that can impact the prognosis of the melanoma patients identified at this stage.Melanoma is a tumor with a low incidence rate, but high mortality. For 2022, the estimated number of new cases of melanoma in situ or invasive in the United States is 97,920 and 99,780, respectively, with an estimated number of deaths of 7650 patients. This indicates an annual decrease of 4%, due to recent improvements in treatments in both adjuvant and advanced disease treatments . This trSurvival rates according to initial disease stage have been extensively described in large cohorts of patients ,13,14,15As mentioned above, fortunately, most melanomas are diagnosed in the very early stages, providing a better prognosis for the disease, in global terms.Interestingly, a recent study presented epidemiological data on the incidence of cutaneous melanoma in Belgium and the Netherlands, using national cancer registries and analyzing different aspects, including stage. Although the incidence of melanoma was higher in the Netherlands than in Belgium, Belgium reported the highest incidence rate of stage IV disease at first diagnosis. Furthermore, this study not only showed different epidemiological aspects of the incidence, but also reported different survival rates. This reflects the difficulty of extrapolating information in this subgroup of patients, since it even appears difficult to explain these different incidences for biological issues in two neighboring countries .On the other hand, a form of presentation of MM at initial diagnosis that is of special interest is melanoma of unknown primary (MUP). Indeed, such diagnosis would be excluded in the following scenarios: (1) Patients who do not receive a complete physical examination ; (2) Patients with evidence of previous orbital enucleation; (3) Patients with surgical procedures without histological documentation; and (4) Patients with lymph node involvement and the presence of a scar in the area of skin drained by the lymphatic basin . AlthougIn recent years, melanoma has been extensively characterized on a molecular basis in several studies. In fact, the latest World Health Organization (WHO) classification establishes nine categories of different melanoma subtypes, depending on the different driver mutations presented . HoweverThe molecular characterization of patients with metastasis at presentation is not clear, nor is that of patients that present with MUP . A recenTherefore, the molecular characterization of patients with metastasis at the first diagnosis is not clearly defined. With these data, it would be difficult to explain whether patients presenting with stage IV at initial diagnosis have a cancer biology that is different from those diagnosed in earlier stages.To search for epidemiological data on how patients respond to different treatments depending on the initial stage at diagnosis, we reviewed published clinical trial information, as well as complementary material. The systematic search methodology is shown in the Currently, there are several studies that establish BRAF-targeted therapy as standard treatment for patients with metastatic melanoma who carry a BRAF mutation. The combinations vemurafenib-cobimetinib, dabrafenib-trametinib and encorafenib-binimetinib constitute the first line of treatment for patients with BRAF-mutated metastatic melanoma. The main characteristics of these studies are shown in The experience and knowledge accumulated over the last few years have elucidated that BRAF-mutated melanoma is a more aggressive tumor than BRAF wild-type melanoma, with greater growth rate and a greater capacity for metastasizing . TherefoFurthermore, new strategies with targeted therapy, such as triplet treatments that include targeted therapy and immunotherapy, may provide data on the clinical evolution and response to treatment in these MM patients. However, data on this subpopulation are thus far not available in these combination strategies trials such as the COMBI-i study, which combines spartalizumab with dabrafenib and trametinib, or the IMspire150 study that combines atezolizumab with vemurafenib and cobimetinib ,38.Similarly, MUP patients were included in the targeted therapy pivotal studies, although their outcomes were not reported. Therefore, the efficacy of these treatments in this subgroup of patients remains to be specified .The data from the pivotal studies with approved immunotherapeutic drugs that constitute the first line of treatment for metastatic melanoma are presented in Information on patients diagnosed with stage IV at debut is not reported in any of the studies. Other similar clinical trials and their updates did not specify this subpopulation in their study population either ,47,48,49Theoretically, it seems reasonable that immunotherapy may play an essential role in for the treatment of patients with MUP, given the implication of immunological mechanisms. However, there is no information regarding the MUP population reported in these studies.In addition, therapeutic strategies that combine immunotherapy with several other drugs are currently being developed. However, none of the new combinations such as pembrolizumab with lenvatinib in the LEAP-004 study , bempeglSimilar to the targeted therapy studies, MUP patients were included in the trials with approved immunotherapy, but specific outcomes were not shown .Although it features in later lines of treatment, chemotherapy continues to be a therapeutic weapon for the treatment of metastatic melanoma. However, the development of this therapeutic strategy has been relegated to a less important priority. In the latest clinical trials reported using chemotherapy-based schemes, the population was described based on the initial stage at diagnosis, so we do not know whether this population would respond to these treatments, based on that variable ,53,54.Since clinical trials did not report data on which we could draw conclusions, our group investigated real-world data.New York University (NYU) recently published a study on their experience with the new systemic treatments for MM. In this article, Utter et al. show the data of patients treated with ICI or TT for MUP at their institution, comparing them with the patients of this subpopulation reported in the literature. Both subgroups were compared with reported MKP patients. MUP patients treated at NYU had better outcomes with ICI but worse with TT than the reported MUP patients in the literature. However, NYU MUP patients had worse outcomes than MKP patients in clinical trials. In the ICI subgroup, most patients were treated with anti-CTLA-4 , which cSubsequently, a German group published their experience with MUP patients treated with anti-PD1 . AlthougA retrospective study was also recently published in which the particularities of MUP patients of an Italian center are described. This study analyzed the characteristics and the different therapeutic modalities established in 127 patients, comparing them with MPK patients. No differences were found between the survival rates of patients treated with immunotherapy or with targeted therapy . DespiteThere are many retrospective real-life studies on the efficacy and safety of drugs in patients diagnosed with unresectable stage III or stage IV melanoma. However, with the initial diagnosis of stage IV at onset, it is not so frequent, and it is necessary to investigate the analysis of subpopulations in previous studies. In this sense, in 2012, a multicenter longitudinal retrospective study of several European countries—the MELODY study—was presented on treatment patterns and outcomes among patients in this population ,59. ThisThis study, which is prior to the establishment of immunotherapy and targeted therapy, reports information on OS in patients with a diagnosis of advanced disease at any time but does not report more information on patients diagnosed at their first diagnosis.In 2016, a prospective and retrospective observational study was reported on the epidemiology of patients with metastatic melanoma in the province of Ontario (Canada) . In thisA recent study, reported by Zhou et al. on data from the Netherlands Cancer Registry (NCR), provides the data that 60% of deaths from metastatic melanoma are due to debut with extended disease. In this study, the characteristics of patients with early stages that progress to metastatic melanoma are analyzed, although they do not provide data on those initially diagnosed with stage IV melanoma, except that they constitute 13.8% of all stages IV 223/1613) [3 [61].Finally, in ESMO 2021, data from a registry of the Spanish Melanoma Group (GEM) were reported. However, only patient data at the time of study inclusion were shown .Our review article highlights the absence of publications on this advanced disease subpopulation at first diagnosis in all of the pivotal studies that led to the achievement of approval of current drugs for patients with metastatic melanoma. We believe that the scant evidence shown could be biasing therapeutic decisions about the treatment of unresectable or metastatic melanoma. Most of the identified studies show bias in terms of the fact that they correspond to a period where diagnosis and treatment do not correspond to current management.Currently, the biological and clinical aspects that may occur between metastatic melanoma diagnosed at first diagnosis or as an early stage recurrence are unknown. MM at initial diagnosis is a more aggressive entity than when melanoma is initially resected at an early stage and recurs over time. In addition, we know that MUP is a form of presentation of MM at first diagnosis, with better prognosis than MKP. Despite being an entity with a different prognosis, no information is available on the efficacy of targeted therapy and immunotherapy treatments. In most cases, the time of the diagnosis of stage IV is not specified, so more data are needed to shed light on this clinical situation that we find in daily medical practice.


As a result of the COVID-19 pandemic, telemedicine has become an important branch of healthcare worldwide. Apart from their undeniable advantages, the virtual visits lack physical examination, which can lead to important diagnostic mistakes. We hereby present a case of a pediatric patient whose weight gain, initially attributed to a sedentary lifestyle was, in fact, due to sub-acute right heart failure in the context of a ruptured sinus of Valsalva aneurysm. The condition was not diagnosed until the patient presented at the emergency. The boy was successfully treated with two percutaneous interventions and returned to his previous stature. The COVID-19 pandemic that has been overwhelming the world for the last 2 years, has led to substantial transformation of healthcare system. In order to reduce the epidemiological risk, a great part of medical appointments has been replaced by virtual visits. This solution has multiple benefits including cost-efficiency, convenience and versatility, however, lack of personal contact with the patient poses a risk of inappropriate assessment of their actual state (Z score = 3.74) with a 15 × 15 mm protuberance at the right sinus of Valsalva. His scheduled follow-up had been postponed due to the COVID-19 pandemic, however his mother's opinion was that his overall condition remained stable, and they did not require any medical help. The only change reported by the family was a gradual increase in the patient's body mass, which was attributed to the COVID-19 lockdown. Indeed, the boy, who was previously overweight, had reduced his daily activity following the introduction of online education in the country. However, when his legs became edematous, his mother brought him into the emergency department. On account of the patient's cardiological comorbidities and symptoms suggesting heart failure, he was transferred to the department of pediatric cardiology.An 11-year-old boy with autism and severe amblyopia presented to the emergency department with dyspnea, peripheral edema, and a decline in exercise tolerance. The patient was under the care of a pediatric cardiologist due to coarctation of the aorta, which was operated on in infancy, and a bicuspid aortic valve without significant dysfunction. Eighteen months prior to presentation, during routine follow-up in the department of pediatric cardiology, a computed tomography angiography (CTA) had been performed. This had revealed good long-term results of his aortic arch plasty, and dilatation of the aortic root  and was found to have sinus tachycardia up to 130 bpm, massive edema of the lower limbs and an increased waist circumference. His vital signs and basic laboratory results are summarized in vena cava diameter and normal flow parameters through the right heart chambers. On the 2nd postoperative day the patient was discharged home. Throughout the hospital course, his body mass reduced by 17 kg as a result of diuretic therapy.The patient was admitted to hospital and treated with diuretics and antihypertensives. This resulted in a 7 kg decrease in weight, together with a reduction in edema and tachycardia. On account of infrequent character of patient's condition, an interdisciplinary case conference was held, in which percutaneous closure of the shunt was chosen as a potentially less invasive treatment strategy for a patient with multiple comorbidities. On the 4th day of hospitalization, a cardiac catheterization was performed  under geSystematic monitoring of body weight is an important element of routine follow-up of patients with cardiovascular conditions , includiOur patient experienced SVA rupture at a relatively young age, and although he may require a cardiosurgical operation for his aortic valve and reconstructed arch in the future, management of his ruptured SVA using a transcatheter approach appeared beneficial in his case. Interestingly, the patient received two devices at two separate attempts, which is not a classic approach. Spontaneous closure of residual leaks is a commonly observed phenomenon in percutaneous interventions , howeverRegular follow-up of patients with congenital heart disease should always include physical examination. Lack of this important element can cause a delay in making the right diagnosis and starting therapy Percutaneous closure is a promising treatment methodology for pediatric patients with ruptured SVA as it can postpone or even replace surgical intervention.The original contributions presented in the study are included in the article/Written informed consent was obtained from the participant's parents/legal guardians for the publication of this case report.PL, AS, and RS contributed to conception and design of the study. PL and AS organized the database and wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, 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.


The reduction in the risk of transfusion-transmissible infections (including HIV infection) is an essential part of transfusion patient care. Here, we report the first incident of HIV transmission via transfusion in north Serbia due to blood donor dishonesty, and the failure of the laboratory screen tests to detect the presence of HIV particles in his blood. Infected blood products were distributed to two recipients, and HIV infection was confirmed in one. This incident finally led to the implementation of Nucleic Acid Amplification Technology as mandatory testing of blood donors for HIV infection in Serbia and raised many questions related to the responsibility and ethics of all the participants in the blood transfusion supply chain. There is a need for the implementation of modern and non-discriminative laws in Serbia in order to reduce transfusion-transmissible infections. In addition, transfusion institutes in Serbia need to be obliged to pursue the constant upgrade of their diagnostic capacities in order to prevent similar incidents and to provide the best possible care for blood donation recipients. Transfusion-transmissible infection (TTI) risk reduction is an essential part of transfusion patient care. The adequate selection of blood donors (BDs) can reduce the risk of TTI up to 90% . For thaThe first transmission of HIV through blood transfusion in Serbia was documented in 1985, before HIV infection screening was implemented. After that incident, a questionnaire for BDs was introduced, which included questions related to HIV-acquiring risk behavior. The system was supposed to work solely by relying on BD ethics as he/she guaranteed the truthfulness of the answers only by signing the questionnaire.Today, Serbian National Regulations for blood donations require that BDs under risk of having TTIs are identified and excluded by the combined implementation of pre-donation selection (questionnaire), medical evaluation, and blood qualification (laboratory testing). As result of the efficient implementation of preventive measures, TTIs in Serbia rarely occur, given that more than 250,000 blood donations are collected annually. Mandatory screening of BDs for HIV exposure started in 1987, while the NAT technology was introduced almost 40 years later , after two HIV-related incidents. The first one occurred in 2002 due to laboratory staff error, where an HIV-positive donation was administered to two patients (data not published), while the second one is described and analyzed in this paper.Here, we are reporting on HIV transmission via blood transfusion after the failure of a screen test to detect HIV infection in a BD who provided a false statement. We discuss the matter of responsibility and ethics of the participants in the transfusion supply chain, with a review of similar incidents worldwide.In July 2017, a thirty-year-old blood donor reported to the Blood Transfusion Institute of Vojvodina (BTIV) wishing to donate his blood. After the passing of several screening phases, he was accepted as a BD, only for it to be confirmed a few months later that he was HIV-positive (during the second visit to the BTIV). All the procedures related to this case are described according to the sequence of implementation.When BD candidates arrive at the BTIV, they provide general information and fill in the BD questionnaire . After tAll BD candidates are required to pass a medical examination and give responses to confidential questions related to their health and lifestyle. The purpose of the anamnestic data is to indicate the existence of possible infection/disease, TTI-related risk behavior, or TTI-related habits not specified in the BD questionnaire. In the case of any positive finding, the BD candidate is excluded from further procedures. The physical examination was focused on parameters such as blood pressure, heart rate, body mass, and body temperature, after which heart and lung auscultation and oral cavity and throat examination were performed. Finally, the existence of enlarged abdominal organs  or lymph glands was checked by a medical doctor via palpation. In this case, the HIV-positive BD passed all the physical exams and did not reveal any excluding information in his anamnesis. During this procedure, the candidate was informed that BDs in Serbia do not receive any financial compensation for their donation.BD candidates who pass the medical examination are subjected to screening for several TTI markers. In the case of any positive finding, the BD candidate is excluded from further procedures. For the detection of HIV particles via enzyme-linked immunosorbent assay (ELISA), 6 mL of blood is collected in a vial with K2EDTA . ELISA was performed on an EVOLIS analyzer using a Genscreen Ultra HIV Ag-Ab commercial assay .Additionally, 5 mL of blood was collected in an SST Advance vial  for the detection of anti-HBc, anti-HCV, and anti-Treponema pallidum IgG. Serology screening was performed via the EVOLIS analyzer using the following commercial assays: Monolisa HBs Ag Ultra (Cat No. 72348), Monolisa HCV Ag-Ab Ultra V2 (Cat. No. 72562), and Syphilis Total Ab (Cat. No. 72531). All the assays were produced by BioRad Laboratories . The HIV-positive BD described in this case was negative in all the screening tests and was therefore accepted for blood donation.ABO and RhD blood type are determined in all persons finally accepted as BDs. For that purpose, 3 mL of blood was collected in a vial with K2EDTA  and analyzed via the Gel card technique using a DiaClon ABO/D+ Reverse Grouping and ABD-Confirmation assay . The HIV-positive BD described here had blood type A RhD+.Finally, 450 mL of blood was collected from the described subject in a quadruple bag containing 63 mL of citrate-phosphate-dextrose adenine anticoagulant with a sampling system  placed on Biomixer-323 . The donation process lasted 7 min, during which time the subject was constantly observed by a medical technician. No adverse reactions were recorded during or after the donation. The blood unit was finally validated for use according to the ISBT 128 Standard, while the plasma sample was archived at −80 °C, according to the BTIV standard operating procedures.Three months later, the same person reported again to the BTIV wanting to donate blood for a second time. Following the same procedure as described previously, the person passed the questionnaire, as well as the medical exam, before his blood was screened for TTI markers. At this point, ELISA yielded a positive result for HIV infection. The result was confirmed on an Abbott Architect i2000sr analyzer using the Abbott Architect HIV I/II Ag/Ab Combo kit . The BD was informed of a possible HIV infection and was permanently excluded from making further blood donations. Simultaneously, the case of a possible HIV infection was reported to the local Center for Disease Control and Prevention.An investigation was initiated due to the possibility that the subject was in the window period of HIV infection at the time of the first blood donation in 2017. The archived plasma sample from the first donation was forwarded to the Laboratory for Viral Diagnostics  where the presence of HIV RNA was confirmed via an Abbott m2000sp Molecular Real-time PCR using the HIV-1 kit . More precisely, the HIV RNA load during the time of the first blood donation was determined to be 22,836 copies/mL.During the interview, the BD admitted that he had had sexual intercourse with other men (MSM) without the use of a condom. The identification of other components in the HIV infection chain was impossible as the BD stated that the intercourse was anonymous, and therefore, he was not able to recall the identities of his sexual partners. Additionally, he confirmed that he had purposely given a false statement on the BD questionnaire in relation to TTI-related risk activities. The BD was finally referred to the HIV Counselling Centre in the local Public Health Institute and Clinic for Infectious Diseases for further diagnostic and treatment procedures.Further investigation revealed that components of HIV-infected blood were administered to two patients. The first patient received a platelet concentrate prepared from the HIV-positive blood donation, due to a diagnosis of systemic sepsis. The patient died shortly afterwards, and further investigation was suspended.The second patient received suspended red blood cells from the HIV-positive blood donation as a part of the treatment for the underlying disease at the Institute of Oncology of Sremska Kamenica. A blood sample was acquired from the receiving patient, and HIV infection was detected via Siemens Advia Centaur HIV I/II Ag/Ab Combo Assay and confirmed via Inno-Lia HIV I/II Score Western Blot . The test results were announced to the immediate family as the patient had died in the meantime from the underlying malignant disease.The described case of HIV transmission opened up many questions of an ethical and professional nature. The first question is whether the aforementioned HIV transmission would have occurred if NAT had already been implemented. If we consider 50 copies/mL as a minimum level of detection  and thatIt is important to highlight that the implementation of NAT for TTI screening in the first place was a response to a similar question raised in a German newspaper article published in 1993 . The exiMandatory screening with NAT for HIV was later introduced in the United States, Austria, and Japan, and in the following years, it was gradually implemented in other countries around the world . It was Despite efforts to prevent the occurrence of TTI by NAT screening, the cases of HIV transmission by blood transfusion still occur worldwide. Two cases of HIV transmission were reported in 2017 in the USA , while aTh sensitivity and specificity of NAT in the preseroconversion infectious window period for HIV vary between the laboratories, depending on the NAT system and the protocol in use, as well as the HIV infection prevalence in the local population ,14,15. TIn response, to protect the integrity of the BD community and prevent TTIs, the Food and Drug Agency recommended screening criteria for potential BDs in the United States and raised ethical, moral, and scientific debates . These sIn some countries, the BD dishonesty remains the only factor that is not placed under legislative control; so, the integrity of the BD community and the blood donation recipients can be legally protected. The problem of dishonesty or misleading answers in BDs is present worldwide, given that 30% of HIV-positive BDs in Italy  and 50% Intentional HIV transmission is considered to be a criminal act in many countries. The USA was the first country in the world to introduce HIV-specific criminal laws, beginning in 1987, and there have been thousands of reported cases since . Until 2Considering all the facts, the BTIV took all the measures it was legally obliged to in order to reduce the risk of transmitting HIV infection through transfusion. Even though the conditions or legal obligations for NAT testing and the process of the pathogenic inactivation of fresh frozen plasma through the law should have been introduced at the time, as in other European countries, it does not diminish the responsibility of the individuals. The use of criminal laws against people based on their HIV status can be ineffective and discriminatory and can represent a barrier to HIV prevention programs. On the other hand, the open question remains with regard to individuals who knowingly give false answers during BD screening and the consequences they should encounter, not only for HIV transmission but for other TTIs.It is expected for BDs to have a strong moral obligation to avoid the harming of others whenever possible. If a person donates blood with the sole purpose of being tested for TTI, without concern for the possible repercussions, the concept of the humanity and altruism of blood donating becomes highly debatable. Therefore, there should be no place for such motives in a community of voluntary anonymous blood donors who donate a part of themselves for free in order to help a person in need. Most countries around the world are continuously introducing measures to increase the safety of blood and blood component usage. This goal can be achieved by rigorous donor selection, appropriate screening testing, and pathogenic inactivation. It is very important that the administration of one country, through its laws, supports all actions to prevent the HIV transmission by a contaminated blood transfusion. There is a need for the implementation of modern and non-discriminative laws in Serbia in order to prevent similar incidents in the future. On the other hand, the responsibility of the transfusion system is to put constant pressure on national decision makers in order achieve a constant upgrade of the diagnostic capacities, to prevent similar incidents, and to provide the best possible care for blood donation recipients.


Adipose, muscle, and bone tissues modulate the metabolic state of mammals. However, the role of bone tissue as a metabolic state modulator in sows has not been studied. During the gestation–lactation transition, sows undergo metabolic adaptations to meet their nutritional requirements. Among these adaptations, bone remodeling is characterized by the synthesis and inhibition of hormones that participate, together with hormones from other tissues, in fetal development and lactogenesis. Osteocalcin is a hormone synthesized by the bone tissue which has been associated in different biological models with the improvement of the metabolic state. However, in sows, published results on the concentration of osteocalcin are scarce, and its concentration throughout the reproductive cycle is unknown. Therefore, with information from published trials on the measurement of serum osteocalcin, a structured review was conducted under the following objectives: (1) to review the promising effect of osteocalcin on energy metabolism in different models and (2) to characterize and model the serum concentrations of osteocalcin during the reproductive cycle of the sow. According to the review, the results obtained for humans and other animal models suggest that osteocalcin regulates energy metabolism, which has been associated with the need for integrated metabolism to cope with the metabolic demand during gestation and lactation in mammals. If these effects are significant in the sow, current recommendations for dietary balance should be reconsidered, particularly during the gestation–lactation transition period. According to mathematical modeling, it was the period in which the lowest concentration of osteocalcin was found. The adoption of recent technologies has resulted in substantial improvements in sow productivity in recent decades . In the Currently, there is still a productivity gap in the systems, which is associated with the fact that modern sows face considerable metabolic challenges. During the transition between gestation and lactation, the sow must resort to metabolic modifications because of the increased demand for nutrients for fetal development and lactogenesis . These mA third important reserve tissue is the bone. The skeleton of the sow is the main source of calcium during pregnancy and lactation . Bone tiBecause the data were obtained from existing data, no approval was applied for from an animal care and use committee.Information from the main research on this topic was used for the characterization and schematic modeling of serum osteocalcin concentration and its relationship with energy metabolism in different biological models. The information was analyzed under the methodological approach of the General Systems Theory, which postulates that, with the integration of different scientific disciplines, the solution of problems is achieved integrally . In the Complex systems, such as swine production systems, are generally composed of four elements: context, humans, animals, and technology . HoweverHence, the serum concentration of osteocalcin in breeding sows was characterized and modeled using two schematic organization models. The first model contained a black box approach, where the factors attributable and not attributable to the phenomenon (and which were likely to condition the operation of the system) were obtained. In the second model, a more formal approach was considered. The data were analyzed considering Goodall’s  criteriaA database containing indicators of the characteristics of the animals used, diet composition, and serum concentrations of osteocalcin, calcium, and phosphorus during gestation and lactation was developed. Information was collected from 12 articles published in scientific journals indexed in PubMed and Science Direct. Studies that met the following criteria were included: 1) adequately described research methods ; 2) the experiments always had a control group. Because of the limited results that the search yielded (17 publications) for the measurement of osteocalcin in reproductive sows, the control group of each selected experiment was used to characterize the osteocalcin concentration in serum during gestation and lactation; 3) the genotypes used in the research were related to the genotypes used in current swine production systems; studies using Guinea pigs and Vietnamese pigs used in research as biological models were omitted; and 4) serum osteocalcin, calcium, and phosphorus concentrations were determined at least during three different points in the reproductive cycle of the sow.The main variables in the database about animals, i.e., their dietary composition and the serum concentrations of osteocalcin, calcium, and phosphorus, are reported in The data were analyzed according to the method of St-Pierre , who conijY = bo = b1D + b2D2 + b3D3 + is = iDa + ije, (1)Yij is the observed result for the dependent variable (Y) in the ith experiment according to evaluation day (D), i = 1, 2,…, 143 ; b0 is a general intercept; D is the evaluation day; b1, b2, and b3 are the regression coefficients for D, D2, and D3 (fixed effects); is the random effect of the study ; is is the random interaction of the study × D ; and is ije the residual error.where, In Equation (1), it is assumed thatAs the data were drawn from various investigations, each with its own experimental design, it was important to properly estimate the observations (the reported means) according to their relative precision (SE). Therefore, observations were weighted by the number of animals in each trial to account for the uneven residual variation between trials . An unstOver the past few decades, several studies, mainly in mice, have been published ,30 that When it was discovered that obesity lowers the incidence of osteoporosis in humans, the idea that the skeleton may play a role in energy homeostasis and homeorhesis was initially put forth in 1993 . The relin vivo evidence of central regulation of bone mass is provided.A hormonal and neurological mechanism that controls bone remodeling was established in 1998 by Corral et al. . Leptin in vivo and decreases bone fragility, and (2) the peripheral effect of leptin (mediated by insulin) outweighs the central effect.Leptin influences energy balance and the neuroendocrine axis through hypothalamic linkages, according to Ahima , who pubIn 2004, it was demonstrated that excessive bone mass in fat-free mice could be rectified with the infusion of transgenic leptin, demonstrating that it is responsible for the bone phenotype . This deEsp-/-mice, it was suggested that Esp regulates the carboxylation of osteocalcin and that non-carboxylated osteocalcin (Glu) is the one that participates as a hormone that regulates glucose metabolism  were large and differed significantly from zero  is associated with their continuous growth during gestation compared to that in multiparous sows. Primiparous sows may require more nutrients for the growth and development of muscle and skeletal tissues than multiparous sows . HoweverThe metabolic adaptations that a sow undergoes during late gestation and lactation  limit the productive potential of the sow, as they affect her energy consumption during lactation. This is reflected in body catabolism and its subsequent effect on post-weaning productive indicators: weaning-estrus interval, repeated services, fertility, and prolificacy. Therefore, strategies should be developed to minimize this problem. Studies on the effect of osteocalcin on energy metabolism in various biological models project this hormone as a possible means to modulate the metabolic state of sows during late gestation and lactation. Manipulating energy metabolism and bone metabolism in a coordinated manner would affect productivity and may have the potential to modify the post-weaning productive gap. If these effects are shown to be significant for pig production, prevailing recommendations for dietary balance should be reconsidered, particularly during the nursery period and lactation. Therefore, it is necessary to quantitatively determine the importance of bone resorption for health, production, and reproductive performance.Mathematical modeling elucidates the relationships between the serum concentrations of osteocalcin, calcium, and phosphorus and the day of sampling (stage of the sow). This model shows that there are factors, such as age, that can interact with the productive stage of the sow to affect the serum concentration of osteocalcin. However, future work is needed to characterize and model the serum concentration of osteocalcin in sows and to more accurately associate the behavior of this hormone with biochemical indicators. This may be even more important for the current genotypes of hyperprolific sows in the context of developing strategies that favorably modulate metabolic state and increase sow productivity. This finding is consistent with the results reported for other animal models on the effect of osteocalcin on the metabolism of lipids and carbohydrates.Obituary: The authors wish to express our posthumous recognition to Dr. José Antonio Rentería Flores, DVSc, who was well known for his lifelong dedication to his work and his research interests, as well as for his active participation in the development of this publication. May he rest in peace!