Ruta Pacifica de las Mujeres who had experienced significant personal violence. Results show that levels of perceived discrimination and lack of social acknowledgment are mediators in the relationship between polyvictimization and posttraumatic stress symptoms. Recognition by significant others, disapproval by family and the larger social milieu affects different posttraumatic stress disorder (PTSD) dimensions and therefore how these women adapt to the effects of trauma. Findings provide strong evidence that the way society and family treats women after a traumatic event affects how the victim recovers from this event. Recognition as a victim and disapproval can coexist and be a burden for women if not adequately addressed. Results stress the importance of understanding and intervening in PTSD recovery through the analysis of social processes, and not only through and individual focus.For decades, in a situation of armed conflict in Colombia, women have suffered polyvictimization and discrimination with severe consequences that last even during the post-war peace process. This study analyzes the impact on posttraumatic stress and recovery of war-related violence against women, discrimination, and social acknowledgment. A cross-sectional study was conducted in 2019–2020. Participants were 148 women with a mean age of 47.66years (range 18–83), contacted through the NGO  Violence perpetrated during periods of armed conflict may have a lasting effect on individuals, and how they reconstruct their lives. Most studies have analyzed periods of active conflict while directing less attention toward the impact of violence during post-conflict transitional periods. Moreover, the role of gender and the effects of conflict and violence on women and their reactions to the experienced trauma have been less studied and merit a significant level of attention . In armeColombia is country which has endured six decades of internal violence and armed conflict, with over 20% of the population, mostly civilians, victims of violent episodes . Social In 2016, a peace accord between the Colombian government and the most relevant guerrilla (FARC) was finally struck, apparently putting an end to an armed conflict which had caused a burden to the personal, social, and economic development of Colombia . FeminisBoth direct and indirect exposure to war and armed conflict have a long-lasting impact on civilian populations leading to responses, such as emotional distress or posttraumatic stress disorder (PTSD), considered to be the most relevant long-term consequence of such events . ExposurA conflict that heavily impacts a society’s social system, such as an armed conflict or persistent low intensity war, affects not only an individual but also the whole social fabric. As such, recovering from trauma caused by suffering violence in these contexts should not only be analyzed as an individual phenomenon. As Meta-analytic reviews have shown that perceived discrimination has negative consequences on an individual’s mental health . NeverthAs PTSD is related to social responses toward a victim, social acknowledgment – defined as referring to how appreciated, as a victim of a traumatic event, an individual feels he or she is by family and the general population is an important factor in the psychological adaptation to the traumatic stressor and future recovery .This article further elaborates on the previously mentioned literature developing and testing a social model of trauma symptoms as shown in The objective of this research is to test a social model of trauma to explain the variance in PTSD symptoms. This study will analyze how experienced violence, and the number of violent acts one has suffered (polyvictimization), affects a group of women’s posttraumatic stress and recovery. This relationship will be mediated both by the levels of perceived discrimination a person has experienced and the degree in which not only individuals, but also social groups influence the person by judging the victim’s unique state and acknowledging, or not, the victim’s current difficult and/or traumatic situation.The sample comprised 148 women contacted through the NGO RPM. RPM is a women’s social movement that has been directly involved for over 25years in making the impacts of war on women’s lives and bodies visible and trying to influence the process, negotiation, and non-violent resolution of conflicts. The 25-year experience of the RPM has generated in many women, victims of the conflict, enough confidence and legitimacy to approach, get involved, and become part of this organizational process. Due to the nature of the NGO and the aims of this study, all the women who voluntarily participated in the study throughout their lives had experienced victimizing events  that in many cases, they did not recognize as such for a long time. However, their membership in the RPM has allowed them to transform and reconsider these personal and social experiences of violence. For many women, the RPM is the only resource they have to recognize and highlight in a safe context all the suffering they have experienced with no judgments made and in which the center of the narrative is a women’s life and experience. The exclusion criteria were as: a) being a minor because research processes with minors require other protocols and authorization from adults that are difficult to obtain; b) women who had participated in the RPM for a period of less than 2years because these women may have fewer resources to face questions about reenacting very painful experiences. Women who have been engaged in some way with the RPM for over 2years probably have more resources to cope with the questions that bring up painful memories without stressing revictimization.The participating women belonged to the areas of Bolívar., Santander, and the Eje Cafetero. The regions and municipalities where the study was carried out were selected for two main reasons: (1) the RPM has recognition and legitimacy among women victims in the regions where the study was carried out, which facilitated the meeting and their willingness to participate in the study; (2) selected regions, such as Bolivar and Santander, have had a history of violence due to the armed conflict that is socially recognized in the country. Also, in the Eje Cafetero region, violence due to the armed conflict has been invisibilized and minimized. Therefore, we intend with this study to contribute to its visibility and recognition.SD=15.65) ranging from 18 to 83years. Mean age of the participants was 47.66years (n=62 women (41.9%) had suffered only a single form of violence: physical, psychological, or sexual; n=60 (40.5%) two of them; and n=26 (17.6%) all three types of violence.An aggregate score of accumulated trauma (polyvictimization) indicated that This is a cross-sectional study conducted in Colombia in 2019–2020. In order to engage participants in the study, first, one of the researchers in Colombia, who is an active member of the RPM for 10 years, contacted the RPM coordinators in the different regions where the NGO has offices. Second, various coordination meetings were held between the research team and RPM representatives to explain the aim and procedure of the research. Third, potential participants were contacted and recruited for the study (by telephone) through the RPM coordinators. Four, meetings of the coordinators with the participating women were held in each of their territories to explain the research project and to set the dates for data collection. Finally, the researchers from Colombia traveled to the territories to ensure the participation of the women without additional effort for them, since many of them live in very isolated rural areas and other are leaders who have been threatened and silenced and the only resource they have to explain their experience is that provided by the RPM. The data collection was carried out in their own personal spaces, such as booths, the offices of partner organizations, and rooms that had optimal conditions  for carrying out the procedure.RPM experts worked with one of the researchers to carry out the data collection in the municipalities of Supía and Pereira (Eje Cafetero), Cartagena, Aragón and San José del Playón (Bolívar) and Santander. Approval for the study was given by the Ethical Committees of the institutions involved as: Burgos University and Basque Country University. Once the informed consent forms had been signed, respecting the ethical principles established in the Declaration of Helsinki, the evaluation protocol was completed in groups of three or four women under professional supervision. The protocol took approximately 90min to complete.ad hoc scale was developed to address information on three types of violence. This review is one of the most recent, specific, and comprehensive in analyzing different types of violence in an armed conflict zone. Eleven forms of sexual violence , 11 categories of physical violence , and 10 types of psychological violence  were identified. The response option was dichotomous (yes/no). An aggregated violence score (polyvictimization) was created to include those women who had suffered one, two, or all three types of violence.Based on the systematic review conducted by The original scale was developed by This scale  has beenThis scale  evaluateAll scales, except the EGS-R, have been translated into the Spanish language following the d=0.20, medium d=0.50, and large d=0.80.A series of descriptive statistics were conducted  to describe the sample and variables under study. Cronbach’s alpha was used to analyze reliability of the instruments. Multivariate analysis and Pearson correlation coefficients between variables included in the study were calculated. Statistical analyses were performed using SPSS v.25. Effect sizes of the mean differences were estimated using The impact of armed conflict-related violence against women, discrimination, and social acknowledgment of posttraumatic stress was analyzed by a path analysis. These path analyses with observed variables were performed on raw data files using the maximum likelihood estimation procedure in the Mplus v.8.5 software .χ2), the root mean square error of approximation value should be less than 0.08 to declare satisfactory fit, the comparative fit index value should be greater than 0.90, the Tucker Lewis index value should be greater than 0.90, and the standardized root mean square residual should be less than 0.05  and recognition as a victim . Post-hoc test showed that victims of physical, psychological, and sexual violence were more discriminated than women who suffered two or one type of violence. Furthermore, women who suffer two types of violence were less recognized as victims than women who suffered one type of violence. Results also showed more discrimination  and family disapproval  in women who suffered sexual violence than among non-victims of this type of violence. Discrimination was also more common among victims of physical violence than among non-victims . There were non-significant differences between victims and non-victims of psychological violence in the variables under study.Differences between women who had suffered one, two, or all types of violence  were found for discrimination  and family disapproval , and recognition as a victim  indicating that discrimination mediates the relationship between polyvictimization and the different dimensions of social acknowledgment as a victim. Discrimination increases the effect of being a victim of more than one type of violence on social and family disapproval and on being recognized as a victim. Nevertheless, discrimination has no direct effect on the PTSD’ dimensions.We hypothesized a PTSD model that yielded an adequate fit to the data see . ResultsIn a second step, the direct effect of social acknowledgment on PTSD and the indirect effect of discrimination on the four dimensions of PTSD through general disapproval, family disapproval, and recognition as a victim were tested.β=0.18, Se=0.05, p=0.0001), cognitive avoidance , cognitive and emotional alterations , and hyperarousal  through general disapproval.First, results indicated that general disapproval had a direct and positive effect on trauma reenactment, cognitive avoidance, cognitive and emotional alterations, and hyperarousal. The indirect paths were significant from discrimination to trauma reenactment .Second, the direct path from family disapproval to cognitive and emotional alterations was also significant. Moreover, the indirect effect showed that family disapproval explained the emotional and cognitive alterations caused by social discrimination   see .The way society treats a person after a traumatic event affects how the victim recovers from this event as well as reflecting the social fabric of communal relationships. Results from this study show that social acknowledgment has an impact on how women who have survived violence in an armed conflict process their traumatic experiences emotional and cognitively. Polyvictimization and discrimination affect PTSD symptoms through how the rest of the community accepts or rejects victims. Recognition or disapproval by family, significant others, and the larger social milieu has an important, and differential, effect on these women’s psychological adaptation to the consequences of trauma .The dose–response relationship literature, and more specifically in the case of Colombia, results from This study shows that society, close relations, or one’s own family disapproval or recognition  increases the negative effect of both discrimination and polyvictimization on a victim’s PTSD symptoms. Moreover, although a victim may receive recognition as such by one’s close social group, at the same time, they may face general and family disapproval. In Colombia during the last few years, there have been developments favoring a holistic reparation of the violence suffered by women mainly through the actions and interventions of social movements . Women fNevertheless, these dispositions have not necessarily been implemented by successive governments. There are still flaws in the support local and national government departments offer women victims of armed conflict violence. This situation does not allow for significant changes in the role and image of women in society and could explain why the more discrimination women victim of armed conflict suffer, the higher both general and family disapproval .Disapproval and recognition not only play a different role in linking polyvictimization and discrimination to PTSD, but family and general disapproval also impact on different PTSD symptoms. General disapproval, the opinion of an abstract set of society members, leads to an increase in the effect of discrimination in all symptoms of posttraumatic stress. That is, a recrudescence of the re-experience of the traumatic event that induces a state of high anxiety, cognitive avoidance, emotional reactivity, and hyperarousal. These findings support the idea that social reactions of disapproval and lack of support are related to PTSD in women survivors. Moreover, these results are consistent with other studies that have found similar results showing that general disapproval was the only factor of the Social Acknowledgment Questionnaire (SAQ) that in different contexts was positively and significantly related to PTSD . Xu et aOn the other hand, both family disapproval and recognition as a victim by significant others mediate the effect of discrimination on the cognitive and emotional PTSD problems. The way disapproval and recognition affect PTSD seems to be completely different: Family disapproval leads to an increase in the cognitive and emotional symptoms while recognition decreases the effect of discrimination and polyvictimization. In a family, its members may suffer different impacts which combined erode family interactions and force the group to reconstruct itself. The social effects of armed conflict not only affect individuals but also the social structure of close kin groups. In many cases, the family milieu has turned into something alien which is no longer a reference for security and identity. Although many families try to reorganize their relationships to continue to support its members, in certain cases, and due to the sequelae of the traumatic situation, we find that blame, rage, hurt, and impotence emerge in family interactions. This is especially the case in victims of sexual violence who suffered more discrimination and family disapproval than those non-victims of such type of violence. This family conflict in situations of armed conflict is sometimes resolved through networks of community sociability.Moreover, as We have seen that polyvictimization suffered by women in a context of armed conflict has two distinct phases. First is the instance in which the violent acts took place. Second, we find the moment of impunity and lack of mechanisms to recognize what has happened, a point in which these acts are “quietly” forgotten. This phase can lead to irreparable repercussions in victims. These are two complementary forms of psychological damage.This study supports placing a stronger emphasis on applying social psychological theories and constructs to the study of traumatic events and their impact on mental health. These results may have important clinical implications in interventions with women victims of violence in armed conflict and post-conflict situations. It is necessary to develop a holistic perspective that includes both the victim and their social environment  .Moreover, the United Nations’ Security Council Resolution 1,325 not only addressed the issue of gender inequalities in conflicts, and how it disproportionally affects women, but also stressed the need to include gender perspective in peace conflict resolution mechanisms. Women are not only victims of armed conflicts, but also leaders and peacemakers. This implies not reducing the role of women to more traditional spheres of peace education but engaging in women peacemaking, peacekeeping, and peacebuilding activities, although everyday interventions show us that women still do not systematically participate in decision making about reconstruction and peace negotiations . This aiThere is a need to develop interventions in women’s most proximal social environments and promote family therapy and community interventions to strengthen a victim’s closest social networks . NeverthThe number of women who participated in the research was low, although the complexity of the questionnaire, and the physical difficulty of accessing the terrain and sites did not allow for a larger sample which would be necessary to explore the mediating effects of social acknowledgment found in this study. The cross-sectional design of the study does not allow for an analysis of causation. To address this problem, more longitudinal studies should be designed and implemented in the future.The nature of the participants and their implication in the actions of an NGO does not allow for a generalization of results to other women who have suffered the same violence but who may lack the assistance of a structured organizational network in which to share one’s experiences. Moreover, participants answered a self-report remembering their actions and feelings years after the events took place in many cases. This may pose a problem of recall and memory reconstruction, although due to the nature of the events, these studies will always be reconstructive since objective data from the moment the events took place, and women suffered these episodes of violence, are very difficult to obtain.Polyvictimization and posttraumatic stress symptoms are related indirectly through discrimination and lack of social acknowledgment. Results of the study stress the importance of understanding and intervening in PTSD recovery through the analysis of social processes and not only as an individual variable. Recognition as a victim and disapproval can coexist and be a burden for women if not adequately addressed. Family, close relations, and the more general society have different impacts on the various symptoms of PTSD, and as such must be considered when intervening and designing programs for women victims of armed conflict induced violence. Enhancing the recognition of women who have suffered violence by significant others and decreasing family and social disapproval can help recover women’s mental health, despite the trauma caused by violence.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethical Committees of the institutions involved: Burgos University and Basque Country University. The patients/participants provided their written informed consent to participate in this study.SU, AP, and JL contributed to the conception and design of the study. GM and AP collected the data. MG and AP organized the database. JL, SU, and AP performed the statistical analysis. JL, SU, AP, DP, and MG wrote the first draft of the manuscript. All authors contributed to the manuscript revision, reading, and approving the submitted version.This work was supported by the grants from the Spanish Ministry of Science and Innovation (PID2020-116658GB-100) (PSI2017-84145-P) and (PID2020-115738GB-I00). Research group grant from the Basque Government , the Development Cooperation Office of the Basque Country University, and grant 2019/00184/001 awarded by the Junta of Castilla y León (Spain) to the Social Inclusion and Quality of Life (SIQoL) research group.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.


Residual stress, a factor affecting the fatigue and fracture characteristics of rails, is formed during the processes of fabrication and heat treatment, and is also generated by vertical loads on wheels due to the weight of vehicles. Moreover, damage to rails tends to accelerate due to the continuous increase in the number of passes and to the high speed of passing vehicles. Because this can have a direct effect on safety accidents, having a technique to evaluate and analyze the residual stresses in rails accurately is very important. In this study, stresses due to tensile loads applied to new rails and residual stresses remaining in used rails were measured by using magnetic Barkhausen noise method. First, a magnetization frequency and noise band suitable for the rails were selected. Moreover, by applying tensile loads to specimens and comparing the difference in magnetization amplitudes for each load, the stresses applied to the rails by using the magnetic Barkhausen noise method were measured, and the analysis of the results was verified. Based on these results, the difference in the results for the loads asymmetrically applied according to the wheel shape was analyzed by measuring for the head parts of used rails. Recently, in the railway field, the conditions during use of important parts, such as rails, wheels, and axles, have become increasingly harsh because the high-speed rail networks operating worldwide have increased. In the last decade, the length of the high-speed networks in commercial operation worldwide has increased by 3.6 times . In partThe residual stresses remain inside materials after manufacture, processing, and heat treatment, which condition is known to cause destruction of structural materials . Rails uVarious approaches to measuring the residual stresses in rails have been studied. The simplest methods of measuring the residual stresses of the rails are the methods of destructive measurement. However, because it is practically impossible to cut rails in use, making measurements by using non-destructive methods is essential. Accordingly, a variety of methods have been tried for measuring residual stresses, involving such as neutrons, laser, magnetism, and ultrasonic waves ,9. BecauMaintenance decision-making is based on the experience of inspectors and the simple inspections of the surface condition of rails. Thus, effective and economical techniques for measuring the residual stresses in rails are required. The railways of advanced countries are already investigated and managed through non-destructive techniques for measuring residual stresses in various rails . NeverthThe magnetic Barkhausen noise method measures voltage-type noises caused by sudden changes in the domain wall when changes in magnetization occur in ferromagnetic materials . MagnetiIn this paper, a study on measuring the stresses on rails named 50 kgN , using tMagnetic measurement technique is a non-destructive testing method that evaluates changes in magnetic properties among the physical properties of materials and verifies the safety of structures in which the materials are used. It has the advantage of being able to obtain data on many variables by measuring ferromagnetic materials. Magnetic variables that could be used to determine the intrinsic properties of materials include magnetizing force, magnetic flux density, coercivity, and permeability, which are closely related to the material’s crystal grain size, stress, plastic deformation, and precipitates.Railway rails, the subject of this study, are made of ferromagnetic materials of which the major component is steel. The ferromagnetic material is not magnetized in its natural state, but when a strong magnetic field is applied from external, the magnetic moments are aligned in magnetic field direction and magnetized. Moreover, the magnetization remains even after the external magnetic field is removed as residual magnetization.When an external magnetic field is applied to a ferromagnetic material having magnetic structures, the magnetic flux density of test object increases, and the magnetic domain wall moves. It is disturbed by retarding fields, such as various defects, including grain boundaries, dislocations, precipitates, nonmagnetic inclusions, dislocations, or voids. Moreover, a discontinuity can appear after which the domain wall jumps ,12. The By understanding this effect, it is possible to understand the changes in the slope of hysteresis curve and the change in magnetic properties due to the change of constraining stress applied to rails according to loads. Basically, a magnetic Barkhausen noise measurement device is configured to measure magnetic Barkhausen noise signals from a detection sensor located on the surface of specimens by applying an alternating voltage after winding a magnetizing coil in a yoke. Depending on the stress state of the specimens, the movement state of a magnetic domain and magnetic walls changes, and the magnitude of the magnetic Barkhausen noise also changes. Accordingly, the parameters revealed by measuring magnetic Barkhausen noise generated through interaction between the magnetic structure and the microscopic and macroscopic structures of the object, provide relevant information about the state of the specimen.The test subject used to measure applied stresses is a rail called 50 kgN , which i2. Magnetization frequencies selected for use in the experiments were 45, 60, 90, and 120 Hz, and magnetic noise filtering ranges were 3–15, 3–200, 3–1000, 20–200, 20–1000, and 200–1000 kHz. First, excitation amplitudes were measured by changing magnetic noise filtering range after fixing each specific test frequency to investigate changes in magnetic Barkhausen noise according to different magnetization frequencies and noise bands. A new rail that has never been used was employed as the test subject in the experiments, and signals were acquired at the head part of the rail. INTROSCAN, an analyzer developed by LLC “NPF Diagnostics” , was used as a magnetic Barkhausen noise measurement device . The devThen, specimens for tensile test were extracted from the new rail. Water-jet cutting was chosen for manufacturing the specimens, because it minimizes the effects of stress disturbance due to rail cutting, compared to other processing methods. The dimensions of the specimens are 150 × 25 × 2.5 mm, and glass-fiber reinforced plastic (GFRP) was used to coat both ends of each specimen fabricated. It is because this prevents the jigs for tensile testing with electrical conductivity and the specimens from being directly attached. This eliminates the possibility that unwanted disturbance in electrical signals rather than magnetic Barkhausen noises could be entered into the experimental data. Each magnetic Barkhausen noise signal was measured while changing the applied loads by placing the magnetic Barkhausen noise sensor in the direction horizontal and vertical to the load direction. Because the magnetic Barkhausen noise signal changes according to the attachment force of the sensor, a jig was manufactured and used to maintain this adhesion force and thus minimize this variation. The same device was used to measure the magnetic Barkhausen noise and a servo-hydraulic test system  used to apply the tensile force. At last, in order to conduct experiments using the magnetic Barkhausen noise on preloaded rails, three used rails were applied. Depending on the shape of wheels of railway vehicles, asymmetric loads were applied to the entire rails, because the wheels contact the upper surface of the rails. To analyze the differences according to response characteristics, using magnetic method, signals were acquired from three regions with the same cross-sectional area, as shown in In Region (1) see , there iWhen the magnetization frequency was varied, magnetic Barkhausen noise intensity values were different for each noise band. The results are shown in The intensity of the magnetic Barkhausen noise, displayed on the vertical axis, is a value proportional to the average value of the sensor’s the output voltage of the pickup coil for a specified number of magnetization reversal cycles. The number of these cycles is determined by a user-selectable measurement time constant. In practice, the system measures the induced voltage generated by Bloch wall jump ,37, but Through this experiment, it was determined that the higher the applied magnetization frequency was, the higher the magnetic Barkhausen noise intensity values. Through this, the magnetization frequency of 120 Hz was determined to be the most suitable for inspecting changes of the magnetic Barkhausen noise according to residual stresses because signals with higher values could be obtained. In addition, 20–200 kHz, which showed high values with stable curves, was most suitable as a magnetic noise filtering range.The magnetic Barkhausen noise intensity values obtained with the sensor placed horizontally and perpendicular in the direction of the load while varying the applied load, using the selected magnetization frequency and noise band, are shown in the Through this result, it was possible to verify the correlation between the magnetic Barkhausen noise signal and the magnetization amplitude obtained from tensile testing of the rail specimens. When the sensor direction was in line with the load direction, the magnetic Barkhausen noise signal increased in proportion to increase in the tensile load, and in particular, the magnetization amplitude showed a large increase within the range 25–100. However, within the range 100–200, the increase was not significant. On the other hand, when the sensor was in the direction perpendicular to the load direction, the signals did not show significant differences even when the tensile load increased. Through these results, it can be seen that magnetic Barkhausen noise patterns differ depending on the stress.To verify that the results of this experiment were accurate, a calibration was performed by using regression analysis  on the sExcitation amplitudes were calculated for three rail specimens. The relationships between these values and the magnetic Barkhausen noise intensity values are shown in Magnetic Barkhausen noise intensity values for the specimens from Region (3) see , where sBy comparing the experimental results while changing the conditions, a magnetization frequency and noise band suitable for 50 kgN rails were selected. The selected magnetization frequency was 120 Hz, and the selected noise band was 20–200 Hz.It was found that the magnetic Barkhausen noise intensity values measured while applying tensile loads increased linearly with the increase in tensile load when the direction of the detection sensor was the same as the load direction. The magnetization amplitude showed a distinct tendency to increase within the range 25–100 of excitation amplitude.When the direction of the detection sensor was perpendicular to the load direction, it was found that the magnetic Barkhausen noise signal hardly changed, even when the tensile load increased.As a result of analyzing the correlation between the stress and the magnitude of the magnetic Barkhausen noise signal, it was found that the correlation coefficient was over 0.988. This indicates that stress can be measured with high reliability, using the magnetic Barkhausen noise method.The magnetic Barkhausen noise method was used to evaluate the stress of 50 kgN rails, using the magnetic properties of the material, and the following results were obtained through this study.Through this study, it was possible to measure the stress applied to 50 kgN rails by using a technique that verifies that the magnetic Barkhausen noise is affected by residual or applied stresses in specimens. Moving forward, future studies can take advantage of these results to extend the analysis to different rail types. As a final remark, the development of portable equipment can be applied to employ this technique to actual sites and to measure residual stress in rails.


The pharmacokinetics profile of active pharmaceutical ingredients (APIs) in the solid pharmaceutical dosage forms is largely dependent on the solid-state characteristics of the chemicals to understand the physicochemical properties by particle size, size distribution, surface area, solubility, stability, porosity, thermal properties, etc. The formation of salts, solvates, and polymorphs are the conventional strategies for altering the solid characteristics of pharmaceutical compounds, but they have their own limitations. Cocrystallization approach was established as an alternative method for tuning the solubility, permeability, and processability of APIs by introducing another compatible molecule/s into the crystal structure without affecting its therapeutic efficacy to successfully develop the formulation with the desired pharmacokinetic profile. In the present review, we have grossly focused on cocrystallization, particularly at different stages of development, from design to production. Furthermore, we have also discussed regulatory guidelines for pharmaceutical industries and challenges associated with the design, development and production of pharmaceutical cocrystals with commercially available cocrystal-based products. More than 80% of marketed formulations are solid dosage forms intended for oral administration because of their simplicity and high compliance among patients. Since the last decade, efforts have been made to identify the purity and associated side effects of their use. Therefore, the safety and efficacy of the administered therapeutic agents need to be assured. With regard to this concern, the physical properties of the solid dosage forms are a major alarm . TherefoConventional methods to improve the solubility and other physicochemical properties of APIs include salt formation, polymorphs, solvate or hydrate formation, amorphous forms, etc., and each of these methods has its own limitations. Salt formation is the most widely used technique to improve solubility, which requires sufficient ionizable groups or acidic or basic groups in the drug molecule . Thus, tSince solid-state properties are determined by the crystal structure of the corresponding solid, changing the crystal structure by introducing other molecules into the crystal lattice leads to a change in the solid-state properties of the parent solid without altering the actual chemical identity of the native molecule. In this context, cocrystallization is an approach to alter the solid-state properties of a crystalline solid by introducing additional components into the crystal lattice through noncovalent interactions . AccordiThe increasing popularity of this field encourages us to bring a summarized article on cocrystallization technology. Thus, the focus of this review is to discuss cocrystallization techniques adopted by the pharmaceutical industries in designing, developing, and manufacturing suitable solid forms of therapeutics, which have improved clinically relevant physicochemical and processability properties. Furthermore, the review also discusses regulatory guidelines that are currently in force for pharmaceutical cocrystals and their scale-up process. In addition, we have also discussed challenges that are associated with the development of pharmaceutical cocrystals and have listed the currently available cocrystal-based drugs that are available in the market.There are various methods available for the preparation of cocrystals, which could be broadly classified into two categories, namely, solid-state based and solution based. Both methods have their own advantages and disadvantages. Solid-state methods are convenient for the preparation of cocrystals on both laboratory and industrial scale, as these techniques can be considered as a convenient, versatile, sustainable, and eco-friendly method for the preparation of cocrystals . SolutioThe contact formation method involves the concept of decreasing the size of the particle by increasing its crystallization rates . It has Solid-state grinding is another method that has been used for many years in the field of research for the preparation of cocrystals. For example, adopting this methodology, liquid-assisted grinding (LAG) in the solid state was used to examine the production of diastereomeric cocrystals of malic and tartaric acids . PrimariIn the DG method, the solid form of the API and conformer get ground together manually using a mortar and pestle or mechanically by using a ball mill . BrexpipThe LAG method incurs the addition of a small amount of the solvent (to the mixture) in order to get the desired cocrystal product. This added solvent can act as a catalyst for the formation of cocrystals . Trask eDespite several advantages of LAG and DG methods such as being inexpensive, easy to perform, and eco-friendly, when it comes to preparing for large-scale production for industries, hot-melt extrusion (HME) is preferred .The HME method is a widely used technique in the pharmaceutical industry. Since the last decade, this method has shown the capability to replace old methods of preparation of cocrystals and be used both in laboratories and commercially . In thisin situ by the wet granulation method. They studied the influence of excipients on the stability of cocrystals during the wet granulation process and found that excipients do not have an influence on the production of ivabradine–mandelic acid cocrystals (The high shear wet granulation (HSG) method includes assembling the powder components in a liquid medium which could be performed in a high shear granulator . HSG cancrystals . The HSGThe solution-based method is another category of preparation method for cocrystals, which includes evaporative cocrystallization, cooling crystallization, reaction cocrystallization, and isothermal slurry conversion . The cocIn this technique, a solution of cocrystal components (API and conformer) is prepared in a volatile solvent. The solution is kept at room temperature. Due to the slow evaporation of the solvent, the solute components reach their supersaturation concentration which leads to nucleation and crystal growth . This teIn crystallization, temperature plays a key role. For some of the compounds, increasing the temperature leads to an increase in solubility, and for some others like supersaturated solutions, allowing to cool leads to the formation of cocrystals as precipitates. The main lead in this technique is the formation of the most uniform cocrystal size with energy efficiency. Latent heat is taken out by heating the solution, and the remaining are allowed to cool. In this system, the warm solution is circulated and cooled at time intervals using pressure as a function, and it is also combined with the evaporative system in some of the other instruments . By usinThe cocrystals under this method were formed by using a solution containing reactants. Upon addition to another solution and stirred in a vessel, the concentration overcomes the solubility in the mixture that leads to the formation of the crystals. Mostly, in this type of technique, reactions are done very quickly and mixing conditions influence the crystal size . NucleatThis is the most efficient screening and scale-up method for cocrystallization . In this2; the advantages of using this fluid is to reduce the processing steps, being eco-friendly solvent, well-finished products (without solvent), a greater tendency for solubility, and mainly product degradation that is less because of the lower temperatures   .2, then the solvent fluid drops gradually to supersaturation in the supercritical CO2. The supersaturation leads to nucleation growth, finally forming the crystals. The solubility of letrozole was improved 7.1 times by this method . Crystals of carbamazepine with saccharin, theophylline, and indomethacin were obtained with high product yield , the following liquid splits  into the form of fine droplets, which are sprayed into a drying chamber under atmospheric pressure in the atomization method and into other chambers at required pressures. Crystals need to be collected which are deposited on the walls of the chamber. In both the methods, CO2 acts as an anti-solvent, while in the secondary stream, CO2 can be replaced by N2 gas  . This coThe freeze drying method works by freezing and lowering the surrounding pressure, which allows the material to undergo sublimation and hence leads to a phase change . Freeze Electrochemically induced cocrystallization can create a potential cocrystallization of ionizable compounds. While preparing a cocrystal of cinnamic acid and 3-nitrobenzamide, the electrochemical application can shift the pH to get neutral carboxylic acids and thus act as a driving tool for the cocrystallization .Resonant acoustic mixing includes the mixing of constituents without grinding in the presence of any suitable liquid to get the desired cocrystal. Several cocrystals of carbamazepine  have beeCharacterization techniques are essential while carrying out research work on cocrystals. There are various characterization methods to determine the structure and properties of pharmaceutical cocrystals. X-ray diffraction (XRD) techniques [both powder XRD (PXRD) and single-crystal XRD (SCXRD)] are crucial techniques to determine the structure of cocrystals as these resolve bond angles, bond strengths, and torsion angles of molecules using an X-ray beam. Both PXRD and SCXRD techniques can be used depending upon the type of the samples, whether they are in the crystalline or powder form. The PXRD technique is used to observe the phase transformation properties of some of the cocrystals . The SCXX-ray photoelectron spectroscopy (XPS) is another important technique for determining the nature of molecular solids  by studying changes in the binding energy of the core electrons on the atoms which participate in hydrogen bonding or proton transfer. XPS gives information about the extent of proton transfer in acid–base molecular crystals. It is used to explain whether the formed product is a salt or cocrystal. In a salt, there is transfer of protons which leads to more shift in the binding energy of core electrons of the atoms participating in proton transfer, but in a cocrystal, there is no proton transfer between the molecules, so there will be very less shift in the binding energy of the core electrons. Schroeder et al. showed for the first time that it is possible to differentiate between a salt and cocrystal by observing the shifts in the binding energies of the core electrons . Srinu eTo harness the ability of cocrystals for the production of improved drug forms, we need to optimize/develop cocrystallization techniques for industrial purposes. Industrial production of cocrystals requires scalable, robust, and environmentally friendly cocrystallization techniques. The quality of the product should not be compromised by large-scale production. API-conformer lability, solubility and stability of components, vulnerability to form polymorphs, amorphous states or solvates of components are the criteria for the selection of the cocrystallization technique. The purity, morphology, and particle size distribution of cocrystals are greatly influenced by the choice of the cocrystallization technique . DespiteSpray congealing is a relatively new cocrystallization technique in which molten API and conformer mixture is passed through an atomizer. The atomizer breaks the liquid into fine droplets, and these droplets are cooled by a cocurrent stream of cooling gas. This process leads to the solidification of liquid into fine particles, forming cocrystals. Since the lack of usage of any solvents, spray congealing is a green technique . It permSpray drying is a solvent-based cocrystallization technique. HME is a solvent-free cocrystallization method. Jafari et al. studied HME as a manufacturing technique for a model cocrystal system ibuprofen:nicotinamide. They succeeded in achieving the total conversion of constituents into a cocrystal product by optimizing the process parameters like screw speed and temperature. They also studied the effect of polymeric excipient (Soluplus) on the cocrystallization temperature and found that the cocrystallization temperature was reduced by the presence of the polymeric excipient, and the mechanical properties of the cocrystals also improved .A recent approach to the quality control of pharmaceutical products is quality by design (QbD), proposed by the International Conference on Harmonization (ICH). ICH defined QbD as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.” The aim of the QbD approach is to produce high-quality pharmaceutical products by understanding product and process and implementing this knowledge in designing the production process. PAT is compatible with the QbD approach . The FDAContinuous manufacturing is a novel process, which was developed as an alternative to the batch process. The batch process is a discontinuous method of manufacturing, whereas continuous manufacturing involves a single continuous process of manufacturing to final products. By implementing a continuous process of manufacturing, we can reduce material waste, energy consumption, and scale-up problems. This method is easy to scale up and facilitates complete automation of product manufacturing. From the above literature examples, HME seems to be the suitable cocrystallization technique in terms of scalability, process control parameters, PAT tools, and continuous manufacturing. But it is not suitable for thermolabile drug molecules .in vitro dissolution and/or solubility studies. From the regulatory perspective, cocrystals of an API are considered as different polymorphs of the same API but not considered as a new API. Drug–drug cocrystals with or without inactive conformer are considered as fixed-dose combination products and not as a new single API  issued guidelines for pharmaceutical industries for pharmaceutical cocrystals. USFDA considers pharmaceutical cocrystals as novel crystalline solid forms that enable the enhancement of stability, bioavailability, and processability properties of APIs. Pharmaceutical cocrystals are clearly distinguished from salts by stating that the components present in the crystalline lattice of cocrystals should interact nonionically. Cocrystals are closely related to solvates except that the conformer is not a liquid when it is in pure form at ambient conditions. For the cocrystal-based drug to get approval from the FDA as an new drug application (NDA) or as an abbreviated NDA (ANDA), the applicant has to prove that the interaction between API and conformer is nonionic with the help of the ∆pKa rule, which states that for the formation of cocrystal, difference between pKa values of cocrystal components should be less than 0 or by any analytical evidence and has to prove that the API and conformer dissociate before reaching the site of action for pharmacological activity by ngle API .EMA considers cocrystals as a subgroup of solvates. Cocrystals of an API are not considered as a new active form because when administered orally, the cocrystals will dissociate and expose the same API to the site of action. New active form status can only be granted to a cocrystal when the efficacy and safety of the cocrystal are significantly enhanced compared to the pure API. Cocrystals are permitted for generic application if they exhibit similar safety and/or efficacy. Safety and quality of the conformer are also very important for regulatory approval if it was not used in medicinal products previously. Drug–drug cocrystals will be considered as another fixed-dose combination but not as a new active compound unless the cocrystal exposes a new active moiety to the site of action .®, Entresto®, and Steglatro® are the marketed drugs that contain cocrystal-based APIs  under storage conditions. Cocrystallization with l-Proline imparts stability against hydrate formation. Suglat® was developed by Astellas Pharma and Kotobuki Pharmaceutical and got approval to market in Japan in 2014  is another example of a drug which has been identified as a cocrystal at a later stage ; this unit is linked into chains by a neutral oxalic acid molecule  is another example, which was identified as a cocrystal at a later stage (2016)  . Chloraltetramer   with fumaric acid, which exhibits similar solubility as the original drug but with improved stability. FDA approval is pending for this cocrystal .The primary challenge in the development of pharmaceutical cocrystals is the selection of suitable conformers. Theoretically, the number of possible conformers is very high, so there is a need to develop a screening tool that can predict the probable conformers. Thereafter, these predicted conformers should be experimentally screened to check for the formation of cocrystals . Due to in vitro–in vivo correlation properties of cocrystals, which can reduce the development time significantly , concentration effects, choosing correct heating and cooling profiles, etc. The solid-state grinding method is better than solvent-based methods for the screening of cocrystals. But sometimes solid-state grinding induces phase transformations in pharmaceutical cocrystals . All theficantly . The avaFrom the above discussion, we can conclude that the phenomenon of cocrystallization is a better alternative than conventional methods like salt formation, solvates, and polymorphs, to improve the physicochemical and processability characteristics of APIs. An inherently limited number of solvates, polymorphs, and lack of suitable ionizable groups in some APIs limit the application of salts, solvates, and polymorphs in the development of APIs into pharmaceutically acceptable forms. The research during the last decade contributed to the evolution of various aspects of cocrystallization, such as cocrystal screening and development, characterization, production methods, and formulations. Guidelines from regulatory authorities  regarding pharmaceutical cocrystals testify the established role of pharmaceutical cocrystals in the development of better candidates with improved characteristics. Still, this method has not become a routine method for the production of pharmaceuticals. For the standard application of cocrystals in the pharmaceutical industry, research needs to be focused on standardizing synthetic procedures of cocrystals, identifying and optimizing the parameters that influence the quality of cocrystals , and cocrystal screening and development should be included in the drug development process.


Neuroimaging is a critical component of triage and treatment for patients who present with neuropathology. Magnetic resonance imaging and non-contrast computed tomography are the gold standard for diagnosis and prognostication of patients with acute brain injuries. However, these modalities require intra-hospital transport to strict, access-controlled environments, which puts critically ill patients at risk for complications and secondary injuries. A novel, portable MRI (pMRI) device that can be deployed at the patient's bedside provides a needed solution. In a dual-center investigation, Yale New Haven Hospital has obtained regular neuroimaging on patients using the pMRI as part of routine clinical care in the Emergency Department and Intensive Care Unit (ICU) since August of 2020. Massachusetts General Hospital has begun using pMRI in the Neuroscience Intensive Care Unit since January 2021. This technology has expanded the population of patients who can receive MRI imaging by increasing accessibility and timeliness for scan completion by eliminating the need for transport and increasing the potential for serial monitoring. Here we describe our methods for screening, coordinating, and executing pMRI exams and provide further detail on how to scan specific patient populations. Timely and accessible neuroimaging is crucial for accurate detection and treatment of neuropathology. High field magnetic resonance imaging (MRI) and computed tomography (CT) are the standard options for neuroimaging in most hospitals. Unless deemed life-threatening or hyper-acute, use of the MRI is subject to scanner availability as it is a shared resource and is balanced against the schedule. Additionally, these require patients to be temporarily disconnected from vital hospital equipment and transported to designated imaging suites, processes which are prone to significant time-delays. Such intra-hospital transport therefore has potential to jeopardize patient safety not only because it interrupts continuous monitoring, but also because it can lead to dangerous secondary injuries including airway displacement, oxygen desaturation, hypotension, hypertension, increased intracranial pressure, and hypoxia –6. Even Concerns with timely access to and the impact of intra-hospital transport, related to both safety and time, suggest an urgent need for point-of-care imaging. We have previously reported the use of a portable, low-field MRI device to obtain neuroimaging at the bedside. Our prior work has demonstrated the ability of this device to produce neuroimages that can detect primary injury like ischemic stroke and intracerebral hemorrhage, as well as other neurological sequelae and relevant biomarkers , 10. TheAll scans were conducted using a bedside pMRI system  which operates at 0.064T magnetic field strength. The device is cylindrical with a height of 140 cm, width of 86 cm, and weight of 630 kg. There is a 5 Gauss (0.5 mT) collapsible ring guard that extends from the top of the scanner into a circle with a diameter of 158 cm and is deployed when the device is in transit . The scaThe scanning environment can contain standard ICU ferromagnetic equipment  but should remain outside the 5 Gauss line. The device allows for 3D, whole brain DWI, FLAIR, T2W, and T1W imaging. This observational study was performed under an Institutional Review Board (IRB) protocol in accordance with guidelines and policies informed by the Yale Human Research Protection Program. Until August of 2020, pMRI exams were acquired after obtaining informed consent from the patient or their legally authorized representative. After this point, when the device was granted specific FDA approval, pMRI exams were obtained as part of the patient's clinical care without research consent.For patients admitted to the ICU or ED, we reviewed demographic data, clinical course characteristics, and available conventional neuroimaging from the electronic medical record. Depending on the type of pathology, clinical characteristics of interest included last known normal, time and date of surgical procedure, size of lesion, and location of lesion. For each patient, institution-specific MRI screening form, adhering to 1.5T MRI guidelines, was completed with the patient or the patient's legally authorized representative. Exclusion criteria included the presence of an MRI contraindication such as: pacemaker, defibrillator, implanted medication pump, vagus nerve stimulator, deep-brain stimulator, or programmable shunt; MRI-incompatible surgical hardware such as metal staples, screws, clips, etc.; suspected metal in eye; presence of spinal fractures. Patients who were pregnant during the time of hospital stay or <18 years old were also excluded. The pMRI device is safe for use with biomedical devices that have been cleared for magnets of field strength 1.5T and below.The bedside nurse was consulted to gauge each eligible patient's ability to lay flat for the duration of a pMRI scan. In the ED, the charge nurse was also consulted. Clinical reasons which limited a patient's tolerance in lying supine included intolerable back pain, elevated intracranial pressure, high risk aspiration, respiratory issues , unstable blood pressure, and uncontrolled agitation. Some of these barriers were particularly relevant in patients with severe COVID-19 infection. If there were concerns for instability, the nurse performed a flat trial to see how the patient tolerated the supine position. A flat trial would allow the bedside nurse to assess if there may be a need for any additional sedation or analgesia needed for the scan and administer medications within ordered parameters.A member of the clinical team  was consulted prior to initiating the scan to ensure that there would be no interference with the patient's treatment pathway. This step was especially relevant in the ED, where patients admitted as stroke codes or intracerebral hemorrhage (ICH) alerts were often considered for emergent thrombectomy or surgical evacuation. If this was the case, pMRI scans were usually postponed so as not to delay those clinical interventions. In future deployments, pMRI could potentially be used as a valuable intraoperative tool during these time-sensitive procedures. If the attending physician desired an emergent pMRI exam, the scan was performed immediately. Otherwise, a time was scheduled with the patient's bedside nurse around other clinical procedures, including conventional neuroimaging, X-ray, echocardiogram, OR/IR procedures, physical therapy, and speech pathology.After a scan was coordinated, the pMRI device would be transported to the patient's hospital room from its secure storage location. In the YNHH ICU, it is kept in a restricted-access equipment room requiring authorized badge access with the 5 Gauss line delineated ; in the The pMRI device is powered by a motor and easily maneuvered by a single person. The device must be in “Transport” mode to move, with the key in the control panel turned to the left; there are also “Scan” and “Locked” modes, which are used for scanning and charging, respectively. There is a joystick located to the left of the control panel with buttons to adjust between five speed settings, depending on surrounding obstacles during transit . There aPrior to the examination, the scanner's head coil, magnets, bridge, and cushioning pads were cleaned and disinfected using Super Sani-Cloth Germicidal Disposable Wipes by PDI, Inc., in accordance with the manufacturer's instructions. To prepare the patient's hospital room, the bed was pulled 4 feet away from the wall to provide clearance for the scanner behind the head of the bed. The relative positions of IV stand(s), ventilator, physiologic bedside monitor, electrical and medical gas booms, and other equipment were adjusted in parallel with the bed so that any wires connected to the patient maintained adequate slack without being disconnected. All electronic equipment was kept outside of the controlled access area, as specified by the manufacturer. To ensure optimal access and safety, room furniture  and personal effects/items were relocated to the far corners of the room. The television was turned off to reduce interference. Any IV bags hanging from the vertical metal poles at the head of the bed were moved to a mobile IV stand, and the poles were folded down. The scanner required a clear path unobstructed by wires, so the bed and IV cords were briefly unplugged if necessary to allow the scanner to clear. These were promptly reconnected after the scanner passed.After the scanner was positioned at the head of the bed, it was plugged in and turned on. The scanner bridge was deployed, and the back cushion was put in place. This cushion provided padding for the back and shoulders when the patient was inside the scanner. The head of the bed was lowered so that the patient was supine. Prior to laying the patient flat, any nasogastric feeding tubes were placed on hold, and any external ventricular drains were clamped. The bed was adjusted so that it was level and flush with the bridge, and all transducers were re-leveled to allow for accurate monitoring during the exam. The bed was locked in place, and all restraints  were undone, if applicable. If present, the patient's Foley catheter was moved from the end to the middle of the bed to avoid pulling or accidental disconnection. If the patient had Intermittent Pneumatic Compression devices attached to the legs, then they were disconnected for the duration of the exam. Any pillows were removed from underneath the patient's head, arms, and legs to aid in moving the patient into the coil. Any metal-containing accessories were removed including glasses, earrings, hair pins, necklaces, hearing aids, and dentures, as they often cause artifacts in the images acquired. Patients were offered ear plugs and an eye mask.Once the bed and the scanner were both in the proper positions, the patient was positioned such that their head was as far back into the coil as possible. With at least one pMRI operator standing on either side of the bed, the bed-sheets underneath the patient were used to slowly move the patient backward until either the top of their head touched the back of the coil or their shoulders reached the base of the coil. The patient was moved in increments of ~10–15 centimeters using the draw sheet such that IV lines and stands could be moved in parallel, and any wires connected to the patient could be untangled. Optionally, a ceiling lift was used to position the patient in the coil then the draw sheet used ensure the patient was properly in the coil. Once the patient was positioned as deep into the coil as possible, a large cushion was placed underneath the legs to reduce any pain or pressure in the lower back . PillowsIf alert and oriented, patients were informed that the best quality of images would be obtained if there was minimal movement inside the coil. They were also notified of the length of the scan and the kinds of noises to expect from the pMRI machine. In the absence of an emergency squeeze ball as with conventional MRI scans, operators remained inside or just outside of the room to make the patient aware of their presence and allow for the patient to communicate any discomfort or desire to be removed from the scanner. During the scan, operators regularly checked in with the patient verbally to avoid feelings of isolation and anxiety. Nurses and clinical staff were able to freely enter and exit the room during the exam to monitor vitals, administer and titrate medications, or draw blood. Cautionary signs were hung at the door to warn any pregnant staff or those with active, programmable implants of the magnet.The scan was configured and run using an electronic tablet  that could connect to the WiFi hotspot provided by the pMRI scanner. After logging into the Hyperfine interface, subject information was entered, and the desired sequences were selected. At minimum, the interface needed a Patient ID and year of birth to be entered before an exam can be initiated. The protocol ran until completion unless otherwise paused or terminated early. The exam could be paused at the end of each sequence, for re-positioning of the patient or other reasons, and restarted without issue. At any point during the exam, additional sequences could be added to the protocol, and sequence order could be altered.The interface has multiple tabs: the “Patient” tab is where patient information is entered ; the “ExOur protocol consisted of a pre-scan calibration, localizer or auto-align, DWI with ADC map, FLAIR, T2W, and T1W sequences . If a patient needed to be removed from the scanner before completion of the full exam, the stop button was pressed on the interface. In case of an emergency, the red E-stop button on the scanner's control panel can also be pushed. Reasons for early termination included patient claustrophobia, agitation, discomfort, declining clinical status, transfer to another unit, or transport for another procedure.When the patient was taken out of the scanner, cushions and pillows were first removed from around the patient's head, arms, and underneath the legs. Using the bedsheets or celling lift, the patient was slowly moved back into the bed, and any restraints were reapplied, if applicable. The bed was lowered to its original height, and the head was raised to a comfortable angle. The scanner was removed from the patient's room, and the bed was returned to its original position against the wall, along with any other objects and furniture that were moved. Outside, the scanner was sanitized again with disinfecting wipes and returned to its appropriate storage location. The device was plugged in to a standard outlet to charge and left on in “Locked” mode to allow for raw data to upload.The process for executing a pMRI scan is outlined in Body habitus occasionally presented challenges for optimal positioning within the scanner's head coil. Factors that hindered positioning and depth included weight, head and nose size, shoulder width, neck length, and chest height. For patients suspected of possibly not fitting into the pMRI, the coil was removed and tested around the patient's head to determine if pMRI was plausible. Some helpful tactics employed for challenging patients included: (1) adjusting the bed into a Trendelenburg position allowing gravity to assist with the positioning if there was no concern for intracranial hypertension; (2) depending on the size of the patient, pulling their arms together around the torso to reduce shoulder width and allow them to pass through the RF shield. If the patient's head was large, or if they had many layers of head dressing after a surgery leaving minimal to no room in the coil, then the need for foam cushions on either side of the face was negated; (3) using the ceiling lift if available. Severely obese patients, especially those with tenuous respiratory status, would sometimes desaturate in the supine position, so their oxygen levels were continuously monitored throughout the scan. Our preliminary evidence has suggested that patients weighing up to ~140 kilograms can be successfully scanned; however, this rule is general and does not apply to all patients. The scanner has an official maximum weight limit of 200 kilograms, beyond which it is unsafe to scan.Ventilators were typically located on the side of the patient's bed closest to the hospital room door, while the bedside monitor and IV stand(s) were located on the opposite side away from the door. When the bed was moved 4 feet away from the wall to accommodate the scanner, the ventilator was moved in parallel to avoid accidental disconnection from the patient. Sometimes, it was useful to adjust the angle of the patient's bed in relation to the wall  to maintain slack in the endotracheal tube and ventilator circuit. There were two methods for navigating the scanner to the head of the bed. One option was to disconnect the patient from the ventilator and temporarily connect to a portable oxygen tank with the help of a trained Respiratory Therapist (RT). This allowed the ventilator to be briefly unplugged from its power outlet and moved out of the way so that the scanner could pass behind. If the RT and/or the bedside nurse was not comfortable doing this, the other option was to bring the scanner around to the other side of the bed. In this case, the IV stand(s) were briefly unplugged to allow the scanner to pass, but the bedside monitor was not disconnected. Instead, the cord(s) were lifted vertically by one operator while the other maneuvered the scanner underneath. When the patient was being positioned inside the coil using the bedsheets, operators moved the patient in small increments so that the ventilator could be moved in parallel. Increasing the pMRI personnel to 3 or 4 people during positioning ensured that one operator had uninterrupted visualization of the endotracheal tube and ventilator tubing to minimize the risk of migration or dislodgement. For some patients, the endotracheal tube would occasionally point directly upward and hit the top magnet. If this was the case, the tubes were shifted to the corner of the patient's mouth to ensure that the head could remain straight . After the patient was positioned, the ventilator was moved as far from the bed as possible—while still maintaining adequate slack in the endotracheal tube—and the monitor was turned away from the scanner's opening to reduce any interference noise. Throughout the setup and scan, the ventilator was kept outside of the controlled access area, based on the manufacturer's indications.Patients who were connected to dialysis machines or continuous renal replacement therapy could be scanned without disrupting those processes. The same cautions were heeded as for ventilated patients regarding positioning the scanner in the room. If a patient had both a ventilator and dialysis machine located on opposite sides of the bed, then the scanner was positioned behind the bed via the side that required minimal disturbance of room equipment. If the room was larger, it was more convenient to bring the scanner around on the side of the dialysis machine. If the room was smaller, it was advantageous to bring the scanner on the side of the ventilator, since the dialysis machine should be kept outside of the 5 Gauss line of the pMRI device when running. Dialyzed patients often had a central venous catheter connected to the neck that was covered with thick dressing, which could not be disconnected or disrupted. If this was the case, the foam cushions placed on the side of the face were omitted to avoid disturbance.Severe COVID-19 patients had multiple IV stands present in the room and were often ventilated and dialyzed due to multiple-organ dysfunction. When scanning patients with COVID-19 infection, a separate designated scanner was used to avoid cross-contamination in non-infected patients. Due to strengthened protocols by the hospitals, the entire surface area of the scanner was sanitized with bleach wipes before and after every scan. Operators of the pMRI wore the appropriate personal protective equipment required under hospital regulations, including surgical scrubs, N95 mask, face shield, disposable gown, bouffant cap, and nitrile gloves. These measures can also be generalized to patients with precautions for other infectious diseases, such as MRSA, E. Coli, VRE, etc.After thrombolysis with tissue plasminogen activator or reperfusion by mechanical thrombectomy, patients required neurological assessments from the bedside nurse every 15 min for the first 2 h. These assessments included measurement of vital signs, pupil check, muscle strength, Glasgow Coma Scale score, and frequent National Institute of Health Stroke Scale scores. If these patients were scanned with pMRI, then one or more neurological checks needed to be omitted during the exam. This required written authorization from the patient's attending physician in the electronic medical record. Additionally, some thrombectomy patients were advised not to bend at the hip if it was a femoral access site for 2–6 h post-procedure . The bedside nurse was consulted to assess whether it was safe to provide the patient with the cushion to elevate the legs after being positioned in the scanner.Patients were sometimes put on cervical/spinal precautions if there was any suspicion of spinal injury, with examples including motor vehicle accident or possible trauma if found down. A cervical collar (C-collar) was often placed out of an abundance of caution, but the patient could still be scanned if there was no spinal fracture or immediate concern for injury. When scanning a patient with a C-collar, at least two people were needed on either side of the bed when sliding the patient into the scanner. This ensured that there was enough assistance to slide the patient very slowly and carefully without abrupt jerking movements. The process of removing the patient from the scanner followed the same method. One person gently held the patient's c-spine under the nape of the neck and guided the head into and out of the coil. While in the scanner, the patient was monitored closely for any signs of neck pain or tenderness.Some patients who reported claustrophobia in conventional 1.5/3T MRI exams seemed to better tolerate the pMRI due to its open-geometry design and the fact that only the head is encased rather than the whole body. For others, claustrophobia or emotional distress during the exam were cited as reasons for early termination. For most patients, we did not administer sedatives or anxiety medications during pMRI scans, unless they were already intubated and receiving continuous sedation/narcotic infusion. Instead, we implemented other strategies to mollify patients and limit agitation, including offering eye masks and ear plugs, remaining in the hospital room during scan acquisition, and giving time updates between each sequence.The pMRI is a useful tool not only because it can provide neuroimaging at the point-of-care, but also because it does so in a convenient and relatively low-stress manner. The device itself is easy to transport, position, and operate. It does not require patients to be disconnected from their equipment and limits the potential risks associated with traveling with critically ill patients and the conventional MRI magnet. It can function in the presence of common hospital ferromagnetic devices, including ventilators, IV pumps, EKG monitors, dialysis machines, and compressed gas tanks, outside of the 5 Gauss line. The pMRI is also a minimally intrusive device since the patient is not disrupted other than being positioned supine. The scanner plugs into a standard wall outlet and does not require a special power source or cryogens. It does not require a licensed MR technician to operate; instead, it can be operated by any non-credentialled staff member who undergoes simple training, thereby reducing the workload and inter-department cooperation that is typically required for transporting patients for neuroimaging. For these reasons, the ease and simplicity of pMRI render it useful in diverse clinical environments as well as outpatient clinics and, in the future, possibly ambulances.A step in the right direction for point-of-care imaging can even be seen with pCT machines, which are currently deployed today in ICUs and may provide similar benefits as pMRI with regards to minimizing transport-associated risks. pCT offers neuroimaging at the patient's bedside, thereby increasing efficiency and providing safe radiological imaging while circumventing transport-associated hazards –15. For Perhaps the greatest utility of the pMRI lies in its ability to broaden the spectrum of patients who can receive MR imaging. By imaging at the bedside, patient populations who may otherwise be unable to transport can now be imaged. For example, we scanned 18 patients suffering from severe COVID-19 infection who did not receive any brain MRI or CT scans at all during their hospital stay. We also scanned an additional 17 COVID-19 patients who did receive conventional neuroimaging, but only after they had successfully undergone a pMRI bedside exam and had stabilized further for safe transport. In some cases, an incidental finding on pMRI aided patient care by detecting previously unknown pathology and giving clinical teams an indication of neurological status, which was especially advantageous for those patients who were sedated and paralyzed for ventilator management. Patients with other, non-COVID infectious diseases would also be prime candidates for pMRI because remote imaging at the bedside would enable contact precautions to be maintained, thereby limiting exposure to other patients and hospital staff. Besides COVID-19-related cases, there are other populations of critically ill patients who are too unstable to be transported from their hospital rooms and may benefit from pMRI imaging. Examples would include cardiac arrest patients, ventilated patients with severe acute respiratory distress syndrome, and those with multiple-organ failure who are connected to continuous renal replacement therapy.The pMRI has immense potential to change the current paradigm in neurological imaging. However, while the device can provide imaging at the point-of-care and increase the frequency of neurological monitoring, we acknowledge several limitations that currently obstruct its widespread clinical implementation. First, the total acquisition time is long compared to conventional MRI, requiring the patient to stay inside the scanner for upwards of 30 min when integrating FLAIR, T2, T1, and DWI with ADC map. However, the overall time frame for setup, scan acquisition, and removal is still less than that of a conventional MRI (when including time from order placement to completion and transport-associated delays). We have also seen significant reductions in scan times since the device was first deployed in 2018 as scanner upgrades improve the performance. Another drawback is the lower resolution of the images when compared with 1.5 or 3T MRI, a tradeoff that is inevitable with a low magnetic field strength. We have found that the image quality can be vulnerable to high interference noise from equipment in the hospital room as well as patient motion inside the scanner. Fortunately, software upgrades and processing reconstruction technology continue to be developed that can mitigate these factors and enhance the quality of the images. There have been significant improvements in quality since the device was first deployed at YNHH just 3 years ago, especially in the consistency and reliability of the FLAIR, T2W, and T1W sequences. A sample non-pathological exam is provided in We obtained neuroimaging at the bedside for patients in the ICU and ED at YNHH and the Neuroscience ICU at MGH. Our preliminary findings demonstrate the safety and feasibility of obtaining point-of-care MR neuroimaging in a wide range of patients who present with neuropathology. Our goal in this report was to describe the ease and convenience of operating the pMRI and incorporating it into the clinical workflow in various settings. We also sought to provide details on some of the barriers and challenges that we have encountered with respect to scan coordination and execution. While we acknowledge that there may be alternative ways of approaching pMRI scanning, our aim was to share the techniques that our team has found successful in different settings at YNHH and MGH. The methods presented here will likely adapt as this approach is used more frequently at multi-center institutions.The pMRI is a novel solution that circumvents the need to disconnect patients from ferromagnetic monitoring devices or life-sustaining equipment for transport to conventional imaging suites, which thereby broadens the population of critically ill patients who can receive MRI. While pMRI is not used as a replacement for conventional CT and MRI at YNHH at this time, the device has expanded the potential for patients to receive serial imaging, which in turn helps clinical teams stay abreast of the status of their patients. Further work is still needed to deploy this technology in a larger variety of clinical settings to determine its full scope and utility.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Yale Human Research Protection Program. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.KS takes responsibility for all independent decisions made regarding study concept and conclusions. AP and KS: design and writing of the manuscript. AC, MM, MY, IC, AW, WH, NT, SQ, JH, CW, GS, MSR, and WK: critical revision of the manuscript. AP, AC, MM, MY, and IC: data acquisition. All authors contributed to the article and approved the submitted version.This study was supported by funding from the American Heart Association . The portable MRI device that was developed, deployed, and provided to Yale was borne out of an academic-industry collaboration, where the AHA grant supported the academic investigators. KS was supported by the NIH  and the American Heart Association . The authors also declare that this study received funding from Hyperfine Research, Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.MSR is a founder and equity holder of Hyperfine, Inc. The remaining 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.


Children with attention deficit/hyperactivity disorder (ADHD) are vulnerable to traumatic injuries. Parents of children with ADHD experience undesirable impacts more frequently than parents of children without ADHD. The aim of this study was to evaluate whether traumatic injuries are more prevalent in parents of children with ADHD than in parents of children without ADHD. We compared the prevalence of traumatic injuries between parents of children with and without ADHD by using data from the Taiwan Maternal and Child Health Database from 2004 to 2017. The Cox proportional-hazards regression model was used to examine differences in burn injury, fracture, and traumatic brain injury between parents of children with and without ADHD after adjustment for age, urbanicity, and income level. In total, 81,401 fathers and 87,549 mothers who had at least one offspring with ADHD and 1,646,100 fathers and 1,730,941 mothers with no offspring with ADHD were included in the analysis. The results indicated that both fathers and mothers of children with ADHD had higher risks of burn injury, fracture, and traumatic brain injury than fathers and mothers of children without ADHD. Mothers of children with ADHD had higher risks for all kinds of traumatic events than fathers of children with ADHD. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder characterized by inattentiveness, hyperactivity, and impulsivity ,2. The pCompared with healthy peers, children with ADHD are more prone to accidental injury and trauma ,15, whicAlthough the association between ADHD and traumatic injuries in children had been explicated, the impact of children’s ADHD on their parents warrants further study. A review of twin studies revealed that the heritability of ADHD ranges from 77% to 88% ; howeverParents of children with ADHD experience undesirable impacts more frequently than parents of children without ADHD. In comparison with parents of children without ADHD, parents of children with ADHD reported lower self-efficacy to help their children, felt less welcome and supported by their children’s schools and teachers, and perceived less time and energy for involvement in their children’s academic lives and social interaction . FamilieWe used the Taiwan Maternal and Child Health Database (TMCHD) to investigate the risk of traumatic injuries in parents of children with ADHD. This study examined the risk of traumatic injuries in parents of children with ADHD. The results of this study may provide knowledge to develop service programs to enhance parental health. We hypothesized that parents who had children with ADHD were more likely to experience traumatic injuries than those who had no children with ADHD.Our study consisted of liveborn children with complete information about the gestational age at birth and identity of both parents in the TMCHD from 2004 to 2017. The data include 99.78% of all births in Taiwan since 2004 . TMCHD dInternational Classification of Disease, 9th revision, Clinical Modification [ICD-9-CM] code: 314 and 10th revision [ICD-10] code: F90) or one inpatient diagnosis of ADHD within the study period , they were identified as having a diagnosis of ADHD.In this study, the children’s ADHD status was the exposure. If the children received more than three outpatient diagnoses of ADHD , urbanicity , and low-income level. The urbanicity was stratified into seven levels from 1 (urbanized cities) to 7  based on the development level of each area . We cateFor descriptive statistics, frequency with proportion and mean with standard deviation (SD) are reported for categorical variables and continuous variables, respectively. To determine the risk of traumatic injuries in parents whose children did and did not have the diagnosis of ADHD, we used the Cox proportional-hazards regression model with time-on-study as the time scale, with adjustment for age, urbanicity, low-income level, and competing risk of death. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to quantify the risk and statistical significance of traumatic injuries, respectively. Parents of children without ADHD served as the reference. An HR value greater than 1 suggested that the risk of traumatic injuries is higher in parents of children with ADHD compared with parents of children without ADHD. If the CI of the HR included the null value of 1, there was no significant difference in the risk of traumatic injuries between parents of children with and without ADHD. We further compared the risks of traumatic injuries between fathers and mothers using the difference of two hazard ratios divided by the square root of the sum of the two squared standard errors .2 = 39.29, p < 0.001), fracture , and traumatic brain injury . For mothers of children with and without ADHD, the proportions of traumatic injuries were as follows: burn injury , fracture , and traumatic brain injury .p < 0.001).The results of the current study confirmed the hypothesis that parents of children with ADHD were more likely to experience traumatic injuries than those of children without ADHD. In addition, mothers had greater risks of traumatic injuries than fathers when having children with ADHD. To our knowledge, this is the first study to examine the risks of traumatic injuries for both fathers and mothers of children with ADHD worldwide. The fathers and mothers of children with ADHD had higher risks of burns, fractures, and traumatic brain injury than those of children without ADHD. The current study benefited from the establishment of the healthcare database in Taiwan. The pairs of data for parents and children were derived from the TMCHD , which wSeveral reasons may account for the higher risk of traumatic injuries in parents of children with ADHD. First, ADHD is a highly heritable neurodevelopmental disorder. A review revealed that the estimated heritability of ADHD is as high as 71–90% . A behavSecond, the undiagnosed ADHD in adulthood may increase the risk of traumatic injuries in parents. Several factors contribute to the underdiagnosis. First, medical record keeping started in 2004 at the TMCHD  and pareThird, although little evidence exists on children with ADHD being violent toward their parents, studies have shown that adults with a history of ADHD are more likely to perpetrate violence to intimate partners than controls ,42. HypeLast, studies have revealed that a high proportion of parents having children with ADHD experience depression  and anxiSeveral limitations of the study must be addressed. First, as a retrospective cohort study, the possibility of missing records for detailed clinical variables limited the presentation of outcome. Second, for a naturalistic observation, confounding factors cannot be controlled to the same extent as that in a clinical trial. However, naturalistic studies could include individuals more representative of real-world clinical settings. Third, individuals included had undergone treatment so that they could be identified in the TMCHD; however, those who did not seek medical help for ADHD or traumatic injuries were not included into the study.This study revealed that parents who had at least one child with ADHD were at a higher risk of burn injuries, fractures, and traumatic brain injury compared with those without a child affected by ADHD; moreover, mothers were at a higher risk than fathers for all types of traumatic events. The current study implicates the importance to be aware of the increased risks of traumatic injury among parents of children with ADHD. Proper education about accident prevention and management may be helpful to the parents of children with ADHD. Given that knowledge is fundamental to act, it is essential to educate the parents of children with ADHD the increased risk of traumatic injuries they may have. It is also to help the parents to look back upon their life experiences and detect the histories of encountering traumatic injuries. Detecting the association of inattention, impulsivity, and psychological burden on parenting with the occurrences of traumatic injuries should help the parents to raise alertness of and develop prevention strategies for the possibility of traumatic injuries. The need for behavioral and pharmacological intervention in parents of children with ADHD should be evaluated, especially in the parents with undiagnosed ADHD or subthreshold ADHD symptoms. It deserves further prospective studies with longer follow-up period to explore whether undiagnosed ADHD, care burden of parents, and children’s aggressive behaviors contribute to the increased risks of traumatic injuries in parents of children with ADHD.