For people with physical disabilities, manual wheelchairs are essential enablers of mobility, participation in society, and a healthy lifestyle. Their most general design offers great flexibility and direct feedback, but has been described to be inefficient and demands good coordination of the upper extremities while critically influencing users’ actions. Multiple research groups have used Inertial Measurement Units (IMUs) to quantify physical activities in wheelchairs arguing that knowledge over behavioural patterns in manual wheelchair usage can guide technological development and improved designs. The present study investigates turning behaviour among fulltime wheelchair users, laying the foundation of the development of novel steering systems that allow directing kinetic energy by means other than braking. Three wearable sensors were installed on the wheelchairs of 14 individuals for tracking movement over an entire week. During detected “moving windows”, phases where the velocities of the two rear wheels differed by more than 0.05 m/s were considered as turns. Kinematic characteristics for both turns-on-the-spot as well as for moving turns were then derived from the previously reconstructed wheeled path. For the grand total of 334 km of recorded wheelchair movement, a turn was detected every 3.6 m, which equates to about 900 turns per day on average and shows that changing and adjusting direction is fundamental in wheelchair practice. For moving turns, a median turning radius of 1.09 m and a median turning angle of 39° were found. With a median of 89°, typical turning angles were considerably larger for turns-on-the-spot, which accounted for roughly a quarter of the recognised turns and often started from a standstill. These results suggest that a frequent pattern in daily wheelchair usage is to initiate movement with an orienting turn-on-the-spot, and cover distances with short, straightforward sections while adjusting direction in small and tight moving turns. As large bends often require simultaneous pushing and breaking, this is, perhaps, the result of users intuitively optimising energy efficiency, but more research is needed to understand how the design of the assistive devices implicitly directs users’ movement. According to the World Health Organisation, approximately 1% of the population with musculoskeletal impairments or disabilities, or worldwide more than 65 million people rely on a wheelchair for mobility . The samWheelchairs generally use four independent wheels and are push-rim controlled, meaning that hand-rims on the large rear wheels act as the interface for propelling and navigating the system: pushing forward on both sides simultaneously results in a forward motion, while braking on one side causes a turn to the respective direction. Although offering great flexibility and direct visual, proprioceptive and kinaesthetic feedback , such a This study aimed to lay the foundations for introducing novel interaction-principles in the design of manual wheelchairs based on the concept of steering systems that allow directing kinetic energy by means other than braking. Multiple groups have argued that knowledge of wheelchair usage in daily life is an invaluable resource to the design, engineering, and manufacture of new, possibly improved models . Here, tTowards improving rehabilitation process, different portable measurement systems have been proposed for tracking wheelchair user’s activity, for example by monitoring and promoting active sitting . Similarhow people negotiate spaces and move from one place to another.Interestingly, rotation behaviour is developing as an important parameter in neuropsychological studies, where the number of left/right turns are thought to be indicative of laterality or rotation biases . HoweverIndividuals who have relied on a manual wheelchair for mobility for a duration of at least 6 months before the measurements were included in this study. Participants were required to be at least 18 years old, active wheelchair users that are able to propel their wheelchairs independently. Exclusion criteria included suffering from an acute injury, such as a pressure ulcer or shoulder injury, as well as untreated mental illnesses such as depression. The study was approved by the ethics committee of ETH Zurich (EK 2020-N-04), and all participants provided written informed consent prior to the start of measurements.For this study, a set of three ZurichMOVE  sensors One sensor was rigidly mounted on the spokes of each wheel and one was fixed to the frame below the seat using custom-made, durable adaptors . Primariz-axis coincided with the rotation axis, zrot, of the wheelchair wheels. For the sensor on the frame, the time periods where the wheelchair was at rest  were used to align the z-axis of the sensor with the direction of the gravitational acceleration, zg . Before further calculations, the orientation of the sensors was corrected. For the sensors on the spokes, time periods with a straight-forward wheeling movement  with a duration longer than one second were identified in order to rotate the sensor’s coordinate systems such that the respective tion, zg . These rTo identify and describe turns and turning patterns, a two-step process was undertaken: firstly, only phases in which the wheelchair was moving were considered of interest, and secondly, a reconstructed movement path served as a basis to estimate turning radii and angles.Phases of wheelchair movement were identified, using the definition of moving windows by Popp and co-workers : The wheTo derive wheeled distances and directions, angular velocities of both wheels were multiplied with the wheel’s radius and then integrated. Knowing the wheelchair’s track width allowed the reconstruction of the wheeled path in a 2-dimensional space over time to provide a basis for identifying turns .To determine start- and end-points of a turn during the recognised moving windows, a distinction between moving straight-forward and turning was made. Segments in which the wheel velocities differed by less than 0.05 m/s were considered as straight. Turns were investigated in the remaining time periods.• The duration of a turn-on-the-spot was greater than 0.5 s.• The mean angular velocity of a turn-on-the-spot was greater than 20°/s.• The turning angle of a turn-on-the-spot is at least 45°.The signs of the wheel velocities enabled a differentiation between “moving turns” and “turns-on-the-spot”. The latter were characterised by one wheel moving forward while the other moved backwards, and were detected by opposite signs in the directional data. Assuming that no notable distance was covered for this type of turn, the turning radius was set to zero. All identified turns-on-the-spot were taken into account if all of the following conditions were met:• The duration of a moving turn was greater than 0.5 s.• The mean velocity during a moving turn was greater than 0.12 m/s.• The wheeled distance of a moving turn was greater than 20 cm.• The turning angle of a moving turn was at least 15°.Two consecutive turns-on-the-spot were merged if they were separated by less than 0.3 s. Moving turns were then analysed based on the previously reconstructed wheeled path. Here, turning radius was approximated for each segment using least squares fitting according to Pratt  Figure . Moving Consecutive moving turns were merged if they were separated by less than 0.3 s, or the wheeled distance in between was less than 20 cm. Furthermore, moving turns with a radius greater than 10 m were considered as straight-forward movements. All parameters were chosen based on repeated test measurements where known movement paths like rectangular trajectories, circles, figure-8s and straight lines with turns-on-the-spot at their ends where wheeled. This helped finding definitions that result in plausible distinctions between different types of movement .To verify circularity, the normalised root-mean-square error (NRMSE) of the turning radius was calculated for each moving turn. Turns with NRMSE <4% were classified as “regular turns”. Non–circular turns with NRMSE >4% were further analysed. Here, the first third and the last third of the moving turn were again approximated with the Pratt method in order to examine whether the turning radius was increasing or decreasing. If both new fitted circles had an NRMSE <4%, then the ratio of the two radii was calculated. Turns with a ratio smaller than 0.5 or higher than 2 were classified as “spiral turn” . All remg) from the sensor on the frame was used for calculation.Turns where the absolute velocity of the right wheel was greater than that of the left wheel were categorised as left turns, and the remaining as right turns. Moving turns were further classified as forward or backward turns based on the signs of the wheel velocities. For all moving turns, turning distance was calculated by integrating the center of mass velocity of the wheelchair. For regular turns, turning angles and radii were derived from the fitted circle. For turns-on-the-spot, the angular velocity in the direction of the axis of rotation . The majority of participants had a thoracic spinal cord injury, although one individual with tetraplegia, one with cerebral palsy, and one with knee disarticulation were also included. Additional descriptions of all participant characteristics are presented in The expected maximum measurement error was added to the individual sensor values in order to analyse the maximum offset of parameters of interest and assess their reliability. A comparison between the directly calculated results with artificially erroneous ones over the entire data collection yielded the error values given in The datasets contained a total of 31′410 moving windows. The mean number of daily moving windows was 331 ± 101. Daily moving time was 71 ± 24 min on average, whereby a mean daily distance of 3.10 ± 1.44 km was covered. A large proportion of moving windows were rather short, with a per person median duration averaging 7.0 ± 0.9 s and a median distance of 2.3 ± 0.6 m. Mean median velocity was 0.35 ± 0.05 m/s.Probing moving windows by duration, 64 ± 5% were found to be shorter than 10 s . During Consecutive moving windows were separated by a median time of 16 s, and a mean time of 151 s 78% were separated by less than 60 s, 57% by less than 20 s.A total of 19′673 turns-on-the-spot and 66′829 moving turns was detected in the collected data. Among the latter, 97.2% were classified as regular and 1.9% as spiral. The remaining 658 irregular turns (0.9%) were excluded from the analysis.No participant showed a clear preference with regards to turning direction, resulting in almost equal number of left and right turns in both moving turns and turns-on-the-spot. The majority of moving turns, 89.1 ± 4.3% were wheeled in forward direction.Overall, the median turning radius was found to be 1.09 ± 0.12 m, whereby 90% of the radii were smaller than 3.33 m . The medMedian mean velocity for moving turns was found to be 0.49 ± 0.09 m/s, while backward turns were slower than turns wheeled forward . DuratioTurning with a radius of 0.6–0.8 m was found to be most frequent . In thisDuring the week-long measurement period, participants wheeled a mean 897 ± 328 turns per day, whereby moving turns accounted for 77 ± 5% of all recognised turns .About 30% of all moving windows started with a turn-on-the-spot. 12% of all windows contained neither a moving turn nor a turn-on-the-spot. In the remaining 88%, a mean of 3.1 turns per moving window, composed of 2.4 moving turns and 0.7 turns-on-the-spot, were detected. During moving windows, a turn was wheeled every 4.9 s, with an interjacent mean distance of 3.6 m. More specifically, every 6.2 s a moving turn, and every 22.8 s a turn-on-the-spot was identified, with a mean distance interval of 4.6 m, and 17.0 m, respectively.A comparison between initial and final velocity of moving turns showed that during 63 ± 3%, velocity was lost during the turn . This asIn order to describe typical movement sequences, actions 1 s before and after each turn were assessed. For actions before moving turns, a straightforward movement was found to be the most common, accounting for 41% of the cases. The second most frequent action was another moving turn (25%), a standstill (19%), or turn-on-the-spot (15%). The majority of turns-on-the-spot started from rest (58%) or occurred immediately after a moving turn (29%). Activities including a turn-on-the-spot following a straightforward movement, or another turn-on-the-spot, appeared less frequently .After a moving turn, participants continued with a straightforward movement in about 47% of cases, wheeled a subsequent moving turn in 25%, and stopped directly afterwards in 20%. Another turn-on-the-spot was least frequent with 8%. More than half of all turns-on-the-spot were directly followed by a moving turn (55%), while the wheelchair was stopped in 25%, or superseded by a straightforward movement in about 19% of cases. Turns-on-the-spot following each other were found to be infrequent (<1%) .As enablers of mobility, participation and health, wheelchairs critically shape users’ actions - knowledge about which can, in turn, guide the design and customisation of future assistive technologies. Towards developing novel wheelchair-user-interfaces, this study characterises the turning behaviour of wheelchair users during normal functional activities of daily living. With about 900 turns per day or a turn every 3.6 m, changing and adjusting direction is fundamental in wheelchair usage. A median turning radius of 1.09 m and a median angle of 39° for moving turns suggest that this is typically achieved in sharp corners rather than large bends. Similarly, turns-on-the-spot account for about a quarter of recognised activities and are typically associated with high angles (in the range of 60°–120°), with a majority starting from a standstill. In summary, manoeuvring manual wheelchairs in daily life is best described as a concatenation of orienting turns-on-the-spot, short straight sections, and tight, corrective moving turns.Adding to a body of research on the study of daily activities using wearable sensors, wheelchairs of 14 active wheelchair users were instrumented with a set of 3 IMUs for measurement of an entire week. From these participants, a total of 2,302 h and 334 km of wheelchair movement distributed over 31′410 moving windows that contained 86′565 turns was analysed within this study. Error analysis substantiated that a valid method was chosen to describe the kinematics of turning wheelchairs in daily life. Maximum theoretical errors were small, 5% (NRMSE) or less for all analysed parameters, implying that the analysis results could only been marginally affected by possible inaccuracies in the measured IMU sensor data.The measured mean wheelchair velocity during moving windows, turns, and straightforward movements of 0.35 m/s, 0.57 m/s, and 0.48 m/s, respectively, are comparable with previous literature ranging from 0.2 to 0.8 m/s . The meaFor a general description of activity, Popp and others’ definition of moving windows was used  instead During the measurement periods, an average of 331 moving windows per day were detected. Echoing other authors’ findings , most ofOn average, a moving window contained about 3 turns, most of which were characterised by small turning radii in the range of up to twice the wheelchairs’ track widths as well as small turning angles of less than 90°. Instead of turning in large curves, wheelchair users seemed to prefer to move larger parts of a distance in a straightforward movement and adjust direction in short, tight turns or–in other words–it appears they favour a polygon over continuous circumscribing circles. Literature that helps explaining these findings is extremely limited. In 1990, Reid and co-workers  attempteAssuming that wheelchair users intuitively optimise energy consumption to at least some degree, both the overall high frequency of turns and the predominance of sharp moving turns with small angles appear to be reasonable consequences of the conventional wheelchair configuration that, at least during movement, requires users to break on one side in order to change direction. The large proportion of turns-on-the-spot further supports this argument, especially given frequent movement patterns: almost 60% of turns-on-the-spot started from standstill and about 25% ended a moving window. Roughly a third of moving windows directly started with a turn-on-the-spot. A typical technique of reaching a desired destination appears to be to first align the wheelchair’s orientation with a turn-on-the-spot, then start moving in the desired direction and later adjust the direction with short moving turns as needed. This explanation is further supported by the finding that moving turns often occur during movement or between straightforward segments.The relevance of these results is two-fold: firstly, they highlight the importance of good maneuverability of wheelchairs. The ability to change direction quickly and fluently seems to be essential. Secondly, the kinematics of manoeuvres in wheelchairs are testimony to the conventional wheelchair-user-interaction principle that offers great flexibility thanks to the usually small and light castor front wheels, but on the other hand, this arrangement is inefficient for the precise control of direction. The present study provides a unique insight into wheelchair users’ daily routines, gearing towards the development of novel, steering wheelchairs. Future wheelchair designs will need to offer effortless turning-on-the-spot, and allow small turning radii together with controlled and efficient turning at higher speeds.One limitation was that only 14 wheelchair users participated in this study. Even though some trends were found, inter-subject variability was relatively large. In addition, 85% of participants in this study had a spinal cord dysfunction. The observed results are likely to differ if more subjects with other walking disabilities were included. Next, long-term data collection in daily live can be influenced by many unknown factors such as sensors getting caught or subjects manipulating their position. Even though several measures to prevent sensor misalignment were taken, slight changes to the sensors positions relative to participants’ wheelchairs could have had a marginal influence on the study results. Equally, this study’s outcomes are the results of chosen methods. Especially the definitions of turns, turns-on-the-spot and straightforward movement clearly influenced the central findings. To avoid arbitrary choices, these central parameters were carefully developed in repeated test measurements. Furthermore, some participants reported that they predominantly stayed at home during the measurement period due to the outbreak of COVID-19 and could have moved further and more frequently under different circumstances. The overall distances travelled however still appeared comparable to or even exceeded those reported in previous studies. These limitations imply that a generalisation about overall wheelchair use is difficult, and further studies with a higher number of participants of greater diversity would be needed in order to obtain more conclusive results.This study aimed at describing manoeuvres of wheelchair users in general and did not consider any potentially stratifying factors such as the types of activities, users’ experience and skills or specific wheelchair models. Such comparisons could be the target of further studies. Similarly, the investigation should be repeated if wheelchairs with new steering concepts become available. Potential differences in movement patterns between different wheelchair technologies would highlight the extent to which assistive device mechanisms are able to influence and support users’ behaviour, and hopefully also decrease the risk of injuries and developing pain due to overuse.It is important to note that the methods developed in this study might also be useful in other fields. Therapists could use similar techniques to monitor patients’ activities in order to tailor treatments and training more specifically to each individual’s skills and abilities–especially as different turning techniques are among the most essential wheelchair skills . In courKnowledge about reoccurring patterns in manual wheelchair movement during everyday life can critically contribute to improvements in rehabilitation and related technologies. Analysis of moving windows, turn characteristics, and typical movement patterns in this study provide deeper insight into how wheelchairs are used. Our data suggest that initiating movements, stopping, covering short distances, and manoeuvring in small circles dominate the daily wheelchair usage. These movements are associated with a change in inertia and requires effort from the user. Future wheelchair mechanisms should reflect this by minimising such energy costs to improve efficiency, and develop more ergonomic, energy-efficient, and user-friendly wheelchairs. More research is needed to investigate if the turning behaviour directly depends on the wheelchair type used, or differs significantly between different activities, for example by differentiating indoor and outdoor use. If movement patterns differ considerably, future wheelchairs should offer adaptive mechanisms to switch to the appropriate environment.


Heterogeneity in drug access throughout Europe may be influenced by differences in drug-assessment strategies. The EUnetHTA’s assessment core model (EUnetHTA-core) and the EVIDEM’s multicriteria framework are reference methodologies in this context, the latter including a wider compromise between non-contextual and contextual criteria. Compliance of 37 European Health Technology Assessment bodies (HTAb) with EUnetHTA-core has been reported, but the use of EVIDEM by this HTAb is still unknown.To describe the uptake and use of multicriteria approaches to evaluate drug value by European HTAb using EVIDEM as reference framework, a multicriteria framework was obtained based on EVIDEM model. The criteria used for drug appraisal by HTAb was extracted from the EUnetHTA report, and completed through search of websites, publications and HTAb reports. Use of EVIDEM assessment model in 37 European HTAb has been described semi-quantitatively and summarized using an alignment heatmap.Aligned, medium or misaligned profiles were seen for 24,3%, 51,4% and 24,3% of HTAb when matching to EVIDEM dimensions and criteria was considered. HTAb with explicit responsibilities in providing specific advice on reimbursement showed more aligned profiles on contextual and non-contextual dimensions.EUnetHTA’s core model is limited in assessing medicines while EVIDEM’s framework provides contextual dimension used by some HTAb in Europe that can be escalated to other agencies. Most of the 37 European HTAb have room to broaden their contextual assessment tools, especially when social and medical perception of need requires to be explicit to support payer’s decision on reimbursement.The online version contains supplementary material available at 10.1186/s12913-021-06784-8. One of the major cost drivers in the European healthcare systems is the pharmaceutical ‘innovation’; even considered more relevant than demographics . At the According to the most recent study from the Organization for Economic Co-operation and Development (OECD) , pharmacA recent study  estimateOccasionally, when the drug can cover clinical unmet needs with poor prognosis, the regulators trend to accept less and poorer evidence and include especial approvals, such as conditional approval related to further of adequate risk benefit rate in real world, after commercialization, or approval under exceptional circumstances when this may not be achieved, in order to ensure an earlier access to market. As described recently  the poteBeyond the general awareness among healthcare authorities to ensure “value for money”, or the link between price and social or clinical value of the pharmaceutical innovation , the reiIn Europe, the European Network for Health Technology Assessment (EUnetHTA) was set up in 2006 and includes all EU Member States to provide strategic guidance and policy orientation on the assessment of health technologies (including drugs), by developing policy papers and discussing areas of potential collaboration. During the last decade the network has focused the efforts on the development of common methodologies, piloting and producing joint early dialogues and Health Technology Assessment (HTA) joint assessment reports, as well as developing and maintaining common tools . One of HTA Network approach is focused on technical aspects while methods to support alignment of decisions with the compassionate impetus of healthcare systems is lacking . In manyEVIDEM criteria overlap with EUnetHTA-core except for 4 non-contextual and 3 social criteria, which are absent or partially included in the EUnetHTA framework. Inversely, 2 EUnetHTA criteria are absent in the EVIDEM framework Table .Table 1Although multicriteria EVIDEM approach is now applied by several healthcare authorities , especiaThus, the main aim of this study is to describe the uptake and use of multicriteria approaches to appraise drug value by 37 European HTAb, using EUnetHTA and EVIDEM as reference frameworks.A quantitative validation of the degree of alignment with the EUnetHTA’s standard framework of 37 European HTAb from 28 countries was done, based on a previous qualitative analysis conducted by the European Commission  and an aThe items reported included those criteria in the HTA Core Model, namely: Relative Effectiveness Assessment (REA) of pharmaceuticals, EUnetHTA methodological guidelines  and procAn updated version of EVIDEM framework (v.10) was analyzed in order to assess how the dimensions and criteria included in the EUnetHTA methodological framework fitted within the EVIDEM’s methodological framework.The EVIDEM framework includes 13 non-contextual dimensions and 6 contextual dimensions  were used to summarize the data and 95% confidence interval for each dimension and HTAb Figs. Most of the non-contextual criteria of EVIDEM are overlapped with the core model of EUnetHTA, except for the type of prevention benefits, non-medical comparative cost consequences, systematic use of expert consensus and use of clinical guidelines to define state-of-the-art, which are not or partially included on the EUnetHTA’s framework Table . RegardiMost of the non-contextual dimensions  show consistently high rates among the HTAb (mean above 85% and standard deviation below 16%); other non-contextual dimensions  and relevant contextual dimensions  are systematically rated low Table .Table 2All HTAb address consistently the health problem and current use of technology, technical characteristics, clinical effectiveness and safety criteria, which are included in the EUnetHTA core model. Choices on comparator, methodology of comparison, endpoints and methods of evidence search and synthesis, are consistently aligned. On the contrary, non-clinical domains, assessment approaches, methodology, modelling algorithms and data are consistently dis-aligned Table .Table 3None of the local HTAb had high heat scores with regards to the use of contextual criteria Table . ConsideNine agencies in Bulgary, Hungary, Italy, Malta, Slovakia, Spain, Sweden and UK showed an “Aligned” profile (average heat score above the 75th percentile) with a consistent alignment on non-contextual dimensions and significantly high alignment scores on political/historical/cultural context, system capacity and appropriate use of the intervention.Most HTAb  showed a “Medium” alignment profile. Alignment rates for non-contextual criteria were mainly high  in these HTAb, and also other contextual dimensions  were rated high. On the contrary, population priorities and access dimension systematically rated below 50%, except for AEMPS.In 9/37 (24%) HTAb the profile was considered “Misaligned”, with low scores on alignment (average score below 25th percentile) in dimensions such as patients perceived health methods, cost-consequence analysis  and quality of the evidence. Considering the non-contextual perspective, the German G-BA and the NIPH in Norway show high scores focused and limited to the technical comparison of alternatives . From the contextual perspective, all the HTAb of this group rated low on the mandate and scope of the healthcare system, population priorities on access, system capacity, appropriate use of the interventions and political/historical/cultural context.HTAb with explicit responsibilities in providing specific advice on pricing and reimbursement  showed higher and similar scores on contextual and non-contextual dimensions.The alignment between EVIDEM and EUnetHTA methodological frameworks is consistently high, especially when assessing domains related to health problem description, current use of the technology, technical characteristics, clinical effectiveness, and safety. However, other non-contextual dimensions of the EVIDEM framework and the EUnetHTA core model are consistently misaligned.The main EUnetHTA core model criteria, such as clinical effectiveness, safety conditions, health problem description and current use of technology; are consistently addressed by all HTAb. As previously reported  the instEVIDEM provides a generic interpretive frame  that can be used to elicit individual values and facilitate deliberations through a common structure that includes interpretive scores (quantitative criteria), qualitative impacts  as well as narrative comments  . EVIDEM A holistic approach is required to consistently assess the social and medical needs to support payer’s decision on prices and reimbursement conditions of certain drugs, such as disruptive innovations or orphan drugs, broadening the need of using EVIDEM-like contextual assessment tools by European HTAb.Additional file 1.


Intimate partner violence against women is a global and persistent public health issue. An extreme manifestation of this problem is intimate partner femicide (IPF), the killing of a woman by a male partner. While declining trends of homicide rates have been observed over decades, rates of femicide and IPF have remained stable. Yet, IPF as a phenomenon has until recently been fairly invisible in Europe, why research from the European countries on rates and characteristics of IPF has been relatively scarce. One area of research, particularly in need of further scrutiny, is to what degree perpetrators of IPF suffer from mental health conditions, and what the clinical features are. The objective of present study was to add to the existing literature by investigating prevalence and types of mental disorders in perpetrators of IPF, and to compare with male-to-male homicide (MMH) perpetrators. Our aim was also to examine life-time contact with psychiatric services, and, with missed opportunities in mind, contacts shortly preceding the homicide. With a retrospective design, this population-based study includes all solved cases of male-perpetrated homicides against intimate female partners (IPF) and other males (MMH) committed in Sweden between January 2007 and December 2009. Primary and secondary psychiatric diagnoses based on ICD, version 8, 9 or 10 from psychiatric inpatient as well as outpatient care have been retrieved. In order to identify mental disorders in perpetrators during commission of the homicidal offense, we also retrieved diagnoses from forensic psychiatric evaluations. Our results demonstrate that approximately one-third of the perpetrators, irrespective of homicide type, had been diagnosed with a mental disorder (excluding substance related disorders) at some point in life. Diagnosis of substance related disorders from psychiatric care was significantly more common in MMH perpetrators (37%) compared to IPF perpetrators (15%). Similarly low rates of major mental disorder were found in both groups (11%) when aggregating life-time diagnoses and diagnoses during commission of the crime. However, homicide-suicide in connection to the offense was relatively common in IPF perpetrators (20%). Thus, our study supports the notion that previous suicide attempts and suicide ideation are important indicators for predicting and possibly preventing IPF. Violence against women perpetrated by intimate partners is a global and persistent public health issue, with detrimental short- and long-term consequences. It has been estimated that approximately one in four women worldwide have been exposed to intimate partner violence (IPV) . While SIPF has until recently been a fairly invisible phenomenon in the European research field, why research from European countries on this topic has been relatively scarce . As suchThe causes to intimate partner violence and IPF are complex; factors that increase or decrease risk appear on multiple levels and interplay , 15, 16.Identification of risk factors specific for IPF is of great importance, as it enables the possibility to predict and to identify individuals at risk of greatest harm. Factors pertaining to different forms of previous IPV have been identified as the strongest risk factors for IPF –21. For Overall, factors related to perpetrators are particularly important when assessing risk for IPF . UnemploMental disorders and substance use disorders have been identified to be risk factors for future IPV and IPF perpetration , 33–35. Findings from a meta-analysis on risk factors for male IPF perpetration suggest that substance abuse by perpetrators significantly increase the risk of IPF, while history of mental health issues was found to be a significant but weaker risk factor . A conseless mentally troubled in some aspects. For example, a nationwide Finnish study reported that psychiatric contact before 18 years of age; antisocial personality disorder and drug abuse decreased the odds for IPF, as did psychoses and being assessed as legally insane  e.g., –45]. The. The45)]in combination with causing another person's death. In terms of defining IPF, the present study refers to homicide against women in heterosexual relationships, in which the couples were or previously had been married, engaged, cohabitants or boyfriend-girlfriend.The adopted definition of homicide is in line with European research  and corrMdn = 43 years) than perpetrators of MMH (Mdn = 29 years), U = 1,442, p < 0.001. In terms of country of birth, 59 % (n = 27) of IPF perpetrators and 68 % (n = 90) of MMH perpetrators were born in Sweden χ2,  = 1.2, p = 0.270  who could not be charged (for example if perpetrator has committed suicide or has gone missing). The unsolved cases of homicide consisted of 17% female victims and 83% male victims. For the purpose of present study, male-perpetrated homicides against intimate partners  were included, and compared to male-perpetrated homicides against other males. As such, male-perpetrated homicides against non-intimate females were omitted from the analyses, which is in line with previous similar studies , 48. OveIn order to identify psychiatric diagnoses prior to the index crime, the National Patient Register (NPR) from the National Board of Health and Welfare was used. The psychiatric inpatient registry provides all primary and secondary discharge diagnoses, with a nationwide mandatory documentation and county participation since 1987, and the psychiatric outpatient registry holds primary and secondary outpatient diagnoses, in which nationwide coverage was reached in 2001. The retrieved data from NPR consisted of information regarding dates (including admission and discharge dates for inpatient care) and diagnosis. The psychiatric diagnoses are coded according to the 8th, 9th, and 10th editions of the International Statistical Classification of Diseases and Related Health Problems . Information was available on individuals treated both in psychiatric inpatient and outpatient facilities, in which some had been treated in both settings.The National Board of Forensic Medicine is a governmental authority under the Ministry of Justice that is responsible for performing forensic psychiatric evaluations (FPE), requested by the courts to assess whether the offender suffered from a Severe Mental Disordern = 24) of the IPF perpetrators and 53% (n = 71) of the MMH perpetrators were subjected to a comprehensive FPE. As there were perpetrators who committed suicide in connection to the homicide offense, some perpetrators could not be subjected to an FPE.In order to identify presence of mental disorders in commission of the offense, primary and secondary diagnoses were retrieved for all perpetrators who underwent a major FPE. In total, 52%  were reported for categorical variables. A binary logistic regression was conducted in order to investigate timing of psychiatric inpatient and outpatient care. SPSS for Mac version 28 was used for all analyses.n = 19) of IPF and 53% (n = 70) of MMH perpetrators had received inpatient and/or outpatient care from psychiatric services prior to the homicide offending, χ2,  = 1.8, p = 0.185. It is also worth mentioning that 33% (n = 15) of IPF perpetrators and 41%  of MMH perpetrators had received inpatient psychiatric care. The time aspect, in which how recent the contacts with the psychiatric services were, is interesting from a point of view of missed opportunities of intervention. A somewhat higher (non-significant) percentage of MMH perpetrators  had consumed psychiatric care during the past year, compared to IPF perpetrators . However, looking in to psychiatric care in closer proximity to the homicide offense, our results demonstrate that 11% (n = 5) of IPF perpetrators and only 6% (n = 8) of MMH perpetrators had sought psychiatric service the same month as the offense (p = 0.323). With an even higher resolution, our results demonstrate that the corresponding figures for contact with psychiatric services the same week as the offense are 7% (n = 3) in IPF perpetrators and 3% (n = 4) in MMH perpetrators (p = 375). Furthermore, two IPF perpetrators had been in contact with psychiatric services the same day as the homicide . Results from a logistic regression (see As illustrated in sion see  confirm n = 2) and MMH perpetrators . However, approximately every third perpetrator, irrespective of homicide type, had been diagnosed with a mental disorder prior to the homicide offense, in which substance related diagnoses had been excluded. Additionally, 15% (n = 7) of the IPF perpetrators had been diagnosed with a substance use disorder, which is significantly lower than in MMH perpetrators . Considering the combination of both psychiatric disorders and substance related disorders based on the NPR, our results demonstrate a significant difference between the two groups; 7% (n = 3) in IPF perpetrators and 20% (n = 26) in MMH perpetrators .Diagnosis of a major mental disorder  from psychiatric inpatient or outpatient care prior to the homicide offense was uncommon in IPF  and MMH perpetrators (n = 71) who underwent a major FPE. Among these, four of the IPF perpetrators suffered from a major mental disorder during commission of the crime, in which two were related to psychosis. The corresponding figures in MMH perpetrators are eight and six. Overall, aggregating both life-time diagnoses (according to the NPR) and diagnoses during commission of the crime (according to the FPEs), it is demonstrated that major mental disorders was found in 11% (n = 5) of IPF perpetrators, and in 11% (n = 15) of MMH perpetrators: similarly low rates in both groups . With regards to personality structure, there were eight IPF perpetrators and 13 MMH perpetrators who were diagnosed with a personality disorder . The findings on combination of psychiatric disorders and substance related disorders, after aggregating data from NPR and FPEs, demonstrate fairly similar rates between IPF perpetrators  and MMH perpetrators .With regard to major mental disorders in commission of the index crime, we investigated the psychiatric diagnoses in all IPF (n = 9) of the IPF perpetrators committed suicide within 24 h after the incident, which is significantly higher compared to MMH perpetrators . Among the nine IPF perpetrators who committed suicide, five had been visiting a psychiatric health service prior to the offense, in which two had the preceding contact within the same month as the homicide offense.A result differentiating IPF and MMH perpetrators is with regards to homicide-suicide; 20% , both prior to and in connection to the homicide. Major mental disorders could be related to longstanding illness rather than sudden onset. Secondly, we intended to investigate the extent to which IPF and MMH perpetrators had preceding contact with psychiatric outpatient and inpatient services prior to the homicide. This approach helps to identify opportunities, or lack thereof, to prevent homicides in terms of perpetrators interacting with different authorities, such as the mental health services.Our results demonstrate that ~40% of IPF perpetrators had received mental health care at some point in life, prior to the offense. With regards to psychiatric inpatient care, our results are nearly identical to the findings by Weizmann-Henelius et al. , in whicIn light of clinical characteristics, the study by Oram et al.  demonstrprior to the homicide offense, IPF perpetrators show significantly less adversity in this regard. However, when the data from the FPE was added, similar rates of substance use disorders were detected in IPF and MMH perpetrators. This could indicate that, rather than having less substance related issues, they may in fact be less likely to be diagnosed with substance use disorders, maybe due to not seeking help or the health care system not acknowledging the substance use in this group.Previous comparable studies have highlighted that IPF and MMH perpetrators differ with regards to substance use disorders, in which IPF perpetrators are less likely to suffer from substance abuse , 39, 41.Considering personality disorders, it has been pointed out that overcontrolled-dependent men have been overlooked in terms of risk for IPF, and that the personality disorder most likely to be involved in IPF is men with dependent and passive-aggressive tendencies . In a siMajor mental disorders, in present study operationalized as psychoses, bipolar disorders, schizoaffective disorders or depressions with psychotic symptoms, were relatively uncommon, even after aggregating information life-time diagnoses (from the NPR) and diagnoses during commission of the offense (from the FPEs). In total, 11% of homicide perpetrators, regardless of homicide type, had been diagnosed with a major mental disorder, prior or in connection to the offense. This percentage is considerably lower than the results found by Belfrage and Rying  demonstrThe rates of homicide-suicide have remained stable over time , 54, andIn national homicide death reviews, so called fatality reviews, possible missed opportunities of intervention and system gaps are identified and analyzed. Fatality reviews in some countries also identify risk factors, which may provide valuable information beyond prediction of repeated IPV , and sheGiven that clinical characteristics of mental disorders, substance use, and suicide are risk factor for IPF, and relatively prevalent among IPF perpetrators, accessible care and services targeting these issues may have a preventive effect. However, one identified system gap is that sufficient treatment for substance use and mental disorders had not been provided to perpetrators of IPF prior to the killing . In geneRisk assessment and management are critical components with regards to preventing IPV recidivism and IPF . There aThe present study is not without limitations. First and foremost, the relatively low rates of homicide in Sweden and, furthermore, the low rates of mental disorders within these subgroups, makes it challenging to sufficiently identify differences with regards to mental disorders and to use satisfactory statistical methods based on the limited time-frame adopted in present study. For example, one would preferably use a multiple logistic regression, in order to control for confounders. An additional limitation related to the time-frame is that the data is based on a sample from previous years. However, except for the extraordinary circumstances related to the Covid-19 pandemic, the rates and characteristic of IPF tend to be relatively stable over time , why theIt is also worth mentioning that a small proportion of the unsolved cases involved femicide (17%), and a previous study based on the current dataset has demonstrated that the unsolved cases predominantly involve young men who are criminally active . A methoUnraveling IPF perpetrators use of psychiatric services, and their clinical characteristics, can be essential for identification of high-risk individuals, and for understanding the prospects of efficient intervention. Our study indicates that there are possible opportunities of risk assessment and intervention, as some IPF perpetrators had recent contact with the mental health services prior to the offense. Overall, approximately one-third of all perpetrators had been diagnosed with a mental disorder at some point in life prior to the homicide, while only a minority of IPF perpetrators displayed characteristics of major mental disorders. On the other hand, homicide-suicide in connection to the offense was relatively common in IPF perpetrators. As such, our study supports the notion that previous suicide attempts and suicide ideation are important indicators for predicting and possibly preventing IPF.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 Regional Ethical Review Board in Stockholm, Sweden (Protocol-ID: 2010/1764–31/5). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JS collected and linked all data and all authors  contributed in coding the data. SC conducted the statistical analyses and wrote the manuscript. All authors contributed in conceptualizing and operationalizing the study aim and approach, development and revision of the manuscript, and read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Sensitivity and figure-of-merit (FOM) can be systematically tuned, by varying the structural parameters of the HMM stack and the doping levels (Fermi energy) in graphene. Finite-difference time-domain (FDTD) analysis demonstrates that the proposed biosensor can achieve sensitivities as high as 4052 nm RIU−1 (refractive index unit) with a FOM of 11.44 RIU−1. We anticipate that the reported graphene/Al2O3 HMM device will find potential application as a mid-IR, highly sensitive plasmonic biosensor, for tunable and label-free detection.Plasmonic biosensors, operating in the mid-infrared (mid-IR) region, are well-suited for highly specific and label-free optical biosensing. The principle of operation is based on detecting the shift in resonance wavelength caused by the interaction of biomolecules with the surrounding medium. However, metallic plasmonic biosensors suffer from poor signal transduction and high optical losses in the mid-IR range, leading to low sensitivity. Here, we introduce a hyperbolic metamaterial (HMM) biosensor, that exploits the strong, tunable, mid-IR localization of graphene plasmons, for detecting nanometric biomolecules with high sensitivity. The HMM stack consists of alternating graphene/Al 2O3 HMM stack, coupled to a gold grating structure, for tunable, label-free, and highly sensitive biosensing in the mid-IR wavelength region. FDTD simulations show that the proposed device can achieve a maximum sensitivity of 4052 nm RIU−1.Graphene/Al At visible and mid-infrared (mid-IR) wavelengths, the electric field, associated with the surface plasmons, is highly sensitive to change in refractive index (RI) of the surrounding medium. The interface RI change may be caused by the adsorption of biomolecules onto the sensing platform, leading to a shift in the resonant wavelength. The sensitivity of plasmonic biosensors is defined as the resonance wavelength shift per refractive index unit (RIU) and can be increased by enhancing the electric field on the metal surface. Sensor performance, in the detection limit, is evaluated in terms of the figure of merit (FOM) which is expressed as the ratio of sensitivity to the full width at half-maximum (FWHM) of the resonance dip.5Plasmonic biosensors have been extensively used for rapid, real-time, and label-free detection of biomolecules, at ultralow concentrations.6 This enables LSPR based plasmonic biosensors to detect small-sized molecules with high sensitivity.7 However, due to high carrier concentrations, metal based plasmonic sensors are more responsive in the visible and ultraviolet (UV) wavelengths.3 On the other hand, absorption in the mid-IR wavelength region (∼3–20 μm) offers the unique capability to probe molecular vibrations that are characteristic of the bonds in the biological samples.8,9 Therefore, plasmonic sensors operating in the mid-IR spectral region, can offer high specificities by detecting the vibrational fingerprints associated with the molecular bonds.10,11 Although, metal based plasmonic biosensors have gained considerable success due to simple, miniaturized, low-cost optical setup, and label-free sensing capabilities, their use is limited by high optical losses in the metal, followed by reduced spectral bandwidth and weak electric field confinements in the mid-IR ranges.12 Moreover, overcoming the large mismatch, between the IR wavelengths and the nanometre size of the biomolecules, presents a considerable challenge, particularly for detecting samples with ultralow concentrations.13–15 In addition, traditional, metal-based plasmonic sensors suffer from low detection speed and limited external tunability.Conventional, state-of-the-art plasmonic biosensors make use of metallic nanostructures to confine the electric field within 5–15 nm of the nanostructure surface, giving rise to near-field enhancements through LSPR.16–24 The two-dimensional (2D) nature of graphene has been shown to support stronger, deep-subwavelength confinement of plasmons in mid- and far-IR part of the spectrum, where the plasmons can be dynamically tuned through electrostatic gating, chemical doping, or modulation of graphene structure. In addition to broadband tunability, graphene plasmons are associated with longer lifetimes and lower losses.25 Furthermore, high surface-to-volume ratio of graphene and π-stacking interactions, between the 2D hexagonal graphene cells and the carbon-based ring structure of the biomolecules, strongly adsorb the biomolecules onto graphene surface, aiding the biosensing process.26–28 Several forms of graphene based plasmonic biosensors have been proposed, including hybrid metal–graphene structures. The seminal work on mid-IR graphene biosensors, by Rodrigo et al. used graphene nanoribbons to sense vibrational fingerprints of protein molecules, where the plasmonic resonance was electrostatically tuned.17 Based on plasmon-induced transparency phenomenon, Vafapour et al. designed a broadband, mid-IR, graphene biosensor, with three slot antennas, achieving an optical sensing coefficient of 99%.19 Besides, Hong et al. combined asymmetric gold (Au) nano-antennas and unpatterned graphene sheets to achieve multi-functional, broadband sensing, covering both near-IR and mid-IR wavelengths.16 Optical conductivity based mid-IR sensors, with ultrahigh sensitivity, was reported by Zhu et al. through the use of Au nanorod antenna array covered by monolayer graphene.29 Furthermore, the study by Wu et al. employed a graphene sheet, integrated on top of a Au grating structure, for mid-IR sensing of vibrational modes from protein molecules.20Recently, graphene is being explored as a promising candidate for plasmonic biosensors.30–32 HMMs are artificially engineered, strongly anisotropic metamaterials, which exhibit hyperbolic dispersion with one of the principal components, either the permittivity or the permeability, having a negative sign. The hyperbolic frequency dispersion in HMMs allows the propagation of highly confined wavevector modes (high-k modes), across a metal/dielectric multilayer structure. These high-k modes are known as bulk plasmon polaritons (BPPs) and decay exponentially outside the structure. BPPs lead to unusual properties of the HMMs, with extraordinary applications like negative refraction, subwavelength imaging, spontaneous emission enhancement, nanoscale light confinement and biosensing.33–35 In practice, highly sensitive HMM biosensors have been realized using alternating layers of metal and dielectric. Each metal/dielectric bilayer evanescently couples the short range, propagating SPPs to its adjacent bilayer, leading to the existence of BPPs. Replacing the metal with graphene, can lead to new possibilities in terms of stronger plasmon response in mid-IR range, smaller material loss and tunable conductivity.36–38 Furthermore, owing to the atomically thin nature of graphene, HMM sensors based on graphene can offer extreme scalability, which is important in realizing portable, POC biosensors. Although, graphene based HMMs have been used in a wide variety of applications, such as, exhibition of negative refraction,39 switchable reflection modulator,40 and perfect absorbers,41 their use, in biosensing platforms have been limited.Plasmonic biosensor platforms, using hyperbolic metamaterials (HMMs), have gained considerable attention in recent times for their extreme broadband sensitivity, arising from enhanced light–matter interactions.2O3 bilayers, patterned on top of a gold grating structure with rounded corners, to introduce plasmonic hotspots and enhance sensitivity. The HMM stack and the sub-wavelength nanograting structure effectively couples incident light into the high-k modes in graphene by mitigating the large k-vector mismatch between propagating modes in free space and in the HMM slab. Moreover, the resonance wavelength can be tuned by changing structural parameters of the HMM stack and the grating, as well as the Fermi energy of graphene. For the biosensor, proposed in this study, resonance wavelength shift, caused by refractive index (RI) change, is calculated, using finite-difference time-domain (FDTD) simulations, in three-dimensions (3D). All simulations were carried out using the commercially available Lumerical software package. The sensor performance is numerically evaluated, in terms of both sensitivity and FOM, for a wide range of RIs that correspond to commonly used biomolecules.In this work, we propose a novel HMM biosensor, consisting of a multi-stack of graphene/Al2.N bilayers of graphene/Al2O3, placed on top of the Au grating structure, with rounded corners of radius g. Several studies in the past have fabricated and characterized grating structures, with rounded corners, for a variety of applications.42,43 In the proposed design, the grating height, h, is fixed at 700 nm while the width, d, changes with change in grating period, p. For the structure in p = 820 nm, d = 410 nm. The topmost layer of the HMM stack, which forms the sensing surface, consists of a graphene sheet, as shown in tg ∼ 0.34 nm, are separated by Al2O3 layers of thickness, td = 10.4 nm, satisfying the metamaterial limit.42 The number of graphene/Al2O3 bilayers, N, can be varied to optimize the absorption properties. Absorption by the HMM structure, can also be tuned, by changing p and g of the grating structure, and the doping levels  in graphene. To avoid diffraction in free space and excite high-k modes in the graphene HMM slab, p is always kept within the sub-wavelength dimension. The incident light, in the mid-IR range, is transverse magnetic (TM) polarized and irradiates the device from the top at an angle, θ. TM mode is chosen because, in general, it shows higher sensitivity than the transverse electric (TE) mode.322O3 HMM structure in the FDTD simulation was described via dielectric functions of Al2O3 and surface conductivity of graphene. The uniaxial dielectric tensor components of this anisotropic HMM can be approximated as:40‖ and ε⊥ are in-plane and out-of-plane permittivity components, respectively. The effective permittivity and thickness of graphene are represented by εg and tg and that of the dielectric by εd and td, respectively. Due to the atomically thin nature of graphene, tg ≪ td and hence we can approximate, ε⊥ ≅ εd. Since the period (=tg + td) of the multilayer graphene/Al2O3 HMM structure is much smaller than the operating wavelength, it can be considered as an anisotropic metamaterial.44 For Al2O3 and Au, the permittivity values are directly taken from the Lumerical material database while, εg can be expressed as:45ε0 and σ are permittivity of vacuum and surface conductivity of graphene, respectively. This relation assumes that the electronic band structure of a graphene sheet is not affected by the neighbouring sheets. Without considering external magnetic field, the isotropic surface conductivity of graphene is calculated by using the Kubo formula where, σ is expressed as the summation of intraband (σintra) and interband (σinter) transitions as:45ω is the frequency of the incident light, τ is the electron–phonon relaxation time, EF is the Fermi energy, T designates the temperature in Kelvin and e, kB and ℏ represent electronic charge, Boltzmann constant and reduced Planck's constant, respectively. The relaxation time is given by, τ = μEF/evF2, with vF as the Fermi velocity and μ as the carrier mobility. The Fermi energy depends on the 2D carrier density (η2D) of graphene sheets, such that EF = ℏvF (πη2D)1/2 and can be tuned by applying an external voltage. Between, λ = 3 to 10 μm, σ is calculated by taking T = 300 K, μ = 10 000 cm2 (V s)−1 and vF = 106 m s−1. 16,45 The uniaxial dielectric tensor components, of the anisotropic graphene/Al2O3 HMM stack, are determined with EMT, where the graphene/dielectric bilayers satisfy the criterion of EMT. The background RI is set at 1.33 (water). The FDTD simulations are carried out with N = 11, g = 30 nm, p = 820 nm, d = 410 nm, and EF = 0.64 eV. Hyperbolic dispersion is observed for wavelengths of λ > 3.58 μm, where ε‖ (εxx = εyy) < 0 and ε⊥ (=εzz) > 0. When λ < 3.58 μm, both ε‖ > 0 and ε⊥ > 0, and the dispersion is elliptical. Since the energy of the incident photon, hω ≪ 2EF, it forbids interband transitions in graphene and therefore, the contributions from σinter can be ignored.The proposed graphene/Al2O3 HMM structure, changes with the Fermi energy and the permittivity or refractive index of the surrounding environment. The change in σ affects the optical properties of graphene and consequently, tunes the resonance wavelength of the HMM structure. The biomolecules, adsorbed onto the graphene/Al2O3 stack, are modelled with a wide range of RIs such as 1.41 (human g-immunoglobulin or IgG), 1.445 , 1.462 (single-stranded DNA or ss-DNA) and 1.53 (double-stranded DNA or ds-DNA).26 The resonance wavelength shifts, caused by these commonly studied biomolecules, are obtained using the FDTD method. Aqueous medium (RI = 1.33) has been used as the reference.3.3.12O3 HMM structure can be tuned by changing the angle (θ) of the TM polarized light, the radius (g) of the rounded grating corners, the number of graphene/dielectric bilayers (N) and the period (p) of the underlying grating structure, respectively. In the hyperbolic region (λ > 3.58 μm) shown in θ = 35°, the high-k modes correspond to wavelengths of 3.95 μm (BPP1), 4.33 μm (BPP2), 4.96 μm (BPP3), 5.82 μm (BPP4) and 8.58 μm (BPP5). Considering zero transmission through the grating coupled HMM, near about 85% absorption is obtained for BPP2, while BPP3 and BPP5 show ∼80% absorption. Modes corresponding to BPP1 and BPP4, on the other hand, absorb ∼40% and ∼50% of the incident TM polarized light, respectively. Furthermore, the fifth high-k mode (BPP5) shows broader and more distinct resonance dips than the rest of the modes. Strong absorption by HMMs is attributed to the indefinite hyperbolic k-space, which results in large number of photonic density of states inside the HMM. The reflection minima represent the highly confined BPPs, which are slightly blue shifted, with increasing angle of incidence. Higher incident angle of the propagating light tends to result in greater contribution of the signal component parallel to the interface. The blue shift is more obvious for longer wavelength modes, as shown in nmodal) of BPPs with incidence angle. For the grating coupled structure, nmodal is given by:46λ is the incident wavelength, p is the grating period, n0 is the refractive index of the incident medium and θ is the incident angle. At higher angle of incidence, the resonant wavelength decreases (blue shift), for a given value of nmodal. g) of the rounded corners in the grating structure and the number (N) of graphene/Al2O3 bilayers, respectively, on the reflectance spectra. In both cases, absorption decreases, and the resonance shifts towards the shorter wavelengths as g and N increase. The shift in reflectance minima, with increasing N, is due to the coupling of the individual graphene plasmon modes. Increasing the grating period (p) causes a red shift of the resonance wavelengths and increases the depth of the reflectance dips, as displayed in p as shown by Chang et al.42 To obtain an optimized sensor performance, by detecting the resonance wavelength shift, the subsequent FDTD simulations are carried out with, θ = 35°, N = 11, g = 30 nm and p = 820 nm.3.2via electrical biasing, has been demonstrated by Chang et al.,36 where the chemical potential of graphene was efficiently tuned by applying a bias voltage across each graphene layer. A similar scheme can be adopted, in our proposed HMM structure, to electrically bias the graphene layer, sandwiched between two layers of Al2O3. The voltage-controlled Fermi energy, EF, can be used to tailor the surface conductivity of graphene and hence control the absorption properties of the graphene/Al2O3 HMM structure.47,48 This is demonstrated in EF value corresponds to a specific doping level in graphene. The absorption decreases, and the resonant wavelengths undergo a blue shift, as EF increases. ε‖vs. incident wavelengths, plotted for different values of EF. The hyperbolic region is seen to shift towards shorter wavelengths (blue shift), as EF increases, further confirming the strong dependence of the HMM's optical characteristics on the Fermi energy of graphene.A feasible scheme for tuning the conductivity of graphene, 3.349 The corresponding linear relationship, between the resonant wavelength and the RI of the surrounding medium, are displayed in S) of the graphene/Al2O3 HMM biosensor is given by:16λr is the resonance wavelength shift caused by Δn change in refractive index of the surrounding medium, with respect to water (RI = 1.33) as the background. The resonance wavelength shift, relative to the reference solution, is calculated for commonly found biomolecules such as human g-immunoglobulin , human serum albumin , single-stranded DNA  and double-stranded DNA .The sensor performance is evaluated by calculating the resonance wavelength shift, for each high-k mode, in presence of the biomolecules represented by their respective RIs. −1 and 3938 nm RIU−1 for IgG (RI = 1.41) and ds-DNA detection (RI = 1.53), respectively. The corresponding RI sensitivities for the other BPP modes are 499 nm RIU−1 (RI = 1.41) and 487 nm RIU−1 (RI = 1.53) for BPP1, 875 nm RIU−1 (RI = 1.41) and 868 nm RIU−1 (RI = 1.53) for BPP2, 1899 nm RIU−1 (RI = 1.41) and 1890 nm RIU−1 (RI = 1.53) for BPP3 and finally, 2774 nm RIU−1 (RI = 1.41) and 2688 nm RIU−1 (RI = 1.53) for BPP4.The sensitivity of the proposed biosensor depends on the BPP modes used for detection. EF) of graphene, through an external bias. This is demonstrated in EF, in aqueous solution (RI = 1.33). The highest sensitivity is achieved for EF = 0.64 eV. The other high-k modes also follow the same trend. Hence, we used EF = 0.64 eV, for evaluating the performance of the proposed biosensor.The sensitivity can be tuned by varying the Fermi energy  and detection accuracy (FOM = 35.37/RIU) is, therefore, obtained for the BPP4 high-k mode.The sensor performance, in the detection limit, is determined by the sharpness of the resonance dips, as quantified by the FOM parameter:42,50E| field plots at the resonance wavelengths of 5.82 μm (RI = 1.33) and 6.04 μm (RI = 1.41) for BPP4. The BPP4 mode is chosen because it exhibits a good balance between sensitivity and FOM. From E| field is enhanced at the interface of the HMM structure and the surrounding medium, but decays rapidly within the HMM slab. Also, the interface |E| fields change with the change in background RI. The other BPP modes (not shown here) were found to generate similar electric field patterns around the HMM structure, with varying electric field strengths.For each BPP mode, the electric field intensity, surrounding the HMM structure, has been derived. To calculate the electric field intensity distribution, the HMM structure was transformed into a homogeneous medium, using the effective medium theory (EMT). This is made possible because the period of the HMM structure is in the sub-wavelength range.−1 for BPP5 mode. However, as described earlier, a FOM of 35.37/RIU can also be obtained, at a slightly reduced sensitivity of 2774 nm RIU−1, for BPP4 mode, when higher detection accuracy is desired. The highest FOM for BPP4 is attributed to the sharpest resonance peak, while, the highest sensitivity, for BPP5 results from the maximum shift in resonance wavelength for a unit change in RI. Although, metal/dielectric based HMM biosensors, as demonstrated by Sreekanth et al.30 can achieve sensitivities between 10 000 nm RIU−1 and 30 000 nm RIU−1, the detection is limited to visible and NIR wavelength regions. Graphene based HMM biosensors, on the other hand, offers mid-IR sensing capabilities in addition to external tunability, extreme scalability and lower loss.The performance of the proposed sensor has been benchmarked against some of the existing, state-of-the-art, graphene based plasmonic biosensors, as shown in 4.2O3 HMM stack, coupled to Au grating structure, for tunable, label-free, and highly sensitive biosensing in the mid-IR region. The absorption characteristics, of the HMM stack, can be tuned by changing the Fermi energy of graphene, using an external voltage, or by changing the structure of the HMM stack. The wavelength dependent effective permittivities, of the HMM layer, are obtained from the well-established EMT. The sensor performance has been numerically evaluated, through FDTD simulations, by determining the resonance wavelength shift, caused by the change in RI of the surrounding medium, where different RIs correspond to different biomolecular entities. The proposed sensor can detect commonly found biomolecules  with detection sensitivities as high as 4052 nm RIU−1 and a corresponding FOM of 11.44/RIU. Both the sensitivity and FOM values of our proposed sensor are either higher or comparable to the previously reported graphene based plasmonic biosensors. HMM structures, like the one proposed here, can be fabricated and characterized using well-established techniques, as demonstrated by Chang et al.,36,42,51 paving the way for the next generation of high-performance, graphene based, mid-IR biosensing platforms.In summary, we proposed a graphene/AlR. Ahmed and M. Hossain conceived the idea. S. Cynthia carried out all the simulations and calculations. Both M. Hossain and S. Cynthia interpreted the results and wrote the manuscript. R. Ahmed, S. Islam and K. Ali provided useful suggestions to improve the scientific content of the manuscript.There are no conflicts to declare.


The morphology of the gold plated patterned substrate was studied by scanning electron microscopy (SEM) and atomic force microscopy (AFM), while the quality of the chemical vapor deposition (CVD) graphene was evaluated by Raman spectroscopy. The electromagnetic (EM) response of the metasurface comprising the graphene sheet and the gold plated substrate was studied by THz time domain spectroscopy in the 100 GHz–1 THz frequency range. We employed the finite elements method (FEM) to model the metasurface EM response by adjusting the ac conductivity of the gold layer covering the patterned SiO2 substrate to reproduce the measured transmission/reflection spectra. The results of the numerical simulation reveal the impact of the imperfectness of the gold layer on the performance of the THz metasurface. The experimental results are well described in terms of the Drude–Smith model of metal conductivity that takes into account the anisotropic scattering of the carriers in thin metal films.We report the performance of a graphene-enhanced THz grating fabricated by depositing a gold layer on the femtosecond micromachined SiO The concept of metamaterials has brought a lot of attention ,2,3,4,5 This is because graphene, a one atom thick graphite layer, absorbs 2.3% of light in optical frequencies owing to interband transitions . At lowe2 diffraction grating enhanced with graphene. Especially, the grating has the specific effect of diffracting the incident wave rather than simply reflecting it; in this way, the energy of the radiating source spreads along different directions. Consequently, multiple reflections are triggered between the grating cavities and the graphene layer, thus improving the overall absorption. The evanescent modes, excited owing to the diffraction of the incident wave on the grating, enable an increase in the absorption in the graphene sheet. Although the considered device is very simple, it provides an efficient playground to visualize the robustness of the graphene-enhanced device in the presence of the defects in graphene and/or metal layers and the imperfectness of the patterned dielectric lattice.Here, we consider the metasurface composed of conventional gold-plated SiO2 substrate, which may affect the uniformity of the gold layer and prevent achieving the perfect absorption condition.It has been demonstrated  that EM It is worth mentioning that metallic reflection requires at least the skin depth thick metal layer. In the THz range (wavelength is 300 μm at 1 THz), this implies deposition of the gold layer thicker than 30 nm. The conductivity of such a nanometrically thin film may be strongly influenced by its integrity and homogeneity, e.g., the density of the voids and pores, granule structure, the presence of micro-cracks, and the dislocations caused by an irregular substrate surface. These defects, which lead to a lower ac surface conductivity in comparison with that of the “bulk” gold, often occur in the films fabricated by conventional magnetron sputtering and thermal evaporation , and are2 lattice, on the THz performance of the metasurface. Further, we demonstrate that the use of the Drude–Smith model for gold conductivity allows introducing into the simulations the experimentally observed oscillations of the THz response.Motivated by the idea of proposing a simple versatile tool for the design and fabrication of graphene-enhanced passive devices based on gold-plated patterned dielectric substrates, in this work, we investigate the influence of the non-homogeneity and roughness of the gold thin film, mostly originating from the surface imperfection of the SiO2 substrate . In the experiments, laser pulses at the central wavelength of λ = 792 nm, pulse duration of 150 fs, and repetition rate of 1 kHz were employed. The pulse energy was fixed at 1.25 mJ. The Gaussian beam of 7.5 mm in diameter was focused on the surface of a substrate using an F = 20 mm focusing lens . The distance between the lens and the sample and the scanning speed of 0.5 mm/s were set to fabricate grooves with a width of w = 100 μm and a depth of h = 80 μm. At such parameters, we fabricated a periodic grooves structure with a period of p = 167 µm. The dg = 30 nm gold conductive layer was deposited on the micromachined substrate using Emitech K675X sputter  at the current of 350 mA in Argon plasma . The next step was to transfer the tpb = 500 nm thick polymethylmethacrylate (PMMA) spin-coated layer  onto the patterned substrate. PMMA was spin-coated at 1800 rpm on the Cu foil , and baked at 150 degrees Celsius for 5 min. The next step is Cu foil etching in FeCl , washing PMMA film in distilled water, and transferring to the prepared patterned SiO2 substrate covered with gold . To improve adhesion, we first cleaned the patterned substrate in acetone and isopropanol, dried it with nitrogen gas, and then finally ran 30 s oxygen plasma . Standard manual technology of ‘fishing out’ the polymer film onto a substrate was used along with further drying it overnight and then baking it on a hotplate at 60 °C for 10 min to further improve the adhesion of the polymer thin layer to the metasurface by removing any residual water molecules. This layer was used to prevent electrical contact between the gold layer and the graphene sheet.The THz grating was fabricated by femtosecond micromachining of the fused silica SiOps < 150 nm, transparent for THz radiation), used for its handling.Graphene was grown on Cu foil in a conventional CVD methane-based process. Methane-based graphene CVD begins with the nucleation of the individual grains dispersed randomly over the copper surface. As time goes on, these grains grow continuously until they integrate and fuse in the end to form a continuous crystalline film . Graphen3  was used as an etchant to remove Cu foil from the synthesized graphene covered with PMMA. The sample was left overnight in the etching solution for better results. Deionized water was used to remove residual FeCl3 solution by transferring it from the etching solution to a beaker filled with deionized water for 1 h. Using microscopic slide glass, the sample was then transferred onto PMMA film supported by the gold-plated patterned SiO2 grating. The metasurface 3D sketch  is shown in The sample was then baked for 10 min at 60 °C. To remove the back graphene from the other side of the Cu foil, oxygen plasma treatment was employed. FeClStructural characterization of the metasurface was performed by Zeiss SEM-LEO 1550 Gemini  and AFM Certus Light V . Raman spectrum of graphene was recorded with HORIBA XploRA PLUS System  at room temperature with a 1200 lines/mm grating. The measurements were performed using excitation at the wavelength of 532 nm and power below 0.8 mW. A 100× objective with NA = 0.95 was used. The sport size on the sample surface was 0.75 µm.The THz transmission and reflection spectra were collected with a THz time domain spectrometer T-SPEC Ekspla . A 1050 nm pumping laser with 100 fs pulse duration at output power > 40 mW and pulse repetition rate of 80 MHz was used to generate THz radiation. All measurements were performed with a normally incident THz radiation and the electric field was oriented with the grooves. The measurement details can be found in . For 2D ® v.5.3a . The structure can be assumed to be infinite in the longitudinal direction; thus, the problem can be reduced to a 2D model. The distance from both ports to the metasurface is much longer than the wavelength. The FEM model is shown in The fabricated structure was modelled using the commercial FEM software. COMSOL MultiphysicsIn the plane wave approximation, we used periodic boundary conditions to replicate one spatial period and took into account the ellipsoidal shapes for the substrate grooves ; therefore, their loss tangent is set to zero.The relative permittivity of the SiOεs = 3.8  and εp =[p = 2.6 , respect[p = 2.6 ,26 for Sgr is mainly determined by intraband transitions. In the numerical simulation, we employed the following equation for graphene surface conductivity [trans= 13 THz, e is the electron charge, ℏ is the reduced Plank constant, ω is the angular frequency, and i is the imaginary unit. The EM response of the graphene sheet was described by introducing the electrical current density at the plane interface between the two PMMA layers, where currents in the x and z directions are functions of the graphene surface conductivity (1) and of the local electric field, while the y-component of the electrical current  is zero.In the terahertz and microwave ranges, the graphene surface conductivity σuctivity :(1)σgr at the frequency of the incident THz radiation . In the Bulk metals can be well described in terms of the Drude model, which predicts very weak frequency dependence of the complex conductivity in the THz range. This is not necessarily correct for thin metal films. Their inhomogeneity, caused by the roughness of the substrate surface, together with the roughness and graininess of the gold, may result in a significant deviation from the classical Drude-like behaviour, especially in the case of layers thinner than the skin depth. Additional electron scattering mechanisms due to impurities lead to a significant decrease in its conductivity compared with bulk . As a reg is the effective sheet conductivity of the gold. In the framework of the Drude–Smith model [0 is the vacuum permittivity, τ is the electron momentum relaxation time, ωp is the plasma frequency, and f is the frequency. The gold layer thickness dg was added in the original formula for conductivity, transforming the volume conductivity into the sheet one. As it was impossible to measure dg in the experiment, it can be used as a parameter in the model. As the thickness of the layer is smaller than the gold skin depth, a linear dependence for the thickness was expected. The second term in the brackets in Equation (3) represents the effect of the persistence of the conduction electron’s initial velocity only during the first collision, following the assumption that the electron fully lost its momentum after the first scattering event. The constant c is c = <cos θ> [In the fabricated metasurface, the gold layer thickness is much smaller than the wavelength; thus, in the FEM model, it can be described by introducing the surface current density in boundary conditions, i.e., the value of the current density on the surface, according toth model ,29,(3)σ <cos θ> , where θThe top and bottom input/output ports are placed above the graphene sheet and below the silica substrate see . By exciThe FEM numerical simulation allows us to reveal how the THz performance depends on the metasurface geometry, providing the guidelines for the design of the best-performing configuration and/or the most robust. In this work, the simulation was performed to estimate the impact of the gold reflector layer conductivity on the overall device performance.In agreement with the experimental procedure, the top port was powered to simulate the radiation propagating from a source located on the top of the patterned surface. The electric field was set parallel to the grooves’ orientation, i.e., the electric field is orientated along z and the direction of propagation is y.2 grating have a porous surface with noticeable roughness at the level of 100 nm–1 μm. Being at least 300 times smaller than the wavelength, this roughness does not influence the THz response of the metasurface. However, it will affect the homogeneity and even integrity of the gold layer deposited on the grating surface.Structural characterization by SEM see a,b shows2 covered with gold  peak, which is 1.5 times more intense than the peak of the G-mode, indicating the good quality of the synthesized graphene.The Raman spectrum of CVD graphene used for metasurface fabrication is presented in 2 leads to the formation of the macroscopic features in the patterned area, which, in addition to the imperfectness of the deposited gold layer, results in a decrease in the overall effective conductivity of the conductive layer and increase in the total transmission. Hence, the transmission and reflection of the PMMA/graphene/PMMA deposited on the grating structure vary in the vicinity of 50% and 10%, respectively. Thus, the measured absorption A = 1 – T − R of the metasurface is close to 40%, which, as one can see, is mainly determined by the PMMA/graphene/PMMA layer.The measured transmission and reflection spectra for the metasurface with and without the PMMA/graphene/PMMA sandwich structure are presented in g → ∞), Drude metal (c = 0 in Equation (3)), and Drude–Smith metal with dominating backscattering [R decreases with respect to those of the Drude metal. Finally, for the Drude–Smith layer at c = −1 (backscattering dominates), the transmission is much higher than that for the Drude metal. This phenomenon can be explained by taking into account that, at c = −1, the material behaves like an insulator. That is, in such a case, the backscattering prevents the propagation of electrons when a static electric field is applied, i.e., σg = 0 at f = 0 in Equation (3) [We performed a comparative study of the metasurfaces based on the perfect conductor  . The fulOne can observe from 2 metasurface. In particular, the value of c that better allows reproducing the experimental result is very close to −1. Although the simulation results do not match perfectly the experimental data, they well reproduce the qualitative features of the spectrum, including the number of oscillations and the amplitude envelope. This demonstrates the efficiency of the proposed approach.By comparing the simulation results with the experiments in 2. This may lead to the significant overestimation of the Au thickness and its sheet conductivity because the effective surface area of the patterned substrate is greater than that of the flat one.In this work, we studied CVD graphene-based metasurfaces for THz radiation. The SEM and AFM images show that the femtosecond micromachining results in the rough and porous surface of the patterned SiOIn order to reveal the impact of the gold layer imperfectness on the metasurface THz performance, we employed FEM numerical simulation by taking into account the asymmetry of the carriers scattering in the thin metal film. Using the Drude–Smith model to describe the gold film ac conductivity, we compared its predictions with those given by the perfect conductor and the Drude models.2 grating covered by the deposited thin gold film. In particular, the developed model well describes the Fabry–Pérot interference pattern, as well as other EM features inherent for the experimental behavior of the metasurface, enabling future investigation of the metasurface performance in different applications. Our experimental findings confirm that the predominant backscattering of the carriers in the thin film does affect the THz properties of the gold layer and strongly influences the performance in the frequency range of interest. One may expect that THz performance of the metasurface can be substantially improved if an alternative physical deposition technique  is used.The obtained results show that the Drude–Smith model is capable of describing the measured spectra of the transmission, absorption, and reflection of the SiO


Nuclear loss and cytoplasmic aggregation of TDP-43 is the most common shared pathological feature of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), a motor neuron disease also known as Lou Gehrig's disease . TDP-43 STMN2), encoding an axonal growth-associated microtubule-stabilizing protein expressed only in neurons [STMN2 and is not conserved in rodents [A key nuclear function of TDP-43 is to regulate alternative splicing, most notably to suppress the inclusion of cryptic exons, intronic sequences that are normally not spliced into mature mRNAs [ neurons , 6. This rodents , 6. The UNC13A  and without TDP-43 pathology, including FTD-FUS, FTD-TAU, and ALS-SOD1 . The patients , 8. ThesUNC13A mRNA is a very interesting target of TDP-43 because it was previously identified as a risk factor for sporadic ALS and ALS/FTD through genome-wide association studies (GWAS) [UNC13A cryptic exon or in the intron near the cryptic exon. In addition, Ma et al. identified a novel variant, also located in the intron that contains the cryptic exon, as a risk factor for disease. Both groups showed a strong correlation between the disease-associated SNPs and the abundance of the cryptic exon in patient brains. Expression of minigenes containing these disease risk variants in cultured cells established a direct effect of these variants in increasing cryptic exon inclusion in TDP-43-depleted cells. These findings support the notion that some disease risk variants promote inclusion of the cryptic exon upon loss of nuclear TDP-43, providing mechanistic insight into why these variants are associated with increased risk for ALS and ALS/FTD and further highlighting the key role of TDP-43 in disease pathogenesis [UNC13A and disease, blocking the splicing of the cryptic exon in UNC13A is another promising therapeutic approach.s (GWAS) . Since Us (GWAS) , loss ofogenesis , 8. BecaUNC13A cryptic exon contributes to disease needs to be further established. Moreover, through its interactions with thousands of target mRNAs, TDP-43 affects many aspects of RNA metabolism. Thus, it remains to be seen whether correcting the expression level of one target mRNA is sufficient to offer tangible clinical benefits while many other downstream pathways remain dysfunctional. Simultaneous blocking of cryptic exon splicing in multiple key target mRNAs of TDP-43 may offer a better chance of success. Nonetheless, the GWAS results strongly suggest that the contribution of UNC13A missplicing to disease pathogenesis may in fact be tangible, and worth pursuing. Thus, these two new studies greatly enrich our understanding of key functions of TDP-43 and suggest another cryptic exon as a novel target for therapy and as a potential biomarker for both familial and sporadic ALS/FTD.Several issues remain to be addressed. Since only a small percentage of neurons in patient brains show loss of nuclear TDP-43 at the end of disease, the extent to which the