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


The PERSEIDS study aimed to estimate incidence/prevalence of interstitial lung diseases (ILDs), fibrosing interstitial lung diseases (F-ILDs), idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated ILD (SSc-ILD), other non-IPF F-ILDs and their progressive-fibrosing (PF) forms in six European countries, as current data are scarce.This retrospective, two-phase study used aggregate data (2014–2018). In Phase 1, incident/prevalent cases of ILDs above were identified from clinical databases through an algorithm based on codes/keywords, and incidence/prevalence was estimated. For non-IPF F-ILDs, the relative percentage of subtypes was also determined. In Phase 2, a subset of non-IPF F-ILD cases was manually reviewed to determine the percentage of PF behaviour and usual interstitial pneumonia-like (UIP-like) pattern. A weighted mean percentage of progression was calculated for each country and used to extrapolate incidence/prevalence of progressive-fibrosing ILDs (PF-ILDs).5 person-years ranged between 9.4 and 83.6 (ILDs), 7.7 and 76.2 (F-ILDs), 0.4 and 10.3 (IPF), 6.6 and 71.7 (non-IPF F-ILDs), and 0.3 and 1.5 (SSc-ILD); and prevalence/105 persons ranged between 33.6 and 247.4 (ILDs), 26.7 and 236.8 (F-ILDs), 2.8 and 31.0 (IPF), 22.3 and 205.8 (non-IPF F-ILDs), and 1.4 and 10.1 (SSc-ILD). Among non-IPF F-ILDs, sarcoidosis was the most frequent subtype. PF behaviour and UIP-like pattern were present in a third of non-IPF F-ILD cases each and hypersensitivity pneumonitis showed the highest percentage of progressive behaviour. Incidence of PF-ILDs ranged between 2.1 and 14.5/105 person-years, and prevalence between 6.9 and 78.0/105 persons.In 2018, incidence/10To our knowledge, PERSEIDS is the first study assessing incidence, prevalence and rate of progression of ILDs across several European countries. Still below the threshold for orphan diseases, the estimates obtained were higher and more variable than reported in previous studies, but differences in study design/population must be considered. The PERSEIDS study provides updated and detailed epidemiological data for ILDs across six European countries. Prevalences ranged between 26.7–236.8 (F-ILDs), 2.8–31.0 (IPF), 22.3–205.8 (non-IPF F-ILDs). A third of non-IPF F-ILD cases showed PF behaviour.https://bit.ly/3wLH7pF Interstitial lung diseases (ILDs) display varying degrees of inflammation, fibrosis or both, and a wide range of clinical courses and prognoses. Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive-fibrosing ILD (PF-ILD), characterised by a usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) or lung biopsy . Its pulDespite their major impact on mortality, quality of life and resource use, in Europe the epidemiological data available for ILDs and particularly their PF forms is scarce , 11. TheA retrospective, database study with a two-phase design  was condThe main objective was to investigate the annual incidence and prevalence of ILDs and their time trends over the study period. The focus was placed on F-ILDs as these show a greater risk of progression, but the epidemiology of non-F-ILDs was also assessed to provide a broad picture of ILDs in the participating countries. The primary outcome was crude incidence/prevalence of ILDs, F-ILDs, IPF, non-IPF F-ILDs and SSc-ILD by country and overall, for the whole study period and annually. Secondary outcomes were: a) crude incidence/prevalence of non-IPF F-ILD subtypes (other than SSc-ILD), including ILDs associated with rheumatoid arthritis (RA-ILD), mixed connective tissue diseases (mixed CTD-ILDs) and other connective tissue diseases (other CTD-ILDs), idiopathic nonspecific interstitial pneumonia (iNSIP), unclassifiable idiopathic interstitial pneumonias (uIIPs), hypersensitivity pneumonitis (HP), exposure-related ILDs, sarcoidosis and other F-ILDs; b) relative percentage of each non-IPF F-ILD subtype; and c) crude incidence/prevalence of non-fibrosing ILDs (non-F-ILDs).supplementary material Section A). These codes/keywords were searched in all centres following a common algorithm, specifically designed to classify cases in ILD subtypes and subsequently, in overarching ILD categories while avoiding duplicates . The methodology for obtaining prevalence/incidence estimates (minimum and maximum), as well as alternative methods and adjustments applied due to centre/country particularities, are detailed in the supplementary material Section B. The relative percentages of non-IPF F-ILD subtypes were obtained by dividing the prevalent cases of each subtype by total prevalent cases of non-IPF F-ILD.To identify incident/prevalent cases of ILD, 10 of the 13 centres participating in Phase 1 conducted a systematic search of the institution's clinical database , and the remaining three in other clinical databases  . The seaThe aim was to further characterise non-IPF F-ILDs. The primary outcome was the relative percentage of cases within each non-IPF F-ILD subtype presenting PF behaviour alone (without UIP-like pattern), UIP-like pattern alone (without PF behaviour), both PF behaviour and UIP-like pattern, and none of them, overall for all countries. Secondary outcomes included: a) crude prevalence/incidence of PF-ILDs by country and overall, for the whole study period and annually; b) positive predictive value (PPV) of the algorithm used in Phase 1, by centre and country; and c) adjusted (by PPV) values for incidence/prevalence estimates obtained in both study phases.Each of the 10 centres participating in Phase 2 reviewed the medical records of their first 100 prevalent non-IPF F-ILD cases identified in Phase 1, sorted by date of healthcare encounter from January 1, 2016 onwards.supplementary material Section C). If necessary, centres could review additional cases to the first 100 until reaching this number. These additional cases were considered when calculating the relative percentages of the primary outcome.The review encompassed the pulmonary function tests and HRCT results available in each patient's file, and either confirmed (true positive) or ruled out  the presence of the fibrosing (non-IPF) condition. The primary outcome was determined on true positives, and it was calculated that at least 80 were required to reach enough precision  within the 2-year period following the healthcare encounter, or between 5 and <10% but with any of the following: ≥1 ILD-related hospitalisation (excluding emergency visits), increasing extent of fibrosis on HRCT, starting or increasing oxygen use, or death due to respiratory event. Owing to the lack of uniformly accepted criteria for PF-ILD, the use of relative decline in FVC was based on previously published expert recommendations . The defTrue and false positives obtained during the Phase 2 review were also used to assess the specificity of the search algorithm at each centre, by calculating its PPV. The PPV was obtained by dividing true positives by the sum of true positives and false positives. Only the first 100 prevalent cases reviewed at each centre  were considered. PPVs of centres in each country were averaged to obtain a country PPV. Simple (not weighted) means were calculated under the assumption that each centre's PPV contributed equally to the country mean.supplementary material Section D).Finally, to account for possible overestimation of incidences/prevalences arising from the use of codes and/or keywords in the systematic search, crude estimates for each country were multiplied by the country PPV to obtain adjusted estimates. Some exceptions to this methodology were made based on country particularities . Categorical variables were summarised as absolute and relative frequencies, and 95% confidence intervals. Pairwise comparisons were conducted to assess differences in the percentage of progression between non-IPF F-ILD subtypes and centre levels (secondary versus tertiary). Significance was set at the 0.05 level.Sample size considerations are presented in the supplementary material Section B, Alternative methods and adjustments). When not, estimates were obtained based on available data.Missing values were completed when possible . The centre/country PPVs are provided in the 5 person-years) ranged between 20.0 and 42.5 (ILDs), 17.9 and 38.3 (F-ILDs), 2.1 and 6.3 (IPF), 14.7 and 33.9 (non-IPF F-ILDs), and 0.5 and 1.0 (SSc-ILD) . The annual prevalences of ILDs in each country are presented in supplementary material sFigure 2. The overall prevalence (cases/105 persons) ranged between 72.1 and 164.2 (ILDs), 66.8 and 152.6 (F-ILDs), 7.8 and 24.3 (IPF), 56.2 and 132.0 (non-IPF F-ILDs) and 2.8 and 5.7 (SSc-ILD). Throughout the study period, incidence/prevalence were generally stable within each country, with few exceptions in Finland, Belgium and Greece .In 2018, the latest year assessed, the lowest (minimum adjusted by PPV) incidence estimates for ILDs, F-ILDs, non-IPF F-ILDs and SSc-ILD were obtained in Portugal, and for IPF in Denmark. The highest (maximum crude) incidence estimates for ILDs, F-ILDs and non-IPF F-ILDs were obtained in Belgium, for IPF in Denmark and for SSc-ILD in Norway. The overall  incidence .supplementary material sTable 6.In 2018, sarcoidosis was the most frequent non-IPF F-ILD subtype in most countries , except for Belgium  and Norway . In these two countries, however, sarcoidosis was the second most common subtype . In the remaining countries, the second most common subtypes were other F-ILDs (24.3% Denmark), exposure-related ILDs (21.2% Finland) and HP . The most prevalent conditions within the other F-ILD category were only assessed in Denmark; in 2017, they were unspecified ILDs  and other ILDs with fibrosis . Relative percentages annually and for the whole study period are provided in the supplementary material sTable 7.The minimum adjusted/maximum crude incidence of non-F-ILDs by country and overall for the whole study period and annually is shown in supplementary material sTable 8. Of total non-IPF F-ILD cases, approximately a third showed PF behaviour; 43% of these had a UIP-like pattern , but not between tertiary and secondary centres (p=0.6181).Absolute numbers and relative percentages of non-IPF F-ILD subtypes are shown in  pattern . Of note5 person-years and prevalence between 15.8 and 40.0/105 persons. Supplementary material sTable 10 (incidence) and sTable 11  show the widest variability observed in the primary and sensitivity analyses, annually and for the whole study period. Within each country, the results of the sensitivity analyses were very similar, and the results for the primary analysis were within the range defined by sensitivity analyses. The I2-statistic obtained in the random effects model for Method 3 (90%)  revealed substantial heterogeneity in PF behaviour among countries.The incidence in 2018 across the participating countries, assessed with the primary methodology, is show in PERSEIDS addressed the paucity of detailed and updated incidence/prevalence data for ILDs and its PF forms. The study has various strengths: the parallel implementation in six countries and the participation of both rheumatology and pulmonology units provides a broad, contemporaneous picture of the burden of ILDs across countries and grants a study population large enough to obtain sufficiently precise initial estimates. Also, the period of 5 years considered was wide enough to observe temporal trends and between-country differences.5 persons/year in 1998) [5 persons/year in 2004) [5 person-years between 1995 and 2005, 3.8–6.6 per 105/year between 2003 and 2009) [5 persons/year in 2009) [5 and 17.3/105, respectively) [5/year), Greece (0.93/105/year), Denmark (7.27/105 person-years between 1995 and 2005 and 1.3/105/year between 2003 and 2009) and the Nordics (0.4–10/105/year) were lower than in PERSEIDS, as was IPF prevalence reported previously for Belgium (1.25/105) and Greece (3.38/105) [5 persons between 2005 and 2012 and the prevalence at 13/105 persons in 2013 [5 persons [The few epidemiological studies on ILDs conducted so far in countries participating in PERSEIDS show quite homogeneous estimates. Incidence data were available for Belgium 1.0/10in 1998) , Greece in 2004) , Denmarknd 2009) , 18, and98 , Greectively) , 16. In .38/105) –19. A No persons ).supplementary material Section B). The extent of overestimation and the strictness of the adjustment applied may explain the highest/lowest estimates compared to other countries.Highest maximum crude estimates for ILDs, F-ILDs and non-IPF F-ILDs were consistently found in Belgium, and lowest in Portugal. Multiple factors may explain these findings. In Belgium, Liege Hospital was the only centre providing data for all ILDs in Phase 1. As rheumatological ILDs are referred to this centre from all over the country, we adjusted the reference population in these ILDs only. However, non-rheumatological referrals cannot be ruled out, so there may have been overestimation of these conditions and of the overarching ILD categories. Other contributing factors may be the concentration of heavy industries in the province of Limburg  and the Incidence of ILDs was relatively high compared to prevalence. This may point to a high mortality rate; but there may be other factors contributing, such as the aged population structure in Europe  and a besupplementary material. The expected bias was reduced by using wider reference populations for calculating incidence/prevalence, applying a different PPV to rheumatological ILDs (Liège) and estimating F-ILDs incidence/prevalence based on data from surrounding countries (Norway), but some bias may have remained. The high percentage of exposure-related ILDs in Finland may due to its prominent ship-building industry [The relative distribution of non-IPF F-ILDs subtypes observed may help clinicians discern which patients should be screened for ILDs, to achieve prompt diagnoses and improved outcomes; and for the most prevalent subtypes, should trigger the development of proper recommendations for management, as they are currently lacking except for SSc-ILD . In mostindustry , with itindustry . The expindustry , 29, botindustry –32. The industry  may haveSarcoidosis was the most frequent non-IPF F-ILD subtype in Phase 1. Though rarely fibrotic in early stages, sarcoidosis was included among non-IPF F-ILDs in PERSEIDS because fibrosis ultimately affects 20% of patients with stage IV disease . The cod2 statistic revealed a considerable heterogeneity among them.Differences in the relative distribution of non-IPF F-ILD subtypes among countries and in their percentage of progression explain the variability in incidence/prevalence estimates of PF-ILDs, and reinforce the primary methodology chosen (weighted mean percentage of progression). Also, primary and sensitivity analyses gave similar results in most countries, further supporting the strength of results. Nevertheless, the primary approach had some limitations, as the weighted percentage was calculated by pooling progression data from all countries, and the Ie.g. Portugal, Norway) did not provide incident/prevalent cases for the whole study period, precluding comparisons among countries for missing years and possibly affecting overall estimates. Between-country differences in ILD management, previously highlighted [Despite the efforts to reduce bias, the study has other limitations. It was not always possible to use a homogeneous methodology due to centre/country particularities, which may limit the comparability of results. Coding particularities/issues may explain some of the variability found between countries, as it may have influenced the ability to capture incident/prevalent cases and may have led to more misclassification in specific countries. Some centres . However, as ≥100 consecutive cases were reviewed per centre, the sample is expected to be representative.Other limitations were not country-specific. ILDs are often rare and diagnosis can be difficult, leading to over/underestimation and misdiagnosis. Also, the use of ICD codes for ILDs has known limitations , but the5 person-years and 6.9–78.0/105 persons, with differences between countries probably explained by the relative distribution of non-IPF F-ILD subtypes and their different rates of progression.To our knowledge, PERSEIDS is the first study assessing the epidemiology and progression of ILDs in parallel across several European countries. The incidence and prevalence of ILDs was higher and more variable between countries than previously reported, but below the threshold for orphan diseases. Overall, approximately a third of non-IPF F-ILDs cases showed a PF behaviour, and nearly half of those (43%) had a UIP-like pattern. The prevalence and incidence of PF-ILDs ranged between 2.1–14.5/1010.1183/23120541.00597-2021.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.00597-2021.SUPPLEMENTSupplementary material