In the more recent years antibody mediated rejection (AMR) which is a major contributor to vascular rejection has evolved as the most important cause of morbidity and mortality in patients undergoing cardiac transplantation. Acute AMR in the first year would be concerning but a long term consequence of chronic AMR is cardiac allograft vasculopathy (CAV) which has devastating consequences accounting for ~60% mortality –5.AMR results largely from development of antibodies to the human leukocyte antigen (HLA classes I and II). Non-HLA antibodies have also been implicated in AMR in solid organ transplant recipients –8. AllosThe pathophysiology appears to be largely driven by three major components- non-HLA antibodies, anti HLA antibodies as well as donor specific antibodies. The specific role of each of these antibodies in the pathophysiology is discussed below.The role of non-HLA antibodies in the pathogenesis of AMR remains less defined with limited data on their clinical significance, as well as pathophysiology of graft injury. A defined screening protocol for these antibodies should be executed post transplantation.via destruction of endothelial cells by DSA causing exposure of normally unseen autoantigens leading to production of non-HLA antibodies  .Patients diagnosed with AMR have recently been shown to have a reactive response to vimentin, beta-tubulin, lamin A/C, and apolipoprotein L2. Such increased reactive response to non-HLA antigens has been associated with AMR graft failure in solid organ transplants –22.In the current literature a number of non-HLA antibodies have been shown to be involved in AMR –23. Non-via complement fixation and a proinflammatory effect. Additionally, the interaction of AVA with neutrophils can lead to platelet activation causing a prothrombotic effect in the graft vasculature.Antivimentin antibodies (AVA) have been implicated in AMR in animal models as well as human solid organ recipients. AVA is commonly seen in patients with autoimmune conditions like lupus/rheumatoid arthritis. Though vimentin is a cytoplasmic intermediary filament protein derived from the mesenchyme noted in leukocytes, fibroblasts, and endothelial cells it is often seen on the cell surface of cells serving as an autoantigen and eliciting an immune response in the autoimmune disease state especially on apoptotic neutrophils and T cells –31. AVA Other notable associations have been between anti cytoskeletal anti endothelial cell antibodies and cardiac allograft rejection and those against agrin, adipocyte plasma membrane-associated protein, Rho GDP-dissociation inhibitor 2 [ARHGDIB], Rho guanine nucleotide exchange factor 6, angiotensin-II type 1 receptor, endothelin type A receptor, lamin B1, BPI fold-containing family B member 1, peroxisomal trans-2-enoyl-coenzyme A reductase, phospholipase A2 receptor, protein kinase C zeta type, tubulin beta-4B class IVb in renal transplant patients suggestive of a significant role for non-HLA antibodies in AMR in solid organ recipients , 36.The activation of endothelial cells by anti HLA antibodies has been postulated to cause proliferation, cytokine production and leukocyte recruitment leading to graft injury and dysfunction. Checking pretransplant anti HLA antibodies should be done imperatively as part of the pre transplant work up algorithm because sensitization has been noted with increasing length of mechanical support. Interestingly, avoidance of perioperative leukocyte-filtered cellular blood product transfusions does not significantly decrease the incidence or degree of HLA sensitization. However, cellular blood product transfusions have been noted in some studies to reduce the possibility of alloimmunization which may reduce the problem in the patients bridged to transplantation , 17, 37.via multifactorial mechanisms to destroy the graft. The most important of these is the complement activation cascade and formation of the membrane attack complex (MAC). Early proinflammatory proteins have recently been shown to drive the complement mediated injury. Other mechanisms include those mediated by the natural killer (NK) cells  cells . Mechanir damage –42.Gender differences in alloreactivity is an important aspect that needs to be taken into account when screening for anti HLA antibodies pre transplantation. Female cardiac allograft recipients have a higher pretransplant diagnosis of idiopathic cardiomyopathy, increase levels of antinuclear antibodies, in addition to HLA-B8, DR3 haplotypes. Female heart transplant patients tend to have a shorter duration to the first episode of rejection, increased number, and frequency of rejection episodes, and tend to produce anti-HLA antibodies sooner than their male counterparts. Infection related mortality seem to be higher in female cardiac allograft recipients. Fatal infections have been in noted in female heart transplant patients due to increased cyclosporine levels. Another interesting observation has been that the incidence of CAV developing after the first year post-transplant was lower in females. Women tend to manifest an autoimmune state prior to transplant which may predispose them to a greater risk of allograft. An algorithm for early diagnosis and management including a more individualized approach will improve clinical outcomes in the female population .de-novo DSAs  are associated with worse outcomes  may be the beginning of a highly sensitive method of detecting AMR even before it can be detected by endomyocardial biopsy which is the current method of diagnosis. This technology is based on the premise that in the setting of acute rejection allograft cell death occurs resulting in elevated levels of dd-cfDNA in the recipient's circulation , 61. Sucvia a complement-independent mechanism. Contrary to the earlier hypothesis de-novo are also associated with poorer outcomes. Currently patients with non-significantly low levels of DSA have been postulated to be safe to transplant with closer follow up of antibody levels which is becoming more feasible with new molecular technologies such as the use of dd-cfDNA , anti-endothelin-1 receptor type A (ETAR), Perlecan and anti-angiotensin II receptor type 1 (AT1R) are equally relevant. In addition to IgG, IgM is associated with worse graft outcomes in the long term. Additionally, DSA that are capable of activating the complement system produce worse outcomes than DSA which act dd-cfDNA , 62–67.de novo DSA post-transplant could provide an early diagnostic strategy for early intervention and better outcomes for graft protection. However, due to lack of existing studies definitive algorithms for surveillance and treatment are non-existent. The surveillance strategies and treatment protocols vary from center to center. More studies are needed at a multicenter level to assess antibodies at pre and post-transplant at different time points to develop more definitive protocols for surveillance and treatment. Building registries would help with defining thresholds for intervention and modifying peri operative management. AMR still remains a challenge and largely responsible for graft loss in the present era. Definitive studies are required in this area to improve outcomes and graft dysfunction and loss.Monitoring for DSA and NN conceived the idea and prepared the entire manuscript.The author declares 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. 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Klebsiella pneumoniae (KPC-Kp) is associated with the risk of developing KPC-Kp infection. The impact of the time elapsed since a patient becomes colonized on this risk is not well known. An observational, prospective, longitudinal cohort study of colonized patients undergoing active rectal culture screening to rule out KPC-Kp colonization (July 2012 to November 2017). Patients with a positive culture at inclusion (colonized at start of follow-up) and those with a negative culture at inclusion who became colonized within 90 days (colonized during follow-up) were included in the analysis. CART analysis was used to dichotomize variables according to their association with infection. Kaplan–Meier infection-free survival curves and the log-rank test were used for group comparisons. Logistic regression was used to identify variables associated with KPC-Kp infection. Among 1310 patients included, 166 were colonized at the end of follow-up. Forty-seven out of 118 patients colonized at start of follow-up developed infection (39.8%) versus 31 out of 48 patients colonized during follow-up . Variables associated with KPC-Kp infection in the logistic regression analysis were: colonization detection during follow-up , Giannella risk score , high-risk ward  and urological manipulation after admission . In 25 out of 31 patients (80.6%) colonized during follow-up who developed KPC-Kp infection, infection appeared within 15 days after colonization. The risk of KPC-Kp infection was higher when colonization is recently acquired during hospitalization. In this prospective study, we concluded that the timing of colonization was a factor to assess when considering empirical treatment for suspected KPC-Kp infection and prophylaxis or infection control.Colonization by KPC-producing IMPORTANCE In this study, it was confirmed that patients who became colonized during hospitalization had a higher risk of developing KPC-Kp infection than hospitalized patients who were already colonized at the start of follow-up. Besides, the risk of infection in the group of patients who became colonized during follow-up was greater in the first weeks immediately after colonization was confirmed. Our findings support the need for designing preventive strategies for patients at the highest risk of infection development, including those admitted in high-risk hospital wards and those undergoing urological procedures. Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) strains have spread worldwide in recent years   is one oThe natural history of intestinal colonization and its clinical impact has been insufficiently studied. It is not known whether the risk of KPC-Kp infection depends on the pathogenic bacterial load or whether it varies with the time elapsed from colonization. This study was designed to investigate whether the risk of KPC-Kp infection is associated with the time elapsed from colonization considering other variables associated with this risk.The overall cohort included 1310 hospitalized patients who were followed during 90 days (except in case of death), of which 166 were colonized at the end of follow-up (78 developed KPC-Kp infection). None uncolonized, unscreened, or patients excluded for any reason developed KPC-Kp infection. Table S1 shows the variables related to the screening protocol.P = 0.02) had fewer intensive care unit (ICU) admissions  and had a higher Charlson index score . Patients who were colonized during follow-up underwent invasive procedures more frequently, including central venous catheter placement , mechanical ventilation , or major surgery in both the previous 3 months  and during follow-up . Patients who became colonized during follow-up had a higher GRS than those colonized at the start of follow-up .The classification and regression trees (CART) analysis  established day 0 of follow-up (colonized at start of follow-up versus colonized during follow-up) as the cutoff point for dichotomizing the variable time to colonization according to the risk of developing KPC-Kp infection. Among 166 colonized patients, 118 (77.1%) were detected by rectal swabs collected at day 0 (colonized at start of follow-up) and 48 (28.9%) by rectal swabs performed within 90 days after the first negative screening (colonized during follow-up) . TherefoP = 0.006). Infections with a higher risk of death (INCREMENT-CPE score >7) occurred in 32 of the 118 (27.1%) patients colonized at the start of follow-up versus 23 of the 48 (47.9%) patients colonized during follow-up (P = 0 0.01). No differences in crude or attributable mortality were observed between the two groups. Table S2 shows the distribution of infection types in the two colonization groups.Forty-seven of the 118 (39.8%) patients colonized at day 0 developed KPC-Kp infection compared to 31 of the 48 (64.6%) patients who were colonized during follow-up , gentamicin (53.6%), tigecycline (64.8%) and colistin (66.5%). All tested isolates were sensitive to ceftazidime-avibactam. Sensitivity to ceftazidime-avibactam was determined by disk diffusion using 14 μg discs (Oxoid) from 2015 to February 2017 and by SensititreTM EURGNCOL commercial microdilution panels  from March 2017 until the end of the study.The KPC-Kp index isolates in our center and some other isolates from this outbreak were previously characterized by multilocus sequence typing (MLST) as corresponding to the same clone (ST512) at the reference laboratory of Virgen Macarena University Hospital of Seville, Spain . These iP = 0.03) in comparison to patients that were colonized at the start of follow-up. Other variables associated with a higher risk of developing KPC-Kp infection were hospitalization in the high-risk ward , manipulation of the urinary tract  and GRS .The high-risk ward and high-risk period (from July 2012 to June 2014) variables were previously established by Treenet  and CART  analyses, respectively, and included in the logistic regression analyses. The multivariate logistic regression analysis  confirmeP = 0.05). Furthermore, the curves showed that the infection-free survival rates decreased in both groups in the first weeks of follow-up until reaching a plateau. Besides, patients colonized during hospitalization developed infections mostly before day 50 of follow-up. The evolution of the number of patients at risk of KPC-Kp infection is shown in P = 0.04) of the previously uninfected patients became infected. P < 0.001). A time window of 30 days with a higher risk of infection can be observed in both groups. We found that 80% (25/31) of the patients colonized during follow-up who finally developed infection became infected within 15 days after colonization was confirmed. These data could not be analyzed in patients colonized at the start of follow-up since it was not possible to know for how long they had been colonized. This suggests the hypothesis that there is a period in the first days after colonization when the risk of developing KPC-Kp infection is higher. The characteristics of these patients with respect to those who did not develop an infection or developed it later are shown in P = 0.001) with higher mortality attributable to infection  than those who developed infection later or did not develop an infection.The Kaplan–Meier curves of KPC-Kp infection-free survival, comparing patients colonized at start of follow-up (day 0) and patients colonized during follow-up, confirmed these differences  than those who were already colonized at the time the first rectal swab screening was performed (colonized at start of follow-up). Furthermore, it shows that the risk of infection in patients colonized during follow-up is higher in the first weeks after colonization is detected until a plateau is reached.Studies on the kinetics of intestinal colonization are needed to determine whether this time window of increased risk corresponds to the quantitative evolution of the kinetics of intestinal colonization or whether it simply reflects the fact that hospitalization increases the probability that the colonizing bacteria will cause infection. What seems important to us is that we have identified a time window for higher infection risk that allows us to design preventive strategies in certain groups of patients temporally limited to the duration of this time window. For example, we have observed that a high GRS, being admitted to a high-risk ward, and urological manipulation are also significantly associated with an increased risk of infection in KPC-Kp-colonized patients. Our study suggests that in situations of KPC-Kp outbreaks or endemicity appropriate infection control and preventive measures may be implemented during these time windows of increased risk of infection .Recent European Society of Clinical Microbiology and Infectious Diseases (ESCMID) consensus guidelines do not recommend routine selective bowel decolonization (SBD) in KPC-Kp-colonized patients . It is cOur study has some important limitations. When patients were colonized in the first rectal swab performed after admission, we could not ascertain how long the patient had been colonized. Furthermore, rectal swab controls may not have been indicated for non-severely ill patients who were discharged and not included in the study. We do not know how many of these patients may have been colonized, so there is an inclusion bias since colonization was only identified in more severely ill patients who were admitted for longer periods. However, the fact that none of the uncolonized, no-screened, or excluded patients developed KPC-Kp infection, may reduce concerns that there was a large pool of colonized, but undetected, patients in this cohort. To carry out a prospective study like this and taking into account that being colonized was a necessary condition for developing an infection, it was necessary to follow up a large number of patients (1310) to finally be able to analyze a much smaller number of colonized patients (166). The higher the incidence and prevalence rates observed in this study compared to other studies  may be eWe conducted an observational, prospective, longitudinal cohort study of hospitalized patients ≥18 years of age undergoing active rectal cultures screening to rule out KPC-Kp colonization at Reina Sofia University Hospital (HURS), a 1000-bed tertiary center in Cordoba, Spain. Patients were included in the cohort (Angel cohort) from July 2012 to November 2017, during an outbreak of KPC-Kp infections that became endemic. KPC-Kp colonization screening was performed by rectal swab culture (the collected specimen was a transport swab) in patients admitted to the intensive care unit (ICU) and hematology unit, patients undergoing abdominal interventions or transplants, patients previously admitted to units affected by the outbreak, and patients sharing a room with a new colonized patient. Patients admitted to the ICU or hematology unit were first screened at admission and weekly during hospitalization. The rest of the patients were screened at admission, when a colonized roommate was detected, or before surgery (when they were transferred to the operating room). Follow-up screening was performed every 2 weeks. For the analysis, day 0 was defined as the date of inclusion in the cohort, when the first rectal swab screening was performed. Patients colonized at day 0 or those who became colonized during hospitalization were included in the cohort. Patients not colonized at day 0 and without at least one positive rectal swab culture during hospitalization were excluded. Patients with an active infection at the time of the first rectal swab (day 0) and those who received intraluminal intestinal decolonization with gentamicin or colistin were also excluded. All consecutive patients who fulfilled inclusion criteria were included in the cohort.All patients were followed according to the center’s clinical protocols. When the patients were discharged before the end of follow-up, they or their family members were contacted by telephone to ascertain their clinical status. The study was approved by the Ethics Committee of the Reina Sofia University Hospital-IMIBIC (code MOR-ANG-2018-09). All the data obtained were anonymized.The primary outcome variable was KPC-Kp infection until day 90 of follow-up. Data were collected using a standardized form. Explanatory variables included: (i) demographics: age and sex; (ii) hospitalization-related variables: admission in the previous 6 months, ICU stay during follow-up, admission ward and date of admission; (iii) invasive procedures performed during follow-up: urological manipulation, use of central venous catheter and need for mechanical ventilation during follow-up; (iv) comorbidities: diabetes mellitus, heart failure, chronic obstructive pulmonary disease, kidney disease, neoplasia, neutropenia (<500/μL), Charlson and McCabe indexes; (v) concomitant treatment in the previous month: steroids, antibiotic drugs against Gram-negative bacilli for more than 48 h, and specifically use of carbapenems; (vi) variables related to KPC-Kp colonization: GRS (predictor of bacteremia in KPC-Kp-colonized patients) ; (vii) vRectal colonization by KPC-Kp was defined as isolation of KPC-Kp from a rectal swab in the absence of clinical signs and symptoms of infection. The first day of follow-up was defined as the day that the first screening rectal swab was collected (day 0). The variable time to colonization was considered zero in patients who were colonized at day 0 (patients colonized at start of follow-up). In patients colonized during follow-up, the time from the first negative swab (day 0) to the first rectal swab positive for KPC-Kp was considered.All Kp-KPC infections were microbiologically tested and defined following the Centers for Disease Control and Prevention criteria . The datEnterobacterales . In some cases, identification was confirmed using a MALDI-TOF  following the manufacturer’s instructions. Analysis of the sensitivity results established the suspicion of carbapenemase production. KPC production was confirmed by a commercial Xpert Carba-R PCR assay  and the KPC K-SeT immunochromatographic assay  from July 2012 to March 2017, and the NG-Test Carba 5 immunochromatographic assay  from March 2017.KPC-Kp strains were isolated and characterized following the usual protocols of the center. Plates with selective medium for carbapenemase-producing strains were employed for rectal swab culture screening as follows: ColorexTM KPC plates  were used from July 2012 to November 2016; CARBA plates  were used from December 2016 to March 2017 and CHROMID CARBA SMART biplates  were used from April 2017 until the end of the study. Identification and antibiogram of isolates were performed from July 2012 to March 2017 using commercial Gram-negative REV.2 WIDER microdilution panels and NC54 combo panels  for the semiautomated WIDER system  following the manufacturer’s recommendations. Subsequently, MicroScan Gram-negative Combo Panels Type NC53  was used from March 2017 until the end of the study. The MIC and clinical category for each antibiotic were interpreted from July 2012 to February 2017 using the CLSI cutoff points  and fromU test. Categorical variables were compared using the Chi-square test or Fisher’s exact test when indicated. To control the influence of the different hospital wards and the risk of KPC-Kp, wards were classified by TreeNet as being at high or low risk for acquiring KPC-Kp infection  for the quantitative variables and as percentages for the qualitative variables. Continuous variables were analyzed using the Mann–Whitney nfection , considenfection  was perf


The capability of emulating neural functionalities efficiently in hardware is crucial for building neuromorphic computing systems. While various types of neuro-mimetic devices have been investigated, it remains challenging to provide a compact device that can emulate spiking neurons. In this work, we propose a non-volatile spin-based device for efficiently emulating a leaky integrate-and-fire neuron. By incorporating an exchange-coupled composite free layer in spin-orbit torque magnetic tunnel junctions, multi-domain magnetization switching dynamics is exploited to realize gradual accumulation of membrane potential for a leaky integrate-and-fire neuron with compact footprints. The proposed device offers significantly improved scalability compared with previously proposed spin-based neuro-mimetic implementations while exhibiting high energy efficiency and good controllability. Moreover, the proposed neuron device exhibits a varying leak constant and a varying membrane resistance that are both dependent on the magnitude of the membrane potential. Interestingly, we demonstrate that such device-inspired dynamic behaviors can be incorporated to construct more robust spiking neural network models, and find improved resiliency against various types of noise injection scenarios. The proposed spintronic neuro-mimetic devices may potentially open up exciting opportunities for the development of efficient and robust neuro-inspired computational hardware. The high computational requirements from data-intensive AI algorithms have placed a pressing challenge for developing efficient AI hardware. At present, while ANNs have demonstrated human-level performance on various cognitive tasks4, the power consumption of most AI algorithms implemented in state-of-the-art hardware is still substantially higher than that of a human brain. Inspired by the ultra-high efficiency and robustness of brains, neuromorphic computing aims to emulate behaviors of biological systems in order to achieve high efficiency at cognitive processing. Spiking neural networks (SNNs), which incorporate temporal dynamics of spikes as inspired by biological neural systems, has become an emerging paradigm that could potentially provide efficient and reliable platforms for AI processing7.The significant advancements of deep artificial neural networks (ANNs) in various domains of artificial intelligence (AI) such as image classification8. Emerging beyond-CMOS technologies, such as various non-volatile memories (NVM), are well-positioned for realizing neuromorphic building blocks efficiently with compact footprints. Prototypes of spiking neurons have been recently demonstrated exploiting various NVM technologies such as Ag-oxide memristor9 and phase change material10, ferroelectric field-effect transistor(FeFET)11, as well as spintronics13. Among the various approaches based on emerging technologies, spintronic implementations provide the highest endurance thanks to the absence of ion motions in the writing process14. Since the state of neurons are updated frequently during both inference and training, the inherent high endurance of spintronics makes it particularly appealing for emulating neurons. While implementations of binary or stochastic neurons can be directly achieved exploiting the bidirectional polarization of magnetization13, mimicking analog-valued functionality  remains challenging using spin-based technologies. Magnetic domain wall motions and skyrmions have been proposed to provide continuous modulation of states in spintronic devices, but large footprints (1 μm) and special designs of device geometry are required15. In addition, the motions of domain walls and skyrmions are unpredictable and difficult to control due to strong sensitivity to shape/defect-related local pinning in fabricated devices, leading to undesirable device variability and repeatability issues that can significantly hinder large-scale system implementations16.In order to construct efficient spike-based computational systems, it is imperative to provide compact and energy-efficient hardware emulation of key building blocks such as neurons and synapses. However, implementing bio-plausible neuronal functionalities based on conventional CMOS circuits typically desires a large number of interconnected transistors, which can be both area expensive and power hungry18. By incorporating an exchange-coupled composite free layer into the magnetic tunnel junction (MTJ), we demonstrate through micromagnetic simulations that near-continuous resistive modulation can be achieved based on the partially switched magnetic domains in the composite MTJ with a lateral dimension of 75 nm x 75 nm. A spin-orbit torque (SOT) MTJ with the proposed free layer achieves continuous modulations of MTJ conductance under input spikes, enabling a direct representation of the analog-valued membrane potential in the LIF neuron dynamics. Moreover, we observe from analyzing the micro-magnetic device simulations that the proposed spintronic neuronal device exhibits intriguing dynamics under spike excitation. In contrast to the standard LIF neuron model which has a constant leak time constant and a constant membrane resistance , we find that the behavior of the proposed device can be characterized by a varying time constant and a varying membrane resistance. Specifically, both the membrane leak time constant and the membrane resistance are dependent on the transient membrane potential. Interestingly, we find that training SNNs for image classifications on the CiFAR-10 dataset19 using the device-inspired neuronal behavior achieves comparable test accuracy within fewer training epochs in comparison to training with the baseline neuron model. Moreover, we observe that the SNN incorporating the behavior of the proposed spintronic neurons demonstrates improved robustness under various types of noise injection, and such noise resiliency maintains under realistic device variations.In this work, we propose a new spintronic device model to provide hardware emulation of leaky integrate-and-fire (LIF) neurons by exploiting the magnetization dynamics of multi-granular structures. Leveraging the significant advances of magnetic storage medium over the past few decades, magnetic granular structures are capable of sustaining multiple domains in devices with critical dimensions well below 100 nmP) or anti-parallel (RAP). The tunneling magneto-resistance (TMR) ratio, defined as TMR = The proposed neuromorphic neuronal device is based on the structure of an MTJ, which has been developed for magnetic random access memory (MRAM). As is shown in Fig. 20. Charge current is spin-polarized as it goes through an MTJ, and the FL can be switched by the spin transfer torque (STT) induced by the spin-polarized current. Depending on the polarity of the current, the FL can be switched between the P and AP directions with respect to the RL21. Recently, it is found that in MTJ-heavy metal(HM) heterostructures, the FL can also be switched by spin-orbit torque (SOT) induced by a transverse electric current flowing in the adjacent heavy-metal layer22. SOT switching provides the opportunity of separate read and write paths, and eliminates the issue of applying large currents through tunnel barriers during STT write operations. Note that an SOT-MTJ requires a larger area than an STT-MTJ due to the 3-terminal configuration, and an extra transistor may be required in addition to the 1T/1R STT-MTJ cell23. But density requirement is less stringent for neuron activation compared to that for implementing synaptic weight storage, and SOT-MTJ may still achieve better density than CMOS-based implementations for emulating neurons.The magnetization of the FL in an MTJ can be switched by various types of stimuli such as external magnetic fields or spin (polarized) currents. Current-driven switching is preferred for scalable device technologies2) with the averaged grain size below 10 nm25. In a typical HDD granular storage medium, weakly coupled magnetic cores formed by Co-rich alloys are segregated by non-magnetic materials as grain boundaries. Since bits of information (“0” or “1”) are recorded as magnetic flux transitions across adjacent magnetic domains, granular boundaries play the critical role of reducing inter-granular exchange coupling and thus bringing down the magnetic cluster sizes. In the state-of-the-art multi-granular recording medium, it is observed that the domain widths in the down-track direction are reduced to 10–30 nm (in contrast to the domain size of 500–1000 nm in continuous ferromagnetic thin films26), providing a cost-effective mechanism for high-density data storage without involving complex processes of lithography. Note that granular materials with both in-plane and perpendicular magnetic anisotropy have been developed over the past decades. Depending on the material synthesis processes, magnetizations in the grains can be oriented following a uniaxial anisotropy direction with some distributions in the energy of magnetic anisotropy and the grain size25.In order to emulate the integration of membrane potential in a LIF neuron, it is desirable to provide reliable devices with continuous conductance modulation. In this work, we consider magnetic granular nanostructures for generating multiple states based on the switching dynamics of multi-domain magnetizations. The advances of magnetic multi-granular materials have been one of the major driving forces behind the recent progress of magnetic data storage in hard disk drive (HDD) industry, reaching an ultrahigh areal density of over terabytes per square inch  in our spin-based neurons for improved writing endurance and speed. Since it is desirable for neuronal hardware to have frequent and fast updates of the activation values, SOT-MTJ with the write current flowing through the HM layer, unlike a standard MTJ where the write current tunnels through the MgO, is preferred for endurance concerns. Depending on the duration and magnitude of input charge currents in the heavy metal layer (IHM), the composite FL can be partially switched. Conceptually, an inactive neuron has most of the device area unswitched, and a larger portion of the total device area being aligned to RL indicates that the neuron is closer to saturation under the input stimuli, as shown in the transition from point A to point D in Fig. X direction. Note that both in-plane and perpendicular anisotropy can be exploited to construct an MTJ with exchange-coupled free layer. We choose to focus on in-plane anisotropy in the rest of the discussions, since deterministic SOT-switching of in-plane magnetization can be realized without the assistance of an external field or additional symmetry-breaking methods29.As is illustrated in Fig. 3 simulation30. MuMax3 is an open-source GPU-accelerated micromagnetic simulation program, where nano-scale temporal and spatial magnetization evolution is solved using a finite-difference discretization. Bilayer structures with lateral dimensions of 75–100 nm comprising the continuous cap layer and granular bottom layer are modeled. The thickness of the top layer is kept at 1 nm to make sure that the top layer can be fully controlled by the bottom layer, while the granular layer is set at 6–10 nm in order to provide sufficient thermal stability based on realistic magnetic anisotropy energy Ku = 0.4e6 J/m3. The inter-layer Ruderman–Kittel–Kasuya–Yosida (RKKY) exchange coupling coefficient is set to be strong between the top and bottom (see “We investigate the magnetization dynamics of the proposed multi-level device based on MuMaxx = − 1) to P  over time under repetitive pulses of input current. The observed sloped switching of the magnetization, instead of a step-like reversal, validates the feasibility of utilizing the magnetic switching to represent a continuously varying membrane potential. Different mechanisms can contribute to the observed gradual magnetization switching. First, the stochastic nature of magnetization dynamics under thermal agitation could lead to the non-uniform onset of switching of individual grains under the input currents. Moreover, our simulations include distributions of switching energy as well as the role of magneto-static interactions among the grains. It is found that reproducible non-coherent partial switching can be achieved when monitoring an ensemble of more than 50 nano-grains, corresponding to a lateral dimension of 75 nm with the averaged grain size of 8–10 nm.As shown in Fig. Noticeably, during the process of switching under current pulses, the total magnetization always shows some decaying at the end of each pulse. The decay is caused by the switching of local magnetic moments under the combined influence of thermal agitation, inter-granular exchange coupling, and the demagnetizing field due to magnetic dipole interaction. When the input pulse is gone, some of the switched grains may flip due to the combined force of thermal attempt and local dipole interactions. As discussed further in the following section, the observed decay of magnetic signal can be exploited to imitate the leak effect for a LIF neuron model. Note that most of the decay in magnetization occurs within the first few nanoseconds after input pulses, and the intermediate states with partially switched domains stabilize, thanks to sufficient average thermal stability of the magnetic grains. The stability of intermediate states enables non-volatility in these analog neuronal devices, potentially leading to high energy efficiency by reducing the need to offload the intermediate neuronal states to off-chip memory.x (ranged between -Ms and Ms). The integration process of membrane potential can be emulated by the gradual non-coherent multi-domain magnetization switching demonstrated in the earlier section. As for the leak, we rely on the observed relaxation of local magnetic moments under the influence of thermal agitation and dipole interaction. The LIF neuron model can now be mathematically expressed as the following: I represents the input current obtained from the weighted summation of spiking inputs from pre-neurons, The key components in hardware emulation of the LIF neuronal dynamics are membrane potential and leak. We use magneto-resistive states of the analog MTJ to represent a  membrane potential, which can be linearly mapped to the magnetization MWe first investigate the simulated device dynamics under the excitation of input currents in more detail. As shown in Fig. entclass1pt{minimasee Fig. c. The vaNeuron. Reference MTJ is set to a fixed configuration and remains unchanged while the neuron device is being excited. As an increasing portion of magnetic domains in the FL of MTJNeuron are switched under input currents, the voltage across the MTJNeuron changes proportionately. The varying voltage over MTJNeuron is connected as an input to the inverter, forming a resistive divider network. Resetting of the SOT-MTJ neuron is done by applying currents with the opposite polarity of the input spikes. It has been demonstrated that the timing of iterative read/write and reset can be achieved by incorporating only 2–3 access transistors, leading to a compact design for generating spiking output based on such resistive divider circuitry31. Based on the proposed device and circuit, we simulate the magnetization dynamics of the multi-state MTJ with the inclusion of the firing and reset operations. We build a behavior model to emulate the magnetization dynamics, and validate the neuronal behavior model by reproducing the firing dynamics obtained from the micromagnetic simulation. In the validation, we consider input currents with varying amplitudes to reflect the scenario that neurons in a multi-layer SNN will receive weighted input spikes of varying magnitudes. As is shown in Fig. Leveraging the multi-domain device dynamics, an exemplary circuit implementation of SOT-MTJ spiking neuron is proposed and illustrated in Fig. Neuron is done by applying the HM metal, we can estimate the device-level energy consumption by calculating HM = 830 8 while requiring a large number of transistors. Moreover, the proposed spin-based device provides non-volatile analog states, which could lead to significant energy saving by eliminating the need of off-chip memory access to store and load the intermediate activation states throughout the accumulation and update of membrane potential in the neuron. The energy and area advantages offered by the spin-based non-volatile spiking neuron can potentially lead to massive improvement in the computational efficiency of neuromorphic hardware.The above simulations demonstrate that the functionality of LIF neurons can be realized directly in the proposed analog SOT-MTJ devices in a very compact fashion. In the following, we discuss the achieved energy efficiency of the proposed spiking spintronic neuron in comparison with CMOS neurons. Since the write and reset of the MTJ32. In our approach, spike-based backpropagation algorithm is enabled for training deep SNNs with LIF neurons following an approximate derivative method that accounts for the leaky behavior of LIF neurons.In this section, we will explore the algorithm-level performance of the proposed neuron when deployed in a deep spiking neural network. The behavior model illustrated in Fig. 7 for image classifications on CiFAR-10 dataset, providing a good reference starting point for the algorithm-level demonstration. Details such as the setting of hyper-parameters for training are included in “We start with the baseline spiking VGG9 model with regular LIF neurons having a constant leak rate 33, are considered. For each type of noise pattern, we look into two scenarios of noise injection to the input7. In scenario-1, random noise is added to image pixels at each time step before the generation of Poisson spike trains, which leads to possible modification of the timing and spiking frequency of spike trains, while the resultant spikes are still binary. In scenario-2, random noise is added at each time step to the already generated spike trains so that the magnitude of spikes is no longer binary due to the addition of noises, although the timing of the spike trains is intact. As is shown in Fig. 7. Our observation demonstrates that incorporating the more complex leaking behavior and membrane potential sensitivity inspired by the characteristics of multi-domain spin devices can further enhance the robustness of spiking neurons against noisy inputs. Note that the tested SNN models are all trained with clean input and have no prior knowledge of the various types of noise injection, and yet the improvement in noise resiliency is clearly observed for all the scenarios. Therefore, implementation of the proposed spintronic analog neuron provides an efficient pathway for gaining robustness from the underlying device technology in hardware implementation, in contrast with the approach of retraining with various types of noisy perturbation, which typically consumes significant additional computational resources.In the following noise experiments, we explicitly show that the neuron models with varying As with all kinds of analog devices, noises associated with device variability can be a concern for practical implementations. We demonstrate the impact of realistic device variation on the performance of deep SNNs incorporating the proposed spintronic neuronal devices. The major contribution to the device variation in this multi-granular MTJ-based design is the stochasticity of the switching of magnetic moments in combination with the switching field distribution among the grains. Fig. We propose a novel spintronic neuro-mimetic device that can emulate the leaky integrate-and-fire neuron dynamics with high energy efficiency and compact footprints. Based on the proposed free layer with continuous-granular composite structure, we achieve gradual switching of the magnetization, which is utilized to emulate both accumulation and leak of membrane potential. Furthermore, we observe unique characteristics of a varying leak rate and a varying membrane channel resistance from the micromagnetic simulations of the proposed device. After incorporating the observed device behavior into the spiking neuron models, we demonstrate improved robustness against various types of input noise injection for image classifications. The proposed analog magneto-resistive devices leveraging memory and storage technologies could open up exciting new avenues for developing emerging neuromorphic hardware. Moreover, our cross-layer exploration suggests that the tuning of the leak and membrane resistance of spiking neurons may lead to an interesting pathway towards efficient and robust bio-plausible learning algorithms.top = 400e3 A/m with large exchange coupling Aex = 1e–11 J/m, while the granular layer has lower magnetiztion Msbottom = 250e3 A/m with inter-granular coupling of 1e–13 J/m. The grains in the bottom layer have an averaged in-plane uni-axial magnetic anisotropy of Ku = 0.4 e6 J/m3 with 20–25% grain-to-grain variation as is observed in actual storage medium. The thicknesses of the top and bottom layers are 1 and 6 nm, respectively, so that grains in the bottom layer can reach a thermal stability factor KuV/kT = 37 at room temperature for grain size = 9 nm and thus maintain thermally stable during the sub-μs neuron dynamics. The inter-layer RKKY exchange coupling is set to be as high as 50% of the lateral exchange coupling (ARKKY = 5e–12 J/m) to ensure a strong coupling so that local magnetic moments from the top layer will follow the local magnetization in the grains of the bottom layer.The magnetization dynamics of composite free layer is simulated in MuMax3 as a bilayer magnetic structure of distinctive magnetic properties in each layer. The top continuous capping layer represents CoFeB, which is most commonly used in MTJ stacks. The capping layer is set as a soft ferromagnetic layer with negligible magneto-crystalline anisotropy and strong lateral exchange coupling. The bottom granular layer setting is based on Cobalt-based granular magnetic medium utilized in mass production of magnetic hard disk drives. Voronoii tessellation as provided by MuMax is used to generate initial granular configuration following a specified random seed. Considering the segregation of non-magnetic materials in granular structures, inter-granular coupling is reduced to 1–10% of the coupling strength in a continuous film. Such reduced inter-granular coupling will enable the occurrence of multi-domain intermediate states during magnetic switching. For the specific data analyzed in the paper, the Gilbert damping constant is set at 0.01 for both top and bottom layers. The continuous top layer has large saturation magnetization Ms32 with a batch size of 16–32. Each model is trained with 150 epochs, where the learning rate reduces at the 70th and 100th epochs. Input encoding to Poisson spike trains of 100 time steps is done after normalization of pixel intensity of input images to the range of  with a mean of 0. For evaluations of those device-based neuron models, the last fully-connected layer uses regular LIF neuron, as it is observed in our experiment that when neurons with varying leakage are used, the last layer of SNN models is required to have LIF neurons with small leak (The SNN models are trained with clean data following the approach of spike-based back-propagation as proposed in


The objective of this study was to evaluate the impact of the COVID-19 pandemic on the circulation of influenza and other seasonal respiratory viruses in the United States. All data were obtained from the US Department of Defense Global Respiratory Pathogen Surveillance Program over five consecutive respiratory seasons from 2016–2017 through to 2020–2021. A total of 62,476 specimens were tested for seasonal respiratory viruses. The circulating patterns of seasonal respiratory viruses have been greatly altered during the pandemic. The 2019–2020 influenza season terminated earlier compared to the pre-pandemic seasons, and the 2020–2021 influenza season did not occur. Moreover, weekly test positivity rates dramatically decreased for most of the seasonal respiratory viruses from the start of the pandemic through spring 2021. After the easing of non-pharmaceutical interventions (NPIs), circulations of seasonal coronavirus, parainfluenza, and respiratory syncytial virus have returned since spring 2021. High rhinovirus/enterovirus activity was evident throughout the 2020–2021 respiratory season. The findings suggest a strong association between the remarkably changed activity of seasonal respiratory viruses and the implementation of NPIs during the COVID-19 pandemic. The NPIs may serve as an effective public health tool to reduce transmissions of seasonal respiratory viruses. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spreads globally, resulting in an unprecedented public health crisis . As of tEvery year, the Department of Defense Global Respiratory Pathogen Surveillance (DoDGRS) program performs routine respiratory pathogen surveillance among the Department of Defense’s service members and their beneficiaries. The objective of this study was based on the DoDGRS data collected over five consecutive influenza seasons (2016–2021), to characterize circulating trends of influenza and other seasonal respiratory viruses among the Department of Defense personnel in the United States during the COVID-19 pandemic, and to compare the trends with those that occurred in the pre-pandemic period.We obtained respiratory pathogen surveillance data on US Department of Defense personnel from the DoDGRS program over five consecutive respiratory seasons from 2016–2017 to 2020–2021. All patients seeking outpatient medical care were selected at sentinel or participating sites throughout the United States, using criteria which meet an influenza-like illness (ILI) case definition. ILI is defined as a patient presenting with (1) a fever (≥38 °C) and a cough or sore throat within 72 h after illness onset, or (2) symptoms determined by a physician to be an ILI case. Respiratory specimens were collected from ILI patients by nasopharyngeal wash or nasopharyngeal swab, and tested via a multiplex respiratory pathogen panel. In addition, a reverse transcription polymerase chain reaction (RT-PCR) and/or viral culture were used to identify and confirm the influenza viruses and other seasonal respiratory pathogens. If the respiratory specimen tested positive for influenza virus, further testing was conducted to identify the influenza virus type and subtype/lineage. During the COVID-19 pandemic, patients who tested for both seasonal respiratory viruses and SARS-CoV-2 were not included for analysis, due to possible changes in test eligibility and testing procedure in detecting respiratory viruses.The weekly test positivity rate for each respiratory virus in a given respiratory season was defined as the percentage of the number of cases over the total number of tests for the epidemic week under surveillance. By using the same thresholds in the study of Feng et al. , the stai = effect of treatment ; and ei = error term. A p < 0.05 was considered statistically significant.The four-week averages of test positivity rates of non-influenza seasonal respiratory viruses during the COVID-19 pandemic were compared with those in the pre-pandemic , using the GLM procedures of SAS  with the modelInfluenza and other seasonal respiratory viruses detected over five respiratory seasons (2016–2017 through 2020–2021) are shown in During three pre-pandemic influenza seasons (2016–2017 through 2018–2019), the influenza epidemic period started in as early as week 46 (18–24 November 2017) and ended in as late as week 19 (13–19 May 2017), lasting an average period of 21.7 weeks (range: 17–24 weeks) . During p < 0.05) observed for human metapneumovirus at the beginning of the 2020–2021 season (p < 0.05) than those in the pre-pandemic, correspondingly  rebounded out of season following the easing of NPIs. Further study is needed to explore and thus have a better understanding of the underlying mechanisms for altering circulation patterns of seasonal respiratory viruses. With the ongoing COVID-19 pandemic, it is important to evaluate transmission dynamics and risks of influenza and other seasonal respiratory viruses in subsequent respiratory seasons. Indeed, assessing the exact prevalence of respiratory viruses in the real world would undoubtedly provide valuable information, and help guide the design of preventive measures in mitigating seasonal respiratory virus epidemics.


Strikingly, the observed back-splice junctions do not follow a unique canonical pattern, compatible with the U2-dependent splicing machinery. Numerous noncanonical junctions were observed in viral circRNA sequences characterized from in vitro and in vivo infections. Given the importance of the genes involved in the transcription of these circRNAs, our study contributes to our understanding and complexity of this deadly pathogen.Circular RNAs (circRNAs) are a recently rediscovered class of functional noncoding RNAs that are involved in gene regulation and cancer development. Next-generation sequencing approaches identified circRNA fragments and sequences underlying circularization events in virus-induced cancers. In the present study, we performed viral circRNA expression analysis and full-length sequencing in infections with Marek’s disease virus (MDV), which serves as a model for herpesvirus-induced tumorigenesis. We established inverse PCRs to identify and characterize circRNA expression from the repeat regions of the MDV genome during viral replication, latency, and reactivation. We identified a large variety of viral circRNAs through precise mapping of full-length circular transcripts and detected matching sequences with several viral genes. Hot spots of circRNA expression included the transcriptional unit of the major viral oncogene encoding the Meq protein and the latency-associated transcripts (LATs). Moreover, we performed genome-wide bioinformatic analyses to extract back-splice junctions from lymphoma-derived samples. Using this strategy, we found that circRNAs were abundantly expressed IMPORTANCE Circular RNAs (circRNAs) were rediscovered in recent years both in physiological and pathological contexts, such as in cancer. Viral circRNAs are encoded by at least two human herpesviruses, the Epstein Barr virus and the Kaposi’s Sarcoma-associated herpesvirus, both associated with the development of lymphoma. Marek’s disease virus (MDV) is a well-established animal model to study virus-induced lymphoma but circRNA expression has not been reported for MDV yet. Our study provided the first evidence of viral circRNAs that were expressed at key steps of the MDV lifecycle using genome-wide analyses of circRNAs. These circRNAs were primarily found in transcriptional units that corresponded to the major MDV virulence factors. In addition, we established a bioinformatics pipeline that offers a new tool to identify circular RNAs in other herpesviruses. This study on the circRNAs provided important insights into major MDV virulence genes and herpesviruses-mediated gene dysregulation. Circular RNAs (circRNAs), a new class of noncoding RNAs, were rediscovered in recent years because of increased interest in the regulation of gene expression by noncoding RNAs (ncRNAs). As their name indicates, circRNAs are different from linear RNAs as they are continuous covalently closed loops without a 5′-cap structure and a 3′-polyA tail. They result from back-splicing events, defined by the head-to-tail “back-splicing” of a downstream splice donor to a more upstream splice acceptor. Most of the characterized circularizations have been linked to the canonical splicing machinery that is dependent on the U2 spliceosome to date , 2. Howe3–14–Herpesviridae family  for the edited repeat long (ERL) (S/TRS) for the latency-associated transcripts (LATs) (Marek's disease is a neoplastic disease of chickens causing severe economic hardships to the poultry industry . In addi31–35–41–ng (ERL)  and the s (LATs) , 45, 46.Because circRNAs have been identified as key regulators in tumorigenesis and more specifically in virus-induced cancers, we set to decipher their expression in MDV infection and tumorigenesis. In this study, we identified viral circRNA expression at key steps of the MDV infection cycle. Complementary approaches demonstrated that major MDV virulence genes express a huge range of circRNAs. Thorough analyses of circularization sites highlighted the use of both the canonical and noncanonical back-splicing machinery. Moreover, analyses of MDV-induced tumors revealed peaks of viral circRNA expression from latency- and cancer-related genes. Consequently, this study broadens the scope of noncoding RNA functions in Marek’s disease development.meq oncogene and the LATs. These two genes are localized in the repeat regions of the genome from which abundant and linear alternative transcripts derived from complex splicing were discovered  thphocytes .meq and LATs transcriptional units. While the meq locus showed a constitutive expression of circRNAs regardless of the tested RNA sample, circRNA expression from the LATs locus varied according to the source of the RNA. PCR signals specific for circular transcripts were more obvious from PBL and splenocytes collected from in vivo infected animals and from lymphoma-derived cells reactivated with 5’azacytidine  were designed to target previously identified exons of pp14, meq/vIL-8, ERL, or LATs loci , the 10 ERL circRNAs were produced from the opposite strand being antisense to parts of pp14 and meq ORFs L/IRL regmeq ORFs , 48–50, L , while only canonical circRNAs covered exons 8 to 12  that was previously exploited to characterize specific host circRNA signatures during Marek’s disease virus infection (+) and five that did not develop tumors   .+ samples  from infected chicken embryo fibroblasts (CEF) was processed to map back-spliced junctions over the MDV genome. This analysis showed a wider distribution of back-splicing sites and a higher proportion of noncanonical circRNAs during lytic MDV replication  and was verified by the expression of VP5 as previously described .The embryonic stem cell-derived line-1 (ESCDL-1)  was cultEx vivo infections of B and T lymphocytes were carried out using the RB-1B strain and following the guidelines described by Schermuly and collaborators , and peripheral blood lymphocytes (PBL)) were obtained from previous experiments . Residual DNA was removed with DNase I (NEB) according to the manufacturer’s instructions. After that, to remove linear RNAs, an RNase R (Lucigen) treatment was performed. 4 μg of total RNA was treated with 20 U of RNase R for 20 min at 37°C. Before and after the RNase R treatment, the samples were extracted with phenol-chloroform (Sigma).RNase R-treated RNA was then reverse-transcribed by using random primers (50 μM) and Superscript III (Invitrogen) reverse transcriptase following the manufacturer’s protocol. The efficiency of the RNase R treatment was evaluated by amplifying one host and one viral circular RNA and their linear counterparts from treated or untreated RNA .The resulting cDNAs were amplified by PCR  in a final volume of 50 μL containing 1.25 U of GoTaq Polymerase G2 (Promega) and 0.2 mM each primer in the reaction buffer provided by the manufacturer. All the primers used in this study are reported in GSE138600 and GSE166240). The first set of data ((GSE138600) was obtained from infected chickens with (TA+) and without (TA−) MDV-induced T CD4+ lymphomas and was analyzed through our pipeline. The second set of data ((GSE166240) were gathered from chicken embryonic fibroblasts (CEF) infected by the Md5 strain of MDV. All the data obtained from this experiment were analyzed through our pipeline. Note that in the present study, the sequence libraries  correspond to the total RNA extract following circular transcripts enrichment.Two data sets from previous experiments , 47 wereof data  for the first time using Burrows-Wheeler Aligner , it was considered a potential circularization signal, and both the back-spliced junction and donor and acceptor splice sites were stored in a new file with the read IDs. To increase the specificity of our circRNA detection, several filters were put in place deleting (i) the reads that map repetitive sequences; (ii) the reads that present back-splice sites distant by more than 5000 bp on the genome; (iii) the reads with no crossmatch between their back-splice junction and the two corresponding splice sites; (iv) the reads reported with incomplete back-splice junctions or splice sites.The back-splice junctions were counted according to their similarity. Ninety-five percent of similarity was considered a match allowing thereby one mismatch in the back-splice junction. The same 95% of similarity was also required between the reported back-splice sites. A filter was designed to delete the reads presenting long stretches (more than 5 nucleotides) of similarities at donor and acceptor back-splice sites. The idea was to avoid false positives due to PCR artifacts.Using the ID list extracted from this count, the complete reads were extracted from the first SAM file to exhibit a proper alignment, processed with Samtools, and drawn using Geneious.damien.coupeau@unamur.be).All data and bioinformatic codes are available on reasonable request to Damien Coupeau (


Cardiovascular diseases (CVDs) are prevalent medical conditions affecting millions of people worldwide and are associated with significant morbidity and mortality. The main precursor of CVDs and the related events, such as hypertension and heart failure, is hyperlipidemia, most commonly an increase in low-density lipoproteins. Lipid-lowering drugs are cardinal in the treatment of CVDs. American College of Cardiology and American Heart Association have issued guidelines for lipid-lowering therapy, and statins are first-line medication. In the recent years, a new class of lipid-lowering agents called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has been identified as the potential lipid-lowering therapy for the statin-resistant patient. In clinical trials and observational studies, PCSK9 inhibitors and statins are both associated with the development of neurocognitive dysfunction in the older population. This systematic review aims to inquire if there is significant neurocognitive dysfunction associated with statins and PCSK9 inhibitors and compare neurocognitive effects associated with statins with those of PCSK9 inhibitors. Hyperlipidemia, with significantly elevated low-density lipoprotein cholesterol (LDL-C), is one of the major known modifiable risk factors for atherosclerosis that subsequently leads to a number of cardiovascular diseases (CVDs). Treatment of hyperlipidemia is imperative to prevent mortality and morbidity in millions of people suffering from CVDs worldwide. American Heart Association (AHA) released guidelines for the management of blood cholesterol . AccordiStatins are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. The liver regulates body lipids; LDL-C is taken up by hepatocytes at a 50% rate from the blood . StatinsSterol regulatory element binding proteins (SREBPs) are cut out of the endoplasmic reticulum when HMG-CoA reductase is inhibited and translocate to the nucleus, where they boost the expression of the LDL receptor genes, which increases the LDL cholesterol uptake resulting in a decrease in intracellular cholesterol. Hepatic LDL receptors rise when hepatocyte cholesterol levels fall, which controls the decline in circulating LDL and its precursors like intermediate-density lipoproteins (IDLs) and very low density lipoproteins (VLDLs). After the administration of a single daily dose, the LDL cholesterol reduction with all statins is nonlinear and dose-dependent. Statins are the single most effective lipid-lowering drugs that decrease both morbidity and mortality associated with CVDs. The rupture of an unstable atherosclerotic lesion and the development of a thrombus is mostly the cause of coronary events. Statins inhibit the advancement of coronary atherosclerosis and cause its regression, as well as the development of new lesions thereby lowering the frequency of coronary events by a number of mechanisms . LDL parStatins are associated with a number of side effects, with the most commonly reported being myopathy ranging from myalgia to rhabdomyolysis . ElevateAmong new lipid-lowering treatment modalities for statin-resistant patients, most important are proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. A number of PCSK9 inhibitors are being developed to block PCSK9 at various points in its life cycle as shown in Table There are a number of side effects associated with PCSK9 inhibitors, like alirocumab and evolocumab, with the most common being nasopharyngitis, and injection site infection . HoweverIn this review, we aim to inquire about the neurocognitive dysfunction associated with statin and PCSK9 inhibitor use and assess if there is any correlation or causation between drug usage and the aforementioned outcome.MethodsWe searched through the articles in PubMed, Google Scholar, and clinical trials to find the relevant articles. After applying inclusion and exclusion criteria and quality assessment tools, we used the 20 articles to extract data and form results as shown in Table Inclusion/Exclusion CriteriaRandomized controlled trials (RCTs), case reports, observational studies, retrospective studies, and review articles were included in this review. Animal studies, articles not in English, and articles that were not free were not part of the review.ResultsWe implemented Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA 2020) guidelines for systematic review as shown in Figure Characteristics of Studies IncludedClinical trials, narrative reviews and case reports were used for our systematic review, and their results pertaining to neurocognitive effects are mentioned in Table Quality AssessmentWe utilized Cochrane Collaboration’s tool for assessing the risk of bias for RCTs. Seven RCTs found to have a low risk of bias and of high quality were included in the systematic review as shown in Table DiscussionNeurocognitive dysfunction is characterized by the decline from a previously attained level of cognitive functioning, and includes delirium, mild cognitive impairment, and dementia. Diagnosis of neurocognitive dysfunction requires the assessment of all cognitive domains such as perceptual-motor function, executive function, complex attention, social cognition, learning and memory, and language . The effStatins and Neurocognitive DysfunctionThe US Food and Drug Administration (FDA) in 2012 changed safety label instructions for lipid-lowering drugs like statins and added information about the possibility of relatively mild and reversible cognitive adverse effects  . They baMuldoon et al. studied the effect of lovastatin on cognition . In thisStone et al. as a part of the American College of Cardiology/American Heart Association (ACC/AHA) Task Force created clinical practice guidelines for assessing cardiovascular risk, making lifestyle changes to reduce cardiovascular risk, manage blood cholesterol in adults, and manage overweight and obesity in adults . They stRojas-Fernandez et al. as a part of the Statin Cognitive Safety Task Force assessed the FDA updated guidelines for statins in 2014 . Out of Ott et al. reviewed 25 RCTs with the primary objective of finding evidence of a causal association between statin therapy and cognitive impairment . The secSuraweera et al. reported two cases of simvastatin-associated cognitive decline . One wasSchultz et al. discussed both cognitive impairing and protective effects of statins in the aftermath of the FDA updates about statins . They stStatin and Neurocognitive Dysfunction: Proposed MechanismCholesterol is crucial for brain functioning; it is a structural component of the myelin sheath, and steroid hormones involved in signaling across the brain and peripheral tissue. It is essential for mitochondrial function, expression of neurotransmitter receptors, development of synapses, and transport of antioxidants like coenzyme Q10 . The proPSCK9 Inhibitors and NeurocognitionPCSK9 inhibitors such as monoclonal antibodies evolocumab (Repatha) and alirocumab  were given the FDA approval to treat high cholesterol. The effectiveness of both of these in treating patients with atherosclerotic cardiovascular diseases (ASCVDs) was later demonstrated. PCSK9 inhibitors and their effect on neurocognition are documented in earlier trials of these drugs.Koren et al. studied the results of the Open-Label Study of Long-Term Evaluation Against LDL Cholesterol 1 (OSLER-1) . OSLER-1Sabatine et al. enrolled 4465 patients in two open-label, randomized trials OSLER-1 and OSLER-2 . PatientRobinson et al. studied the results of long-term safety and tolerability of alirocumab versus placebo on top of lipid-modifying therapy in high cardiovascular risk patients with hypercholesterolemia  . They raKastelein et al. studied the efficacy and safety of alirocumab versus placebo on top of lipid-modifying therapy in patients with heterozygous familial hypercholesterolemia (FH) not adequately controlled with their lipid-modifying therapy (ODYSSEY FH I and ODYSSEY FH II) . In thesGinsberg et al. studied the efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia, with an LDL-C level of 160mg/dL or higher with a maximally tolerated statin (ODYSSEY HIGH FH) . Every tKhan et al. studied the results of 11 studies to assess the safety with a focus on neurocognitive adverse events of PSCK9 inhibitors . Out of Giugliano et al. recruited 1204 patients for evaluating PSCK9 binding antibody influence on cognitive health in high cardiovascular risk subjects  . This prPCSK9 Inhibitors and Neurocognitive Dysfunction: Proposed MechanismThe exact mechanism that causes neurocognitive dysfunction in patients receiving PCSK9 inhibitors is not known. These monoclonal antibodies due to their larger size cannot cross the blood-brain barrier; therefore, the cognitive damage is due to the effect of lowered LDL-C in the body from their use. There are four proposed mechanisms: dysregulation of lipid and glucose metabolism, N-methyl-D-aspartate (NMDA) receptor modulation, alteration in neuronal cell membrane integrity, and predisposing risk factors like genetic variance .Statins Versus PSCK9 Inhibitors: Neurocognitive EffectsZhao et al. studied the lipid-lowering medication's comparative effectiveness and safety in people with hypercholesterolemia . In termLimitationsSmall patient groups of the clinical studies included in this systematic review, to evaluate the neurocognitive effects of statins and PCSK9 inhibitors, may not have been representative of the general population. Also, studies included in this review were only those that were available as free full text that may have affected the results of this review.Statins and PCSK9 inhibitors both are imperative in the treatment of hyperlipidemia to reduce the risk of mortality and morbidity associated with CVDs. The neurocognitive dysfunction associated with these lipid-lowering agents includes reversible dementia, amnesia, delirium (including confusion), cognitive and attention disorders and disturbances, thinking and perception abnormalities, and mental impairment disorders. There was no causal relation found between low LDL-C levels and cognitive impairment among patients. The role of statins in both reversible cognitive impairment and treatment of cognitive dysfunction is conclusive. The association between neurocognitive dysfunction and lipid-lowering agents is not well established and there is a need for extensive long-term clinical trials to reach a conclusive decision. However, lipid-lowering agents' benefits far exceed the risks associated with them and should be part of the treatment regime of prospective patients. Healthcare workers have the responsibility of recognizing patient subgroups that are more vulnerable to the aforementioned side effects and performing cognitive assessment tests and informing patients about the possible side effects and managing them accordingly.


Intensification of the hydrological cycle resulting from climate change in West Africa poses significant risks for the region’s rapidly urbanising cities, but limited research on flood risk has been undertaken at the urban domain scale. Furthermore, conventional climate models are unable to realistically represent the type of intense storms which dominate the West African monsoon. This paper presents a decision-first framing of climate research in co-production of a climate-hydrology-flooding modelling chain, linking scientists working on state-of-the-art regional climate science with decision-makers involved in city planning for future urban flood management in the city of Ouagadougou, Burkina Faso. The realistic convection-permitting model over Africa (CP4A) is applied at the urban scale for the first time and data suggest significant intensification of high-impact weather events and demonstrate the importance of considering the spatio-temporal scales in CP4A. Hydrological modelling and hydraulic modelling indicate increases in peak flows and flood extents in Ouagadougou in response to climate change which will be further exacerbated by future urbanisation. Advances in decision-makers’ capability for using climate information within Ouagadougou were observed, and key recommendations applicable to other regional urban areas are made. This study provides proof of concept that a decision-first modelling-chain provides a methodology for co-producing climate information that can, to some extent, bridge the usability gap between what scientists think is useful and what decision-makers need.The online version contains supplementary material available at 10.1007/s10113-022-01943-x. Intensification of the hydrological cycle as a result of global warming is disrupting our ability to cope with hydrological risks in urbanised areas and placing an increasing number of people at risk UN . The sitWest Africa is particularly at risk from an increase in high-intensity storm events as a result of changes to the West African Monsoon (WAM) which have been found to be increasing in recent years , which sought to address the challenge of understanding how the West African monsoon will change in future decades and how this information can effectively be used to support climate-compatible strategies in the region. This paper demonstrates the approach used to interact with decision-makers and collect their needs for scientific outputs and tools to support flood-resilient urban planning. We present the climate-hydrology-flooding modelling chain resulting from the interaction process that integrates the most up-to-date tools and models in the region. The simulations of this modelling chain are discussed in terms of urban and climate impacts with respect to important scientific advances made in the region, as well as emerging learning with regard to strengthening capacities for climate-resilient planning.The aim of this study is to present an experience of developing a modelling chain that links scientists working on state-of-the-art regional climate science with decision-makers involved in city planning for future urban flood management in the city of Ouagadougou, Burkina Faso. This was a pilot-study undertaken within the UK Department for International Development (DFID) FCFA programme-funded AMMA2050 project  and through regular meetings within Ouagadougou. These brought regional and local stakeholders engaged in urban planning, water management and governance into direct contact with multi-disciplinary teams of regional, national and international scientists working on various aspects of climate, hydrology, meteorology and socio-economy. The process of engagement and development of climate information . This enabled identification of relevant agencies and decision-makers and key local challenges and decision-maker needs. These included requiring city-scale climate information, providing local hydro-meteorological data, considering future urbanisation, using existing or openly available data modelling tools where possible and providing outputs that would be for engineers. Further workshops (2017) identified how climate information could support local decision-making processes in the urban context of Ouagadougou.www.2ie-edu.org) and technically focused Ouagadougou decision-makers operating within the Ministry of Urbanism (MoU) and local Mayor’s office to enable engagement and identify decision-making contexts relating to resilient urban flood policy and planning. A technical workshop (2018) involved technical presentation and open-table discussion between scientists and local mayors and decision-makers using a science café model  process framework for incorporating information into decision-making—outlined in Audia et al. . This guwww.wascal.org), engaging local decision-makers to strengthen linkages between researchers and policymakers. Subsequent breakouts involved scenario selection and discussions on operationalising the science. Key directives from decision-makers that involved this co-development included selecting return periods from design storms, considering associated drainage provision alongside urban development projections and providing flood maps that incorporate hydraulic infrastructure. Ultimately, this process shifted the focus from changes in peak flows resulting from regional climate change patterns to a linked hydrological-hydraulic modelling approach fed by design storms.Additional direction was achieved in a joint workshop (2018) with the West African Competence Centre in Ouagadougou on Climate Change and Adapted Land Use  to reduce the most important biases identified at hourly time scales , each with two design storms , and one land cover, either 2016 or 2050. To account for requests by stakeholders to consider city plans to upgrade localised urban drainage, model runoff and routing parameters were adjusted for future land cover to increase runoff and conveyance speeds.www.athys-soft.org). The model was selected as it has proven urban application in the location of interest  extent. For the model domain, this results in widespread infill and densification of existing areas and expansion to the North-West, with new nodes of development appearing in the previously rural West. Comparison of projections against the Ouaga 2025 future planning map . Peak flows are highest in the two largest catchments , as expected, but when standardised against catchment area, peak flows as a ratio of catchment area are actually higher in the smaller more urban catchments and generally highest in catchments SE and ESE. For these small urban catchments, the high overall proportion and density of urban land cover are driving significantly higher overall runoff ratios than in the less urbanised and less dense catchments to the west. Interestingly, despite the western catchments having the greatest relative increases in urban land cover in the future, the higher increases in runoff ratios remain in the small urbanised catchments, with SCE and SC exhibiting the largest increases (> 300%) compared to a 260% increase in WSW and WNW. However, this could simply be a result of the storms’ spatial distributions.Model results (Table S6) suggest that peak flows across most catchments are set to increase as a result of climate and land-use change. The mean of 10-year and 100-year flow peaks across the nine catchments increase by 57% and 168%, respectively, by 2100 compared to control period values. However, the highest modelled peak flow values were observed in the WNW catchment in the intermediate (2050) time-period, despite the future (2100) having higher mean areal rainfall totals. Given both periods utilise the same land cover data, such variation is due to the spatial and temporal distribution of rainfall as the storm propagates from east to west over the catchment and the higher maximum point intensities of rainfall over the WNW catchment Fig. .2 , this safety limit was exceeded. Results for the spillway of Dam 2_3, modelled using design criteria from site observations, simulated overtopping and no capacity to manage such HIW events. This agrees with observations of frequent overtopping and transport disruption.Assessing spillway performance, engineering design calculations AGEIM  indicateThe AR5 IPCC report found only low-to-medium confidence of precipitation changes across West Africa and a need for higher resolution products  and future (2100) periods, which fits well with initial findings from Kendon et al.  of futurThe results of this first analysis of CP4A data over an urban-scale domain in West Africa provide insights on possible ways that extreme rainfall which might lead to flooding might change in the future. Hydrological modelling outputs indicate significant increases in future peak flows (57–168%) from contributing catchments as a result of climate and land-use change. The scale of changes in future inflows to the city demonstrates the challenge of mitigation and suitable engineering design faced in Ouagadougou. Comparing rates of change in future urban land cover and rainfall, it is clear that climate is the primary driver of increased flooding, further exhibited in the large runoff increases from areas that are currently highly urbanised. However, this study uses only conservative assessments of land-use change compared to other studies  suggest are effective knowledge systems. Examples of such knowledge systems provided include (i) project workshops involving local decision-makers and boundary organisations, (ii) technical reports that include decision-maker–led scenarios for future urban adaptation, (iii) training of researchers locally and in Europe and (iv) transfer of monitoring equipment and models. There were major problems encountered curtailing opportunities for further engagement with decision-makers from Ouagadougou, which included a national insurgency problem, a lack of clarity on the ‘entry points’ and channels for informing the ‘Grand-Ouaga’ planning process and the evolving COVID-19 situation. Despite these setbacks, a successful final project communication workshop was held in Ouagadougou in December 2021  forced by a single GCM. Using an ensemble of GCMs to drive CP4A, or an ensemble of RCMs to drive Stochastorm, would inevitably introduce a substantial range into the underpinning rainfall statistics used here and considering less extreme scenarios, and shorter time horizons, could all reduce uncertainty. This could inform an updated technical report in local rainfall and flooding and should form part of local planning. Furthermore, scale, uncertainty and bias issues are not given explicit quantitative analysis in the paper or modelling-chain. Likewise, the hydrological-hydraulic modelling chain relied on simplified terrain representation and limited flow data for parameterisation. Further work should focus on improving data availability and more quantitative uncertainty assessment. Lastly, it should be a priority that continued engagement with local, national and regional decision-makers is undertaken to realise the full potential of the work undertaken.This paper presents a decision-maker–led climate-hydrology-flood modelling-chain approach for bridging the usability gap between emerging high-resolution climate science and information needs for future flood management within a West African city, Ouagadougou. The approach used is in line with research suggesting participatory modelling can provide a tool to support planning and negotiation in fragile, climate-sensitive contexts Supplementary file2 (MP4 570 kb)Supplementary file3 (MP4 682 kb)Supplementary file4 (MP4 618 kb)Supplementary file5 (MP4 566 kb)Supplementary file6 (MP4 612 kb)Supplementary file7 (DOCX 2334 kb)Below is the link to the electronic supplementary material.


It is very natural to use silicon as a primary material for microelectronics. However, silicon application in nanophotonics is limited due to the indirect gap of its energy band structure. To improve the silicon emission properties, it can be combined with a plasmonic part. The resulting metal–dielectric (hybrid) nanostructures have shown their excellence compared to simple metallic dielectric nanostructures. Still, in many cases, the fabrication of such structures is time consuming and quite difficult. Here, for the first time, we demonstrate a single-step and lithography-free laser-induced dewetting of bi-layer nanoscale-thickness gold–silicon films supported by a glass substrate to produce hybrid nanoparticles. For obtaining hybrid nanoparticles, we study nonlinear photoluminescence by mapping their optical response and morphology by scanning electron microscopy. This method can be used for the fabrication of arrays of hybrid nanoparticles providing white-light photoluminescence with a good control of their microscopic sizes and position. The developed approach can be useful for a wide range of photonic applications including the all-optical data processing and storage where miniaturization down to micro- and nanoscale together with an efficiency increase is of high demand. The development of white-light photoluminescence (PL) micro- and nanoscale sources is of great interest to many prospective photonic applications. Silicon is a perfect candidate for building such kinds of light sources due to its compatibility with available well-known technologies. However, silicon has an indirect gap, and the quantum yield of bulk material is very small  is the most common approach to provide deterministic nanoscale distributions on metallic or dielectric material. Zuev et al.  demonstrSpherical NPs can be obtained by laser-induced techniques ,17 due t4− ions . Si@Au N4− ions , where b4− ions .The formation of hybrid NPs requires at least two different materials to be combined with a certain accuracy of component position with respect to another part, resulting in quite complex fabrication steps. So far, EBL together with a direct patterning with a focused ion beam are prime choice to get hybrid structures due to great capabilities for design manipulation. However, both techniques are still quite expensive, unsuitable for the patterning of large areas and limited in the production of spherical geometries. Therefore, laser machining  can be uHere, for the first time, we demonstrate a single-step and lithography-free laser-induced dewetting of bi-layer nanoscale-thickness gold–silicon films supported by a glass substrate to produce hybrid nanoparticles. We study their nonlinear PL by mapping their optical response and morphology by scanning electron microscopy.Au/Si bi-layers were fabricated using the magnetron sputtering method. The thicknesses of gold films are chosen in accordance with the results , which dE) can be calculated as F) is Hybrid NPs are obtained from gold/silicon bi-layer films using an experimental setup  based onThe geometry characterization and size distribution of produced NPs were analyzed by scanning electron microscopy (SEM). SEM measurements were performed by an Inspect microscope  with an accelerating voltage of 20 kV in mode of secondary electrons detection. The quantitative composition analyses of NPs was performed by energy-dispersive X-ray spectroscopy (EDX). Analyzed hybrid NPs were located onto carbon tape and investigated by a transmission electron microscope  in STEM mode with 20 nm spatial resolution.Nonlinear signal measurements were performed via pumping of NPs by a femtosecond YbLaser beam scanning of the film surface along a circular path provides the fabrication of nanoparticles arrays for all considered bi-layer films as confirmed by the SEM images in Early on ,19,40, tThe assumption about the formation of a complex internal microstructure is confirmed by several experimental results. First, EDX measurements of single NPs  demonstrProduced NPs demonstrated both SHG and broadband PL signals a–c under10−5  and lowe10−5 . NeverthAccording to our results, NPs fabricated from the bi-layer film of Au (30 nm)/Si 180 nm) thickness demonstrate the strongest PL signal among considered films, as it appears both from PL signal mapping g–i and P0 nm thicFinally, it should be mentioned that the main limitations factors for reproducibility as well as size control of produced hybrid NPs are laser source long-term stability during the fabrication process along with the proper adjustment of setup and uniformity of initial bi-layer film.To the best of our knowledge, for the first time, we demonstrate a single-step and lithography-free laser-induced formation of hybrid nanoparticles from bi-layer nanoscale-thickness gold–silicon film caused by the simultaneous cutting and dewetting of the initial film. The presented fabrication method makes it possible to produce large nanostructures (up to 1