Sc) and BSE infectivity to the nervous system. However, analysis of samples collected under identical conditions from both atypical H- and L-BSE forms allowed us a more precise assessment of the grade of involvement of different tissues during the clinical end stage of disease as compared to C-BSE. One important feature is the involvement of the peripheral nervous and musculoskeletal tissues in both L-BSE and H-BSE affected cattle. We were, however, able to show that in H-BSE cases, the PrPSc depositions in the central and peripheral nervous system are dominated by a glial pattern, whereas a neuronal deposition pattern dominates in L-BSE cases, indicating differences in the cellular and topical tropism of both atypical BSE forms. As a consequence of this cell tropism, H-BSE seems to spread more rapidly from the CNS into the periphery via the glial cell system such as Schwann cells, as opposed to L-BSE which is mostly propagated via neuronal cells.After the discovery of two atypical bovine spongiform encephalopathy (BSE) forms in France and Italy designated H- and L-BSE, the question arose whether these new forms differed from classical BSE (C-BSE) in their pathogenesis. Samples collected from cattle in the clinical stage of BSE during an intracranial challenge study with L- and H-BSE were analysed using biochemical and histological methods as well as in a transgenic mouse bioassay. Our results generally confirmed what had been described for C-BSE to be true also for both atypical BSE forms, namely the restriction of the pathological prion protein (PrP Sc), predominantly in the nervous system. Classical BSE (C-BSE) in cattle has been shown to be causatively linked to the feeding of BSE-contaminated meat and bone meal and milk replacers [Bovine spongiform encephalopathy (BSE) in cattle belongs to the group of transmissible spongiform encephalopathies (TSEs), also called ‘prion diseases’. These inevitably fatal neurodegenerative disorders can affect numerous mammalian species. Hallmarks of TSEs are spongiform changes in the central nervous system (CNS)  and the eplacers ,3. The pSc accumulation and infectivity to the central nervous system of clinically affected cattle is well acknowledged [Sc depositions after the animal has entered the clinical stage of the disease. In addition, BSE infectivity has been detected in the peripheral nervous system (PNS) and in the adrenal gland of cattle naturally infected or experimentally challenged with classical BSE by using a highly sensitive transgenic mouse bioassay [Musc. semitendinosus sample of a natural C-BSE case in the final disease stage by transgenic mouse bioassay [Sc in tissues of the digestive tract [For C-BSE, the general restriction of the PrPowledged –6. The bowledged –9. Howevbioassay . Minor ave tract . Studiesve tract –17.Sc and infectivity, with only the tonsils [Sc and infectivity are easily detected throughout the peripheral nervous system and the LRS of scrapie-affected sheep and goats [The lymphoreticular system (LRS) of BSE-affected cattle was found to be generally free of detectable PrP tonsils , the Pey tonsils  and the  tonsils  represennd goats ,21.The aetiology as well as the pathogenesis of both atypical BSE forms, designated H- and L-BSE are less understood so far, due to their relatively late discovery in France and Italy ,23, and Sc was detectable in the central nervous system (CNS) by biochemical methods (BSE rapid test as well as precipitation with phosphotungstic acid (PTA) followed by western blot), whereas samples from the peripheral tissues, including the PNS and LRS, remained negative [Sc deposits and infectivity in the skeletal muscle of H-BSE and L-BSE affected cattle were observed [Sc accumulation in peripheral nervous samples, while no PrPSc was detectable in any lymphoid tissues [Sc accumulations in peripheral tissue samples of intracranially challenged cattle, precisely in muscle spindles and in the trigeminal ganglion, as detected by immunohistochemical analysis, while the LRS and the enteric nervous system (ENS) displayed no involvement [Sc and infectivity in the late stages of both atypical BSE forms [We recently challenged cattle intracranially with H- and L-BSE . First rnegative . In othenegative  as well observed . In anot tissues . Other aolvement . Taken tSE forms ,29,30.Sc and BSE infectivity distribution in cattle.In this present study, we further analysed peripheral samples collected from cattle that were at different stages of the clinical phase of disease after intracranial challenge with H- or L-BSE  and compAll tissue samples of animal RA01 sacrificed 5 month after challenge with L-BSE and which was in the preclinical stage of the disease, were negative in all biochemical tests that were performed. From the cattle challenged with H-BSE, no animal was sacrificed in the preclinical phase.For all animals sacrificed at the clinical stage of the disease (12 mpi to 16 mpi), the obex and the spinal cord samples gave strong positive results in the IDEXX BSE EIA . The optic nerve samples were also detected positive for all animals sacrificed between 14 and 16 mpi, with slightly higher OD values (1.266 on average) for the samples collected from H-BSE infected cattle as compared to 0.896 on average for the L-BSE infected animals . PeriphePTA-WB of the CNS samples was positive in dilutions up to 1:1024 for all 10 animals challenged with H- and L-BSE that had been in the clinical stage of the disease . The optSc purification protocol using ultracentrifugation followed by Western blot . Doing so, we revealed low amounts of PrPSc in the trigeminal ganglion samples from H-BSE affected cattle, while the same samples collected from L-BSE affected cattle were negative . Meanwhnegative ). Stellaganglion ).10.1080For immunohistochemical analysis, the mab cocktail 6C2/F99 was applied in order to benefit from a synergistic effect on the sensitivity of two PrP-specific antibodies. To verify the results obtained with the mab cocktail 6C2/F99, we repeated the IHC staining procedure on the samples listed in Supplementary Sc accumulation pattern in the obex, especially in the nucleus of the solitary tract, the nucleus of the spinal tract of the trigeminal nerve and the dorsal motor nucleus of the vagus nerve (DMNV) as well as the spinal cord was dominated by a glial, coarse granular PrPSc deposition pattern. In contrast, the samples from L-BSE affected cattle majorly displayed intraneuronal depositions. Corresponding deposition patterns were determined for both the thoracic (T7) and the lumbal segments (L3) of the spinal cord. Interestingly in H-BSE affected cattle, only few individual glial cells within the white matter of the spinal cord displayed immunoreactivity . In cony matter ).10.1080Sc depositions in the dorsal root ganglia (DRG) of the animal sacrificed at 12, 15 and 16 mpi, while no PrPSc was detectable in the animal sacrificed at 14 mpi, which may well be due to individual variation. The DRG in L-BSE affected cattle were consistently detected positive from 14 to 16 mpi. Once again, in H-BSE affected cattle we observed a glial deposition pattern  with a low number of positive neurons (<1%), while for L-BSE, we only determined individual neurons or glial cells with PrPSc deposition .For H-BSE affected cattle, we detected PrPSc accumulation in the trigeminal ganglia, we could detect only traces of PrPSc accumulation in the trigeminal ganglion of one cattle challenged with L-BSE  and for one L-BSE affected animal sacrificed at 15 mpi (RA03) . Anali (RA03) .10.1080/Negative control sections from the respective tissues of one of the mock-infected animals are presented in Supplementary All other peripheral tissue samples of the lymphoreticular system, the alimentary, respiratory and reproductive system as well as from the musculoskeletal systems tested negative in this analysis.Sc depositions between both atypical BSE forms during the course of the disease, especially at the late stage of disease (16 mpi). Cattle challenged with H-BSE showed generally low quantities of small vacuoles in the neuropil of the obex , whilthe obex ,d). For −3,71 LD50 for H-BSE and a titre of 10−4,77 LD50 for L-BSE, with generally longer incubation times in H-BSE infected mice  and shorter incubation times for L-BSE (185 days) in comparison to 230 days that had been repeatedly determined for C-BSE in the same mouse model . Similar0 days an3 lower infectivity titre (as deduced from the titration experiments). Challenge of transgenic mice with samples from the dorsal root ganglion, the cervical cranial ganglion, the thoracic part of the vagus nerve, the N. saphenus and N. medianus from L BSE affected cattle resulted in incubation times and transmission rates that were prolonged by more than 80% and lower attack rates as compared to the obex sample, indicating infectivity titres that are by a factor 104 or more lower than determined for CNS samples , and we detected BSE infectivity in the Musc. semitendinosus sample from both L-BSE challenged cattle analysed in the mouse bioassay. This is confirmed by the results of other studies that revealed the involvement of skeletal muscles. Lombardi et al. [Sc accumulations in some skeletal muscles. The dissemination of PrPSc and infectivity via the neuronal pathway into skeletal muscle seems highly plausible in the case of L-BSE. Other studies revealed PrPSc depositions in muscle tissues of both H- and L-BSE affected cattle [The biochemical analysis of representative tissue samples confirmed what had been described regarding the general restriction of PrPi et al.  reportedi et al.  detectedd cattle . This coSc accumulation in the trigeminal ganglion and in the optic nerve than L-BSE challenged cattle, whereas L-BSE infected cattle displayed a stronger involvement of the vagus nerve, the peripheral motoric nervous system and the musculoskeletal system. By transgenic mouse bioassay, we were also able to detect abundant amounts of BSE infectivity in the peripheral nerves of L-BSE infected cattle, but not to the same extent in the same samples collected from animals challenged with H-BSE. This may be partly due to the distinctly prolonged incubation times in transgenic mice after challenge with H-BSE as compared to C-BSE or L-BSE, possibly extending the incubation time in some experiments beyond the lifespan of the mice. This is in line with our results from parallel titration experiments of L-BSE and H-BSE in bovine PrP transgenic mice, where we found at least a tenfold increase in the LD50 titre for the L-BSE material as compared to H-BSE.Our analyses of samples collected from cattle challenged with all three BSE types and analysed using identical procedures allowed a more detailed comparative analysis of the deposition patterns. According to our IHC results, H-BSE infected cattle displayed an earlier and more extensive PrPSc accumulations, L-BSE affected cattle displayed a PrPSc distribution with a predominant intraneuronal immunolabelling pattern in the vicinity of the nucleus, confirming reports from earlier studies [While H-BSE challenged cattle displayed a predominantly glial immunolabelling pattern and only to a lesser extent intraneuronal PrP studies ,35,40,41Sc accumulation patterns and histopathological changes indicate different cell tropisms correlated with these BSE forms, as it has already been described for different scrapie strains in sheep [Sc propagation. We suggest that both atypical L- and H-BSE forms have their origin in the nervous system, while classical BSE ascends after oral  infection from the gut via peripheral nerves to the brain [Sc concentrations in the neurons of all analysed brain regions with peaks in the rhinencephalon, midbrain and thalamus [Sc depositions in the vagus nerve and in the peripheral motoric nervous system. A primary PrPSc formation in the neurons of the CNS and possibly simultaneously in the PNS with a neuronal spread throughout the body seems a feasible scenario for this BSE form.These divergent PrPin sheep . We, thehe brain ,15. L-BSthalamus , in combSc signals in all brain regions [Sc deposition pattern. In this BSE form, the spinal cord, optic nerve, DRG and trigeminal ganglion were more prominently involved at early stages of the clinical disease. From this, we postulate that while L-BSE may first replicate solely in the neurons of infected cattle, H-BSE displays a strong tropism to glial cells within the CNS. Meanwhile, we observed a trend towards a stronger involvement of efferent fibres as compared to afferent fibres of the white matter of the spinal cord in H-BSE affected cattle, suggesting the CNS as the primary location of PrPSc propagation in the case of H-BSE.Meanwhile, H-BSE affected cattle displayed similarly even, albeit overall lower PrP regions , with a Due to the at least 10-fold increased susceptibility of Tgbov XV mice to challenge with L-BSE as compared to H-BSE, the results of the mouse bioassay were not used for the direct comparison of the infectivity load.Sc and infectivity distribution patterns of atypical BSE seem to be generally similar to that known for classical BSE, with a clear restriction to the central and peripheral nervous and the musculoskeletal system. Taken our results together, we postulate distinct cell tropisms and propagation pathways for both atypical BSE forms, which both have their putative location of origin in the central nervous system. While L-BSE strongly affects the neurons of the CNS followed by the PNS, H-BSE initially affects CNS and PNS glia and only at later stages spreads to neurons. This is in sharp contrast to what is well acknowledged for C-BSE, which is the uptake of the infectious agent in the digestive tract, followed by a neuronal transport to the CNS.The PrPThe details of the intracranial challenge study with atypical BSE have been published previously . Eleven One half of the samples was formalin-fixed for histological examinations while the other half was frozen (−20°C and −70°C) for biochemical analysis.In this study, we describe the detailed analysis of 38 selected organ samples per animal  and 3. TThe correlating tissue samples collected during an oral C-BSE pathogenesis study  had eithSc using the IDEXX HerdChek® BSE enzyme immunoassay (EIA), which is one of the approved BSE rapid test systems. This test system is based on a PrPSc-specific ligand immobilized on a microplate to bind the BSE antigen and it was performed according to the manufacturer’s instructions (short protocol).First, the peripheral tissue samples were analysed for the presence of PrPSc precipitation protocol using phosphotungstic acid with subsequent Western blot (PTA WB) and mAb L42  as a detection antibody, as previously described [For Western blot analysis of 10% tissue homogenates, we performed a PrPescribed . In ordeSc including an ultracentrifugation protocol followed by Western blot [To increase the sensitivity for the analysis of neuronal samples in order to decipher the origin and dissemination of the BSE prions in the three different BSE forms, selected samples were also analysed using an optimized protocol for the purification of PrPern blot . These s2O2 (Merck) in methanol for 30 min, followed by an autoclave step for 20 min at 121°C in citrate buffer . These primary antibodies were applied at a concentration of 0.72 µg/ml for mab 6C2 and 0.25 µg/ml for mab F99/97.6.1 in TBS  with 10% goat serum and 0.03% sodium azide, and incubated for 2 h at room temperature. Negative control sections were treated with a solution of 10% goat serum in TBS with 0.03% sodium azide. As a secondary antibody system, we used the EnVisionTM reagent  containing a peroxidase-conjugated polymer backbone. Incubation time on these sections was 30 min at room temperature. The slides were finally developed with diaminobenzidine tetrahydrochloride  for 10 min and counterstained with Mayer`s haematoxylin for 15 min. All sections were examined by light microscopy.Spongiform alterations were assessed by histopathological analysis of Haematoxylin-Eosin (HE) stained tissue sections. Tissue samples were also processed for immunohistochemical analysis as described previously , with soIn order to verify the results obtained using the mab cocktail, the samples collected from the central and peripheral motoric nervous system, the sympathetic and parasympathetic autonomous nervous system, as well as the musculoskeletal system were also analysed using mab 6C2 alone with the same protocol as described above.−1 to 10−9 of brain tissue from the initial H- and L-type BSE field cases diagnosed in Germany. Thirty microlitres per dilution were instilled intracranially into eight mice per group. The titres were calculated using the Logit Model with R, Version 2.15.2.In order to determine the sensitivity of Tgbov XV bovine PrP transgenic mice to both atypical BSE forms, we performed a parallel titration experiment, using serial tenfold dilutions from 10Sc accumulation, and only mice with positive results were included in the calculation of incubation times.Selected samples that had been collected under TSE sterile conditions from the central and peripheral nervous system as well as from the musculoskeletal system of two animals challenged with L-BSE and sacrificed at 16 mpi  and two animals challenged with H-BSE and sacrificed at 16 mpi  were also analysed by a highly sensitive transgenic mouse bioassay [


The central nervous system (CNS) is generally resistant to the effects of radiation, but higher doses, such as those related to radiation therapy, can cause both acute and long-term brain damage. The most important results is a decline in cognitive function that follows, in most cases, cerebral radionecrosis. The essence of radio-induced brain damage is multifactorial, being linked to total administered dose, dose per fraction, tumor volume, duration of irradiation and dependent on complex interactions between multiple brain cell types. Cognitive impairment has been described following brain radiotherapy, but the mechanisms leading to this adverse event remain mostly unknown. In the event of a brain tumor, on follow-up radiological imaging often cannot clearly distinguish between recurrence and necrosis, while, especially in patients that underwent radiation therapy (RT) post-surgery, positron emission tomography (PET) functional imaging, is able to differentiate tumors from reactive phenomena. More recently, efforts have been done to combine both morphological and functional data in a single exam and acquisition thanks to the co-registration of PET/MRI. The future of PET imaging to differentiate between radionecrosis and tumor recurrence could be represented by a third-generation PET tracer already used to reveal the spatial extent of brain inflammation. The aim of the following review is to analyze the effect of ionizing radiations on CNS with specific regard to effect of radiotherapy, focusing the attention on the mechanism underling the radionecrosis and the brain damage, and show the role of nuclear medicine techniques to distinguish necrosis from recurrence and to early detect of cognitive decline after treatment. In nuclear medicine ionizing radiations represent the main tool physicians use for both diagnostic and therapeutic purposes. From a radiobiological point of view, ionization can be defined as the process that leads to the production of ions through ejection of electrons from either atoms or molecules secondary to different stresses such as high temperature, electrical discharges, or electromagnetic and nuclear radiation . The cenThe aim of the following review is to analyze the effect of ionizing radiations on the CNS with specific regard to effect of radiotherapy, focusing the attention on the mechanism(s) underlying radionecrosis and the brain damage. These aspects are relevant in clinical practice when ionizing radiation significantly modifies the anatomy and the function of brain cells, resulting in new opportunities for nuclear medicine techniques to distinguish necrosis from recurrence and to detect cognitive decline after treatment early.Despite having been the object of research for the last decade, the molecular pathways and pathophysiological mechanisms involved in radio-induced cerebral damage are still to be completely understood. Previously, it was thought to be solely related to DNA damage of vascular endothelial and/or brain glial cells that consequently reduced their proliferative capacity leading to irreversible damage . HoweverAll forms of ionizing radiation (IR), ranging from low energy photons to heavy charged particles such as protons or carbon ions, have the potential to produce toxicity in the central nervous system. IR particles have in common the physical ability to generate free radicals that may cause direct or indirect DNA damage, but may also provide a source of metabolic stress to which the central nervous system (CNS) is particularly susceptible compared to other tissue types . AlthougDepletion of vascular and glial clonogens;Decreased of neurogenic cells, mainly located in hippocampi;Altered neuronal function and loss of synaptic plasticity;Neuro-inflammation secondary to the production of pro-inflammatory cytokines by glial cells.In 2013, Greene-Schoesser et al. tried to describe the molecular pathogenesis of cognitive impairment suggesting four different mechanisms  methionine  is a PEormation . In a reormation .18F] fluoroethyl)-l-tyrosine , with the area of significant 18F-FET uptake that was always included within the area of MR signal abnormality, which means that the latter could be often overestimate the extension of disease. More in particular, 30 out of 34 gliomas demonstrated an increased 18F-FET uptake (T/NT ratio > 1.6), with an overall sensitivity and specificity for the distinction of tumors from non-neoplastic tissues of 88% and 88%, respectively.  and although there was no statistically significant difference both 18F-FDG and 18F-FLT proved to be accurate in the differentiation between recurrent glioma and radiation necrosis. Unfortunately, even if dynamic kinetic modeling of 18F−FLT-PET has proven to be crucial and its superiority could not be demonstrated only for the small number of patients included in the study, due to the complexity of the procedure, it is unlikely that it will be broadly accepted in clinical practice [The combination of semiquantitative measures of SUV max  and kinetic analysis has been performed in several studies, not only in cell lines and animal models but also in humans, in order to define either recurrent disease or RN. In a recent meta-analysis Li et al. compared the aforementioned tracers in this clinical setting and demonstrated that  lesions . Enslow  lesions  made thepractice .Epidemiologic reports of cancer patients show that up to 30% of them develop brain metastases during their lifetime, showing a poor prognosis with a median survival time that ranges from 9 to 18 months, even in the absence of systemic disease. Conversely, primary CNS tumors represent a smaller portion of patients (19 cases per) with gliomas, which include several subtypes with different prognoses that account for almost 80% of all intrinsic primary brain tumors.In the management of patients with either primary brain tumors or metastatic diseases which involve the brain, multimodality therapy approaches which combine surgery, chemotherapy and radiation therapy (RT), improved survival rates for many cancer patients. In particular, in case of CNS, at least half of these patients receive whole brain radiotherapy (WBRT), therefore RT long-term side effects on cognitive performance represents a major concern that can significantly impact in terms of QoL on both patients and caregivers. Although in these patients RT occupies a pivotal role, due to the interaction of ionizing radiations on brain cells, it also has side effects that could appear as early as 3–4 months later with cognitive decline being the most common and affecting patients with memory loss and/or impairments in executive functions, particularly in case of WBRT .18F-FDG PET is the most used tracer in general oncology but in the case of the CNS and more in particularly at the brain level, it is not often used in gliomas due to the high physiological uptake in cerebral parenchyma which could hamper a correct assessment of the underlying malignancies. Nonetheless, in untreated tumors, low-grade gliomas demonstrate lower metabolic activity than high-grade gliomas, thus showing a direct relationship between 18F-FDG uptake and grade of the tumor, with a tumor/non-tumor uptake ratio higher than 1.5 compared to white matter (or 0.6 for gray matter) as cut-offs to discriminate between low- grade (grades I and II) and high-grade tumors (grades III and IV). However, after RT, this correlation between tumor grade and 18F-FDG uptake is not strict anymore, with high- grade tumors that could present similar uptake values or slightly above to that of white matter.Preclinical molecular studies have clarified that radio-induced brain damage has a multifactorial pathogenesis, but is mainly related radiation exposure in terms of total administered dose, dose per fraction, tumor volume, duration of irradiation. In this sense, RT planning is based upon neuroimaging, which must be as precise as possible in order to minimize radiation damage to healthy tissues . In this11C-MET PET was superior to 18F-FDG-PET in differentiating RN from tumor recurrence, mainly in patients that already underwent gamma knife radiosurgery. In particular, they made a direct comparison of the two techniques by performing both of them on the same patients. [11C-MET PET over 18F-FDG-PET in a direct per-lesion comparison. In a recent meta-analysis, Li et al. evaluated 15 studies focusing on amino acids and FDG-PET, but only two of them commented on the added value of PET over conventional imaging techniques [18F-FDG, 11C-MET, 18F-FET, 18F-FDOPA, 18F-FMISO and 18F-FLT included in our analysis, based on the pathophysiological hypothesis that amino acid transport is upregulated in tumor cells, other PET tracers, such as 18F-fluorocholine and 11C-choline, could also be used to differentiate tumor recurrence from RN [11C-MET, 18F-choline and 18F-FDG performance in 50 patients post-resection and RT in order to assess the different metabolic activities specific for glioma recurrence and RN [11C-MET over both FDG and 18F-choline due to a lower uptake in RN than in recurrence and with a sensitivity of 91.2% and a specificity of 87.5%. Additionally, they suggested that 11C-MET uptake in RN may be through passive diffusion , while in case of tumor recurrence there should be active transport of 11C-MET across cell membranes.At the time of writing, is still unclear which PET tracer is superior in distinguishing tumor recurrence from RN . One of atients.  Unfortunchniques . In theichniques .In addit from RN . In a ree and RN . In partA possible direction in the future of PET imaging to differentiate between RN and tumor recurrence could be represented by a third-generation PET tracer already used in both preclinical and clinical stage to reveal the spatial extent of brain inflammation. The translocator protein (TSPO), formerly known as peripheral benzodiazepine receptor, is an 18-kDa cholesterol-transporter protein expressed throughout the body and localized in the outer membrane of mitochondria of cells of monocyte lineage, therefore including microglial and ependymal cells of the brain . TSPO ba11C-(R)-PK111956  on 17 patients with relapsing remitting multiple sclerosis and subsequent static images in order to obtain SUV ratios that exhibited high values (ranging from 1.3 to 3.2) compared to frontal cortex, which was chosen as a pseudo-reference region as the least disease-affected brain area [18F-GE180 that dates back to 2016, in which the authors evaluated after a 210-min acquisition on 10 healthy patients, five different kinetic models and concluded that the best represented brain 18F-GE180 kinetics across regions was the reversible two-tissue compartment model (2TCM4k).More recently, efforts have been made to develop new selective radioligands for TSPO. These so-called ‘second generation’ PET radioligands have been developed in order to better reveal the extent of microglial activation. In particular, F-GE-180  is a novain area . The dur18F-GE180 has also been tested preclinically to identify brain inflammation during epileptogenesis and in case of traumatic spinal cord injury where 18F-GE180 PET imaging can reveal areas of increased TSPO expression that can be visualized and quantified in vivo, offering a minimally invasive approach to the monitoring of neuronal injury in animal models, thus providing a translatable clinical readout for the testing of new therapies. With respect to brain neoplastic lesions, 18F-GE180 PET imaging has also been tested in patients with gliomas, where a high T/NT ratio was detected in untreated and pretreated GBM thanks to the high cellular expression of TSPO; however, discrimination between tumor mass and normal brain tissue can be more difficult at tumor edges where inflammatory cells which also express TSPO such as glia-associated microglia/macrophages are known to be present. Despite these preliminary results, the promising data suggests a possible application also in the differentiation between RN and tumor recurrence in patients that underwent radiation therapy for both primary and metastatic lesions, however further studies are needed to validate this possible application of 18F-GE180 PET [E180 PET .All the aforementioned imaging techniques may be useful to differentiate tumor recurrence from RN possibly supporting patient work up in the clinical setting. However, it is clear that RN may also have increased biological activity in the context of inflammatory reactions and that the most difficult scenario is the simultaneous presence of both RN and residual/recurrent tumor cells. Therefore, without a proper standardization of PET techniques, it would be impossible to compare and interpret these promising results; in fact, although studies may suggest increased amino acid uptake in recurrence, their validation can be done only through larger prospective multi-center studies, in order to provide larger quantitative data sets for comparisons.


Mobile electroencephalogram (EEG)-sensing technologies have rapidly progressed and made the access of neuroelectrical brain activity outside the laboratory in everyday life more realistic. However, most existing EEG headsets exhibit a fixed design, whereby its immobile montage in terms of electrode density and coverage inevitably poses a great challenge with applicability and generalizability to the fundamental study and application of the brain-computer interface (BCI). In this study, a cost-efficient, custom EEG-electrode holder infrastructure was designed through the assembly of primary components, including the sensor-positioning ring, inter-ring bridge, and bridge shield. It allows a user to (re)assemble a compact holder grid to accommodate a desired number of electrodes only to the regions of interest of the brain and iteratively adapt it to a given head size for optimal electrode-scalp contact and signal quality. This study empirically demonstrated its easy-to-fabricate nature by a low-end fused deposition modeling (FDM) 3D printer and proved its practicability of capturing event-related potential (ERP) and steady-state visual-evoked potential (SSVEP) signatures over 15 subjects. This paper highlights the possibilities for a cost-efficient electrode-holder assembly infrastructure with replaceable montage, flexibly retrofitted in an unlimited fashion, for an individual for distinctive fundamental EEG studies and BCI applications. Mobile electroencephalogram (EEG)-sensing technologies has rapidly progressed and made the access of neuroelectrical brain activity outside the laboratory in everyday life more realistic. The integrity of mobile systems by various manufacturers has been thoroughly validated and reported ,2,3. OwiSeveral research-grade and consumer-oriented mobile EEG devices are available in the market, such as Quick/Mobile series , ENOBIO series , Smarting , Ultracortex , EPOC , and MindWare . Their general technical specifications or other devices can be referred to ,8,21. AsTherefore, in this study, an electrode-holder assembly infrastructure for EEG recordings was developed, which allows a user to (re)assemble a compact holder grid to accommodate a desired number of electrodes to the brain regions of interest in an unlimited fashion, in accordance to the EEG and BCI study of interest to be performed. During the assembly, the formed headset can iteratively adapt to a given head size and shape, practically ensuring electrode-scalp contact and signal quality. All the conceived assembly elements  were manufactured via a low-end consumer 3D printer and the practicability of the assembled headset was validated through the study of event-related potentials (ERP) and steady-state visual evoked potential (SSVEP) tasks. This study demonstrated exceptional possibilities for a cost-efficient electrode-holder assembly infrastructure with replaceable montage retrofitted for an individual in unlimited manner, for distinctive fundamental EEG investigations and BCI applications.The assembly infrastructure developed in this study has the following practical benefits for EEG recording as well as BCI deployment. First, the infrastructure allows (re)assembling without limit to accommodate a desired number of electrodes over brain regions of interest, leading to a compact headset without the need for redundant electrodes attached to the head . In addition, the infrastructure is capable of optimally retrofitting the headset to a certain head size/circumference for each individual during assembly. This provides the advantage of not only positioning the sensors over the target brain regions as consistently as possible for different age groups in the same study or task but also ensuring the attached electrodes to be in good contact with the scalp for better signal quality. As such, the proposed infrastructure can be considered a design of multi-purpose, with a montage-replaceable headset to record EEG signals from only the brain regions of interest.The assembled infrastructure was conceived to compose of three primary components including sensor positioning ring, inter-ring bridge, and bridge shield  were recruited to validate the practicability of the assembled electrode-holder grid. They were all students from the Colleges of Science and of Engineering and had normal hearing and normal or corrected-to-normal vision. Participants gave their written informed consent approved by Human Research Protections Program of the local ethics committee and received monetary compensation.In this study, two stereotypical paradigms were conducted underpinning different modalities of visual perception and cognitive processing through SSVEP and oddball ERP protocols, respectively. These two tasks allowed us to assess the signal quality in terms of time- and phase-locked temporal  and spectral  context while wearing the assembled headset. The four central midline electrodes were intended to capture not only the N100 ERP  of early sensory perception but also the P300 ERP  for the endogenous process of attentional relocation, engaging in an oddball paradigm ,35,36. OThe oddball paradigm consisted of two pure tones in different occurrences. A high-pitched tone (1000 Hz) was infrequently formed  as compared to the frequently presented low-pitched tone . Both these tones lasted for 500 ms and were played through the speakers. Each participant was instructed to focus their gaze at the fixation cross located at the center on a 27” LCD monitor, attentively responding to the target tone by pressing a handheld button as fast as possible, while ignoring the frequent standard tone. The paradigm was composed of four blocks; each contained 100 trials with both tones in random order and with an inter-trial jitter of 0.5–1.5 s. The oddball paradigm for each participant corresponded to a total of 120 target trials versus 280 standard trials for sequential ERP analysis.Three repetitive black/white visual flickers  located at the vertices of a triangle were presented on a 27-inch LCD monitor. A fixation cross at the triangle center (no flickering) was also presented as control. The participant was instructed to attentively gaze at the fixation cross or at one of the three flickers for four seconds in turn. The paradigm contained four 20-trial blocks; each block presented one of four visual targets five times in a random order. An auditory cure guided the participant to shift their gaze to the next target within an inter-trial duration of 2.5 s. The SSVEP task collected 80 trials (20 per target) from each participant.During the recording, each participant sat comfortably on a chair in a dimly lit room. They underwent both the aforementioned tasks on different days in a random order. Each task lasted approximately 30 min, which comprised experiment briefing, headset capping, and data recording. The assembled headset was cleaned simply by a wet wipe with a bit of sanitizer before the capping. During the capping, the initial inter-ring bridges with respect to certain positioning rings could be replaced by different lengths for certain individuals because of a distinctive head size. In the meanwhile, the participant was informed about mild to moderate pressure needed for attaching dry electrodes well to the scalp. This procedure typically took 5–10 min to confirm the comfort and ensure the contact between the fronto-central midline and/or parieto-occipital electrodes and the scalp. This study employed the following procedures to pre-process and analyze the collected ERP and SSVEP sessions, including (1) bandpass filtering , (2) trial segmentation , (3) trial analysis  estimation, and (4) signal-to-noise (SNR) calculation on the peaks of interest . Other signal modality-specific parameters or steps are depicted below. Data preprocessing, analysis, and visualization were performed using the open source EEGLab toolbox/scripts  and selfFollowing trial segmentation, the trials containing extreme amplitudes (>±100 µV) or corresponding to erroneous behavioral responses were removed from further analysis . In addition, the z-score standardization was applied to the averaged ERP profile of each individual prior to calculate the grand average ERP. The P300 SNR was derived by dividing the P300 peak amplitude (300–500 ms) by the standard deviation of the prestimulus baseline (−200 to 0 ms) as the procedure in ,38. FinaSynchronized averaging calculation was also applied to the 4-s SSVEP trials corresponding to each of the visual targets after trial segmentation. The short-time Fourier transform (STFT) with 1-s Hamming window (with 80% overlap) was subsequently employed to estimate the EEG spectrogram with a frequency resolution of 1 Hz and yield the averaged PSDs across all time windows. Lastly, SSVEP SNR was defined by the ratio of spectral amplitude in the target frequency  versus the mean amplitude of its six neighboring frequencies , as referred to .p < 0.01). The N100 peak (at ~170 ms) time-locked to the stimulus onset was also seen for both events. The topographic mapping of P300 SNR further showed that the highest value was located at Pz as compared to other electrodes for the target event only  and only available in three head circumference sizes. Our assembly holder departed from the Ultracortex frame substantially with respect to unlimitedly (re)assembling of a compact holder grid for different purposes or even head sizes given one assembly set of the primary components  without additional cost. In addition, as assembling an Ultracortex-like headset frame, our design will cost only about 10 USD  by PLA and EVA filaments. Aside from continuous innovation for electrode and amplifier technologies ,29,30,31To validate the practicability of the conceived electrode-holder assembly, this study implemented an 8-ch electrode-holder grid embedded with Cognionics dry electrodes for incorporation with a portable, custom EEG amplifier ,36. The There are several possibilities or advantages far beyond the current demonstration of EEG recording. First, the sensor-holder ring can be fabricated with different specifications to organize either homogeneous/heterogeneous sensors or sensors and stimulators on the same headset, e.g., comparing EEG electrodes made by different materials at very adjacent sites ,5,35,40,Although this study presented a promising start to a cost-efficient, montage-replaceable headset assembly in mobile EEG technologies, future effort should be devoted to further demonstrating and improving its robustness and generalizability. First, EEG recordings can be replicated on non-stationary subjects . This wIn this study, a cost-efficient, custom EEG-electrode holder infrastructure was developed through the assembly of primary components, including sensor positioning ring, inter-ring bridge, and bridge shield. For different studies or BCI tasks, the user can (re)assemble a compact holder grid in an unlimited fashion to accommodate a desired number of electrodes only to the brain regions of interest and iteratively adapt it to a given head size for optimal electrode-scalp contact and signal quality. This study empirically demonstrated the easy-to-fabricate nature of the infrastructure through a low-cost 3D printer and its practicability in measuring ERP and SSVEP signals was proven over studies with 15 participants. Through this study, a montage-replaceable headset tailored to be applicable for a variety of purposes was explored.


Expanding contraceptive options through self-injection may improve access and confidentiality. There are few published studies on contraceptive self-injection in sub-Saharan Africa and none in West Africa, a region with high unmet need. This study was performed to assess feasibility of subcutaneous DMPA self-injection in Senegal; objectives were to (1) measure the proportion of participants who self-injected competently 3 months after training, (2) measure the proportion who self-injected on time (defined conservatively as within 7 days of reinjection date), and (3) assess acceptability of self-injection.In this prospective cohort study, 378 women aged 18–49 years were trained to self-inject by study nurses. Three months later, women returned unprompted to the clinic to self-inject, and technique and visit timing were evaluated. Women continuing with a third self-injection were followed up at home after their next scheduled injection date. At each interaction, participants were interviewed to learn about their experience; additional questions during the final home visit focused on storage and disposal practices, and acceptability.Among the 337 participants followed up 3 months post-training, 310 self-injected, and 87% did so competently. Factoring in women who declined to self-inject, electing to have the provider administer the injection instead, a total of 80% [95% confidence interval (CI) = 75–84%] self-injected competently 3 months post-training, and 84% [95% CI=80–88%] reinjected on time, while 72% [95% CI=67–77%] were both on time and competent. The vast majority (93%) expressed a desire to continue.Self-injection is feasible and acceptable among most study participants in Senegal.These first research results on contraceptive self-injection in West Africa indicate initial feasibility and acceptability of the practice. Results underscore the importance of designing self-injection programs that empower and support women, including those with limited education. DMPA is effective and safe in either form. A review of 14 studies concluded that DMPA-SC and DMPA-IM are therapeutically equivalent, with similar side-effects profiles The DMPA-SC product Sayana® Press is manufactured by Pfizer Inc. and packaged in the Uniject™ injection system. PATH designed and developed Uniject™ with collaboration from Horizon Medical, Inc. In 1996, PATH licensed the Uniject™ device technology and related patents for commercialization to Becton, Dickinson and Company (BD). PATH also helped connect BD with the DMPA manufacturer, which ultimately led to Pfizer Inc.’s development of the product now marketed as Sayana® Press. Sayana® Press received regulatory approval in Europe in 2012 and Senegal in 2014. Acceptability studies found that most injectable clients and providers in Senegal preferred this DMPA-SC product over DMPA-IM The studies published on contraceptive self-injection have found that, overall, women found the practice convenient and easy, and there were no pregnancies among women practicing self-injection in Pfizer Inc.’s original clinical trials of DMPA-SC delivered in a prefilled syringe The purpose of this study was to assess feasibility and acceptability of self-injection with DMPA-SC in Senegal. The study's primary objectives were to measure the proportion of participants who demonstrate competent self-injection technique 3 months after training, and to measure the proportion who self-inject on time. The secondary objective was to assess the acceptability of self-injection, expressed as the desire to continue with self-injection and likelihood of recommending the practice to others.22.1This prospective cohort study was conducted in eight public facilities in two regions of Senegal from September 2015 to July 2016: three periurban health centers in the Dakar region, and three health posts and two peripheral health huts in the Thiès region. Women aged 18–49 years were asked to provide written informed consent to undertake self-injection and participate in interviews. Participants were family planning clients who had chosen injectable contraception and met the standard eligibility criteria for injectable use, as per Ministry of Health guidelines. Women who did not permanently reside in the area, felt unwell on the day of enrollment, or did not speak either French or Wolof were excluded from the study. The study was approved by the Senegal National Health Research Ethics Committee (CNERS) and the PATH Research Ethics Committee.Study procedures were implemented by licensed nurses and midwives who were trained in DMPA-SC administration, research ethics , interviewing, data management, and counseling women for self-injection.Study staff trained participants one-on-one to do self-injection, guided by a client instruction booklet  [14]. InImmediately after training, women self-injected under supervision of study staff. Their self-injection technique was evaluated using an observation checklist  [15]. InThree months later, participants who wished to continue self-injection (regardless of whether competent at the previous visit) returned to the clinic to self-inject again while study staff evaluated the woman's technique. No additional training or guidance was provided at the second clinic visit prior to self-injecting, since the intent was to assess whether women would recall the injection technique without additional instruction (as if she were unsupervised at home). Participants seeking guidance were reminded to refer to the client instruction booklet. If a woman had not returned to the clinic when due for her reinjection, she was contacted after 7 days had passed since her scheduled injection date. Women not having returned prior to the contact were considered to be late.In interviews conducted at the second visit, women were queried about their experience with side effects (including injection site reactions) since their previous injection, their self-injection experience, and their desire to continue (or not) with self-injection.Women continuing with self-injection were then given one DMPA-SC unit, client instruction booklet, and reinjection calendar with the reinjection date marked to take home. Participants were instructed to self-inject independently at home when due for their next injection.Home visits were conducted at least 1 week after the next scheduled injection (the third injection). At the follow-up home visit, the study nurse interviewed each woman about her injection experience, the timing of the reinjection, and any injection-site reactions she experienced. If she forgot to give the injection, she could do so at that time, but women who had not reinjected prior to the home visit were considered late. If she decided not to give herself the injection, the study nurse gave the injection or referred her to the clinic for another method, if desired. Every woman not lost to follow-up completed an interview  with self-injection), regardless of whether she had continued with self-injection.2.2Structured, private, face-to-face interviews were conducted with each study participant. Interviews were conducted in French or the local language, Wolof (as preferred by participants), by female interviewers. Data were entered electronically on Android phones. The same study staff who enrolled women conducted the follow-up visits.A sample size of 380 self-injectors was calculated to achieve a desired precision of 5 percentage points around the point estimate of 80% of women competent in self-injection at 3 months [95% CI=75–85%] and a precision of 5 percentage points around the point estimate of 80% of women reinjecting consistent with the schedule. We identified 80% as an appropriate competency estimate based on other studies that found observed or self-reported self-injection capability between 87% and 93% End points for the primary objective of evaluating competency in self-injection, measured at the 3-month follow-up visit, were the percentage of women who demonstrated correct self-injection technique consistent with the observation checklist, and the percentage who reinjected on schedule, within 1 week of their reinjection date.To qualify as competent, a participant had to successfully demonstrate five critical injection steps from the 19-step observation checklist  [15]. OmSecondary end points on acceptability were measured at 3 months (for those discontinuing self-injection at that time) and 6 months (for those continuing with self-injection). Secondary end points on home storage and disposal practices were measured at 6 months, after the unsupervised self-injection.Data analysis was performed using STATA version 14.1. 95% CIs for the primary end points were calculated using exact CIs for binomial proportions.33.1A total of 380 participants were enrolled in the study, though two were later withdrawn due to undetected pregnancy (screening failure), leaving a sample of 378 participants at baseline. 3.2Of these 378 women, 90% achieved competency at their first injection immediately post-training . On averOf the 310 women who self-administered the second injection 3 months later, 87% injected competently without additional guidance, other than the client instruction booklet, which they were advised to reference. Ninety-eight percent reported that the booklet was “very easy” or “easy” to understand (data not shown). For the calculation of the total percent competent, 27 women who changed their mind about self-injection either immediately after the first injection or when due for the second injection were added to the denominator under the assumption that they declined to self-inject due to a lack of competence and/or confidence, resulting in a total competency finding of 80%. Women lost to follow-up between the enrollment visit and the clinic follow-up visit (n=13) and those who discontinued the injectable altogether (n=28) are not included in the calculation of total competency. For the second injection, not pressing the reservoir slowly and failing to push the needle shield and port together to activate the device were the most common causes of failure (data not shown). With respect to the timing of reinjection, 84% of women returned to the clinic on time (within 1 week of their scheduled injection date). Taking into consideration injection technique as well as timing, 72% of women were both on time for reinjection and administered the injection correctly.n=3) or too late (n=6). Two women were lost to follow-up between the second and third injections.Though the third injection was not observed, women were asked to provide the date that they reinjected. Of the 283 women who self-injected independently at home, 91% reported self-injecting within 1 week of their scheduled injection date . Notably3.3In terms of subjective confidence, there is a pronounced increase in the percent that report feeling “very confident” that the injection was administered correctly, from 64% for the first self-injection to 82% for the third self-injection . Consist3.4More than 9 (93%) in 10 women reported that they would like to do self-injection in the future if it were available, and nearly 3 (73%) in 4 women reported that they were “very likely” to recommend self-injection to others  .Fig. 2Li3.5There were no pregnancies or serious adverse events. The most common adverse events were known side effects of DMPA: amenorrhea and other changes in menstrual bleeding patterns. After the first injection, 15 women reported experiencing an injection-site reaction (ISR) in the form of a dimple, bruise, blister, or nodule, and one woman sought advice or treatment. After the second injection, five women reported experiencing an ISR, of whom one sought treatment. All adverse events were mild to moderate in severity.3.6The vast majority of women (97%) reported that they were able to store the device at home securely, without discovery by children or others . Nearly In terms of disposal, about half of women (49%) disposed of the spent device in a pit latrine . Most of4Two studies from sub-Saharan Africa, one in Senegal and one in Uganda, have now demonstrated that self-injection of DMPA-SC is feasible and acceptable for the vast majority of participants Considering the similarities and differences in the two studies and contexts yields insights for potential self-injection program design. These findings align with previous studies that found higher acceptability of self-injection in Uganda than Senegal among DMPA-SC users Underlying differences in the samples may explain the differences in outcomes observed. A much larger proportion of participants in Senegal had never attended school than in Uganda (about one-third compared with less than 10%). Strategies specifically designed to empower, train, and support women with limited education to self-inject can ensure that this service innovation is an option for all women; women in sub-Saharan Africa with the least education also have the lowest levels of contraceptive use Notably, women in Senegal returned to the clinic for their second self-injection, which was observed, while women in Uganda self-administered their second injection independently at home and later demonstrated their injection technique on a model. Women in Senegal may have encountered challenges returning to the clinic during the proscribed study window, reducing the proportion of women reinjecting “on time”. While we cannot know the extent to which competency differences between Uganda and Senegal is due to instrumentation, it is possible that performing injections under health worker supervision made participants feel less confident. Self-injection programs will need to be designed to offer sufficient support  without compromising accessibility, autonomy, and discretion.4.1Requiring women to return to the clinic to demonstrate competence when due for the second injection may have reduced motivation to try self-injection — since the benefits were less immediate — and altered in unknown ways the profile of women for whom self-injection is appealing.The conservative measurement of ‘on-time’ reinjection, with follow-up by a study nurse 7 days following the scheduled injection, precluded measurement of whether women would have self-injected within the established DMPA reinjection window (−2/+4 weeks). Nonetheless, the finding that a high percentage of women respected the very narrow reinjection window is encouraging for adherence to the more forgiving DMPA reinjection schedule.Because of the study design — recruiting participants from among injectable clients — it was not possible to assess whether self-injection could attract new users to contraception. Future research should explore the appeal of self-injection among hard-to-reach populations  in order to evaluate its potential to increase contraceptive use.


Robust and accurate visual tracking is one of the most challenging computer vision problems. Due to the inherent lack of training data, a robust approach for constructing a target appearance model is crucial. The existing spatially regularized discriminative correlation filter (SRDCF) method learns partial-target information or background information when experiencing rotation, out of view, and heavy occlusion. In order to reduce the computational complexity by creating a novel method to enhance tracking ability, we first introduce an adaptive dimensionality reduction technique to extract the features from the image, based on pre-trained VGG-Net. We then propose an adaptive model update to assign weights during an update procedure depending on the peak-to-sidelobe ratio. Finally, we combine the online SRDCF-based tracker with the offline Siamese tracker to accomplish long term tracking. Experimental results demonstrate that the proposed tracker has satisfactory performance in a wide range of challenging tracking scenarios. Target tracking is a classical computer vision problem with many applications. In generic tracking, the goal is to estimate the trajectory and size of a target in an image sequence, given only its initial information . Target Danelljan et al.  proposedAdvances in visual tracking have been made for the features learned from deep convolutional neural networks (DCNNs). However, the outperforming deep features rely heavily on training on large-scale datasets. Thus, most state-of-the-art trackers use pre-trained networks to extract deep features. However, these improvements in robustness cause significant reductions in tracking speed. Siamese Networks have also been used to solve the tracking problem. The matching mechanism in Siamese Network approaches prevent model contamination and achieve better tracking performance. To perform long-term tracking, some methods implement a failure detection mechanism to combine multiple detectors with complementary characteristics at the different tracking stages. However, these approaches only use online update tracking and cannot unite the Siamese Trackers.Based on the discussion above, we propose a novel SRDCF tracking framework that synthetically uses DCNN and failure detection combined with Siamese trackers. The main contributions of this paper are as follows: (1) We propose a method to obtain a specific feature map considering the tradeoffs between spatial information and semantic information though convolutional feature response, and use an adaptive projection matrix to obtain the principal component of the corresponding feature map, which reduces the computational complexity during feature extraction. (2) We propose a novel adaptive model updating method. First, we obtain the confidence of the target position based on the peak-to-sidelobe ratio (PSR), and then explore the confidence map to obtain the PSR, which is highly reliable. Finally, the weight is calculated by the given PSR and is used to achieve adaptive model updating. (3) We also combine the SRDCF frameworks with a Siamese Tracker by assigning the threshold; we infer the tracker status and warn of potential tracking failures in order to achieve long-term tracking by switching two different trackers.The rest of the paper is organized as follows: in Discriminative Correlation Filters (DCFs) ,8,9 haveThe introduction of CNNs has significantly progressed the field of computer vision, including visual tracking. Wang et al.  proposedDimensionality reduction is widely used in visual tracking due to the computational complexity. Danelljan et al.  minimizeSiamese architecture has been exploited in the tracking field, performing impressively without any model update. Tao et al.  trained The SRDCF tracker  is a spakx and l is the dimension of feature. The desired output ky is a scalar valued function over the domain that includes a label for each location in the sample, In the learning stage, the SRDCF tracker introduces a spatial weight function By applying Parseval’s theorem to Equation (1), the filter The symbol MN×MN matrix, By applying unitary Finally, the regularized correlation filter is obtained by solving the normal equation The SRDCF model is updated first by extracting a new training sample By applying the convolutional features of the pre-trained VGG-Net , we usedConvolutional neural networks (CNNs) have successfully applied to large image classification and detection by extracting features or by directly performing the task, such as with AlexNet , GoogleNResearch indicates that the features extracted by convolution layer features are better than extracted from fully-connected layers. As shown in kth frame and ith adjacent eigenvectors, and h represents the feature space.The feature mapping of Pool5 is only 7 × 7. Achieving accurate location depending on such low resolution is impossible. Bilinear interpolation is typically used to solve this problem in mapping space,The feature dimension of Conv3-4 layer is 56 × 56 × 256, which contains less information and increases computation time. We used an adaptive dimensionality reduction to preserve the main component of Conv3-4, depending on the principal component analysis (PCA) of the related layer. After applying this method, the feature dimension was reduced to 130 from 256. As shown in D1-dimensional feature learned from frame t. Adaptive dimensionality reduction results in the projection matrix D2-dimensional feature space:We used singular value decomposition (SVD) of the matrix We obtain the adaptive projection matrix though a fixed learning rate At the detection stage, the location of the target in a new frame Use an interpolation approach that allows computation of pixel-dense detection scores. The detection scores are efficiently interpolated with trigonometric polynomials by using the computed DFT coefficients. Let The SRDCF framework uses the fixed learning rate to update the tracking model. Once the target is occluded, the appearance model is negatively affected, which leads to tracking drift. The proposed method uses the PSR position . ThroughThe PSR distribution of the David3 dataset is shown in Therefore, it is possible to determine whether the target is affected by the occlusion according to PSR in order to assign weight to the model update:The model is updated by using the learning rate Studies have shown the impressive performance of Siamese networks without any model update ,27,28. CIn long term tracking, tracking-learning-detection (TLD)  implemenus study . The ablAlgorithm 1: Proposed tracking algorithm.Input: Image Output: Estimated object position For each Extract the deep feature space  Update matrix  Update the low dimensional appearance feature space  Compute the confidence of the target position using Equation (18); Update the tracking model  Compute the estimated object position  If  Update the estimated object position and scale using the offline Siamese tracker; Else Output the estimated object position and scale directly;EndThis section presents a comprehensive experimental evaluation of the proposed tracker. The configuration used was an Intel (R) Core ™ I74790 CPU, 3.6 GHz, 16 GB RAM, NVIDIA Tesla K20 m GPU standard desktop. The weight function tConvNet .An ablation study on VOT2016 was conducted to evaluate the contribution of the adaptive dimensionality reduction, adaptive model update, and Siamese tracker in the proposed method. The results of the VOT primary measure expected average overlap (EAO) and two supplementary measures, accuracy (A) and robustness (R), are summarized in Applying the adaptive dimensionality reduction reliability is equivalent to extracting the principle component from the original image feature space. It not only reduces the computational complex, but also improves the sematic representation during the procedure. The performance drop in EAO compared to the proposed method was 11%.Replacing the adaptive model updating means that Replacing the Siamese tracker from the proposed method mainly affected the performance of long-term tracking. The performance drop in EAO compared with the proposed method was around 10%, and the The OTB100  benchmarWe compared the proposed tracker with other state-of-the-art trackers in VOT2016, which contains 60 sequences. The trackers were restarted at each failure. The set is diverse, with the top-performing trackers come from various classes including correlation filter methods such as CCOT , Staple The proposed method outperforms the compared trackers, except for ECO and CCOT, with an EAO score of 0.329. The proposed method significantly outperformed the correlation filter approaches that apply deep ConvNets, and also outperforms the trackers that apply different detection-based approaches. The detailed performance scores for the 10 top-performing trackers are shown in The VOT2016 dataset is per-frame annotated with visual attributes to allow the detailed analysis of per-attribute tracking performance. ® Core™ I74790 CPU, 3.6 GHz, 16 GB RAM, NVIDIA Tesla K20 m GPU standard desktop. Compared with the two best-performing methods, ECO and CCOT, the proposed method was slower than ECO, while being four times faster than CCOT. Compared with other trackers that apply deep ConvNets, such as DeepSRDCF [Speed measurements on a single CPU were computed using an InteleepSRDCF  and SiamThe average speed of the proposed tracker measured on the VOT 2016 dataset was approximately 4.6 fps or 217 ms/frame. In this section, we focus on the tracking results for objects experiencing severe occlusion, illumination, and in-plane rotation on OTB100. The compared trackers included the baseline SRPDCF, MUSTER, LCT, RPT, and SAMF. The tracking results are shown in In this section, we focus on the tracking results of objects undergoing severe occlusion, scale change, and camera motion on VOT2016. The compared trackers included CCOT, ECO, Staple, SiamFC, and the baseline SRDCF. The tracking results are shown in In this paper, we propose a visual tracking framework that combines deep ConvNet features, adaptive model updates, and an offline Siamese tracker. The proposed tracker outperformed other state-of-the-art methods in complex attributes. The adaptive dimensionality reduction provides low dimensional features for the correlation filter to reduce computational complexity. The adaptive model updating method improves the tracking performance in occlusion situations. The offline Siamese tracker enables long-term tracking. Numerous experimental results demonstrated that the proposed tracker outperforms state-of-the-art trackers, highlighting the significant benefits of our method.


Examine cost-driving factors of schizophrenia in Germany for patients prior- and post-switch from an oral antipsychotic therapy to aripiprazole-depot and perform a budget impact analysis (BIA) referring to the context of German health care.A single-armed, retrospective, non-interventional pre-post comparison study with 132 patients to compare the total psychiatric hospitalization rates and the associated costs of both, the treatment with oral antipsychotics and aripiprazole-depot. The BIA was performed to compare both treatment periods with respect to health-related costs. A subsequent univariate sensitivity analysis examined the robustness of the results.p < 0.001) lower (14%) compared to the hospitalization rates when treated with oral antipsychotics (55.1%). 18.2% of the patients reported to be employed, with 29.2% having work incapacities. The mean number of schizophrenia episodes was 2.58 episodes per patient during the oral-antipsychotic treatment compared to 0.41 episodes per patient during the aripiprazole-depot phase (p < 0.001). The treatment with aripiprazole-depot also significantly reduced the mean number of hospitalizations per patient  and the mean number of hospitalized days  compared to the oral antipsychotic treatment. Additionally a significant reduction of the mean stay in day-clinics and psychiatric institute ambulances (PIAs) was observed .After switching the treatment to aripiprazole-depot, the total psychiatric hospitalization rates for the 6-month treatment period were significantly , while aripiprazole-depot generated costs of 4557.56€ (direct costs: 4449.83 €) per patient for a one-year observation period. This resulted in total costs of 6,517,606,265.43€ for the oral antipsychotic treatment and 2,989,756,603.05€ for aripiprazole-depot treatment from the perspective of the German health care system. The results remained robust during sensitivity analysis, with aripiprazole-depot being the more cost-effective strategy.The results suggest that aripiprazole-depot treatment for schizophrenia patients has major potential in terms of cost savings for the German statutory health insurance. Schizophrenia is estimated to affect 24 million individuals worldwide  estimates the costs of schizophrenia in western countries in a range between 1.6% and 2.6% of total health care expenditures. The social and economic consequences of mental illnesses are considerable high, with its treatment costs surpassing even heart diseases, cancer, and diabetes treatment .The direct costs generated by schizophrenia comprise all resource consumption resulting from a treatment or therapy and are directly attributable to this disorder like medication costs, hospitalizations, outpatient and long-term care .The indirect costs occur not directly in relation to the treatment of the disease but arise from the fact that schizophrenia is a very disabling disease. Schizophrenia is associated with productivity losses by the patient and the patient’s family members. Work incapacities (temporary or definitive) and disability pensions due to schizophrenia can be very cost-intensive for the health care system . Less reAnother reason for the high costs of schizophrenia arises from the fact that it is a chronic and lifelong condition. The resource consumption of patients with schizophrenia in Germany has not been evaluated in detail. Due to the cost-intensive characteristics of schizophrenia a reduction of these costs could result in significant savings from the perspective of the German statutory health insurance.The reduction of the direct and indirect costs of schizophrenia can be realized by different procedures. Better and more cost-effective medications can be recognized as one of those solutions. Sustained release drugs (like aripiprazole-depot) are reported to have significantly higher adherence rates than traditional oral antipsychotics .The findings on the effectiveness of aripiprazole-depot are also consistent with several clinical studies that associate reduced psychiatric hospitalization rates and durations with sustained release drugs compared to traditional oral anti-psychotic therapies .P = 0.023) ○ Productivity loss (days of sick leave)○ ○ Days in day-clinics / PIAs○ ○ Number of hospital days○ ○ Number of emergency physician treatments○ ○ Number of emergency service treatmentsProbability of occurrence of:○ Days in day-clinics / PIAs○ Number of hospital daysAdditionally costs were varied due to non-standardized costs for the following variables:The results of the BIA remained robust to the modification of all seven uncertain cost-factors and probabilities during sensitivity analyses, with aripiprazole-depot being the more cost-effective strategy, with hospitalizations as the main cost-driving factor.Costs for medication, psychiatrist services and non-drug-interventions were kept constant in the sensitivity analyses due to their characteristics , as no meaningful interpretable standard deviation could be calculated for the total costs.The results of the sensitivity analysis are displayed in Table The base case analysis was already introduced in Table n = 132) while Table The parameters hospital days and the associated costs of hospital days revealed the largest cost range and were identified as the parameters with the largest impact on parameter uncertainty. The variation of the occurrence-probability of the number of hospital days led to cost ranges of 4282.58€ to 18,473.38€  and 3269.52€ to 9352.96€ (aripiprazole-depot). Because of the fact that the hospitalization-costs are not standardized and differ significantly, costs for hospitalizations were varied as well. The cost-variation led to a cost range of 4282.58€ to 29,351.33€ for oral medication treatment and 3269.52€ to 12,843.47€ for aripiprazole-depot treatment. The parameters for emergency physician treatments / services achieved the lowest cost range. Therefore they achieved the smallest impact on parameter uncertainty. Table The pre-post comparison study demonstrated significantly lower psychiatric hospitalization rates for patients switched from an oral antipsychotic therapy to aripiprazole-depot, as well as significantly less non-drug interventions and a reduced amount of productivity losses due to days of sick leave. The reduction of the hospitalization rates remained significant when being compared to a recent study and its reported hospitalization rate .The BIA evaluated the costs and financial consequences of both schizophrenia treatments for the German health care system from the perspective of the German statutory health insurance. Treatment with oral-medication causes total costs of 6,517,606,265.43€, which are significantly higher than the total costs for treatment with aripiprazole-depot . Considering the six-month observation period per treatment, these extrapolated costs for oral schizophrenia were significantly higher that the estimated annual schizophrenia costs in Germany  [Based on the study data, treatment with aripiprazole-depot is clearly more cost-effective than treatment with oral-medication for schizophrenia, which is mainly associated with less and shorter hospitalizations. These results support recent analyses which reported reduced health-care related costs for sustained release drugs compared to oral antipsychotics .Regardless of the hospitalization-costs, aripiprazole-depot resulted in lower costs on all economical variables, including total drug-acquisition costs, which is an unexpected result considering the often reported greater initial acquisition costs associated with sustained release drugs . These rPossible limitations of the pre-post comparison study are a potential selection bias of patients and psychiatrists due to missing randomization as well as reduced sample-sizes on variables that were analysed for the employed subsample only. There was no inclusion of a control group as the patients served as their own control. The pre-post study design additionally can be prone to biases because of time-changing context factors.Additionally the sample sizes were comparatively low, especially with regard to the employed sub-population, as the study provides a pilot project to investigate the care situation of schizophrenia patients in Germany. The results should be tested and confirmed by future projects with significantly larger case numbers. These future research efforts should also focus more on the side effects of schizophrenia.Some cost-variables were accessed by estimations. These estimations were documented and considered during sensitivity analyses, but despite that are inferior to empirically accessed cost data.In that regard, the collection of additional economic data of the affected patients could complement the study data efficiently. Larger sample-sizes could help to enable inferential statistical procedures for subpopulations (like employed people only) and randomization in a prospective research design could lead to a reduction of selection bias. The present evaluation is also solely dealing with costs to the health insurance system and the patient himself and does not take into account other costs in terms of work productivity or time lost or burden to family members. The sensitivity-analysis which considered the estimated market-share of aripiprazole-depot was based on data for the UK . Future Another potential limitation is the fact that productivity losses were analyzed for the employed sample population only, which resulted in a reduced sub-population. It was not considered if the unemployment was caused by the schizophrenia. In this case, productivity losses and the associated costs would be systematically underestimated in the study results.The BIA contributes relevant data on the discussion of schizophrenia treatment in Germany that are in line with recent publications on the health-economic advantages of sustained release drugs like aripiprazole-depot compared to oral antipsychotic medication.The results suggest that schizophrenia treatment with aripiprazole-depot instead of an oral antipsychotic treatment leads to significant cost reductions from the perspective of the German statutory health insurance.The cost-saving potential is primarily explained by less and shorter hospitalizations combined with a smaller amount of productivity losses and a significant reduction of the mean stay in day-clinics and psychiatric institute ambulances (PIAs) for patients with aripiprazole-depot treatment.


This prospective cohort investigation analyzed the long-term functional and neurologic outcomes of patients with Zika virus-associated Guillain-Barré syndrome (GBS) in Barranquilla, Colombia.Thirty-four Zika virus-associated GBS cases were assessed a median of 17 months following acute GBS illness. We assessed demographics, results of Overall Disability Sum Scores (ODSS), Hughes Disability Score (HDS), Zung Depression Scale (ZDS), and Health Related Quality of Life (HRQL) questionnaires; and compared outcomes indices with a normative sample of neighborhood-selected control subjects in Barranquilla without GBS.Median age at time of acute neurologic onset was 49 years ; 17 (50%) were male. No deaths occurred. At long-term follow-up, 25 (73%) patients had a HDS 0–1, indicating complete / near complete recovery. Among the group, HDS , ODSS  and ZDS score  indicated mild / moderate ongoing disability. Adjusting for age and sex, Zika virus-associated GBS cases were similar to a population comparison group (n = 368) in Barranquilla without GBS in terms of prevalence of physical or mental health complaints, though GBS patients were more likely to have an ODSS of ≥ 1  and to suffer from moderate / moderate-severe depression  than the comparison group.Long-term outcomes of Zika virus-associated GBS are consistent with those associated with other antecedent antigenic stimuli in terms of mortality and ongoing long-term morbidity, as published in the literature. Persons with Zika virus-associated GBS more frequently reported disability and depression after approximately one year compared with those without GBS. Campylobacter jejuni, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus.[Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy resulting in limb and cranial nerve weakness, often with respiratory compromise, with variable consequent limitations on physical function. The disease is commonly precipitated by an infection, and infectious agents previously associated with GBS include rr virus. The incirr virus. but thesrr virus.–7GBS is heterogeneous in severity of neurological deficits and prognosis. People wStudies of GBS outcomes suggest that by one year from onset of the neurologic signs, 62%-92% of patients achieve complete / near complete recovery, regaining the ability to perform manual work and other motor activities.–14 HowevAlthough the prognosis for recovery in GBS patients is generally favorable, with most patients experiencing complete recovery or only minor sequelae, anecdotal reports have suggested that ZIKV-associated GBS has a worse outcome or prognosis than that seen with GBS associated with other antecedent antigenic triggers. However, the long-term neurological and functional outcomes of patients affected by GBS during the ZIKV outbreaks have undergone limited prospective systematic assessments. ThereforThe human subjects review committee at the U.S. Centers for Disease Control and Prevention (CDC) determined this investigation to be public health emergency response and not research, and as such did not require full Institutional Review Board approval. The Colombian National Institute of Health relied on CDC's determination. All subjects provided written informed consent prior to investigation participation.The enrollment process of the patients with GBS for this investigation was previously published by Salinas et al. in 2017. Briefly,In the present study, a follow-up survey to determine long-term disability was conducted between May and July 2017. We re-contacted 34 of the previous 40 patients; four had moved out of Barranquilla, one refused participation, and one was unable to be located. The 34 patients were included in this follow-up investigation .The patients at follow-up were administered a structured in-person interview to assess functional disabilities, including the Hughes Disability Scale and the Because there were no first assessment data for certain indices , we wanted to compare these results from GBS patients to a referent population in order to determine whether there were differences between the GBS group and the general population of Barranquilla. A population sample used for a prior study of health-related quality of life in Barranquilla  was used for the comparison population. Briefly, 368 non-hospitalized adults ≥ 18 years old who were living at home and were without neurological symptoms were sampled from four geographic regions of the city of Barranquilla in May 2017. The comparison population was selected to be similar in age group and residence to the GBS patient population. The comparison population was assessed for demographic information and measurements of disability, depression and health-related quality of life.Descriptive statistics were calculated for demographic, clinical, disability, depression, and health-related quality of life data at time of follow up.Odds ratios were used to compare prevalence of disabilities at the baseline and follow-up surveys. For comparison of cases to the non-hospitalized comparison group, multivariable logistic regression was utilized for questions related to self-reported health status, the health related quality of life, the ODSS, and the Zung scale, adjusting for age and sex. For analyses on individual Zung items, which were answered on a scale of 1  to 4 (most depressed), we used proportional odds logistic regression, adjusting for age and sex. For Zung index comparisons, in order to avoid excluding patients who were missing answers for a small number of items, we utilized multiple imputation based on available Zung item answers for each patient using ordered logit modeling from the R package “mice” (multiple imputation by chained equations) .Demographic differences between the case and comparison groups were assessed by the Mann Whitney U test and the chi-squared test with Yates continuity correction.All data were analyzed using R version 3.3.3 .The median time from neurologic symptom onset to first assessment survey for the 34 GBS patients was three months .[Fifty percent (17/34) of the cohort were male, and the median age at onset of acute GBS was 49 years (IQR 35.0–60.75). The median time between prodromal illness and onset of neurological symptoms was seven days (IQR 2–15). All patients (100%) were admitted to the hospital and median duration of hospitalization was 14.5 days (IQR 9.25–28.75). Sixty-eight percent were admitted to intensive care unit/critical care unit (ICU/CCU) and seven patients (21%) received mechanical ventilation. Treatment received by GBS patients included intravenous immunoglobulin (91%), steroids (38%), and plasma exchange (18%). During acute GBS illness at clinical nadir, 41% of patients were not able to walk without assistance, and 31% were unable to walk at all.Ninety-one percent of patients went to rehabilitation services after hospital discharge for physical therapy, and 12% received home health therapy .The neurologic signs demonstrated by the GBS patients at baseline and follow up are summarized in At baseline 94% of these patients reported leg weakness and 91% reported arm weakness. The proportion of patients reporting face weakness, leg numbness, and arm numbness was 53%, 77%, and 68%, respectively. At follow-up the proportion of patients reporting neurological symptoms decreased significantly for all five domains evaluated. Aside from a single patient who reported face weakness at follow-up but not at baseline, all individuals who reported any of these neurologic signs at follow-up had previously reported those signs at baseline.The results of neurologic evaluation using the Hughes score at baseline and follow-up are represented in Ongoing issues with health-related quality of life were captured in the follow-up survey .Incidence of GBS in Barranquilla during the study period was substantially higher than incidence reported in 13 previous studies of GBS incidence conducted in Europe and North America Fig 4),,Fig 4), The demographic characteristics of the non-GBS comparison population is shown in The non-GBS comparison group had a median age of 44.5 years and an IQR of 30 to 59 years (as compared to a median of 49 years and an IQR of 35 to 60.75 years for cases); the difference in age between the comparison population and cases was not statistically significant (p = 0.33). The proportion of the comparison group that was male (56%) was not significantly different from the proportion of cases that was male (50%) (p = 0.65).Our investigation evaluated the long-term outcomes of ZIKV-associated GBS at 14–20 months after initial GBS illness. Our findings suggest that the long-term morbidity in ZIKV-associated GBS are consistent with that described in GBS literature for GBS associated with other antecedent antigenic stimuli. The proportion of patients requiring mechanical ventilation during hospitalization (20%) is consistent with estimations in other GBS assessments.–30 The pAt long-term assessment, we found that GBS patients were more likely than the comparison population group to have ongoing disability as evidenced by an ODSS of 1 or greater as assessed by neurologic examination; this is not necessarily a surprising finding, but does demonstrate ongoing morbidity in the GBS group. GBS patients were also more likely to experience moderate or moderate-severe depression than the general population of Barranquilla, conceivably due to a reactive depression after experiencing a disabling illness. However, on quality of life indices assessing the occurrence of physical or mental difficulties or functional problems due to physical or mental difficulties in the 30 days prior to interview, there were no substantial differences between the GBS patients and the comparison population group. This suggests that, despite ongoing weakness and depression in some, overall quality of life indices did not differ significantly between those with and without GBS in this population.The proportion of patients with complete or near-complete recovery at follow-up  is similar to other investigations assessing the outcomes of Zika-associated GBS., 37 HoweOther investigations assessing long-term (one year or greater) outcomes of GBS have had variable findings. Cheng et al. determined that 40% of 60 GBS patients remained with physical and functional sequelae at one year. AlternatAs previously demonstrated, incidence of GBS increased with age. However,Our investigation has limitations. Not all cases were laboratory-confirmed ZIKV infections; a proportion of cases were diagnosed using clinical criteria; thus, misclassification of some cases may be possible. However, all cases met clinical compatibility criteria for ZIKV infection as published elsewhere. The factIn summary, long-term outcomes of ZIKV-associated GBS are consistent with GBS presentations associated with other etiologies in terms of mortality and ongoing long-term morbidity, as published in the literature. Additionally, long-term physical and mental status among persons with ZIKV-associated GBS after one year were similar to persons without GBS, though disability and depression were more common among GBS patients after one year. Further long-term clinical and epidemiologic assessments of ZIKV-associated GBS using larger sample sizes are needed to substantiate these findings and identify prognostic indicators for outcome.