Recent advancement has been accomplished in the field of biosensors through the modification of cellulose as a nano-engineered matrix material. To date, various techniques have been reported to develop cellulose-based matrices for fabricating different types of biosensors. Trends of involving cellulosic materials in paper-based multiplexing devices and microfluidic analytical technologies have increased because of their disposable, portable, biodegradable properties and cost-effectiveness. Cellulose also has potential in the development of cytosensors because of its various unique properties including biocompatibility. Such cellulose-based sensing devices are also being commercialized for various biomedical diagnostics in recent years and have also been considered as a method of choice in clinical laboratories and personalized diagnosis. In this paper, we have discussed the engineering aspects of cellulose-based sensors that have been reported where such matrices have been used to develop various analytical modules for the detection of small molecules, metal ions, macromolecules, and cells present in a diverse range of samples. Additionally, the developed cellulose-based biosensors and related analytical devices have been comprehensively described in tables with details of the sensing molecule, readout system, sensor configuration, response time, real sample, and their analytical performances. Acetobacterxylinum [Cellulose is a biopolymer of β-1,4 D-glucose units, a widely used biomaterial that exhibits unique properties and is used in various industries including textiles, electronics, biomedical, etc. , obtainerxylinum . Glucoserxylinum . Due to rxylinum ,8,9. As rxylinum  have alsrxylinum , and in rxylinum . In addirxylinum ,14,15, arxylinum . In recerxylinum . It is arxylinum . They carxylinum . The remrxylinum . Cellulorxylinum  and is urxylinum ,23,24. Drxylinum .In this review, we have critically evaluated the cellulose-based sensors that have been fabricated through distinct modification techniques and their varying applications for analyzing diverse sample types including small molecules, ions, macromolecules, and cells. While the studies on cellulose-based biosensors continue, major advances have been achieved in this field. Thus, we have performed a scientific survey for the research documentation concerning cellulose-based sensors through the online database “Scopus”, the result of which is quite a convincing indicator that cellulose-based biosensors have gained a major focus in recent times considering their multipotent abilities. According to this survey, it was found that more than 7000 research articles have been published in the last decade, following an exponential increase . In the A biosensor is defined as an analytical device that detects the biological molecule through electrical, thermal, or optical signals ,27. It cIn the structure of cellulose, each glucose unit consists of three hydroxyl groups at which chemical modifications are performed. These modifications can be majorly performed on the surface without disturbing the main chain, which results in the formation of the required cellulosic matrix . The imm3O4 and (S-CNC)-Fe3O4 nanoparticles to determine glucose, using glucose oxidase (GOx) and H2O2  positioned on the surface of a screen-printed carbon electrode (SPCE) [n = 5 at 90% confidence level). In addition to these, other glucose biosensors are mentioned in Small molecules are the low molecular weight organic molecules, normally less than 900 Daltons. They perform various types of biological functions such as a signaling molecule, drugs, effector, and even sometimes changes the function of the target. Due to their size, they readily diffuse across the membranes. Due to their wide range of functions, it is required to monitor the small molecules involved in maintaining the biological functions. In this section, cellulose-based biosensors that are developed for the determination of numerous small molecules have been discussed. One of the most important small molecules is glucose, which has a tremendous role in clinical laboratories and other industries. Glucose is a monosaccharide ubiquitously present in humans and acts as a fuel of human body, and when it is present in the blood, is called blood sugar . To deteand H2O2 B. Here, e (SPCE) . For gluIn addition to glucose, other molecules are also detected using a cellulose-based sensor such as phenol, which is a major component of various industries and industrial waste that leads to its deteriorating effects on the environment. Phenol is one such toxic pollutant present in wastewater, released from industrial products, and causes harmful effects to aquatic life, plants, and also humans, sometimes leading to organ damage ,57. An e2 QDs into cellulose membranes. The developed biosensor shows the detection range between 10 to 800 μM. The LOD observed for the fluazinam sensor was 2.26 μM [3 pg mL−1 having a determination coefficient of 0.995. The estimated LOD for the immunosensor was observed to be 27 pg/mL [A cellulose-based fluorescent biosensor has been developed for the sensing of various amines by Nawaz et al., 2020. The biosensor was manufactured by using the phenanthroline (Phen) as a color-imparting molecule and 4,4′-methylene diphenyl diisocyanate (MDI) immobilized on cellulose acetate (CA) to form a Phen-MDI-CA sensor for the visualization of amines . Differe 2.26 μM . Apart f27 pg/mL . The autThe cellulosic paper provides unique geometry and hydrophilic nature which are explored to develop paper-based analytical devices ,65. Phen2+) plays a significant role in different physiological processes, excess of which causes liver and kidney damage, and which is one of the frequently occurring ions causing the contamination of drinking water. A cellulose-based biosensor has been developed for the unaided detection of Cu2+ ions present in biological fluids by Wang et al., 2019 [2+ ions in the biological fluids and showed rapid response time, high sensitivity, and selectivity , which is present in water and its high concentration causes adverse effects in the environment and on public health [+ in an aqueous solution by Wang et al., 2020 [+ with N and S atoms of DAC-Tu to form N-Ag, S-Ag, and Ag2S and it shows different colors based on different concentrations of Ag+ , and X-ray photoelectron spectroscopy (XPS) analysis. The signal response of the sensor reduces with an increase in the concentration of Ag+ and the LOD was found to be 10−6 mol/L within 10 min. Apart from these ions, cellulose-based sensing devices are also fabricated for the identification of zinc ion (Zn2+), which is found abundantly in the environment due to industrial processes and causes harm to human health. Such a cellulose-based optical biosensor was designed for the sensing of Zn2+ by Daniyal et al., 2019 [2+ interacts with the negative charge present on the modified-gold film and such an interaction has been investigated by XPS. The XPS scans into the region of 0 to 1400 eV and the recorded data were equipped with the Gaussian–Lorentzian curve program. The developed biosensor possessed a wide dynamic range with the LOD of 0.01 ppm and illustrates the sensitivity of about 1.892 ppm−1.Cellulose-based biosensors are not simply used for the sensing of small molecules as discussed above; they are also used for the screening and detection of heavy metals. Heavy metals are detrimental to living beings beyond a particular concentration as they are not biodegradable and can accumulate in the body . Cellulol., 2019 . The bioectivity E. Apart c health . A cellul., 2020 . The bios of Ag+ F. The col., 2019 . The sur2+), which is a major threat to human health due to its toxicity. Timely detection is necessary to decrease the level of Hg2+ in industrial waste. Zheng et al., 2021, have prepared a paper-based fluorescent biosensor for the determination of Hg2+ [2+ at micro molar concentration in presence of other molecules and ions within 5 min. In addition to these examples, other developed biosensors for the determination of metal ions have been discussed in Interestingly, not only these ions but cellulose-based sensors have also been fabricated for the identification of mercury  on cellulose paper by divinyl sulfone-mediated conjugation . PNA is Cellulose-based sensors are not only for the nucleotides but are also developed for the sensing of different types of proteins. In this direction, several proteins have been detected using a novel sensor system. In one such example, the transcription factor (TF) has been detected, which is a DNA binding protein essential for gene regulation. Lin et al., 2019, have developed a paper-based biosensor for the visual detection of TF, which was fabricated through dopamine coating onto the cellulose paper and was used to obtain the analytical signals . Charact2 nanoparticles and the formed SiO2@Au were anchored with the dsDNA to enhance the signal. CeO2 nanoparticles were used as an indicator that binds with the dsDNA, which leads to the formation of the SiO2@Au/dsDNA/CeO2 signal tag. The boron ate affinity-based MIPs were immobilized on a paper matrix to recognize the target glycoprotein OVA, through the covalent bonding formation between the boronic acid and glycoprotein. The detection range of the developed biosensor was measured to be 0.001 ng/mL to 1μg/mL and the LOD was 0.87 pg/mL (S/N = 3). Cellulose-based sensors have also been fabricated for the identification of another protein such as Bilirubin, which is related to jaundice and other clinical conditions. Tabatabaee et al., 2019, have prepared a photo lumines cent nano paper-based biosensor for early diagnosis of jaundice through the detection of Bilirubin in infants’ blood samples. This provides an easy, effective, non-toxic, disposable, and inexpensive biosensor with a smartphone readout [−1.Apart from these, cellulose-based devices have also been explored for the sensing of glycoproteins, which plays a critical role in cell division, cell signaling, cell migration, and also as a biomarker for various disease diagnoses . Another readout . Smartph readout . It was Furthermore, the cellulose-based matrix is explored for fabricating the biosensor for the detection of numerous types of enzymes. A cellulose-based calorimetric biosensor was manufactured by Ling et al., 2019, for the identification of the enzyme human neutrophil elastase (HNE) . HNE is Staphylococcus aureus which produces enterotoxins and is the main reason for food poisoning and skin infections [S. aureus. An electrochemical cellulose-based biosensor was manufactured for the early determination of living S. aureus cells from a sample of food containing both live and dead cells by Farooq et al., 2020. The biosensor was fabricated by immobilizing the bacteriophage onto a modified surface of the BC matrix. BC has a poriferous and fibrous structure that provides a larger effective surface for the impregnation of carboxy late multiwalled carbon nanotubes (c-MWCNTs), which enables greater density and phage immobilization. BC/c-MWCNTs nanocomposites modified through surface polymerization with polyethylene eimine provide a positive charge, which assists in the correct orientation of the phage on the matrix. Detection of anti-staphylococcus activity of the immobilized phage was measured through optical density and the density was determined through confocal microscopy. The developed biosensor effectively detects S. aureus up to 3 and 5 CFU⋅mL−1 in the phosphate buffer saline and milk sample, respectively, using DPV in 30 min [Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes are the three most crucial microorganisms which disperse through food and cause food borne diseases [Escherichia coli O157:H7 present in food samples through naked eye detection by You et al., 2021. The biosensor was fabricated by using Poly-L-lysine-coated starch magnetic particles (PLL@SMPs) for magnetic separation. The signal amplification is performed by using an antibody conjugated with Horseradish peroxidase and 3, 3′, 5, 5′-tetramethylbenzidine. The developed PLL@SMPs show an efficiency of >90% in a large volume for the target bacteria. The LOD of the biosensor was observed to be as low as 30.8 CFU/mL with a probability of 95% [In addition to small molecules, macromolecules, and metal ions detection cellulose-based biosensors are also being developed for the visualization of cells. These biosensors are effective in determining both prokaryotic and eukaryotic cells. Here, we have discussed the previously developed sensors, focusing upon the identification of various kinds of bacteria, viruses, fungi, and also some cancer cells. In recent years, cellulose-based biosensors have been developed for bacteria detection where some interesting work has been carried out towards fections ,100. Forn 30 min . The biodiseases ,103. Anoy of 95% . This tey of 95% . For det32+ and showed a high affinity towards the target cell  outbreaks were announced as a global pandemic by WHO. Rapid and sensitive detection of the virus has become the need of the hour and various methods have been explored by scientists across the globe ,121,122.Cellulose is a widely used material showing various advantages over other materials. Cellulose exhibits unique properties such as biocompatibility, flexibility, mechanical strength, biodegradability, electrical properties, and cost-effectiveness. Apart from the cellulose derived from plants, bacterial cellulose, which is obtained from bacteria, shows more advantageous properties such as mechanical strength, water-holding capacity, and biocompatibility. These advantages of cellulose have made it a significant matrix substance in recent times for the fabrication of biosensors. Many applications have been reported concerning cellulose-based sensing of biomarkers for various disease conditions such as cancer, diabetes, liver and kidney disorders, etc., and also in the detection and monitoring of food quality and various pollutants and heavy metals present in surrounding samples, such as in wastewater. Owing to the significant advances, various methods have been examined to modify cellulose to nanocomposite material, which shows unique structures and desirable properties. In this review, a detailed discussion has been carried out on various modifications required for the formation of cellulose matrix and engineering aspects of the cellulose-based sensors for their applications in different areas.These sensors are used for sensing the numerous types of small molecules, macromolecules, metal ions, and cells, which are discussed through the numerous examples of sensors. We have tried to include the fabricated sensors to date for various categories of molecules possible, and the techniques/methods used for their modifications. Despite the great progress achieved, there are still some issues that need to be addressed. Recent advances in cellulose-based biosensors typically exhibiting a single function type only and lack the multi-functionality, which leads to its limitation in function and also affects the performances and customer satisfaction. In the future, numerous innovative technologies could be introduced in developing cost-effective multifunctional cellulose-based biosensors.


Premature ejaculation (PE) is a common sexual dysfunction and is found to be associated with abnormal emotion. The amygdala plays an important role in the processing of emotion. The process of ejaculation is found to be mediated by the frontal-limbic neural circuits. However, the correlations between PE and emotion are still unclear.Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired in 27 PE patients with stable emotion (SPE), 27 PE patients with abnormal emotion (NPE), and 30 healthy controls (HC). We used rs-fMRI to explore the underlying neural mechanisms in SPE, NPE, and HC by measuring the functional connectivity (FC). Differences of FC values among the three groups were compared when choosing bilateral amygdala as the regions of interest (ROIs). We also explored the correlations between the brain regions showing altered FC values and scores of the premature ejaculation diagnostic tool (PEDT)/Eysenck Personality Inventory about neuroticism (EPQ-N) in the PE group.When the left amygdala was chosen as the ROI, the SPE group exhibited an increased FC between the left medial superior frontal gyrus (SFGmed) and amygdala compared with the NPE or HC group. When the right amygdala was chosen as the ROI, the NPE group exhibited a decreased FC between the left SFGmed and right amygdala compared with the HC group. In addition, FC values of the left SFGmed had positive correlations with PEDT and negative correlations with EPQ-N scores in the PE group. Moreover, FC values of the left superior temporal gyrus had positive correlations with EPQ-N scores in the PE group.The increased FC values between the left SFGmed and amygdala could reflect a compensatory cortical control mechanism with the effect of stabilized emotion in the limbic regions of PE patients. Abnormal FC between these brain regions could play a critical role in the physiopathology of PE and could help us in dividing PE into more subtypes. Premature ejaculation (PE) is a common sexual dysfunction with 3% prevalence in Chinese population . AccordiPremature ejaculation was found to be associated with psychological factors, especially abnormal emotion . MeanwhiAccording to previous neuroimaging studies, the volume of the amygdala had been found to have a positive association with sexual drive, and amygdala activity was found to be enhanced when men and women were viewing sexually arousing images . The amyEmotional stability (neuroticism) is a personality trait that is associated with brain activity during emotion processing, especially in the amygdala . PreviouN < 9: SPE, PE with stable emotion; N > 14: NPE, PE with abnormal emotion). We hypothesized that SPE and NPE patients could exhibit different FC values in the prefrontal cortex connected with the amygdala. Then, we used the fMRI data to explore the functional connections of the amygdala in these two subtype PE groups using the whole brain FC analysis. Moreover, we explored the associations between FC values of abnormal regions and premature ejaculation diagnostic tool (PEDT) scores, EPQ-N scores in the PE group.According to a PET-neuro-imaging study, significant changes of regional cerebral blood flow (rCBF) were not being observed in men during ejaculation. Thus, rs-fMRI was chosen to investigate the long-term effects of PE, abnormal emotion on the brain regions, and show their usual working situation . In the A total of 54 right-handed patients with PE were recruited from the Department of Andrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, as well as 30 age and education matched healthy controls . The detailed information about the demographic and clinical features of these participants can be found in In this study, patients were selected based on the following inclusion criteria according to the ISSM PE Guidelines by two experienced andrologists : (1) ageExclusion criteria for all participants were as follows: (1) any history of serious medical illness and psychiatric or neurological illness; (2) any history of head trauma or loss of consciousness; (3) any history of alcohol dependence or substance abuse; (4) low or loss of sexual desire; (5) with genital abnormalities; and (6) MRI contraindications.In addition, the test of EPQ was performed to evaluate the stability of emotion. Patients with scores of EPQ-N >14 were classified as the SPE group while patients with scores of EPQ-N <9 were defined as the NPE group.The present study was approved by the Ethical Committee of Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine. Apart from that, written informed consents were obtained from all subjects.Magnetic resonance imaging (MRI) data were acquired using a 3.0T Siemens Verio scanner at the Affiliated Hospital of Nanjing University of Chinese Medicine. Each participant was positioned comfortably in the scanner and fitted with ear plugs to reduce scanner noise. Prior to scanning, each patient was asked to minimize head and body movements as much as possible while staying awake with eyes closed. The T1-weighted images were obtained in the following scanning parameters: repetition time (TR) = 1,900 ms and echo time (TE) = 2.48 ms, flip angle (FA) = 9°, slice number = 176, slice thickness = 1 mm, field of view (FOV) = 250 mm × 250 mm, voxel size = 1 mm × 1 mm × 1 mm, and scan time = 4 min, 18 s. Resting-state functional images were acquired with the following parameters: TR = 3,000 ms and TE = 40 ms, FA = 90°, slice number = 32, slice thickness/gap = 4/0 mm, FOV = 240 mm × 240 mm, matrix = 64 × 64, 32 axial slices, acquisition time = 6 min, 45 s, resulting in 133 volumes.x = −24, y = −1, z = −17) and right amygdala  were selected as regions of interest (ROIs) which were represented by a sphere with a 6-mm radius.After image acquisition, preprocessing was performed with the Data Processing Assistant for Brain Imaging . The firPearson’s correlation coefficients between ROIs and the whole brain regions represented the strength of the FC values. The correlation coefficients were converted to z-scores with Fisher’s r-to-z transform for further analysis. Thus, 54 patients (27 SPE and 27 NPE) and 30 HC were included for FC analysis.t-test was performed to identify differences between two groups. The threshold was set at P < 0.005, and the minimum cluster was 12 voxels. Finally, the Pearson’s correlation analysis was used to obtain the correlations between the FC values of the significant brain regions and the PEDT/EPQ-N scores by using the Statistical Package for Social Science (SPSS 23.0) software.A one-way analysis of variance (ANOVA) was performed to obtain the FC differences among the three groups by using the Resting-State fMRI Data Analysis Toolkit 1.8 (REST) software. Two sample F = 1.8, p = 0.17), educational level , and IIEF-5 scores  among the three groups. Both the NPE and SPE groups had higher scores of PEDT than the HC group . NPE group had higher scores of EPQ-N compared with the SPE and HC groups .As is shown in By ANOVA analysis, there were significant differences in the FC values between the left amygdala and medial superior frontal gyrus (SFGmed) among groups .By ANOVA analysis, there were significant differences in the FC values between the left amygdala and right posterior central gyrus among groups .Compared with the NPE group, the SPE group exhibited increased FC values between the left amygdala and SFGmed .There were no significant differences in the FC values of the right amygdala between the SPE and NPE groups .Compared with the HC group, the SPE group had increased FC values between the left amygdala and SFGmed .Compared with the HC group, the NPE group had increased FC values between the right amygdala and left Rolandic operculum, right Rolandic operculum, and right precentral gyrus .There were no significant differences in the FC values of the left amygdala between the NPE and HC groups .Compared with the HC group, the NPE group had increased FC values between the right amygdala and left superior temporal gyrus (STG), right precentral gyrus. In contrast, the NPE group had decreased FC values between the right amygdala and left SFGmed .r = 0.33, P < 0.05). Meanwhile, FC values of the left SFGmed had negative correlations with the EPQ-N scores in the PE group . Moreover, FC values of the left STG had a positive correlation with the EPQ-N scores  in the PE group  had been proved to play an important role in sexual behavior. Previous studies on rats and gerbils had shown that MeA and bed nucleus of the stria terminalis had enhanced c-Fos expression through olfactory pathways, especially the vomeronasal-accessory olfactory system, which in turn activated the medial preoptic area, and finally led to ejaculation .However, neuroimaging findings were inconsistent. The results of brain activity in human males in a PET-scan study showed that the amygdala was deactivated not only during ejaculation or orgasm, but also during sexual stimulation and erection . There wIn this study, patients with SPE were found to be associated with increased FC values between the left SFGmed and amygdala. In contrast, patients with NPE were found to have decreased FC values between the left SFGmed and right amygdala compared with HC. In a previous study with PET, increased rCBF was found in the left SFGmed while parts of the amygdala were found to be deactivated during ejaculation . In anotIn addition, previous studies showed that the left hemisphere had a stronger involvement in the regulation of positive emotions while the right hemisphere had a closer relationship with negative emotions . On the According to these previous studies, it was suspected that the increased FC values between the left SFGmed and amygdala were related to PE and emotional stability. These two regions might be involved in the inhibition of ejaculation and the regulation of emotional stability. For SPE, the changes of the left amygdala could lead to the secondary compensatory activation of the left SFGmed, which could help improve the abnormal emotion caused by PE. However, the compensatory activation of the left SFGmed could not improve the symptom of PE. For NPE, the left SFGmed had decreased FC values with the right amygdala. The decreased FC values between the left SFGmed and right amygdala might be a decompensation, which might be associated with the impaired inhibition of ejaculation and regulation of emotional stability.Pearson’s correlation, while it is known to suffer with limitations (There were several limitations in this study. Firstly, this was a relatively small sample, cross-sectional study, which might limit the generalization of our results. Secondly, emotion affects hormone level and hormone level affects transduction of synapses. Though we used questionnaires to categorize the emotional level of the participants, physiological data were not acquired. Finally, we have done analysis using itations . Future The increased FC values between the left SFGmed and amygdala could reflect a compensatory cortical control mechanism with the effect of stabilized emotion in the limbic regions of PE patients. Abnormal FC between these brain regions could play a critical role in the physiopathology of PE and could help us to divide PE into more subtypes.The data used to support the findings of this study are available from the corresponding author upon request.The studies involving human participants were reviewed and approved by the Ethical Committee of Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine. The patients/participants provided their written informed consent to participate in this study.JC, JY, and YC designed the experiments. JC, JY, YX, XZ, ZX, QW, XH, TL, ZY, and XJ contributed to clinical data collection and assessment. JC, YX, XZ, and ZX analyzed the results. JC, YX, XZ, and ZX wrote the manuscript. JC and JY approved the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Neuroblastoma (NB) is the most common pediatric extracranial solid neoplasm after leukemia. Intracranial metastases (IM) rarely occur in patients with NB. The present study aimed to review the clinical characteristics of NB patients from a single center presenting with IM.Methods: Two hundred children (aged 3–91 months) with NB admitted to the Fourth Affiliated Hospital of China Medical University between January 2009 and December 2015 were enrolled, and their clinical characteristics were recorded. The patients were divided into two groups based on the presence of IM. Their clinical characteristics, including demographics, clinical features, and laboratory and imaging studies, were retrospectively analyzed.Results: IM occurred in 22 of 200 (11%) neuroblastoma patients, with a median age of 42.5 months , with a male-to-female ratio of 1.4:1. Seven patients had IM at the initial diagnosis. Among the 15 children who did not have IM at initial presentation, the median interval from presentation to the diagnosis of IM was 17.3 months . Compared with the control group, NB patients with IM tended to be asymptomatic at the time of NB diagnosis, which was made incidentally during routine physical examination . In addition, this group had more primary intra-abdominal sites  and worse prognosis .Conclusions: NB patients with IM have insidious onset in the early stage and a lower survival rate, especially patients with primary intra-abdominal lesions. Regular neurological monitoring could improve the rate of early diagnosis and prognosis of NB children with IM. Familiarity with the characteristic findings of NB with IM is necessary to avoid misdiagnosis and initiate necessary interventions. Neuroblastoma (NB) is the most common extracranial solid malignancy that arises from neural crest cells in children , 2, accoNB is an embryonal tumor of the peripheral sympathetic nervous system that typically originates from the adrenal glands, although it can develop along the paravertebral sympathetic chain , or anywDistant metastases, which frequently involve the bone, bone marrow, and liver, are present in up to 70% of children with NB at the time of diagnosis and confer a poor prognosis –11. HemaIM in neuroblastoma patients are rare, and although some case series have focused on some specific topics such as treatment , 18, theFrom January 2009 to December 2015, 200 pediatric patients who were diagnosed with NB at the Fourth Affiliated Hospital of China Medical University were included and reviewed in our study. Patients with IM were defined as the IM group, while those without IM were defined as the control group. Staging was performed according to INSS. Pre-treatment risk classification was performed according to the International Neuroblastoma Risk Group system.All NB patients were regularly followed up, and CNS imaging was deemed necessary when the patients presented with neurological symptoms, or at each half-year time point during the follow-up period. IM was confirmed by CNS imaging and was defined as all lesions located in the brain parenchyma and meninges.The sex, age of onset, symptoms at onset, primary site of NB, time interval from symptom onset to diagnosis, metastatic sites, grade of differentiation, risk grade, N-Myc status, primary histopathology, differentiation degree, and outcome of all enrolled patients were collected and analyzed. Other clinical data, including initial neuroimaging at diagnosis, primary tumor size, histology, initial treatment, time interval from diagnosis to brain metastasis, location of IM, number of brain lesions, maximum lesion diameter, presence of edema, contrast enhancement of the lesions, type of treatment upon diagnosis of IM, neurologic outcome after treatment, concomitant extra-CNS disease at the time of IM, and survival of NB patients with IM, were reviewed. When available, autopsy reports were reviewed to determine whether the children had IM at death.t-test. Continuous data with abnormal distribution were analyzed using the Wilcoxon Mann–Whitney U test. Categorical data were expressed as absolute numbers and percentages and analyzed using the chi-square test or Fisher's exact test. Data on sex, age at onset, symptoms of onset, primary site of NB, other metastatic sites, stage, risk grade, N-Myc status, primary histopathology, differentiation degree, and outcome were analyzed using multiple logistic regression analysis. Statistical significance was set at p < 0.05.Statistical analyses were performed using SPSS version 22.0. Continuous data with a normal distribution were expressed as the mean ± SD and further analyzed using an independent sample n = 125) than in girls (n = 75), with a male-to-female sex ratio of 1.7:1. Of the 200 children almost all  were older than 18 months. According to the neuroimaging results, the 200 patients were divided into the IM group (n = 22) and control group (n = 178). The demographic and clinical characteristics of the two groups are shown in p < 0.05). The primary site of enterocoelia was significantly more common in the IM group than in the control group . Survival  in the IM group was significantly worse than that in the control group .This study included 200 patients with NB. NB was more common in boys (n = 10), adrenal glands (n = 8), and mediastinum (n = 3).Non-contrast computed tomography scan was performed in nine patients, ultrasound scanning was the initial imaging modality of choice for 11 patients, and in two patients only contrast-enhanced magnetic resonance imaging was performed. The primary site of NB was the retroperitoneum  and 2 of 200 (1%) NB patients, respectively. Meningeal metastasis was found in 12 of the 200 patients (6%).The number of brain lesions ranged from 1 to 10. In all patients with IM, brain contrast-enhanced magnetic resonance imaging was performed , 2. Mostn = 9 patients) and bone marrow (n = 19 patients).The treatment modalities for the 22 NB children with IM included chemotherapy in 17, chemotherapy plus surgery in 2, chemotherapy, surgery plus stem cell transplantation in 2, and chemotherapy plus intrathecal injection in 1. Twenty patients had concomitant extra-CNS disease at the time of brain metastases; the other common sites of extra-CNS involvement were bone (n = 1), abdominal skin (n = 1), lymph node (n = 4), bone (n = 3), bone marrow (n = 4), and femur (n = 1).Seven patients had IM at initial presentation. Concurrent non-brain distant metastasis was present in five of these seven cases, including metastasis to the liver  . During The objective of the present retrospective study was to describe the relevant clinical findings in NB patients with IM at our institution. We tried to gain updated insights into the phenomenon of CNS involvement by NB, including incidence rates and treatment options. To our knowledge, the present study is the largest case series to date on IM in NB patients, based on a comprehensive review of clinical features. The present study may define the natural history of IM in NB and eventually lead to a better understanding of the associated clinical characteristics with the goal of contributing to the existing knowledge of this rare disease.NB is one of the most common extracranial solid tumors in children to metastasize to the CNS among pediatric malignant non-epithelial tumors, with an incidence of 1.7–11.7% , 22–24. Certain lines of evidence suggest that IM in neuroblastoma patients are rare and usually occur during disease progression , 17, 19,The imaging features of IM in NB varied from single brain lesions to diffuse meningeal involvement, with a mean number of four brain lesions range, 1–10), which is consistent with previous studies , which i, 29, 30.n = 16). Two patients received more aggressive treatment with surgery plus chemotherapy, which may result in a longer median survival in a limited number of patients, although death from subsequent systemic recurrence seems inevitable.It is disheartening that, by the time IM is clinically evident, it is usually too late. No consistent or effective treatment strategy exists for such patients , 32. TheIn summary, IM remains an uncommon (10%) complication in children with NB. This study was based on a retrospective review of 22 cases with IM and aimed to describe the relevant clinical features of these patients in our institution. Despite being a single institution study, our report represents the largest series of children with IM described to date. Our findings lend support to the idea of routine CNS screening of children with NB to diagnose IM at earlier stages. Whether earlier diagnosis corresponds to improve survival should be the goal of prospective randomized studies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Ethics Committee of the Fourth Affiliated Hospital of China Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.Material preparation, data collection, and analysis were performed by YL (1st author), LH, JZ, and YL (4th author). The first draft of the manuscript was written by YL (1st author). All authors contributed to the conception and design of the study, commented on previous versions of the manuscript, and read and approved the final manuscript.Shenyang Science and Technology provided financial support in the form of Shenyang Science and Technology Funding (F13-221-9-43). The sponsor had no role in the design or conduct of this study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: Between the ages of 12 and 25 the onset of mental disorders typically occurs, and the burden of mental health problems is greatest for this group. Indicated preventive interventions to target individuals with subclinical symptoms to prevent the transition to clinical levels of disorders have gained considerable traction. However, the threshold to seek help appears to be high even when help is needed. Online interventions could offer a solution, especially during the COVID-19 pandemic. This scoping review will present an overview of the recent research of indicated online preventive interventions for youth (12–25 years) experiencing the early stages of mental health complaints with the aim of identifying the nature and extent of the research evidence.Methods: The 5-stage framework by Arksey and O'Malley was used. Academic literature published from 2013 onwards in printed or electronic format was included from Scopus, PsychINFO, and Ovid MEDLINE(R) ALL.Results: The search yielded 11,122 results, with the final selection resulting in inclusion of 30 articles for this review. In total, the articles included 4,950 participants. 26.7% of the selected articles focused on youth between 12 and 25 years. Of the articles 60% did not screen for, nor exclude participants with clinical levels of symptoms. Most studies used a common evidence-based therapy for the disorder-category targeted. More than half of the online interventions included some form of human support. Adherence levels ranged between 27.9 and 98%. The results indicate general effectiveness, usability and acceptability of online indicated preventive interventions. The most commonly used approach was CBT (n = 12 studies). Studies varied in their size, rigor of study, effectiveness and outcome measures. Online interventions with a combination of clinical and peer moderation (n = 3 studies) appear to result in the most stable and highest effect sizes.Conclusion: Online indicated preventive mental health interventions for youth with emerging mental health issues show promise in reducing various mental health complaints, and increasing positive mental health indicators such as well-being and resilience. Additionally, high levels of usability and acceptability were found. However, the included studies show important methodological shortcomings. Also, the research has mainly focused on specific diagnostic categories, meaning there is a lack of transdiagnostic approaches. Finally, clear definitions of- as well as instruments to measure- emerging or subclinical mental health symptoms in youth remain are missing. Mental health can be defined as “a state of well-being in which every individual realizes his or her own potential, can cope with the normal stresses of life, can work productively and fruitfully, and is able to make a contribution to her or his community” . NonetheIncreased attention has been paid at interventions aimed at youth with emerging symptoms to treat them as early as possible in the development of a mental disorder, for example, during the peak period of risk for onset, with a focus on both symptomatic as well as functional recovery . PreventOnline interventions might offer a solution to the perceived barriers. Advantages of online interventions are the possibility to receive help anonymously, and increased convenience because individuals can choose when and where they access help –29. MoreOnline indicated preventive interventions for individuals with an indicated need for care, that is, youth with emerging complaints, offer a promising approach to address this unmet need. From a resource perspective, it may be more feasible to target individuals with subclinical symptoms than non-symptomatic individuals who may not have a need for an intervention . The cliThe effectiveness of online indicated mental health preventive interventions for young people has been addressed in four systematic reviews and two meta-analyses between 2014 and 2016. In these reviews “youth” is defined as between the ages of 12 and 25, in concordance with most international definitions of youth as well as governmental and youth mental health institutions , 43. Intg = 0.72, reflecting a decrease in symptom severity. Again, the authors reported high heterogeneity and long-term effects of the studies. In the most recent meta-analysis of Conley et al. . The eligibility criteria were determined to find all articles relevant to the research question. A highlighted summary of the main inclusion/exclusion criteria covered here is provided in Studies eligible for inclusion were those containing a sample of youth, defined in concordance to most international, governmental and youth institutional definitions , 43 as pStudies were also excluded if they had selected participants with a known mental disorder (either self-reported or diagnosed by a clinician). However, since most indicated preventive interventions did not screen for the presence of a mental disorder, studies were not excluded if they did not screen for mental disorders. The risk of reducing specificity by including these articles was deemed essential in order to have a broader scope to best summarize the relevant research.Interventions needed to be delivered primarily in an online  setting  and focused on indicated prevention of mental disorders in youth aged 12–25 with signs or symptoms of a mental disorder. Only online indicated preventive interventions were included .Interventions that are primarily face-to-face with some additional online content were also excluded. Lastly, process evaluation studies were excluded .Studies comparing online prevention programs, websites, apps, games, social media or smartwatch interventions compared to no intervention, waiting list, or face-to-face interventions were included. No exclusion criteria were applied to the type of comparator used. RCTs, quasi-experimental study designs and experimental studies without a comparison group were eligible for inclusion in this review. No minimum follow-up time period was specified. Observational studies or protocols were excluded. There were no restrictions by timing or type of setting. Only articles written in English or Dutch were included.The following a priori determined outcome measures were included: negative mental health indicators, for example, depression, anxiety, psychological distress and suicidal behavior, and transition to symptom levels above clinical diagnostic threshold; positive mental health indicators, for example, self-efficacy, coping skills, resilience, emotional well-being, self-esteem; and well-being indicators, for example, social participation, quality of life, social functioning, empowerment, communication, social support. Outcomes that were not indicative of mental health and well-being were excluded.Data were extracted by two out of five reviewers independently and in duplicate with the use of standardized data extraction forms. Any disagreements were resolved through discussion and by a third reviewer. To ensure accuracy, the extracted data was reviewed by experts in the field based on relevance. Data that was extracted included: intervention characteristics, methodology, program outcomes and information about program completion, engagement rate, and inclusion of human support.The following data items were extracted: (1) intervention name, author, country where research was conducted, year of publication, (2) intervention characteristics , (3) method , (4) program outcomes, and (5) adherence (non-completion/dropout rates). In case of deficient or missing outcome data, authors were contacted and data were requested.To determine the extent and nature of the studies, a numerical analysis was conducted, using tables and chart mappings. Using conventional content analysis the descriptive data was analyzed. The user-centered design framework was followed, which states that two reviewers have to examine the data and identify codes relative to the findings. The codes were grouped according to themes to summarize the literature and answer the research question.The search conducted by the university librarian (JD) yielded 11,122 results. After the screening process, the remaining 77 articles were assessed for relevance using the eligibility criteria in For all study characteristics, see n = 5) and 2018 (n = 4), followed by a spike in publications occurring in 2019 (n = 13). At the present moment, there have been an additional two studies published in 2020.Six studies were published in 2016. The number of studies regarding preventative online measures for youth saw a slight decline in the years 2017 (n = 9) and the United States of America (n = 7), accounting for more than half (53%) of the contributions in this scoping. The remaining studies were conducted in the Netherlands (n = 5), Canada (n = 1), Finland (n = 1), Germany (n = 1), Japan (n = 1), Sweden (n = 1), Switzerland (n = 1), and the United Kingdom (n = 1). See The included studies were predominantly conducted in Australia (n = 23). Of these 23 RCTs, two were stratified and one was clustered. The remaining were experimental designs without comparison groups (n = 6). Another study that was included based on the preliminary inclusion criteria was identified as a mixed design (n = 1). Almost half (46%) of all included studies made use of a follow-up procedure, either within 3 months (n = 4), between 3 to 6 months (n = 6), or after 7 months and beyond (n = 4). See The included studies consisted primarily of RCTs  to a structured DSM-5 interview with clear cut-offs for clinical levels of mental disorders. A specific and validated clinician-rated instrument was used only for identifying the subclinical complaints of psychosis (UHR-state) . Lastly,n = 17), of which several studies (n = 5) combined this approach with another, for example Interpersonal Therapy  were used to measure a single psychological construct such as depression. For a complete overview, see For a full overview of the overall findings, including the outcome variables, the study design, the number of participants in each study and whether human support was used in the intervention, see n = 14 to n = 536). Moreover, various articles did not provide data on effect sizes of significant effects (n = 7). In addition, some articles deconstructed or created questionnaires without reporting their psychometric properties. Lastly, some studies did not have a control group to compare the effects of the interventions to (n = 6). Therefore, the results are to be interpreted with caution, and the authors refrain from making conclusive comparisons between studies.The quality of the selected articles differed considerably. Firstly, the number of participants included in the selected studies showed a wide range (from n = 16), anxiety (n = 5) and stress (n = 6). As for the positive outcome measures, the majority of articles measuring positive health indicators showed that online preventive interventions significantly improves positive mental health factors such as well-being (n = 4) and social functioning (n = 2). However, a large part of the selected articles measuring positive health indicators also showed non-significant improvement intervention on factors such as self-efficacy (n = 4) and self-esteem (n = 4).The results of the selected articles show that online preventive interventions are generally effective in reducing negative outcome measures such as depressive symptoms (d (d) between 0.36 and 1.25). Studies that combined CBT with other approaches reported small to large effect sizes (d = −0.17 to 0.99). CT was found to have a small effect size (d = 0.45). ACT interventions reported a medium effect size (d = 0.62 to 0.78). Mindfulness and strength-based interventions found medium to large effect sizes (d = 0.66 to 1.83). Cognitive bias modification found a large effect size (d = 0.86) and attentional bias modification a medium effect size (d = 0.57). The motion picture producing app found a large effect size (d = 0.94). For an app used as adjunct to face-to-face therapy a small to medium effect size was reported (d = 0.25 to 0.50). For music therapy and the decision aids the Cohen's d was not reported. Online interventions without human support resulted in small to large effect sizes (d = −0.09 to 0.99). Online interventions with robot support yielded small effect sizes (d = 0.37 to.44). Studies that included clinical moderation found small to large effect sizes (d = 0.33 to 1.25). Finally, online interventions with the combination of clinical and peer moderation found small to large effect sizes (d = 0.25 to 1.83).Overall, studies varied in their size, rigor of study, effectiveness and outcome measures; the effect sizes were highest for the mindfulness and strength-based intervention , CBT , and the motion picture app . Online interventions with a combination of clinical and peer moderation  appear to result in the most stable and highest effect sizes. See For studies using CBT as the intervention, small to large effect sizes were found (Cohen's d = 0 to 1.83). Studies using CBT as the intervention found small to large effect sizes (d = 0.36 to >1.0). One study using an ACT intervention found no significant treatment effects, and one found significant effects . The motion picture app found a large effect size (d = 0.94). Mindfulness and strength-based interventions found medium to large effect sizes (d = 0.66 to 1.83). Online interventions without human support resulted in no effect to large effect sizes (d = 0 to 0.94). Studies that included clinical moderation found small to large effect sizes (d = 0.36 to 89). Finally, online interventions with the combination of clinical and peer moderation found medium to large effect sizes (d = 0.5 to 1.83). Overall, studies using mindfulness and strength-based interventions, a motion picture app or CBT found the highest effect sizes. The studies using ACT as the intervention type show varying results and no effect sizes are known for one study, making it difficult to draw conclusions on the effectiveness of ACT. Moreover, online interventions with the combination of clinical and peer moderation appear to result in the most stable  and highest effect sizes.Even though the scope of this review was indicated prevention, 60% of the articles did not exclude participants who met criteria for a mental disorder. However, clinical stages 1a and 1b are not synonym with the absence of a mental disorder as assessed with the DSM/ICD (ref). But to give a complete overview, we summarize the 12 studies that excluded participants with a mental disorder below and in n-range of studies from 413 to 536) and their RCT design. These studies provide general support for the effectiveness of online preventive interventions for youth. (1) Radomski et al. (d >1.0), high levels of treatment satisfaction and no significant differences between the online intervention group and the routine care group.The most robust data for the effectiveness of online preventive interventions are from the following three articles due to their high number of participants . We aimed to identify the nature and extent of the relevant research evidence from treatment studies. This led to the following guiding question: The findings of the included articles of the scoping review indicate the overall importance of online indicated preventive intervention. The results show that online preventive interventions are generally effective to reduce subclinical symptoms of various mental illnesses and improve several outcome measures such as quality of life and mindfulness. In addition, young people commonly reported good satisfaction, acceptability and usability of online interventions.However, the included studies pose several limitations and therefore conclusions should be made with caution. Also the research published to date has focused predominantly on specific diagnostic categories, suggesting there is a lack of studies that have targeted transdiagnostic mechanisms. Finally, clear definitions of- as well as instruments to measure- emerging or subclinical mental health symptoms are missing. In the next section, the found gaps in the research, and the limitations of this scoping review will be discussed, as well as recommendations for future research.n = 24). Nonetheless, the included studies showed important shortcomings. For example, effect sizes were often not reported, psychometric qualities of used instruments were not investigated, and control groups were missing. Moreover, it remains unclear how long these positive effects last. The majority of articles had no follow-up data exceeding 3 months, and only four articles had follow-up data exceeding 7 months. The limited availability of long-term data is an issue, since it does not provide adequate insight whether online indicated preventive interventions for youth with emerging mental health issues delays the onset of a consequent mental illness, or whether it prevents the onset altogether. To provide an answer to this issue, future research regarding online indicated preventive interventions needs to investigate the long-term effects.Overall, the included articles show that online indicated preventive mental health interventions for youth with emerging mental health issues show promise in reducing various mental health complaints, and increasing positive mental health indicators such as well-being and resilience. From the 30 articles selected for our scoping, the vast majority of the included studies were RCTs with adequate use of control groups  reported acceptable levels e.g., , 66, 68], 6866, 6Several limitations and strengths to this review should be highlighted. First of all, this study is a scoping review as opposed to a systematic review. Although this review has an ambitious breadth, it is not meant to be exhaustive in nature. For example, only three databases were searched. However, the advantage of a scoping review is that it aims to map key concepts, main sources, types of evidence available, volume, nature and characteristics rapidly, especially in areas where less research has been conducted. In contrast to most systematic reviews, the scoping review included not only RCTs, but different methods and study designs, implicating that the literature is potentially described more broadly . In addiAnother limitation is that studies with certain disorder categories were excluded, for example eating disorders. One could argue this disorder would justify inclusion. Moreover, even though clear inclusion and exclusion criteria were drafted a priori, it was difficult to apply these criteria with a high degree of precision. Existing studies were often not explicitly based on concepts of clinical staging. Furthermore, the majority of the studies treated youth between the ages of 12 and 25 as two separate groups, contrary to our conceptualization of treating this age group as a whole. As a result, the identified articles varied in nature, population, methods, definitions and outcome measures, making it difficult to draw conclusions about online indicated preventive interventions for youth.A strength of this review is that we used a transparent methodological framework to find key trends in the literature, which potentially gives a preliminary basis for future systematic reviews. Further, the review identified important gaps in the existing literature. Lastly, to our knowledge, this review is the first in the past 5 years to shed light on indicated preventive mental health intervention for youth.Overall, high-quality investigations of the effectiveness of online indicated preventive interventions with follow-up data exceeding a few months for youth are missing. Further good quality research is needed to assess the effectiveness of the different online interventions using different therapeutic approaches. We suggest that researchers develop standardized definitions and instruments concerning subclinical symptoms in addition to clear definitions of “adherence.” Moreover, a gap in transdiagnostic approaches is evident; as well as research that has specifically targeted the adolescent population in the age range from 12 to 25 years, which crosses the divide between the child and adult mental healthcare systems. Future research should include clinical trials of indicated preventive interventions for youth between the ages of 12 and 25 based on the clinical staging model with a focus on transdiagnostic mechanisms.In order for effective online interventions to be implemented in large numbers of youth with emerging mental health issues, it is the authors' opinion that representatives of this youth should be involved in the development process of the interventions and the online platform . The platform should be adaptive and improve continuously in response to feedback, thereby enabling idiosyncratic or personalized support. The review also shows that there are many different platforms and online interventions. Uniformity could prevent reinventing the wheel and contribute to the improvement of quality over time, both of the interventions and platforms, through research and the sharing of experiences. Lastly, it is of importance to that these services are financially compensated on a structural basis, for example from governments to enable ongoing innovation and development and keep up with the fast pace of development of technology. This requires commitment of governments and participation of “offline” (in-person) care parties to improve blended online and offline care adjusted to the needs of young people at different time points during their development.MD, DN, ME, and KA completed initial study design. MD, ME, LN, KA, and ER assessed the provided articles. MD, ME, and LN made the final inclusion selection. DN, JDa, CM, AP, and TvA provided an expertise assessment and contributed extra articles to the scoping. The manuscript was written by MD, ME, and LN. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Peptide receptor radionuclide therapy (PRRT) is an emerging therapeutic option for the treatment of neuroendocrine tumors (NETs), and the number of publications in this field has been increasing in recent years. The aim of the present study was to present the research status and summarize the key topics through bibliometric analysis of published PRRT literature.Methods: A literature search for PRRT research from 2000 to 2019 was conducted using the Science Citation Index Expanded of Web of Science Core Collection (limited to SCIE) on August 4, 2020. The VOSviewer, R-bibliometrix, and CiteSpace software were used to conduct the bibliometric analysis.Results: From 2000 to 2019, a total of 681 publications (523 articles and 158 reviews) were retrieved. Annual publication outputs grew from three to 111 records. Germany had the largest number of publications, making the largest contribution to the field . Active cooperation between countries/regions was observed. Kwekkeboom from the Erasmus Medical Center is perhaps a key researcher in the field of PRRT. The European Journal of Nuclear Medicine and Molecular Imaging and Journal of Nuclear Medicine ranked first for productive  and co-cited  journals, respectively. Important topics mainly included matters related to the efficacy of PRRT , the long-term adverse effects of PRRT , standardization of NETs and PRRT in practice, the development of medical imaging techniques, and the individual dose optimization of PRRT.Conclusion: Using bibliometric analysis, we gained deep insight into the global status and trends of studies investigating PRRT for the first time. The PRRT field is undergoing a period of rapid development, and our study provides a valuable reference for clinical researchers and practitioners. Our search strategy was adapted from a recently published systematic review  as folloe = 2), time span (2000–2019), years per slice (1), links , selection criteria (Top N: top 50), and minimum duration (MD = 5). The data were managed using Microsoft Office Excel 2019 .The annual output (number of publications per year), publication languages, and document types of PRRT research were analyzed by the online data analysis function  of the WoSCC. Journal impact factors were obtained from the 2019 Journal Citation Reports . VOSviewer (1.6.15) was used to identify productive countries/regions , journals, main co-cited journals , and key references. The desired bibliometric maps were created. On the VOSviewer maps, different bubbles represent elements , while the size of the bubbles represents the number of publications or co-occurrence frequency. A line between two bubbles reflects the relationship, and the thickness of the lines reflects the strength of the relationship between the elements . In thisn = 111, 16.30%).We identified 681 publications associated with PRRT in the WoSCC from 2000 to 2019. Of these 681 publications, 523 (76.80%) were indexed as “article” and 158 (23.20%) as “review.” English was the predominant language for publications on PRRT, constituting 97.06% (661/681) of the total. The most common non-English language was German, which constituted 1.32% (9/681) of the total, followed by French , Spanish , Hungarian , and Polish . The annual publication outputs in the PRRT field are shown in n = 151), followed by the Netherlands (n = 142), the United States (n = 132), Italy (n = 106), England (n = 57), Switzerland (n = 48), and France (n = 39). The top 15 countries/regions were distributed across four continents, of which 11 were located in Europe (T = 15) were used to construct a country/region co-authorship network  had published papers on PRRT research. There were four journals with more than 20 publications, of which European Journal of Nuclear Medicine and Molecular Imaging  was the most productive journal publishing 84 scientific publications in the field, followed by Journal of Nuclear Medicine , Cancer Biotherapy and Radiopharmaceuticals , and Nuclear Medicine Communications . The top 12 journals with the greatest contribution to PRRT research accounted for 44.35% (302/681) of the total publications included in this study (T = 9) were used to construct the citation network map. As can be seen from European Journal of Nuclear Medicine and Molecular Imaging, Journal of Nuclear Medicine, Cancer Biotherapy and Radiopharmaceuticals, and Nuclear Medicine Communications had larger sized bubbles representing a higher number of publications. European Journal of Nuclear Medicine and Molecular Imaging had active citation relationships with Journal of Nuclear Medicine, Seminars in Nuclear Medicine, and Cancer Biotherapy and Radiopharmaceuticals.More than 200 scholarly journals , followed by European Journal of Nuclear Medicine and Molecular Imaging  and Journal of Clinical Oncology  (T = 241) were used to construct the co-citation network. As shown in Journal of Nuclear Medicine and European Journal of Nuclear Medicine and Molecular Imaging had larger bubbles due to higher co-citations, and Journal of Nuclear Medicine had active co-citation relationships with European Journal of Nuclear Medicine and Molecular Imaging and Journal of Clinical Oncology.When two journals are cited simultaneously in one or more publications, the two journals have a co-citation relationship . There w956, Q1) . JournalA dual-map overlay of journals was displayed using CiteSpace . The citJournal of Clinical Oncology had the highest number of co-citations   were used to construct the co-citation map. As shown in Journal of Clinical Oncology  , followeMedicine , Imhof eOncology , and RinOncology . The numOncology ” had theOncology ” and “Bo Imaging .”177Lu-DOTA0,Tyr3] octreotate: toxicity, efficacy, and survival” published in Journal of Clinical Oncology by Kwekkeboom et al. with citation burstness lasting from 2010 to 2016  and top 12 co-cited journals (58.33%), which indicated that the United States has considerable influence in this field. The dual-map overlay of journals analysis may provide a reference for beginners to conduct research in the field of PRRT. As for scholars in the PRRT research field, in the top 12 co-cited references, Kwekkeboom from Erasmus Medical Center published three papers  was published in 2008 by Kwekkeboom et al.  published in 2001  but was three- to fourfold higher in most tumors. In 2005, Kwekkeboom et al. presented the preliminary results of treatment with 177Lu-dotatate in 131 patients with GEP-NETs showing tumor remission in a high percentage of patients. The second co-cited publication (n = 140) was published in the New England Journal of Medicine by Strosberg et al. (177Lu-dotatate) in the United States and Europe was primarily based on the positive results of this multinational phase III clinical trial, which compared 177Lu-dotatate treatment with high doses of long-acting release octreotide. In 2011, Imhof et al. published the third co-cited reference in Journal of Clinical Oncology (n = 134). In this clinical phase II trial, patients with neuroendocrine cancers were treated with repeated cycles of 90Y-dotatoc. The results showed morphologic response and longer survival in 34.1 and 79% of the patients, respectively; meanwhile, hematologic and renal toxicity was reported in a small number of patients  and unlabeled somatostatin analogs. One of the results demonstrated in vitro that the somatostatin analog  octreotate had an approximately nine fold higher affinity for somatostatin receptor subtype 2 than  octreotide. The authors believed that these observations might represent basic principles relevant to the development of other peptide radioligands  compared to placebo . However, considering the bone marrow function of patients and the presence of risk factors for kidney toxicity, it seemed safer to divide cumulative activities into lower activity cycles (90Y-dotatoc and 177Lu-dotatate), adverse effects  of PRRT, epidemiologic characteristics, and other therapies  for NETs .Co-cited references represent how frequently two publications are cited together by other publications and may be regarded as a knowledge base of a specific field or subject . In our m et al. , which d in 2001  and 2005 in 2001 , respectg et al. . Approvapatients . Journale et al. . Unlike for NETs . The eigoligands . Yao et oligands , which eoligands , two otholigands . They we placebo . The ele placebo . The arty cycles . Based o177Lu or 90Y) or a combination of radioisotopes (177Lu and 90Y)  (177Lu-dotatate or 90Y-dotatoc. The article with the third highest citation burstness (strength = 8.2677) published by Villard et al. in 2012 evaluated the efficacy of PRRT with 90Y-dotatoc vs. 90Y-dotatoc plus 177Lu-dotatoc in patients with NETs, and results showed that the combination of radioisotopes was associated with improved overall survival compared with a single radioisotope , long-term adverse effects , standardization of NETs and PRRT in practice, development of medical imaging techniques, and individual dose optimization.Papers with high citation burstness can, to a certain extent, reflect the emerging trends or topics within a field . The topand 90Y) . Among tand 90Y) . The pub13–2017) . Simply oisotope . The fournatives . Neuroenced NETs . Finallyand safe . Five ofand safe . The guiand safe  issued band safe , where Pand safe . The fortic NETs . The sect decade . Given tt decade . The stut decade . The otht decade . Two artt decade . One stut decade . Individ213Bi and 225Ac) in PRRT. Therefore, there is still a need to observe the latest published achievements. Finally, all information was extracted using tools, so there are some issues that we encountered in our study that need attention . Despite these limitations, this study provides a solid global view on PRRT research from the last two decades.Our study has several strengths. First, the present study provided a deep insight into the global status and trends of research on PRRT using bibliometric analysis for the first time. Second, widely used tools were applied in our study, which assures the reliability of the data. Third, compared with traditional literature reviews, bibliometric analysis is relatively more objective and comprehensive. Nevertheless, this study should also be considered in light of several limitations, which are similar to other bibliometric analyses. First, we only surveyed publications in the WoSCC database; other databases, such as PubMed, Embase, and Cochrane library, were not searched, which may result in some omitted publications. However, it should be noted that the WoSCC is the most frequently used database for bibliometric analysis . Second,European Journal of Nuclear Medicine and Molecular Imaging and Journal of Nuclear Medicine ranked first in the productive journals and co-cited journals, respectively. The key research topics identified in our study included the efficacy and safety of PRRT, standardization of NETs and PRRT in practice, the development of medical imaging techniques, and individual dose optimization of PRRT. The topics regarding PRRT deserve continued following up by researchers, and we believe that our study provides a valuable reference for clinical researchers and practitioners.We used bibliometric analysis to provide a comprehensive overview of the research status of PRRT worldwide during the past two decades. The PRRT field is undergoing a period of rapid development and attracting increased attention from researchers. Germany ranked first for productivity and closely cooperated with other countries, such as the Netherlands and the United States. Kwekkeboom from Erasmus Medical Center is perhaps a key researcher in the field of PRRT.


The purpose of this study was to examine multiple direct and indirect pathways of the association between older age and mental health through COVID-19-related stress perceptions, meaning in life, and forgiveness of situations. Participants were 1,382 U.S. adults who were part of the Harvard Digital Lab for the Social Sciences panel who volunteered to complete a 12 min survey in the spring of 2020. The sample had an average age of 56 years, was slightly more male (55%) than female (44%) or other (2%), mostly White (88%), well-educated (70% bachelors degree or more), and middle-income . Measures included: COVID-19-related stress perceptions , presence of and search for meaning in life, forgiveness of situations, psychological distress, hopelessness, and optimism. A latent mental health variable was created that was comprised of psychological distress, hopelessness, and optimism. All hypothesized direct effects were in evidence, and all but one indirect effect were observed. Specifically, older age was related to better mental health through higher presence of meaning and lower search for meaning. Older age was also related to better mental health through a serial indirect pathway from lower COVID-19-related stress perceptions to higher presence of and lower search for meaning and higher forgiveness of situations to mental health. The proposed model was largely supported and confirms existing theory and research on aging, positive psychological processes, and mental health. Findings also offer new insights on the unique potential role of forgiveness of situations and its theoretical relevance to offending situations such as the COVID-19 pandemic. The present study offers a beginning for theorists, researchers, and practitioners to consider the connections between aging and mental health and the intricate interconnections between stress appraisal and positive coping resources that may serve to support it. The COVID-19 pandemic presents challenges in all walks of life for people around the world . This is an international panel of 16,000 volunteer respondents who participate in social science research. For the present study, a U.S. national sample of 1,382 respondents completed, on average, a 12 min survey between April 17, 2020 and July 17, 2020 that included multiple measures of health, psychosocial, religious and spiritual, and COVID-19-related stress perceptions and anxiety. Respondents provided their birth year. Birth year was subtracted from 2020 to obtain an individual's age. Although age was collected and computed in this continuous form, for the purposes of this study and special issue, we chose to focus on the differences between individuals 65 years of age and older compared to adults who were younger than 65.not at all) to 5 (extremely) response scale. Internal consistency for this scale in the present study was 0.67.COVID-19-related stress perceptions were assessed by asking respondents to indicate their levels of concern regarding four issues facing them in the pandemic. The issues included concerns about: oneself or one's family members being infected with the coronavirus, one's job, business, or personal finances, and running out of necessities like food, toilet paper, or medications. Each item was rated on a 1 (absolutely untrue) to 5 (absolutely true) response scale. Internal consistency of the presence and search subscales in the present study was 0.87 and 0.75, respectively.Meaning in life was assessed using four items from the Meaning in Life Questionnaire-Short Form  to 7 . Internal consistency for this scale in the present study was 82.Forgiveness of situations was assessed using a shortened form of the scale developed by Thompson et al. . Forgivenone of the time) to 3 (most of the time). The Kessler-6 is one of the most commonly used measures of psychological distress and has excellent psychometric properties  to 5 (strongly agree) response options. The scale has good construct validity and has been used in several population-based studies  to 4 (I agree a lot) response options. This scale is one of the most widely used measures of optimism and possesses excellent reliability and validity  included sex, race, education, and income and were included as covariates in the model.N = 1,000) as recommended by Hayes , root mean-square error of approximation (RMSEA), and standardized root mean residual (SRMR) and recommended by Kline  was 0.99. Model estimation was performed using maximum likelihood with full information maximum likelihood used to account for missing data. The Bollen-Stine χ2 statistic (p < 0.0001) indicated a significant departure from multivariate normality so robust, bootstrap-adjusted fit indices are reported. All reported parameter estimates controlled for biological sex, race, education, and income. Statistical significance was set at p < 0.05.Descriptive statistics and bivariate analyses were conducted. The hypothesized model was tested using the lavaan package in R. The lavaan package offers the ability to test the proposed serial mediation model and examine direct, indirect, and serial indirect effects. Indirect effects were tested using bias-corrected bootstrapped confidence intervals (by Hayes . Model fby Kline . Evidencby Kline . Power trs = −0.12 to −0.25), and more presence of meaning, forgiveness of situations, and optimism (rs = 0.08–0.26). More COVID-19-related stress perceptions was associated with less presence of meaning, forgiveness of situations, and optimism (rs = −0.12 to −0.37), and more search for meaning, psychological distress, and hopelessness (rs 0.18–0.53). More presence of meaning was associated with less search for meaning, psychological distress, and hopelessness (rs = −0.12 to −0.41), and more forgiveness of situations and optimism (rs = 0.32–0.46). Search for meaning was associated with more psychological distress and hopelessness (rs = 0.18–0.28) and less optimism (r = −0.14) but was unrelated to forgiveness of situations (r = −0.03). Forgiveness of situations was related to less psychological distress and hopelessness (rs −0.23 to −0.26) and more optimism (r = 0.38). Psychological distress was related to more hopelessness (r = 0.66) and less optimism (r = −0.54) and more hopelessness was related to less optimism (r = −0.58).2 = 52.39, p < 0.001; CFI = 0.99; RMSEA = 0.03; SRMR = 0.03. Participants age 65 and older showed less COVID-19-related stress perceptions , more presence of meaning , less search for meaning , no relation to forgiveness of situations , and better mental health . COVID-19-related stress perceptions was related to less presence of meaning , more search for meaning , less forgiveness of situations , and poorer mental health . Presence of meaning  and forgiveness of situations  were related to better, and search for meaning  was related to poorer mental health.The hypothesized serial mediation model was tested and results are summarized in B = 0.32, β = 0.04, 95% CI of B = 0.15–0.50). Participants age 65 and older experienced less COVID-19-related stress perceptions which was associated with less presence of meaning, and the indirect association was statistically significant . Participants age 65 and older experienced less COVID-19-related stress perceptions which was associated with more search for meaning, and the indirect association was statistically significant . Participants age 65 and older experienced less COVID-19-related stress perceptions which was associated with less forgiveness of situations, and the indirect association was statistically significant . Participants age 65 and older experienced more presence of meaning which was associated with better mental health, and the indirect association was statistically significant . Participants age 65 and older experienced less search for meaning which was associated with poorer mental health, and indirect association was statistically significant . Age was not associated with forgiveness of situations which was associated with better mental health, but the indirect association was not statistically significant .There are several indirect effects that are of interest in this study see . There wB = 0.04, β = 0.01, 95% CI of B = 0.02–0.07). Participants age 65 and older experienced less COVID-19-related stress perceptions which was associated with more search for meaning which was associated with poorer mental health, and this serial indirect association was statistically significant . Participants age 65 and older experienced less COVID-19-related stress perceptions which was associated with more forgiveness of situations which was associated with better mental health, and this serial indirect association was statistically significant .There were three serial (two-mediator) indirect associations to examine. Participants age 65 and older experienced less COVID-19-related stress perceptions which was associated with more presence of meaning which was associated with better mental health, and this serial indirect association was statistically significant (The present study sought to examine direct and indirect pathways through which older age was associated with better mental health during the height of the first wave of the COVID-19 pandemic in the United States from April 2020 to July 2020. Our results provide the first known data linking age, COVID-19-related stress perceptions, meaning and forgiveness, and mental health. Older age was directly associated with less COVID-19-related stress perceptions, less search for meaning, and more presence of meaning and forgiveness of situations, and better mental health. Of equal interest in this study was the indirect association of older age with mental health through single and serial indirect pathways. Older age was associated with better mental health through single indirect pathways including COVID-19-related stress perceptions as well as presence of and search for meaning, but not forgiveness of situations. Older age was associated with better mental health through serial indirect pathways including older age and less COVID-19-related stress perceptions as the first association and COVID-19-related stress perceptions and each of the meaning and forgiveness variables as the second association in which each of these, in turn, was associated with mental health. In the case of both direct and indirect associations, the associations demonstrated in this model provide theoretical confirmation and empirical basis for continued examination in future studies.More specifically, all of the hypothesized direct effects in this model were confirmed and were the most robust associations identified. Perhaps most importantly, the hypothesized direct associations between older age and lower COVID-19-related stress perceptions and better mental health were confirmed. This offers support for our theoretical model, grounded in lifespan theories Erikson, , suggestFindings from this study also support empirical research regarding meaning and forgiveness. That is, the present findings confirm that, compared to younger individuals, older individuals experience higher presence of and lower search for meaning (Steger et al., Testing the indirect associations of older age with mental health through COVID-19-related stress perceptions and meaning and forgiveness of situations revealed several unique findings. First, single-mediator models revealed that lower COVID-19-related stress perceptions and higher presence of and lower search for meaning all served as routes for indirect associations between older age and better mental health. The only hypothesized indirect effect that did not get supported was that older age was not connected to better mental health through higher levels of forgiveness of situations. Because this indirect association was being tested simultaneously with other indirect associations to mental health, this likely reflects the relative importance of meaning over forgiveness of situations in the context of the COVID-19 pandemic.Examination of the serial indirect associations included in the model showed that all three hypothesized associations were confirmed. Older age was associated with lower COVID-19-related stress perceptions which was associated with more presence of and less search for meaning, and more forgiveness of situations, and presence of meaning and forgiveness of situations were associated with better mental health while search for meaning was associated with poorer mental health. Confirming the existence of these three indirect pathways from older age to better mental health is important. These findings offer what might be initial evidence of a model of positive aging that emphasizes the role of stress perceptions and positive psychological processes that promote mental health. This model could be expanded to include other positive psychological states and traits likely to develop in older age such as wisdom and awe (Krause and Hayward, Limitations regarding sample, measurement, and design and analysis of this study should be considered. First, despite the Harvard DLABSS panel being a diverse one (Strange et al., The present study seeks to examine a model of older age, COVID-19-related stress perceptions, meaning and forgiveness, and mental health and better understand the multiple routes of connection that older age has to better mental health during the COVID-19 pandemic. The strongest routes are through reduced COVID-19-related stress perceptions and improved presence of meaning in life. However, more intricate connections do exist, and while smaller in magnitude, offer important avenues to consider in continued theoretical and empirical work. Furthermore, knowing that COVID-19-related stress perceptions and presence of meaning have been important mechanisms through which older adults might have experienced better mental health during the pandemic, and further, knowing that COVID-19-related stress perceptions and both meaning and forgiveness may act in direct, indirect and serial-indirect ways to promote mental health in older adults, it may be wise for gerontologists, counselors, and other practitioners to consider the implications of these findings, continue to observe theoretical and empirical developments in these areas, and envision how these findings may impact their own practice with older adults. As older adults continue to develop into one of the largest segments of our population and as the threat of more frequent pandemics in the future looms, all relevant tools for protecting vulnerable older adults from mental health impairments should come to the fore and be considered for possible use in the collection of tools for psychotherapeutic uses in these times. Of course, this will require further theoretical and empirical development, and we hope that the present study can serve as a beginning in that way.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation upon reasonable request.The studies involving human participants were reviewed and approved by Human Research Protection Program, Harvard University. Written informed consent was not provided because informed consent was obtained electronically in the electronic survey.DW and AC led data collection with all authors contributing to measure selection and survey development. AC cleaned, checked, and organized the database and codebook. LT performed the statistical analysis and wrote the first draft of the manuscript. All authors contributed to conception and design of the study, manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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