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This study aimed to assess the perception of the information provided about COVID-19 and the health protective behavior as potential factors of feelings of anxiety and happiness among the general population in Indonesia during the outbreak. We conducted an online survey using snowball sampling techniques. The online survey collected information about demographic data, self-report on information provision of COVID-19, health prevention behaviors, and feelings of anxiety and happiness. This study involved 3,686 participants from 33 provinces in Indonesia in the period from 2 nd of April to 4 th of April 2020. We found that the most frequent source of information reported was social media (91%), including WhatsApp, Instagram and Facebook. The majority of participants were satisfied with the amount of information provided (98%), however, 54% of the participants reported that no information or very little information about the screening/test and the treatment of COVID-19 was provided. With regard to health protective behaviors, 90% of participants reported that they implemented cough and sneezing etiquettes, 89% avoided handshakes, 84% applied physical distancing, 82% stayed at home, 78% were wearing a mask, 64% consumed multivitamins, 57% avoided touching the face, 51% did sun bathing, 45% did wash their hands, and 33% of participants exercised regular at home. High exposure of Information about COVID-19 and doing preventive measures were associated with greater anxiety. Nonetheless, some preventive measures appeared to be positively associated with feelings of happiness. Our results give an indications about the information provision, application of preventive measure and the factors associated with feelings of anxiety and happiness. This outcome can be valuable to formulate ways of information distribution and provision of psychological support for vulnerable groups during the COVID-19 pandemic.

The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [11C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [11C]PHNO binding potential relative to the non-displaceable component (BPND) in all regions examined (16–28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BPND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BPND was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [11C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development.

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [ 11 C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [ 18 F]BCPP-EF, and the presynaptic vesicular protein SV2A with [ 11 C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ −28%) and SV2A (≥ −25%) radioligand binding, brain volume (≥ −23%), and CBF (≥ −26%). [ 18 F]BCPP-EF PET MC1 binding (≥ −12%) and brain volumes (≥ −5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.

Funder: Medical Research Council; FundRef: https://doi.org/10.13039/501100000265, INTRODUCTION: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. METHODS: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. RESULTS: Following sodium acetate administration, 2.5-6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. CONCLUSIONS: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

BACKGROUND University students are susceptible to excessive stress. A web-based stress management intervention holds promise to improve stress but is still at a novel stage in Indonesia. OBJECTIVE The aim of this paper was to report the feasibility of the intervention we developed—Rileks—among university students in Indonesia in terms of acceptability and usability, and to propose recommendations for future improvements. METHODS A single-group pretest and posttest design was used. Participants with scores of 15 or higher on the stress subscale of the 42-item Depression Anxiety Stress Scales were given access to the intervention (N=68). The main outcome measures were the 8-item Client Satisfaction Questionnaire (CSQ-8) score, the System Usability Scale (SUS) score, and intervention uptake. Participants’ experience in each session was evaluated using closed- and open-ended questions for future improvements. Descriptive statistics were used to examine primary outcome and qualitative session evaluations. Participants’ responses to each topic of the open questions were summarized. RESULTS The intervention was evaluated as being satisfactory (CSQ-8 mean score 21.89, SD 8.72; range 8-32). However, the intervention’s usability was still below expectation (SUS mean score 62.8, SD 14.74; range 0-100). The core modules were completed by 10 out of 68 participants (15%), and the study dropout rate was 63% (43/68) at postassessment. In general, the module content was rated positively, with some notes for improvement covering content and technical aspects. CONCLUSIONS This study indicates that Rileks is potentially feasible for Indonesian university students. In order to be optimally applied in such a context and before scaling up web-based interventions in Indonesia, in general, further development and refinement are needed. INTERNATIONAL REGISTERED REPORT RR2-10.2196/11493

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand 18F-BCPP-EF. Here we evaluate the test–retest reproducibility of 18F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio – SUVR). Thirty healthy volunteers had a 90-min dynamic 18F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test–retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (VT). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test–retest variability of VT ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test–retest variability in the range 2%–7%. SUVR-1 was highly correlated with DVR-1 (r2 = 0.97, n = 30). In conclusion, 18F-BCPP-EF has suitable test–retest reproducibility and can be used to quantify MC-I in clinical studies.

PurposeIntegrin αvβ6belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [18F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αvβ6in rodent lung to support human translational studies.MethodsThe synthesis of [18F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αvβ6antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software.Results[18F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [18F]FB-A20FMDV2 with a molar activity of up to 150 GBq/μmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [18F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30–60 min post-administration of [18F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 μSv/MBq.Conclusion[18F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvβ6 integrin occupancy in lung. The effective dose, extrapolated from rodent data, is in line with typical values for compounds labelled with fluorine-18 and combined with the novel fully automated and GMP-compliant synthesis and allows for clinical use in translational studies.

PurposeThe RGD-integrin, αvβ6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFβ). This study sought to quantify expression of αvβ6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvβ6-selective [18F]FB-A20FMDV2 PET ligand.Methods[18F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease. Standard uptake values (SUV) and volume of distribution (VT) were used to quantify αvβ6 expression. In subjects with fibrotic lung disease, qualitative assessment of the relationship between αvβ6 expression and the distribution of fibrosis on high resolution computed tomography was conducted.ResultsA total of 15 participants (6 healthy, 7 with idiopathic pulmonary fibrosis (IPF) and 2 with connective tissue disease (CTD) associated PF) were enrolled.VTand SUV of [18F]FB-A20FMDV2 were increased in the lungs of subjects with pulmonary fibrosis (PF) compared with healthy subjects. Geometric meanVT(95% CI) was 0.88 (0.60, 1.29) mL/cm3for healthy subjects, and 1.40 (1.22, 1.61) mL/cm3for subjects with IPF; and SUV was 0.54 (0.36, 0.81) g/mL for healthy subjects and 1.03 (0.86, 1.22) g/mL for subjects with IPF. The IPF/healthyVTratio (geometric mean, (95% CI of ratio)) was 1.59 (1.09, 2.32) (probability ratio > 1 = 0.988)) and the SUV ratio was 1.91 (1.27, 2.87) (probability ratio > 1 = 0.996). Increased uptake of [18F]FB-A20FMDV2 in PF was predominantly confined to fibrotic areas. [18F]FB-A20FMDV2 measurements were reproducible at an interval of 2 weeks. [18F]FB-A20FMDV2 was safe and well tolerated.ConclusionsLung uptake of [18F]FB-A20FMDV2, a measure of expression of the integrin αvβ6, was markedly increased in subjects with PF compared with healthy subjects.

Current synaptic vesicle 2A (SV2A) positron emission tomography (PET) imaging agents include the nanomolar affinity probes [11C]UCB-J and [18F]UCB-H derived from the anti-epileptic drug levitaracetam (Keppra®). An industry-utilized “de-risking” approach was used to carry out initial pharmacological characterization and to assess potential next-generation candidates amenable to F-18 radiolabeling for preliminary evaluation. Radioligand binding methods were employed in mammalian brain homogenates to determine the SV2A affinity (Kd) and maximal binding capacity (Bmax) of [3H]UCB-J. Novel leads were then screened to identify compounds minimally with comparable binding affinities with UCB-J in order to select a F-18-labeled candidate for subsequent in vivo assessment in rat. In parallel, mammalian brain tissue section autoradiography was performed to assess specific SV2A distribution. [3H]UCB-J bound with high affinity to a single population of sites in the rat brain (Kd = 2.6 ± 0.25 nM; Bmax = 810 ± 25 fmol/mg protein) and control human cortex (Kd = 2.9 ± 0.54 nM; Bmax = 10,000 ± 640 fmol/mg protein). Distribution of specific SV2A binding was shown to be homogeneous throughout the rodent brain and primarily in gray matter regions of rodent and human brain sections. Analog screening identified MNI-1038, MNI-1126/SDM-8, and SDM-2 as having comparable binding affinities with the currently available PET ligands. Subsequent [18F]MNI-1126/[18F]SDM-8 dynamic micro-PET imaging in rats revealed in vivo uptake and accumulation in the brain with favorable kinetics. Chase studies using 30 mg/kg levetiracetam confirmed that in vivo brain uptake of [18F]MNI-1126/[18F]SDM-8 was reversible. Taken together, these data suggest [18F]MNI-1126/[18F]SDM-8 (since renamed as [18F]SynVesT-1) characterized via an in vitro screening cascade provided a measurable in vivo SV2A specific signal in the rodent brain. This tracer as well as the close analog [18F]SDM-2 (since renamed as [18F]SynVesT-2) is currently undergoing further evaluation in preclinical and clinical studies.

Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 hours after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 minutes, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum)-1. BPNDfrontal = 1- (BPNDfrontalpost-dose/ BPNDfrontalbaseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal . Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13 % (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson’s disease is enabled.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field. Results: This commentary of highlights has resulted in 19 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

1.ABSTRACTBackgroundSynaptic loss and neurite dystrophy are early events in Alzheimer’s Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo.MethodsMRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes.ResultsThe AD patients showed expected relative decreases in regional brain volumes (range, -6 to - 23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 × 10−9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD.ConclusionsWe interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease-associated differences and the feasibility of measuring FISO on commercially available imaging systems makes it a potential surrogate for pathology related to synapse loss that could be used to support early-stage evaluations of novel therapeutics for AD.

Background University students are susceptible to excessive stress. A web-based stress management intervention holds promise to improve stress but is still at a novel stage in Indonesia. This present paper reports the feasibility of the intervention we developed ( ‘Rileks’ ) among university students in Indonesia in terms of acceptability and usability, and to propose recommendations for future improvements. Methods A single-group pre-test and post-test design was used. Participants with DASS-42 Stress scale score ≥ 15 were given access to the intervention (N= 68). The main outcome measures were the Client Satisfaction Questionnaire-8 (CSQ-8), the System Usability Scale (SUS), and intervention uptake. Participants’ experience in each session was evaluated using closed and open-ended questions for future improvements. Descriptive statistics were used to examine primary outcome and qualitative session evaluations. Participants’ responses to each topic of the open questions were summarized. Results The intervention was evaluated as being satisfactory (CSQ-8 average score 21.89 (SD 8.72), range 8-32). However, the intervention’s usability was still below expectation (SUS average score 62.8 (SD 14.74), range 0-100). The core modules were completed by 10 participants (14.7%) and the study drop out rate was 63.23% at post-assessment. The module content was rated generally positively with some notes for improvement covering content and technical aspects. Conclusions The study indicates that Rileks is potentially feasible for Indonesian university students. In order to be optimally applied in such context and before scaling up web-based intervention in general in Indonesia a further development and refinement are needed.

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R (≤ 27%) and regional decreases in MC1 (≥ -28%), SV2A (≥ -25%), brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 density (≥ -12%) and brain volumes (≥ -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful.

The Covid-19 pandemic has significant consequences for the many self-help psychoeducational programs for patients with cancer (symptoms), especially in Low-Middle-Income Countries. We recommend several measures to adapt these programs to the COVID-19 era, such as the use of mobile versions, the addition of preventive measures to be taken by health care providers and patients concerning a hospital visit and the inclusion of psychological advice for coping with COVID-19 related stress. In this way, the double task of preventing the (progression of the) target disease and a contamination by COVID-19 might be optimally fulfilled.

Background: Delay in the diagnosis of breast cancer (BC) may lead to an advanced stage of the disease and a poor prognosis. A psychoeducational intervention can be crucial in helping women with BC symptoms complete the examination procedures and reduce diagnosis delay of BC. Objective: To develop a psychoeducational intervention to reduce the delay of BC diagnosis among Indonesian women with BC symptoms. Methods: The development of the intervention included an inventory of crucial elements in developing psychoeducation through literature review as well as consultation with BC patients and healthcare providers. Additionally, we developed PERANTARA as the first pilot version of the self-help guided psychoeducational intervention. PERANTARA is an abbreviation for "Pengantar Perawatan Kesehatan Payadura", which means an introduction to breast health treatment. The pilot feasibility study combined an expert review and a pilot testing in hospital settings. A semi-structured interview and the client satisfaction inventory were utilized to measure feasibility and acceptability of the intervention for Indonesian women with BC symptoms. Results: PERANTARA contained an oncologist's explanation about BC and the BC survivors' testimony to reduce the time to diagnosis. The pilot study results showed that most patients were satisfied with and trusted on PERANTARA. Conclusion: PERANTARA was feasible and acceptable for Indonesian patients with BC symptoms. The development framework suggested in this study can be applied to develop psychoeducational packages for other patients group, in particular, those interventional packages aimed at reducing diagnosis and treatment delays and non-adherence.

Background There is an increasing prevalence of mental health problems among university student populations. In Indonesia, treatment rates are low among university students because of the high cost of treatment, stigma and the limited availability of mental care services. Internet-based interventions have been found to be effective in treating anxiety and depression in Western countries. However, little is known about the effectiveness of Internet-based interventions in low- and middle-income countries (LMICs) such as Indonesia. In this paper, we describe how we culturally adapted an Internet-based intervention to meet the needs of Indonesian students with depression and anxiety based on the theoretical framework of Barrera et al. (2013). Method We culturally adapted a Western Internet-based student intervention for depression and anxiety. This intervention consists of 8 guided online sessions. 50 students from Universitas Gadjah Mada Yogyakarta who have mild to moderate depression or anxiety as assessed with the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), will participate in a feasibility study in which we will test participants' satisfaction, system usability and uptake. Secondary outcomes include assessment of participants' depression, anxiety and quality of life. Outcomes will be measured pre and post intervention. Discussion The present paper presents the protocol of a pilot study aimed at assessing the feasibility and acceptability of a culturally adapted intervention for Indonesian university students with depression and anxiety. The results from the feasibility study will further guide the development of the intervention and may inform the protocol of a future randomized controlled trial (RCT) examining the effectiveness of the Internet-based intervention., Highlights • The first Internet-based intervention to target university student population in low-and middle-income countries with depression and anxiety. • A systematic pilot study protocol to assess the feasibility and acceptability of a culturally adapted Internet-based intervention. • This study has involved end users in the cultural adaptation of the Internet-based intervention.

Objectives: To explore the test-retest reliability of the composite time trade-off (C-TTO) and discrete choice experiment (DCE) used in the Indonesian five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) valuation study. Methods: A representative sample aged 17 years and older was recruited from the Indonesian general population by stratified quota sampling with respect to residence, sex, and age. Trained interviewers conducted computer-assisted face-to-face interviews using the EuroQol valuation technology. Each respondent valued 10 health states using C-TTO and 7 pairs of health states in a DCE exercise. The retest interview was conducted after 2 weeks by the same interviewer. The Wilcoxon matched-pairs signed-rank test, intraclass correlation coefficient, and multilevel regression were applied in comparing the C-TTO test and retest data. For DCE, the analysis of proportions was used. Results: A total of 226 respondents with characteristics similar to the Indonesian population completed the retest interview. For C-TTO, 82 (95.3%) of 86 health states had no significant mean value differences between test and retest. The mean value of the second test was statistically significantly higher than that of the first test by 0.042. For DCE, 72.5% of responses were identical. DCE retest showed a different pattern concerning the relative importance of the dimensions, whereas the C-TTO remained the same. Conclusions: C-TTO is stable over time, whereas in DCE the relative values of the dimensions shift. The results support the use of the C-TTO, in particular the Indonesian EQ-5D-5L value set, and suggest a critical examination of the reliability of DCE results over time.

Background University students with depression and anxiety do not easily receive or seek treatment; therefore, internet-based interventions have been suggested to be a promising way to improve treatment accessibility and availability. However, it has not been examined whether a guided, culturally adapted, transdiagnostic, internet-based intervention is effective for treating symptoms of depression, anxiety, or both among university students in Indonesia. Objective This study aims to investigate the feasibility (acceptability and satisfaction, usability, and uptake) of a guided, culturally adapted, transdiagnostic, internet-based intervention among university students with symptoms of depression, anxiety, or both in Indonesia. Methods Students from Universitas Gadjah Mada, Yogyakarta, Indonesia, were screened for symptoms of depression, anxiety, or both, and filled online informed consent, demographic questionnaires, and a quality of life measure at pretreatment assessment (T0). Subsequently, the participants started the intervention. Seven weeks after T0, the primary outcomes of this feasibility study were analyzed at posttreatment assessment (T1) using the 8-item Client Satisfaction Questionnaire (CSQ-8) and the System Usability Scale (SUS). Mean and SDs for the CSQ-8 and SUS were calculated to examine feasibility. Within-group secondary outcomes (depression, anxiety, and quality of life) were inspected for outliers and normal distribution. Paired-sample t tests were used to investigate differences between time points of secondary outcomes. A mixed-method approach of quantitative and qualitative analyses was adopted. Both the primary and secondary outcomes were additionally explored with an individual semistructured interview and synthesized descriptively. Results A total of 50 participants completed the intervention. We found a moderate to high level of satisfaction and acceptability, a slightly below-average level of desirable usability (≥70), and an adherence rate of 52% which was higher than expected given the novelty of the intervention. Results for the secondary outcomes indicated a decrease in depression and anxiety. For depression, the overall mean difference between the 2 time points for depression was 3.92 (95% CI 2.75-5.1; Hedges g 1.15; P Conclusions A culturally adapted, transdiagnostic, internet-based intervention appears to be acceptable and feasible for reducing symptoms of depression, anxiety, or both, and increasing quality of life in university students in Indonesia. Future studies should include a randomized controlled trial to assess the effectiveness of such interventions as they may supplement existing counseling services in universities, reduce the treatment costs, and maximize treatment accessibility in low-resourced settings. International Registered Report Identifier (IRRID) RR2-10.1016/j.invent.2018.11.002

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand (18)F-BCPP-EF. Here we evaluate the test–retest reproducibility of (18)F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio – SUVR). Thirty healthy volunteers had a 90-min dynamic (18)F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test–retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (V(T)). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test–retest variability of V(T) ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test–retest variability in the range 2%–7%. SUVR-1 was highly correlated with DVR-1 (r(2) = 0.97, n = 30). In conclusion, (18)F-BCPP-EF has suitable test–retest reproducibility and can be used to quantify MC-I in clinical studies.

BACKGROUND University students with depression and anxiety do not easily receive or seek treatment; therefore, internet-based interventions have been suggested to be a promising way to improve treatment accessibility and availability. However, it has not been examined whether a guided, culturally adapted, transdiagnostic, internet-based intervention is effective for treating symptoms of depression, anxiety, or both among university students in Indonesia. OBJECTIVE This study aims to investigate the feasibility (acceptability and satisfaction, usability, and uptake) of a guided, culturally adapted, transdiagnostic, internet-based intervention among university students with symptoms of depression, anxiety, or both in Indonesia. METHODS Students from Universitas Gadjah Mada, Yogyakarta, Indonesia, were screened for symptoms of depression, anxiety, or both, and filled online informed consent, demographic questionnaires, and a quality of life measure at pretreatment assessment (T0). Subsequently, the participants started the intervention. Seven weeks after T0, the primary outcomes of this feasibility study were analyzed at posttreatment assessment (T1) using the 8-item Client Satisfaction Questionnaire (CSQ-8) and the System Usability Scale (SUS). Mean and SDs for the CSQ-8 and SUS were calculated to examine feasibility. Within-group secondary outcomes (depression, anxiety, and quality of life) were inspected for outliers and normal distribution. Paired-sample t tests were used to investigate differences between time points of secondary outcomes. A mixed-method approach of quantitative and qualitative analyses was adopted. Both the primary and secondary outcomes were additionally explored with an individual semistructured interview and synthesized descriptively. RESULTS A total of 50 participants completed the intervention. We found a moderate to high level of satisfaction and acceptability, a slightly below-average level of desirable usability (≥70), and an adherence rate of 52% which was higher than expected given the novelty of the intervention. Results for the secondary outcomes indicated a decrease in depression and anxiety. For depression, the overall mean difference between the 2 time points for depression was 3.92 (95% CI 2.75-5.1; Hedges g 1.15; Pg 1.02; Pg=0.50). Overall, participants were positive about the online intervention and ECoaches (online guidance), and they found the intervention to be culturally appropriate. CONCLUSIONS A culturally adapted, transdiagnostic, internet-based intervention appears to be acceptable and feasible for reducing symptoms of depression, anxiety, or both, and increasing quality of life in university students in Indonesia. Future studies should include a randomized controlled trial to assess the effectiveness of such interventions as they may supplement existing counseling services in universities, reduce the treatment costs, and maximize treatment accessibility in low-resourced settings. INTERNATIONAL REGISTERED REPORT RR2-10.1016/j.invent.2018.11.002

Objective: We investigated the effectiveness of a self-help intervention named PERANTARA, which aims to improve adherence to diagnostic procedures among women with breast cancer (BC) symptoms to reduce the time to a definitive diagnosis. Methods: With a cluster randomized crossover design across four hospitals, PERANTARA and treatment as usual (TAU) or TAU only was provided at successive periods in a randomly determined order. The main outcome was the time between the first medical consultation and the definitive diagnosis. Secondary outcomes were BC knowledge, measured by the Breast Cancer Knowledge Test (BCKT); symptoms of anxiety and depression, measured by the Hospital Anxiety and Depression Scale (HADS); quality of life, measured by the World Health Organization Quality of Life-BREF (WHOQOL-BREF); and health status, measured by the EQ-5D-5L. A linear mixed model analysis was conducted to analyse the outcomes. Results: We recruited 132 women with BC symptoms from four hospitals; 67 participants were in the intervention group, and 65 participants were in the control group. PERANTARA reduced the time to definitive diagnosis by 13.3 days (M [SD]: 25.90 [23.20] in the intervention group vs 39.29 [35.10] in the control group; mean difference = −13.26, 95% CI = −24.51 to −2.00, P =.02). No significant difference was found between the groups in BC knowledge, symptoms of anxiety, depression, quality of life, or health status. Conclusions: PERANTARA reduced the time to definitive diagnosis among Indonesian women with BC symptoms. Psychoeducation may be an important addition to regular BC care to prevent undue delays in diagnostic procedures.

18F labeling strategies for unmodified peptides with [18F]fluoride require 18F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C-H 18F-trifluoromethylation. We report a one-step route to [18F]CF3SO2NH4 from [18F]fluoride and its application to direct [18F]CF3 incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin. The fully automated radiosynthesis of octreotide[Trp(2-CF218F)] enables in vivo positron emission tomography imaging.

Background We measured whole body distribution of 11C-BU99008, a new PET biomarker for non-invasive identification of the imidazoline2 binding site. The purpose of this phase I study was to evaluate the biodistribution and radiation dosimetry of 11C-BU99008 in healthy human subjects. Methods A single bolus injection of 11C-BU99008 (296 ± 10.5 MBq) was administered to four healthy subjects who underwent whole-body PET/CT over 120 min from the cranial vertex to the mid-thigh. Volumes of interest were drawn around visually identifiable source organs to generate time-activity curves (TAC). Residence times were determined from time-activity curves. Absorbed doses to individual organs and the whole body effective dose were calculated using OLINDA/EXM 1.1 for each subject. Results The highest measured activity concentration was in the kidney and spleen. The longest residence time was in the muscle at 0.100 ± 0.023 h, followed by the liver at 0.067 ± 0.015 h and lungs at 0.052 ± 0.010 h. The highest mean organ absorbed dose was within the heart wall (0.028 ± 0.002 mGy/MBq), followed by the kidneys (0.026 ± 0.005 mGy/MBq). The critical organ was the heart wall. The total mean effective dose averaged over subjects was estimated to be 0.0056 ± 0.0004 mSv/MBq for an injection of 11C-BU99008. Conclusions The biodistribution of 11C-BU99008 has been shown here for the first time in humans. Our dosimetry data showed the total mean effective dose over all subjects was 0.0056 ± 0.0004 mSv/MBq, which would result in a total effective dose of 1.96 mSv for a typical injection of 350 MBq of 11C-BU99008. The effective dose is not appreciably different from those obtained with other 11C tracers.

The imidazoline2 binding site (I2BS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C-BU99008 has previously been identified as a putative PET radioligand. Here, we present the first in vivo characterization of this PET radioligand in humans and assess its test-retest reproducibility. Methods: Fourteen healthy male volunteers underwent dynamic PET imaging with 11C-BU99008 and arterial sampling. Six subjects were used in a test-retest assessment, and 8 were used in a pharmacologic evaluation, undergoing a second or third heterologous competition scan with the mixed I2BS/α2-adrenoceptor drug idazoxan (n = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid (n = 4; 50 mg). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure V T (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. Results: Brain uptake of 11C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment model was preferred. V T estimates were high in the striatum (105 ± 21 mL⋅cm-3), medium in the cingulate cortex (62 ± 10 mL⋅cm-3), and low in the cerebellum (41 ± 7 mL⋅cm-3). Test-retest reliability was reasonable. The uptake was dose-dependently reduced throughout the brain by pretreatment with idazoxan, with an average block across all regions of about 60% (V T, ∼30 mL⋅cm-3) at the highest dose (80 mg). The median effective dose for idazoxan was 28 mg. Uptake was not blocked by pretreatment with the monoamine oxidase inhibitor isocarboxazid. Conclusion: 11C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I2BS distribution, and good test-retest reliability.

The αvβ6 integrin is involved in the pathogenesis of cancer and fibrosis. A radiolabeled 20-amino-acid αvβ6-binding peptide, derived from the foot and mouth virus (NAVPNLRGDLQVLAQKVART [A20FMDV2]), has been developed to image αvβ6 levels preclinically. This study was designed to translate these findings into a clinical PET imaging protocol to measure the expression of αvβ6 in humans. Methods: Preclinical toxicology was undertaken, and a direct immunoassay was developed for 4-fluorobenzamide (FB)-A20FMDV2. Four healthy human subjects (2 male and 2 female) received a single microdose of 18F-FB-A20FMDV2 followed by a multibed PET scan of the whole body over more than 3 h. Results: There were no findings in the preclinical toxicology assessments, and no anti-A20FMDV2 antibodies were detected before or after dosing with the PET ligand. The mean and SD of the administered mass of 18F-FB-A20FMDV2 was 8.7 ± 4.4 μg (range, 2.7-13.0 μg). The mean administered activity was 124 ± 20 MBq (range, 98-145 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the subjects. No significant changes in vital signs, laboratory study results, or electrocardiography results were observed. Uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, kidneys, ureters, and bladder. Time-activity curves indicated that the highest activity was in the bladder content, followed by the kidneys, small intestine, stomach, liver, spleen, thyroid, and gallbladder. The largest component of the residence times was the voided urine, followed by muscle, bladder, and liver. Using the mean residence time over all subjects as input to OLINDA/EXM, the effective dose was determined to be 0.0217 mSv/MBq; using residence times from single subjects gave an SD of 0.0020 mSv/MBq from the mean. The critical organ was the urinary bladder, with an absorbed dose of 0.18 mGy/MBq. Conclusion:18F-FB-A20FMDV2 successfully passed toxicology criteria, showed no adverse effects in this first-in-humans study, and has an effective dose that enables multiple scans in a single subject.

The pharmaceutical industry is facing key challenges to improve return on R&D investment. Positron emission tomography (PET), by itself or in combination with complementary technologies such as magnetic resonance imaging (MRI), provides a unique opportunity to confirm a candidate's ability to meet the so-called 'three pillars' of drug development. Positive confirmation provides confidence for go/no-go decision making at an early stage of the development process and enables informed clinical progression. Whereas fluorine-18 has probably gained wider use in the community, there are benefits to using carbon-11 given the greater flexibility the use of this isotope permits in adaptive clinical study design. This review explores the scope of available carbon-11 chemistries and provides clinical examples to highlight its value in PET studies in support of drug development.

Background Breast cancer (BC) is the most frequent cancer occurring in women across the world. Its mortality rate in low-middle income countries (LMICs) is higher than in high-income countries (HICs), and in Indonesia BC is the leading cause of cancer deaths among women. Delay in breast cancer diagnosis negatively impacts cancer prognosis. Only about 30% of patients who come to the hospital to check on their breast abnormalities, continue thorough examination to biopsy to get a diagnosis based on the results of anatomical pathology. Many Indonesian women with breast cancer were already in an advanced stage when starting treatment. Therefore, delay in diagnosis is a serious problem that needs to be addressed. The present study will investigate whether our newly developed self-help psycho-educational programme, “PERANTARA”, for women with breast cancer symptoms is effective to reduce patient diagnosis delay in Indonesia. Methods A cluster-randomized controlled trial will be conducted in 106 patients in four hospitals in Bandung, West Java, Indonesia. Data will be collected at baseline (pre-assessment), 7 days after the intervention (post-assessment), and at 3 months (follow-up assessments). The primary outcome is delay in diagnosis and treatment. Secondary outcomes are breast cancer knowledge, anxiety and depression, and quality of life. Exploratively, adherence with treatment will be measured too. Data will be analysed by hierarchical linear modelling (HLM) to assess differential change over time. Discussion If proven effective, PERANTARA will be evaluated and implemented in a diversity of settings for local cares (such as in POSYANDU, PUSKESMAS) that provide health education/psycho-education for women with breast symptoms. Trial registration ISRCTN12570738. Date: November 19th, 2016. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3268-7) contains supplementary material, which is available to authorized users.

Objectives: The purpose of the present study was to determine whether pain is associated with specific aspects of academic performance, that is, poorer grades, and with factors critical to an adolescent's academic performance, that is, decreased emotional well-being and attention problems. We hypothesized that the association between pain and school grades is mediated by emotional well-being and attention problems. Methods: In a cross-sectional study, we collected data from 2215 pupils, ages 12 to 13 years. Pain (no, occasional, and frequent), emotional well-being, and attention problems were measured with self-rating scales. Dutch, English, and math grades were taken as an index of academic performance. Results: Frequent pain in adolescents was associated with poorer grades (Dutch P=0.02 and math P=0.01). Both occasional and frequent pain were associated with reduced emotional well-being (P

Background The EQ-5D is one of the most used generic health-related quality-of-life (HRQOL) instruments worldwide. To make the EQ-5D suitable for use in economic evaluations, a societal-based value set is needed. Indonesia does not have such a value set. Objective The aim of this study was to derive an EQ-5D-5L value set from the Indonesian general population. Methods A representative sample aged 17 years and over was recruited from the Indonesian general population. A multi-stage stratified quota method with respect to residence, gender, age, level of education, religion and ethnicity was utilized. Two elicitation techniques, the composite time trade-off (C-TTO) and discrete choice experiments (DCE) were applied. Interviews were undertaken by trained interviewers using computer-assisted face-to-face interviews with the EuroQol Valuation Technology (EQ-VT) platform. To estimate the value set, a hybrid regression model combining C-TTO and DCE data was used. Results A total of 1054 respondents who completed the interview formed the sample for the analysis. Their characteristics were similar to those of the Indonesian population. Most self-reported health problems were observed in the pain/discomfort dimension (39.66%) and least in the self-care dimension (1.89%). In the value set, the maximum value was 1.000 for full health (health state ‘11111’) followed by the health state ‘11112’ with value 0.921. The minimum value was −0.865 for the worst state (‘55555’). Preference values were most affected by mobility and least by pain/discomfort. Conclusions We now have a representative EQ-5D-5L value set for Indonesia. We expect our results will promote and facilitate health economic evaluations and HRQOL research in Indonesia. Electronic supplementary material The online version of this article (doi:10.1007/s40273-017-0538-9) contains supplementary material, which is available to authorized users.

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) e4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1–42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.

Mitochondrial complex 1 (MC1) is involved in maintaining brain bioenergetics, the sigma 1 receptor (σ1R) responds to neuronal stress and synaptic vesicle protein 2A (SV2A) reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here we characterise the kinetic behaviour of three positron emission tomography (PET) radioligands 18F-BCPP-EF, 11C-SA-4503 and 11CUCB- J, for the measurement of MC1, σ1R and SV2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans including associated arterial blood sampling with each radioligand. A range of kinetic models were investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All three radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution (VT) were multilinear analysis 1 (MA1) and the 2-tissue compartment (2TC) model for 18F-BCPP-EF, MA1 for 11C-SA- 4503, and both MA1 and the 1-tissue compartment (1TC) model for 11C-UCB-J. Acquisition times of 70, 80 and 60 minutes for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional VT values. An effect of age was observed on 18F-BCPP-EF and 11C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases.