ARAS: an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes.

BackgroundAutomated protocols for measuring and dispensing solutions containing radioisotopes are essential not only for providing a safe environment for radiation workers but also to ensure accuracy of dispensed radioactivity and an efficient workflow. For this purpose, we have designed ARAS, an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes with particular focus on fluorine-18 ((18)F).MethodsThe key to the system is the combination of a radiation detector measuring radioactivity concentration, in line with a peristaltic pump dispensing known volumes.ResultsThe combined system demonstrates volume variation to be within 5 % for dispensing volumes of 20 μL or greater. When considering volumes of 20 μL or greater, the delivered radioactivity is in agreement with the requested amount as measured independently with a dose calibrator to within 2 % on average.ConclusionsThe integration of the detector and pump in an in-line system leads to a flexible and compact approach that can accurately dispense solutions containing radioactivity concentrations ranging from the high values typical of [(18)F]fluoride directly produced from a cyclotron (~0.1-1 mCi μL(-1)) to the low values typical of batches of [(18)F]fluoride-labeled radiotracers intended for preclinical mouse scans (~1-10 μCi μL(-1))

Workload: friend or enemy? :The role of goal orientation for the appraisal of workload

In the research literature, workload is considered a challenging task requirement which can lead to both exhaustion and engagement. This study questions this a priori categorization and aims to provide more insight into the processes that relate workload to exhaustion and engagement. The first assumption holds that individuals’ appraisal of their workload determines whether workload will relate to engagement or exhaustion. It is also assumed that workers’ goal orientation will moderate the relationship between workload and appraisal. These assumptions were investigated in a cross-sectional study with 233 workers. The findings showed that hindrance appraisal was positively related to exhaustion while challenge appraisal was positively related to engagement. Moreover, learning goal orientation (GO) played a role; with workers high in learning GO appraising their workload as more challenging; an effect that sharply decreased with increasing workload. No moderating effect was found for performance-prove GO and performance-avoid GO. This research contributes to a better understanding of the role of appraisal processes in the relationship between workload and employee well-being. Implications for future research and practical implications are discussed

A Systematic Review and Meta-Analysis

Funding Information: A.P. received an educational grant from Cambrooke Therapeutics and grants from Vitaflo International, Nutricia, Merck Serono, Biomarin, Mevalia and Applied Pharma Research to attend scientific meetings. This project is also part of A.P’s. PhD, which is funded by Vitaflo International. J.C.R. was a member of the European Nutritionist ExpertPanel (Biomarin), the Advisory Board for Applied Pharma Research, Vitaflo, Synlogic, Biomarin and Nutricia, and received honoraria as speaker from APR, Merck Serono, Biomarin, Nutricia, Vitaflo, Cambrooke, PIAM and Lifediet. A.M. has received research funding and honoraria from Danone Nutricia, Vitaflo International, Biomarin, MetaX, Applied Pharma Research, and Merck Serono; she is a member of the advisory board for Danone Nutricia, Arla, and Applied Pharma Research. The remaining authors declare no conflicts of interest. ® Publisher Copyright: © 2023 by the authors.In phenylketonuria (PKU), natural protein tolerance is defined as the maximum natural protein intake maintaining a blood phenylalanine (Phe) concentration within a target therapeutic range. Tolerance is affected by several factors, and it may differ throughout a person’s lifespan. Data on lifelong Phe/natural protein tolerance are limited and mostly reported in studies with low subject numbers. This systematic review aimed to investigate how Phe/natural protein tolerance changes from birth to adulthood in well-controlled patients with PKU on a Phe-restricted diet. Five electronic databases were searched for articles published until July 2020. From a total of 1334 results, 37 articles met the eligibility criteria (n = 2464 patients), and 18 were included in the meta-analysis. The mean Phe (mg/day) and natural protein (g/day) intake gradually increased from birth until 6 y (at the age of 6 months, the mean Phe intake was 267 mg/day, and natural protein intake was 5.4 g/day; at the age of 5 y, the mean Phe intake was 377 mg/day, and the natural protein intake was 8.9 g/day). However, an increase in Phe/natural protein tolerance was more apparent at the beginning of late childhood and was >1.5-fold that of the Phe tolerance in early childhood. During the pubertal growth spurt, the mean natural protein/Phe tolerance was approximately three times higher than in the first year of life, reaching a mean Phe intake of 709 mg/day and a mean natural protein intake of 18 g/day. Post adolescence, a pooled analysis could only be performed for natural protein intake. The mean natural protein tolerance reached its highest (32.4 g/day) point at the age of 17 y and remained consistent (31.6 g/day) in adulthood, but limited data were available. The results of the meta-analysis showed that Phe/natural protein tolerance (expressed as mg or g per day) increases with age, particularly at the beginning of puberty, and reaches its highest level at the end of adolescence. This needs to be interpreted with caution as limited data were available in adult patients. There was also a high degree of heterogeneity between studies due to differences in sample size, the severity of PKU, and target therapeutic levels for blood Phe control.publishersversionpublishe

Long-Term Growth in Phenylketonuria: A Systematic Review and Meta-Analysis

There is an ongoing debate regarding the impact of phenylketonuria (PKU) and its treatment on growth. To date, evidence from studies is inconsistent, and data on the whole developmental period is limited. The primary aim of this systematic review was to investigate the effects of a phenylalanine (Phe)-restricted diet on long-term growth in patients with PKU. Four electronic databases were searched for articles published until September 2018. A total of 887 results were found, but only 13 articles met eligibility criteria. Only three studies had an adequate methodology for meta-analysis. Although the results indicate normal growth at birth and during infancy, children with PKU were significantly shorter and had lower weight for age than reference populations during the first four years of life. Impaired linear growth was observed until the end of adolescence in PKU. In contrast, growth impairment was not reported in patients with mild hyperphenylalaninemia, not requiring dietary restriction. Current evidence indicates that even with advances in dietary treatments, "optimal" growth outcomes are not attained in PKU. The majority of studies include children born before 1990s, so further research is needed to show the effects of recent dietary practices on growth in PKU.info:eu-repo/semantics/publishedVersio

Gene expression plasticity across hosts of an invasive scale insect species

For plant-eating insects, we still have only a nascent understanding of the genetic basis of host-use promiscuity. Here, to improve that situation, we investigated host-induced gene expression plasticity in the invasive lobate lac scale insect, Paratachardina pseudolobata (Hemiptera: Keriidae). We were particularly interested in the differential expression of detoxification and effector genes, which are thought to be critical for overcoming a plant's chemical defenses. We collected RNA samples from P. pseudolobata on three different host plant species, assembled transcriptomes de novo, and identified transcripts with significant host-induced gene expression changes. Gene expression plasticity was pervasive, but the expression of most detoxification and effector genes was insensitive to the host environment. Nevertheless, some types of detoxification genes were more differentially expressed than expected by chance. Moreover, we found evidence of a trade-off between expression of genes involved in primary and secondary metabolism; hosts that induced lower expression of genes for detoxification induced higher expression of genes for growth. Our findings are largely consonant with those of several recently published studies of other plant-eating insect species. Thus, across plant-eating insect species, there may be a common set of gene expression changes that enable host-use promiscuity

PRIMMO study protocol : a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer

Background: Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature.In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement.We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. Methods: PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma.Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6cycles. Radiation (3x8Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose.The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity.The primary objective is objective response rate at week 26 according to immune-related response criteria.Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life.Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. Discussion: In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. Trial registration: EU Clinical Trials Register: EudraCT 2016-001569-97, registered on 19-6-2017. Clinicaltrials.gov: NCT03192059, registered on 19-6-2017

Decreased Doublecortin (DCX) immunoreactivity in hippocampus after profound sensorineural hearing loss and vestibular dysfunction in adult mice

Objective: sensorineural hearing loss (SNHL) and bilateral vestibulopathy (BV) have been associated with cognitive decline and incident dementia. Our aim was to investigate the combined effect of profound SNHL and BV on spatial cognition and hippocampal neurogenesis in adult mice. Methods: Single oral intake of allylnitrile produces otovestibular failure in less than a week. Behavioral assessment included recording of spontaneous activity, motor activity, spatial cognition, etc. Evaluation of hippocampal neurogenesis was performed 8 weeks after treatment by quantification of neural precursor cells and proliferating cells in the dentate gyrus by staining with doublecortin (Dcx) and Ki67, respectively. Results: Profound SNHL and BV were confirmed in the allylnitrile-treated mice respectively by means of auditory brainstem response (ABR) and acoustic startle response, and several vestibular tests. Spatial cognitive deficits, i.e. higher latency to target, were observed with the Barnes maze. In the right hemisphere, no statistically significant difference was observed between groups. In the left hemisphere, the difference in mean cell densities of Dcx positive cells was statistically significant when compared to the control group, whereas the difference in mean cell density of Ki67 positive cells did not differ significantly. Conclusion: Spatial cognitive deficits and decreased immunoreactivity to DCX in the left hippocampus were observed 8 weeks after adult mice acquired profound SNHL and BV

Characterisation of tetraspanins from Schistosoma haematobium and evaluation of their potential as novel diagnostic markers

Schistosoma haematobium is the leading cause of urogenital schistosomiasis and it is recognised as a class 1 carcinogen due to the robust association of infection with bladder cancer. In schistosomes, tetraspanins (TSPs) are abundantly present in different parasite proteomes and could be potential diagnostic candidates due to their accessibility to the host immune system. The large extracellular loops of six TSPs from the secretome (including the soluble excretory/secretory products, tegument and extracellular vesicles) of S. haematobium (Sh-TSP-2, Sh-TSP-4, Sh-TSP-5, Sh-TSP-6, Sh-TSP-18 and Sh-TSP-23) were expressed in a bacterial expression system and polyclonal antibodies were raised to the recombinant proteins to confirm the anatomical sites of expression within the parasite. Sh-TSP-2, and Sh-TSP-18 were identified on the tegument, whereas Sh-TSP-4, Sh-TSP-5, Sh-TSP-6 and Sh-TSP-23 were identified both on the tegument and internal tissues of adult parasites. The mRNAs encoding these TSPs were differentially expressed throughout all schistosome developmental stages tested. The potential diagnostic value of three of these Sh-TSPs was assessed using the urine of individuals (stratified by infection intensity) from an endemic area of Zimbabwe. The three Sh-TSPs were the targets of urine IgG responses in all cohorts, including individuals with very low levels of infection (those positive for circulating anodic antigen but negative for eggs by microscopy). This study provides new antigen candidates to immunologically diagnose S. haematobium infection, and the work presented here provides compelling evidence for the use of a biomarker signature to enhance the diagnostic capability of these tetraspanins

Intercontinental distributions, phylogenetic position and life cycles of species of Apharyngostrigea (Digenea, Diplostomoidea) illuminated with morphological, experimental, molecular and genomic data

When subjected to molecular study, species of digeneans believed to be cosmopolitan are usually found to consist of complexes of species with narrower distributions. We present molecular and morphological evidence of transcontinental distributions in two species of Apharyngostrigea Ciurea, 1924, based on samples from Africa and the Americas. Sequences of cytochrome c oxidase I and, in some samples, internal transcribed spacer, revealed Apharyngostrigea pipientis (Faust, 1918) in Tanzania (first known African record), Argentina, Brazil, USA and Canada. Sequences from A. pipientis also match previously published sequences identified as Apharyngostrigea cornu (Zeder, 1800) originating in Mexico. Hosts of A. pipientis surveyed include definitive hosts from the Afrotropic, Neotropic and Nearctic, as well as first and second intermediate hosts from the Americas, including the type host and type region. In addition, metacercariae of A. pipientis were obtained from experimentally infected Poecilia reticulata, the first known record of this parasite in a non-amphibian second intermediate host. Variation in cytochrome c oxidase I haplotypes in A. pipientis is consistent with a long established, wide-ranging species with moderate genetic structure among Nearctic, Neotropic and Afrotropic regions. We attribute this to natural dispersal by birds and find no evidence of anthropogenic introductions of exotic host species. Sequences of CO1 and ITS from adult Apharyngostrigea simplex (Johnston, 1904) from Egretta thula in Argentina matched published data from cercariae from Biomphalaria straminea from Brazil and metacercariae from Cnesterodon decemmaculatus in Argentina, consistent with previous morphological and life-cycle studies reporting this parasite—originally described in Australia—in South America. Analyses of the mitochondrial genome and rDNA operon from A. pipientis support prior phylogenies based on shorter markers showing the Strigeidae Railliet, 1919 to be polyphyletic.Facultad de Ciencias Naturales y MuseoCentro de Estudios Parasitológicos y de Vectore

The Impact of Age and Phenylketonuria Severity

Funding Information: A.P. received an educational grant from Cambrooke Therapeutics and Biomarin and grants from Vitaflo International, Nutricia, Merck Serono, Biomarin, Mevalia, Galen, PIAM, and Applied Pharma Research to attend scientific meetings. This project is also part of A.P.\u2019s PhD, which is funded by Vitaflo International. A.D. received research funding from Vitaflo International and financial support from Nutricia, Mevalia, and Vitaflo International to attend study days and conferences. J.C.R. was a member of the European Nutritionist Expert Panel (Biomarin) and the Advisory Board for Applied Pharma Research, Vitaflo, Synlogic, Biomarin, and Nutricia and received honoraria as a speaker from APR, Merck Serono, Biomarin, Nutricia, Vitaflo, Cambrooke, PIAM, and Lifediet. S.E. received research funding and financial support to attend study days and conferences from both Nutricia and Vitaflo International. C.A. received honoraria from Nutricia and Vitaflo International to attend study days and conferences. A.M. received research funding and honoraria from Nutricia, Vitaflo International, and Biomarin. She is a member of the Advisory Board Element (Danone-Nutricia). F.F. was a member of the Advisory Board for Vitaflo, Biomarin, Chiesi, Sanofi-Genzyme, and Nutricia and received honoraria as a speaker from Recordati, Biomarin, Merck Serono, Vitaflo, Travere Therapeutics, PTC Therapeutics, Lucane, and Alexion. M.G. received financial support and honoraria as a speaker from Biomarin, Nutricia, Vitaflo, Nestl\u00E9 Polska, Mead-Johnson, PTC Therapeutics International, and APR Applied Pharma Research. The remaining authors do not have any conflicts of interest. The funders had no role in the design of this study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results. Publisher Copyright: © 2024 by the authors.In phenylketonuria (PKU), natural protein intake is thought to increase with age, particularly during childhood and adolescence. Longitudinal dietary intake data are scarce and lifelong phenylalanine tolerance remains unknown. Nine centres managing PKU in Europe and Turkey participated in a retrospective study. Data were collected from dietetic records between 2012 and 2018 on phenylalanine (Phe), natural protein, and protein substitute intake. A total of 1323 patients (age range: 1–57 y; 51% male) participated. Dietary intake data were available on 1163 (88%) patients. Patient numbers ranged from 59 to 320 in each centre. A total of 625 (47%) had classical PKU (cPKU), n = 357 (27%) had mild PKU (mPKU), n = 325 (25%) had hyperphenylalaninemia (HPA), and n = 16 (1%) were unknown. The mean percentage of blood Phe levels within target ranged from 65 ± 54% to 88 ± 49%. When intake was expressed as g/day, the mean Phe/natural protein and protein equivalent from protein substitute gradually increased during childhood, reaching a peak in adolescence, and then remained consistent during adulthood. When intake was expressed per kg body weight (g/kg/day), there was a decline in Phe/natural protein, protein equivalent from protein substitute, and total protein with increasing age. Overall, the mean daily intake (kg/day) was as follows: Phe, 904 mg ± 761 (22 ± 23 mg/kg/day), natural protein 19 g ± 16 (0.5 g/kg/day ± 0.5), protein equivalent from protein substitute 39 g ± 22 (1.1 g/kg/day ± 0.6), and total protein 59 g ± 21 (1.7 g/kg/day ± 0.6). Natural protein tolerance was similar between males and females. Patients with mPKU tolerated around 50% less Phe/natural protein than HPA, but 50% more than cPKU. Higher intakes of natural protein were observed in Southern Europe, with a higher prevalence of HPA and mPKU compared with patients from Northern European centres. Natural protein intake doubled with sapropterin usage. In sapropterin-responsive patients, 31% no longer used protein substitutes. Close monitoring and optimisation of protein intake prescriptions are needed, along with future guidelines specifically for different age groups and severities.publishersversionpublishe