Astatine-211 radiolabelling chemistry: from basics to advanced biological applications.

BACKGROUND: 211At-radiopharmaceuticals are currently the subject of growing studies for targeted alpha therapy of cancers, which leads to the widening of the scope of the targeting vectors, from small molecules to peptides and proteins. This has prompted, during the past decade, to a renewed interest in developing novel 211At-labelling approaches and novel prosthetic groups to address the diverse scenarios and to reach improved efficiency and robustness of procedures as well as an appropriate in vivo stability of the label. MAIN BODY: Translated from the well-known (radio)iodine chemistry, the long preferred electrophilic astatodemetallation using trialkylaryltin precursors is now complemented by new approaches using electrophilic or nucleophilic At. Alternatives to the astatoaryl moiety have been proposed to improve labelling stability, and the range of prosthetic groups available to label proteins has expanded. CONCLUSION: In this report, we cover the evolution of radiolabelling chemistry, from the initial strategies developed in the late 1970's to the most recent findings.

Priorities and barriers for research related to primary ciliary dyskinesia.

Background: Despite advances in primary ciliary dyskinesia (PCD) research, many questions remain; diagnosis is complex and no disease-specific therapies exist. Using a mixed-methods approach, we aimed to identify priorities for clinical and epidemiological research and explore barriers to research. Methods: To obtain rich, relevant, diverse data, we performed in-depth semi-structured interviews with PCD specialists selected using purposive sampling. We transcribed, coded and analysed interview data using thematic analysis. Based on interview themes that we identified, we developed an anonymous survey and circulated it widely through the BEAT-PCD network. Results: We interviewed 28 participants from 15 countries across different disciplines and expertise levels. The main themes identified as priorities for PCD research were improving diagnosis; understanding prevalence and disease course; phenotypic variability; disease monitoring; treatment strategies; clinical trial end-points; and poorly researched areas. In total, 136 participants (49% paediatric pulmonologists) from 36 countries completed the survey. Most commonly reported barriers for research were low awareness about PCD and difficulties securing funding - in more than one-third of cases, participants reported undertaking predominantly unfunded research. Research questions ranked highest included priorities related to further improving diagnosis, treating PCD, managing upper and lower airway problems, and studying clinical variability and disease prognosis. Conclusion: We need to overcome barriers of limited funding and low awareness and promote collaborations between centres, disciplines, experts and patients to address identified PCD priorities effectively. Our results contribute to the ongoing efforts of guiding the use of existing limited research resources and setting up a roadmap for future research activities.

A human DCC variant causing mirror movement disorder reveals that the WAVE regulatory complex mediates axon guidance by netrin-1-DCC.

The axon guidance cue netrin-1 signals through its receptor DCC (deleted in colorectal cancer) to attract commissural axons to the midline. Variants in DCC are frequently associated with congenital mirror movements (CMMs). A CMM-associated variant in the cytoplasmic tail of DCC is located in a conserved motif predicted to bind to a regulator of actin dynamics called the WAVE (Wiskott-Aldrich syndrome protein-family verprolin homologous protein) regulatory complex (WRC). Here, we explored how this variant affects DCC function and may contribute to CMM. We found that a conserved WRC-interacting receptor sequence (WIRS) motif in the cytoplasmic tail of DCC mediated the interaction between DCC and the WRC. This interaction was required for netrin-1-mediated axon guidance in cultured rodent commissural neurons. Furthermore, the WIRS motif of Fra, the Drosophila DCC ortholog, was required for attractive signaling in vivo at the Drosophila midline. The CMM-associated R1343H variant of DCC, which altered the WIRS motif, prevented the DCC-WRC interaction and impaired axon guidance in cultured commissural neurons and in Drosophila. The findings reveal the WRC as a pivotal component of netrin-1-DCC signaling and uncover a molecular mechanism explaining how a human genetic variant in the cytoplasmic tail of DCC may lead to CMM.

Clinical profiles of older adults in French Caribbean nursing homes: a descriptive cross-sectional study.

Background: Nursing homes in the Caribbean are scarce and the characteristics of their residents have not been previously documented. This study aimed to describe the clinical profiles of residents living in nursing homes in Guadeloupe and Martinique (French West Indies). Methods: This is a cross-sectional study of the baseline screening data from the KASEHPAD (Karukera Study of Ageing in nursing homes) study. Clinical characteristics and geriatric scale scores, including the Activities of Daily Living (ADL), Mini-Mental State Examination (MMSE), Mini Nutritional Assessment Short-Form (MNA-SF) and Short Physical Performance Battery (SPPB) were collected and analysed. Results: A total of 332 older adults were recruited between September 2020 and November 2022. The mean age of the residents was 81.3 ± 10.1, with a male-female ratio of 1:1. Diabetes was reported in 28.3% of the residents, hypertension in 66.6% and heart disease in 18.4%. Dementia was diagnosed in 52.3% of the residents and 74.9% had a MMSE score ≤18. The prevalence of Parkinson's disease was 9.0%. Additionally, 18.4% were unable to perform any basic activities of daily living (ADL score of 0). The prevalence of physical impairment (SPPB < 8) was 90.0%. One-quarter of the residents were classified as undernourished (MNA-SF score ≤ 7). Conclusion: Residents in Caribbean nursing homes are younger than in metropolitan France, whereas they present quite similar clinical profiles. Notably, a high prevalence of diabetes, cardiovascular diseases and neurodegenerative diseases was observed. This study represents a preliminary effort to address the knowledge gap regarding the aging trajectories of older adults in the Caribbean and could guide the development of future nursing homes in these countries.

Galantamine combined with cognitive rehabilitation on post-stroke cognitive impairment: a proof-of-concept study.

PURPOSE: We conducted a proof-of-concept study to evaluate the effects of galantamine treatment versus placebo combined to cognitive rehabilitation (CR) after stroke. MATERIALS AND METHODS: In this 12-week, double blinded, randomized, controlled trial, patients were assigned to either combined approach of galantamine and CR (G-CR) or placebo and CR (P-CR). Primary outcome was the proportion of patients who crossed over from vascular cognitive disorder (VCD) to no-VCD at 12 weeks. Secondary outcomes included changes in cognition, mood, quality of life and the N-back fMRI paradigm, assessed at baseline, 6 and 12 weeks and after an 8-week washout period. RESULTS: Ten patients were allocated to G-RC group, 12 to the P-RC group. After 12 weeks, 40.1% of all patients converted to no-VCD with similar proportions between groups. Both groups showed improvements in episodic and working memory, executive and quality of life after 6 weeks of CR. Decreased depression and anxiety were noted, and all benefits persisted after the washout period. An interaction effect was observed in the right parietal lobule during the N-back task. CONCLUSIONS: Interventions lead to improved cognition and distinct cortical reorganization without being able to establish correlation between neural changes and behavioral measures.

Indeterminate DC histiocytosis is distinct from LCH and often associated with other hematopoietic neoplasms.

Indeterminate dendritic cell histiocytosis (IDCH) is a rare and poorly understood entity characterized by accumulation of CD1a+/S100+ histiocytes (as Langerhans cell histiocytosis (LCH)), but with reduced-absent expression of Langerin/CD207. We assembled 43 cases of IDCH (defined by CD1a+/CD207<20% immunophenotypic profile) examining the clinical, pathologic, and molecular landscape. Median age at presentation was 70 years (IQR: 44-80 years) with cutaneous (31/43; 72%) and nodal (11/43; 26%) involvement predominating. Eighteen (42%) individuals had an associated non-histiocytic hematopoietic neoplasm ('secondary' IDCH) while 7 of 43 (16%) had a concurrent non-IDCH histiocytosis ('mixed' histiocytosis). Most cases exhibited morphology indistinguishable from LCH but with a CD1c+/CSF1R(CD115)-phenotype, mirroring the signature of normal indeterminate cells and conventional dendritic cell type 2. Mutational analysis revealed frequent KRAS (13/32; 41%), and BRAF p.V600E (11/36, 31%) mutations that were nearly mutually exclusive. RNAseq analysis uncovered ETV3::NCOA2 fusion in 6 other patients presenting as a sole genetic alteration without any other concurrent histiocytic or hematopoietic neoplasm. BRAF and MAP2K1 alterations were significantly associated with partial/retained (1-20%) Langerin expression (P = .005) and mixed histiocytosis (P = .002). Remarkably, myeloid alterations (DNMT3A, TET2 and SRSF2) co-occurred in IDCH tissues of several individuals. Paired sequencing of IDCH and concurrent non-IDCH hematopoietic neoplasm in four individuals revealed shared mutations. Age at diagnosis and any nodal involvement at diagnosis predicted inferior overall survival, but BRAF/RAS pathway alterations did not impact outcome. These data have implications for the diagnostic evaluation, classification, and therapeutic management of IDCH.

TRU-IMP: techniques for reliable use of images in medical physics; a graphical user interface to analyze and compare segmentations in nuclear medicine.

BACKGROUND: In the context of pharmacokinetic analyses, the segmentation method one uses has a large impact on the results obtained, thus the importance of transparency. Innovation: This paper introduces a graphical user interface (GUI), TRU-IMP, that analyzes time-activity curves and segmentations in dynamic nuclear medicine. This GUI fills a gap in the current technological tools available for the analysis of quantitative dynamic nuclear medicine image acquisitions. The GUI includes various techniques of segmentations, with possibilities to compute related uncertainties. Results: The GUI was tested on image acquisitions made on a dynamic nuclear medicine phantom. This allows the comparison of segmentations via their time-activity curves and the extracted pharmacokinetic parameters. Implications: The flexibility and user-friendliness allowed by the proposed interface make the analyses both easy to perform and adjustable to any specific case. This GUI permits researchers to better show and understand the reproducibility, precision, and accuracy of their work in quantitative dynamic nuclear medicine. Availability and Implementation: Source code freely available on GitHub: https://github.com/ArGilfea/TRU-IMP and location of the interface available from there. The GUI is fully compatible with iOS and Windows operating systems (not tested on Linux). A phantom acquisition is also available to test the GUI easily. .

Updimensioning strategy derived from synthetic equiaxed grain structures for approximating 3D grain size distributions from 2D visualizations with 1D parameters.

We generated synthetic equiaxed grain structures using computer graphics software to explore the relationship between various grain size determination methods and true three-dimensional (3D) grain diameters. Mirroring grain measurement techniques, the synthetic 3D grain structures are imaged as 2D micrographs which are measured to yield 1D grain size parameters. Synthetic grain structures provide data at a mass scale and permit exploration of both polished and fractured surface micrographs, revealing one-to-one correspondence between exposed 2D grain cross-sections and individual 3D grains. Analysis of this correspondence yielded a procedure to approximate 3D equiaxed grain size and volume distributions based on the mode of the 2D fractograph grain size distribution. The 3D approximation procedure is shown to be less susceptible to different imaging conditions that affect small, undiscernible grains compared to the standard planimetric and linear intercept methods, which by design also tend to underestimate the 3D grain diameter. The procedure requires larger sample sizes to lower variance and a deeper analysis which could become more practical with machine learning (ML) models for grain boundary segmentation, which synthetic grain structures can help train. This work lays the foundation for analyzing other grain distributions such as columnar and composite grains in similar depth.

Efficacy of a pharmacist care protocol to manage uncomplicated female cystitis in community pharmacies: an open-label, multicenter, randomized, controlled, cluster study: the PharmaCyst' protocol.

BACKGROUND: Urinary tract infections are common affections, especially for women. Difficult access to a general practitioner to obtain a prescription has led France to offer dispensing under protocol by community pharmacists. The primary objective of this study is to evaluate the effectiveness of a pharmacist care protocol provided to manage women with urinary tract infection symptoms. This objective will be assessed using the Acute Cystitis Symptom Score. METHODS: PharmaCyst' is an open-label, multicenter, controlled, cluster-randomized study conducted in the Loire region, France. Women aged between 18 and 65 years presenting to a pharmacy complaining of at least one symptom of an uncomplicated urinary tract infection present over the last 3 days (including burning pain during micturition, dysuria, pollakiuria, urgent urination) will be considered for inclusion. All patients will be contacted on day 3, 10, and month 3. A total of 480 patients need to be recruited for the 24 clusters participating in the research. The quantitative data will be described using means and standard deviations and compared using Student's t-test. The qualitative data will be described using numbers and percentages and compared using chi2 test (or Fisher's exact test if necessary). The primary and secondary outcomes analyses will consider the intention-to-treat population. DISCUSSION: PharmaCyst' is the first clinical trial conducted in France only by community pharmacists. Its results could lead to an extension of the protocol. TRIAL REGISTRATION: The protocol has been approved by the French ethics committee on 2022/12/02 and is registered under the number 49RC22_0240 on ClinicalTrials.gov.

Optimizing oilseed rape growth: Exploring the effect of foliar biostimulants on the interplay among metabolism, phenology, and yield.

The current agricultural system is in search of new strategies to achieve a more sustainable production while keeping or even increasing crop yield and quality. In this scenario, the application of biostimulants constitutes a potent solution. In the current study, the impact of a blue-green microalgal extract (MB) and a pig tissue hydrolysate (PTH) on rapeseed plants' development was characterized. Obtained results revealed a positive effect on yield parameters of plants treated with MB and, especially, PTH; this was associated to an improvement on the photosynthetic performance. Moreover, this study remarked the effects of biostimulants on plant phenology through their pivotal role in modulating developmental processes. More specifically, proteomic, metabolomic, and hormone content analyses revealed distinct alterations associated with the acceleration of phenology induced by biostimulant application. Additionally, some antioxidant enzymes and stress-related compounds were up-regulated upon MB and PTH treatments, indicating enhanced plant defense mechanisms in response to accelerated phenological transitions. Such findings highlight the intricate interplay between biostimulants and plant physiology, wherein biostimulants orchestrate rapid developmental changes, ultimately influencing growth dynamics. Altogether, the current study reveals that the application of both MB and PTH biostimulants promoted rapeseed plant phenology and productivity associated with an improvement in the photosynthetic machinery while boosting other physiological and molecular mechanisms.

Neurological conditions and community-based physical activity: physical therapists' belief and actions.

Introduction: Physical therapists (PTs) are key actors in physical activity (PA) promotion. However, it remains unclear whether PTs in community settings promote community-based PA such as adapted physical activity (APA) and adaptive sports (AS) to their patients with neurological conditions (NCs). The main purposes were to evaluate the beliefs PTs have of APA and AS, and to explore actions they undertake to promote it to their patients with NCs. Methods: An online survey was created specifically for the study. PT associations and institutions were contacted and licensed PTs working in community-based settings, treating at least one patient with a NC, were invited to participate. Questionnaires were analyzed only if all mandatory questions had been answered. Results: A total of 165 questionnaires were analyzed. PTs reported prioritizing active treatment. They viewed APA and AS as beneficial for their patients with NCs; however, its promotion remained largely infrequent due to a number of barriers. The PTs' own level of PA seemed to significantly influence their beliefs of the benefits of APA and AS (p = 0.001), while being specialized in neurologic physical therapy enabled the PTs to increase frequency of promotion (p = 0.003). Conclusion: Though community-based PTs are aware of the importance of PA for individuals with NCs, they face difficulties in promoting it to their patients. However, these difficulties are reduced among PTs who are specialized in neurologic physical therapy. Efforts should be made toward educating PTs to neurological pathologies and their specificities when it comes to PA.

Identification of an ionic mechanism for ERα-mediated rapid excitation in neurons.

The major female ovarian hormone, 17ß-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-α (ERα), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E2, but the ionic mechanisms remain unclear. Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERα with a preference to the membrane-bound ERα. Clic1-mediated currents can be enhanced by E2 and reduced by its depletion. In addition, Clic1 currents are required to mediate the E2-induced rapid excitations in multiple brain ERα populations. Further, genetic disruption of Clic1 in hypothalamic ERα neurons blunts the regulations of E2 on female body weight balance. In conclusion, we identified the Clic1 chloride channel as a key mediator for E2-induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E2.

The biogeography of the Amazonian tree flora.

We describe the geographical variation in tree species composition across Amazonian forests and show how environmental conditions are associated with species turnover. Our analyses are based on 2023 forest inventory plots (1 ha) that provide abundance data for a total of 5188 tree species. Within-plot species composition reflected both local environmental conditions (especially soil nutrients and hydrology) and geographical regions. A broader-scale view of species turnover was obtained by interpolating the relative tree species abundances over Amazonia into 47,441 0.1-degree grid cells. Two main dimensions of spatial change in tree species composition were identified. The first was a gradient between western Amazonia at the Andean forelands (with young geology and relatively nutrient-rich soils) and central-eastern Amazonia associated with the Guiana and Brazilian Shields (with more ancient geology and poor soils). The second gradient was between the wet forests of the northwest and the drier forests in southern Amazonia. Isolines linking cells of similar composition crossed major Amazonian rivers, suggesting that tree species distributions are not limited by rivers. Even though some areas of relatively sharp species turnover were identified, mostly the tree species composition changed gradually over large extents, which does not support delimiting clear discrete biogeographic regions within Amazonia.

Two-scale concurrent simulations for crack propagation using FEM-DEM bridging coupling.

The Discrete element method (DEM) is a robust numerical tool for simulating crack propagation and wear in granular materials. However, the computational cost associated with DEM hinders its applicability to large domains. To address this limitation, we employ DEM to model regions experiencing crack propagation and wear, and utilize the finite element method (FEM) to model regions experiencing small deformation, thus reducing the computational burden. The two domains are linked using a FEM-DEM coupling, which considers an overlapping region where the deformation of the two domains is reconciled. We employ a "strong coupling" formulation, in which each DEM particle in the overlapping region is constrained to an equivalent position obtained by nodal interpolation in the finite element. While the coupling method has been proved capable of handling propagation of small-amplitude waves between domains, we examine in this paper its accuracy to efficiently model for material failure events. We investigate two cases of material failure in the DEM region: the first one involves mode I crack propagation, and the second one focuses on rough surfaces' shearing leading to debris creation. For each, we consider several DEM domain sizes, representing different distances between the coupling region and the DEM undergoing inelasticity and fracture. The accuracy of the coupling approach is evaluated by comparing it with a pure DEM simulation, and the results demonstrate its effectiveness in accurately capturing the behavior of the pure DEM, regardless of the placement of the coupling region. Supplementary Information: The online version contains supplementary material available at 10.1007/s40571-024-00788-x.

Plain language summary: 5-year results from the CROWN study of lorlatinib vs crizotinib in non-small-cell lung cancer.

WHAT IS THIS STUDY ABOUT?: This is a summary of the results of an ongoing study called CROWN. In the CROWN study, researchers looked at the effects of two medicines called lorlatinib (Lorbrena) and crizotinib (Xalkori) for people with advanced non-small cell lung cancer (NSCLC) who had not been treated yet. Everyone in the study had changes in a gene called anaplastic lymphoma kinase, or ALK, in their cancer cells. The changes in the ALK gene can make cancer grow. This analysis looked at how well lorlatinib and crizotinib worked and their side effects in people with advanced ALK-positive NSCLC after 5 years. WHAT DID THIS STUDY FIND?: After observing people for an average of 5 years, researchers found that more people who took lorlatinib were still alive without their cancer getting worse than the people who took crizotinib. At 5 years, the probability of being alive without their cancer getting worse was 60% in people who took lorlatinib compared with 8% in people who took crizotinib. Fewer people who took lorlatinib had their cancer spread within or to the brain than the people who took crizotinib. In more than half of the people who took lorlatinib, tumors that had spread to the brain did not get worse, and no new tumors spread to the brain after 5 years. In contrast, in about half of the people who took crizotinib, tumors that had spread to the brain got worse or new tumors spread to the brain after 16.4 months. More people who took lorlatinib (115 out of 149, or 77%) had severe or life-threatening side effects than people who took crizotinib (81 out of 142, or 57%). These side effects were like the ones reported in the earlier 3-year analysis. WHAT DO THE FINDINGS OF THE STUDY MEAN?: The 5-year results from the CROWN study showed that more people who took lorlatinib continued to benefit from their treatment than those who took crizotinib. The 5-year benefit of lorlatinib in people with ALK-positive NSCLC has never been seen before.Clinical Trial Registration: NCT03052608 (Phase 3 CROWN study) (ClinicalTrials.gov).

Postoperative rectovaginal fistula: stoma may not be necessary-a French retrospective cohort.

BACKGROUND: Postoperative rectovaginal fistula leads to a loss of patients' quality of life and presents significant challenges to the surgeon. The literature focusing specifically on postoperative rectovaginal fistulas is limited. The objective of the present study is to identify factors that can enhance the success of the management of this postoperative rectovaginal fistula. METHODS: This retrospective multicentric study included all patients undergoing surgery for rectovaginal fistulas, excluding those for whom the etiology of rectovaginal fistula was not postoperative. The major outcome measure was the success of the procedure. RESULTS: A total of 82 patients with postsurgical fistulas were identified, of whom 70 were successfully treated, giving a success rate of 85.4%. On average, these patients required 3.04 ± 2.72 interventions. The creation of a diversion stoma did not increase the success rate of management [odds ratio (OR) = 0.488; 95% confidence interval (CI) 0.107-2.220]. Among the 217 procedures performed, 69 were successful, accounting for a 31.8% success rate. The number of interventions and the creation of a diversion stoma did not correlate with the success of management. However, direct coloanal anastomosis was significantly associated with success (OR = 35.06; 95% CI 1.271-997.603; p = 0.036) as compared with endorectal advancement flap (ERAF). Other procedures such as Martius flap did not show a significantly higher success rate. CONCLUSION: The creation of a diversion stoma is not necessary in closing a fistula. ERAF should be considered as a first-line treatment prior to proposing more invasive approach such as direct coloanal anastomosis.

The Difference in Cognitive Profiles Between Patients With Alzheimer Dementia With and Without Psychosis: A Rapid Review.

BACKGROUND: Psychosis in Alzheimer disease (AD) is a major burden for patients and their family. Identifying the characteristics of delusions and hallucinations in the AD population is key to understanding the interconnection between the psychiatric and cognitive symptoms in neurocognitive disorders. The aim of this study is to compare the cognitive profiles of AD patients with and without psychosis. METHODS: We conducted a rapid review to explore the relationship between psychotic symptoms and cognitive performances in patients with AD. We used MEDLINE, Embase, and PsychINFO literature databases between January 2015 and January 2023. This rapid review was guided by the Cochrane Rapid Reviews Methods Group. RESULTS: We identified 2909 records from the initial searches. After reviewing the titles, abstracts, and full texts, we selected 8 cross-sectional and 5 cohort studies for the qualitative analysis. Among them, 6 studies were included in the final quantitative analysis. Most studies suggested a correlation between general cognitive decline and the risk of presenting psychotic symptoms. Three studies found an association between hallucinations and deficits in the visuocognitive domains (visuospatial, visuoperceptual, and visuoconstructive skills). Two studies found a relationship between psychotic symptoms and executive dysfunction. Two studies also found a correlation between psychotic symptoms and language. Our results are in line with previous data in the literature, especially regarding the outcome of psychosis on executive function and visuocognitive abilities. CONCLUSIONS: There appears to be an association between cognitive deficits and psychotic symptoms in AD, but the direction of causality is still unclear, and further studies using longitudinal designs would give more insight into the pathophysiological process of psychosis in AD.

Relationship Between Dental Trauma and Orthostatic Balance in Children.

BACKGROUND: Dental trauma (DT) and falls have shown to be associated. On the other hand, postural balance is associated with falls and depends on the integration of the body's regulatory systems. The aim of this study was to investigate the potential relationship between DT and alteration of orthostatic balance in children. METHODS: This was a population-based case-control study involving 296 six-year-old schoolchildren. The case group included children with previous history of DT. The control group included children with no previous history of DT. Stabilometric measurements were the main exposure of this study. Logistic regression analyzes were performed to estimate potential differences in terms of chance of occurrence. RESULTS: The cases reviewed showed a 4.37 times chance of reduced balance in the measurement of the anteroposterior trajectory speed of the orthostatic center of pressure (COP), when children had their eyes closed. It also presented a chance of 3.06 times reduced balance in the measurement of the orthostatic center of pressure latero-lateral sway, with children with open eyes and stepping on a foam pad, and 4.00 times of reduced balance in the width of the latero-lateral sway of the orthostatic center of pressure, with children with open eyes and stepping on a foam pad. CONCLUSION: Children with previous history of DT showed a higher chance of experiencing a reduced orthostatic balance in different conditions when compared to children without the occurrence of trauma.