Serotoninergic antidepressants combination in psilocybin-assisted psychotherapy: a case report.

Psilocybin has reemerged as a promising treatment for difficult-to-treat depression (DTD). Although there is limited evidence regarding interactions between psilocybin and other psychotropic drugs, clinical trials require that patients discontinue their antidepressants before study entry to isolate the benefits of psilocybin and to minimize the risk of adverse events. We present the first case of an adult patient with DTD who received psilocybin-assisted psychotherapy (PAP) in combination with two serotoninergic antidepressants (duloxetine and vortioxetine). Since he displayed a partial response after the first PAP session, he agreed to discontinue duloxetine (but refused to stop vortioxetine) before the second PAP session to see if it could improve the therapeutic efficacy of psilocybin. However, his anxiety and depressive symptoms worsened. Psilocybin was well-tolerated in both PAP sessions; mild headaches were the main adverse effects experienced by the patient, and there were no cardiovascular safety concerns. This case report suggests that serotoninergic antidepressants combination with psilocybin appears to be safe and that antidepressant discontinuation prior to PAP may not be necessary. Since the continuation of antidepressants during PAP has the potential to improve treatment acceptability and accessibility, future research should assess whether psilocybin can be administered concurrently with antidepressants.

Clinical Characteristics of Older Adults Living in Foster Families in the French West Indies: Baseline Screening of the KArukera Study of Aging in Foster Families (KASAF) Cohort.

Background and Objectives: Foster families for older adults could represent a transitional or alternative model to nursing homes. The aim of this study was to describe the clinical characteristics of older adults in foster families and to compare them with those of residents in nursing homes in French West Indies. Research Design and Methods: This study is a cross-sectional analysis of the KArukera Study of Aging in Foster Families (KASAF) cohort. Sociodemographic and clinical characteristics were extracted. Dependency was assessed using the Activities of Daily Living (ADL) scale and cognition using the Mini-Mental State Examination (MMSE) scale. Age, gender, ADL, and MMSE scores were compared with nursing home residents from a twin study of KASAF (n = 332). Results: A total of 107 older adults (mean age 81.8 years; 61.7% women) were recruited in 56 foster families between September 2020 and May 2021. In all, 25.5% had diabetes mellitus and 45.8% suffered from hypertension. The mean MMSE score was 9.3 ± 10.1 and 76.0% had major cognitive impairment (MMSE score <18); 12.5% were diagnosed with Parkinson's disease, and 42.0% of the residents were confined to bed or in a wheelchair, with a mean ADL score of 1.5 ± 1.8. Almost all the residents (96.3%) benefited from a medical follow-up by a nurse who visited once or twice a day. Compared to older adults living in nursing homes, those in foster families were more frequently women (61.7% vs 49.4%) and had lower ADL score (1.5 vs 2.4) and lower MMSE score (9.3 vs 11.3). Discussion and Implications: The clinical profile of foster families' residents was quite similar to that of nursing home residents in terms of demographics, dementia, and dependency. Foster families might represent an interesting strategy to address the unmet clinical and social needs of dependent older adults, especially in countries where nursing homes are not sufficiently developed. Clinical Trials Registration Number: NCT04545775.

Surface-Enhanced Raman Scattering Nanosensing and Imaging in Neuroscience.

Monitoring neurochemicals and imaging the molecular content of brain tissues in vitro, ex vivo, and in vivo is essential for enhancing our understanding of neurochemistry and the causes of brain disorders. This review explores the potential applications of surface-enhanced Raman scattering (SERS) nanosensors in neurosciences, where their adoption could lead to significant progress in the field. These applications encompass detecting neurotransmitters or brain disorders biomarkers in biofluids with SERS nanosensors, and imaging normal and pathological brain tissues with SERS labeling. Specific studies highlighting in vitro, ex vivo, and in vivo analysis of brain disorders using fit-for-purpose SERS nanosensors will be detailed, with an emphasis on the ability of SERS to detect clinically pertinent levels of neurochemicals. Recent advancements in designing SERS-active nanomaterials, improving experimentation in biofluids, and increasing the usage of machine learning for interpreting SERS spectra will also be discussed. Furthermore, we will address the tagging of tissues presenting pathologies with nanoparticles for SERS imaging, a burgeoning domain of neuroscience that has been demonstrated to be effective in guiding tumor removal during brain surgery. The review also explores future research applications for SERS nanosensors in neuroscience, including monitoring neurochemistry in vivo with greater penetration using surface-enhanced spatially offset Raman scattering (SESORS), near-infrared lasers, and 2-photon techniques. The article concludes by discussing the potential of SERS for investigating the effectiveness of therapies for brain disorders and for integrating conventional neurochemistry techniques with SERS sensing.

Small microplastics have much higher mass concentrations than large microplastics at the surface of nine major European rivers.

Understanding the fates and impacts of microplastics requires information on their sizes, polymer types, concentrations, and spatial and temporal distributions. Here, we focused on large (LMPs, 500 µm to 5 mm) and small (SMPs, 25 to 500 µm) microplastics sampled with the exact same protocol in nine of the major European rivers during the seven months of the Tara Microplastic Expedition. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and pyrolysis coupled with gas chromatography and mass spectrometry (Py-GC-MS) analyses were used to determine the microplastics contents by number and mass. The median LMP concentration was 6.7 particles m-3, which was lower than those in other regions of the world (America and Asia). The SMP mass concentration was much higher to the LMP concentrations, with SMP/LMP ratios up to 1000 in some rivers. We did not observe a systematic positive effect of urban areas for the two size classes or polymers; this could be explained by the fact that the transport of microplastic is highly heterogeneous in rivers. We believe that this study has important implications for predictive models of plastics distribution and fate in aquatic environments.

Untargeted metabolomic insights into plastisphere communities in European rivers.

Every year, rivers introduce a staggering amount of hundred kilotons of plastic into the Oceans. This plastic is inhabited by microorganisms known as the plastisphere, which can be transferred between different ecosystems through the transport of microplastics. Here, we simulated the microbial colonization of polyethylene-based plastic pellets that are classically used to manufacture large-scale plastic products. The pellets were immersed for 1 month in four to five sampling stations along the river-to-sea continuum of nine of the major European rivers. This study presents the first untargeted metabolomics analysis of the plastisphere, by using ultra high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). The plastisphere metabolomes were similar in the Rhine and Rhone rivers, while being different from the Tiber and Loire rivers, which showed greater similarity to the Thames and Seine rivers. Interestingly, we found a clear distinction between plastisphere metabolomes from freshwater and marine water in most of the river-to-sea continuum, thus suggesting a complete segregation in plastisphere metabolites that is not consistent with a major transfer of microorganisms between the two contrasted ecosystems. Putative annotations of 189 discriminating metabolites suggested that lipid metabolism was significantly modulated. These results enlightened the relevance of using environmental metabolomic as complementary analysis to the current OMICs analysis.

Mass balance and economic study of a treatment chain for nickel, cobalt and rare earth elements recovery from Ni-MH batteries.

The aim of this project is to develop and evaluate the economic performance of a complete process for recovering nickel, cobalt, and rare earths (REEs) from nickel metal hydride (Ni-MH) battery waste. The main elements contained in the battery powder are Ni (523 g/kg), La (58 g/kg), Co (39 g/kg), Zn (21 g/kg), Nd (19 g/kg), Sm (19 g/kg) and Ce (14 g/kg). Metal leaching was carried out with 2 M sulfuric acid, solubilising 100% of Ni, 93% of Co and 94% of REEs. Rare earths were precipitated with NaOH, then purified after resolubilization in nitric acid. Solvent extraction with bis(2-ethylhexyl) phosphoric acid (D2EHPA) followed by bis(2,4,4-trimethylpentyl) phosphinic acid (Cyanex 272) was used to separate Ni and Co. At the end of the process, REEs, nickel, and cobalt were recovered as oxides after precipitation as oxalates. The REE, nickel and cobalt oxides obtained have purities of 97.6%, 97.2% and 93.2% respectively. A techno-economic study was carried out using SuperPro Designer software. In this scenario, plant capacity was set at 1.0 t of used battery powder per hour for an operating period of 8 h/d and 250 days per year. The total investment was estimated at $26.9 million, with a payback period of 1.58 years. For a 15-year life, the net present value of this project is estimated at $95.9 million, with an interest rate of 7%. The internal rate of return is estimated at 46.1%, which is considered acceptable and economically viable.

What Determines the Adoption of Conservation Agriculture? Evidence from Quebec.

Conservation agriculture (CA) is promoted by various organisations and scholars as alternative to conventional agriculture to meet growing food demand with minimal damage on environment; but its factors of adoption have not been well identified. The study uses the recent composite index of adoption of CA developed by Takam Fongang et al. (2023) to analyse the factors of adoption of conservation agriculture among maize and soybean farmers in Quebec. Using data from 93 maize and soybean producers and a Fractional logit model, the study shows that adoption of CA increases with farmer's favourable perceptions of yield and easiness of implementing CA, off-farm employment and higher education. The study therefore indicates that higher education, technical assistance and popularisation of performance of CA can play a significant role in boosting adoption of CA in Quebec.

Changes in appetite during acute passive intermittent and continuous hypoxemia in postprandial and fasting states: a combined analysis of four laboratory-based randomized crossover trials.

Hypoxemia occurs during exposure to high altitude (continuous hypoxemia) or in the context of breathing disorders such as obstructive sleep apnea (OSA; intermittent hypoxemia). Growing evidence demonstrates that hypoxemia induces an anorexigenic effect on appetite; however, few studies have assessed hypoxemia-related reductions in appetite during acute passive exposures and during intermittent hypoxemia. This study thus pooled together four same-single-site randomized crossover trials using simulated models of high altitude (fraction of inspired oxygen = 0.1200, ∼5000 meters) and moderate OSA (∼15 hypoxemic cycles per hour, ∼85 oxyhemoglobin saturation). Changes in appetite were evaluated during six hours of passive normoxia and intermittent or continuous hypoxemia in postprandial or fasting states among healthy young adults (n = 40) and middle-aged individuals living with OSA (n = 7). Our results demonstrate that (1) acute passive intermittent hypoxemia leads to statistically significant, but likely not clinically significant reductions in appetite in the postprandial state, (2) the anorexigenic effect of acute passive hypoxemia on appetite is not consistent across hypoxemic methods and nutritional states, and (3) variations in individual factors may influence appetite responses during normoxia and hypoxemia. These findings indicate that the effect of acute passive hypoxemia on appetite is heterogeneous, particularly across different hypoxemic methods and nutritional states.

Easy Processable Photomechanical Thin Film Involving a Photochromic Diarylethene and a Thermoplastic Elastomer in Supramolecular Interaction.

A novel supramolecular photoactuator in the form of a thin film of centimetric size has been developed as an alternative to traditional liquid crystal elastomers (LCE) involving azobenzene (AZO) units or photochromic microcrystals. This thin film is produced through spin coating without the need for alignment or crosslinking. The photoactuator combines a photochromic dithienylethene (DTE) functionalized with ureidopyrimidinone (UPy) units, and a telechelic thermoplastic elastomer, also functionalized with UPy, allowing quadruple hydrogen bonding between the two components. Upon alternating ultraviolet (UV) and visible light exposure, the film exhibits reversible bending and color changes, studied using displacement and absorption tracking setups. For the first time, the photomechanical effect (PME) is quantitatively correlated with photochromism, showing that DTE units drive the movement under both UV (photocyclization) and visible (photoreversion) light. In situ illumination techniques reveal that the PME arises from photoinduced strain within 160 nm UPy-bonded DTE domains, which expand and contract by approximately 50% under UV and visible light, respectively. The semicrystalline nature of the elastomer and a robust supramolecular network connecting both components are critical in converting microscopic photostrain into macroscopic actuation.

Redox-Driven Formation of Mn(III) in Ice.

Redox-driven reactions involving Mn(II) species adsorbed at Mn(IV) oxide surfaces can release Mn(III) in the form of dissolved Mn(III)-ligand species in natural waters. Using pyrophosphate (PP) as a model ligand, we show that freezing accelerates and enhances Mn(III) formation in the form of Mn(III)-PP complexes. This freeze-promoted reaction is explained by the concentration of Mn(IV) oxides and solutes (Mn(II), Na+, and Cl-) into the minute fractions of liquid water locked between ice (micro)crystals - the Liquid Intergrain Boundary (LIB). Time-resolved freezing experiments at -20 °C showed that Mn(III) yields were greatest at low salt (NaCl) content. In contrast, high salt content promoted Mn(III) formation through chloride complexation, although yields became lower as the cryosalt mineral hydrohalite (NaCl·2H2O) dehydrated the LIB by drawing water into its structure. Consecutive freeze-thaw cycles also showed that dissolved Mn(III) concentrations increased within the very first few minutes of each freezing event. Because each thaw event released unreacted PP previously locked in ice, each sequential freeze-thaw cycle increased Mn(III) yields, until ∼80% of the Mn was converted to Mn(III). This was achieved after only seven cycles. Finally, temperature-resolved freezing experiments down to -50 °C showed that the LIB produced the greatest quantities of Mn(III) at -10 °C, where the volumes were greater. Reactivity was however sustained in ice formed below the eutectic (-21.3 °C), down to -50 °C. We suspect that this sustained reactivity was driven by persistent forms of supercooled water, such as Mn(IV) oxide-bound thin water films. By demonstrating the freeze-driven production of Mn(III) by comproportionation of dissolved Mn(II) and Mn(IV) oxide, this study highlights the potentially important roles these reactions could play in the production of pools of Mn(III) in natural water and sediments of mid- and high-latitudes environments exposed to freeze-thaw episodes.

Unveiling the molecular mechanisms of the type IX secretion system's response regulator: Structural and functional insights.

The type IX secretion system (T9SS) is a nanomachinery utilized by bacterial pathogens to facilitate infection. The system is regulated by a signaling cascade serving as its activation switch. A pivotal member in this cascade, the response regulator protein PorX, represents a promising drug target to prevent the secretion of virulence factors. Here, we provide a comprehensive characterization of PorX both in vitro and in vivo. First, our structural studies revealed PorX harbors a unique enzymatic effector domain, which, surprisingly, shares structural similarities with the alkaline phosphatase superfamily, involved in nucleotide and lipid signaling pathways. Importantly, such pathways have not been associated with the T9SS until now. Enzymatic characterization of PorX's effector domain revealed a zinc-dependent phosphodiesterase activity, with active site dimensions suitable to accommodate a large substrate. Unlike typical response regulators that dimerize via their receiver domain upon phosphorylation, we found that zinc can also induce conformational changes and promote PorX's dimerization via an unexpected interface. These findings suggest that PorX can serve as a cellular zinc sensor, broadening our understanding of its regulatory mechanisms. Despite the strict conservation of PorX in T9SS-utilizing bacteria, we demonstrate that PorX is essential for virulence factors secretion in Porphyromonas gingivalis and affects metabolic enzymes secretion in the nonpathogenic Flavobacterium johnsoniae, but not for the secretion of gliding adhesins. Overall, this study advances our structural and functional understanding of PorX, highlighting its potential as a druggable target for intervention strategies aimed at disrupting the T9SS and mitigating virulence in pathogenic species.

An Unusual Cause of Shock: Bursting a Bubble.

This study presents the case of a previously healthy 68-year-old woman who presented with shock from tamponade due to hemopericardium. Initial noninvasive imaging did not provide a clear etiology for the hemopericardium. Given the ongoing clinical deterioration and need for diagnosis and treatment, an exploratory sternotomy was performed with successful outcome.

Emergence of power-law distributions in self-segregation reaction-diffusion processes.

Many natural or human-made systems encompassing local reactions and diffusion processes exhibit spatially distributed patterns of some relevant dynamical variable. These interactions, through self-organization and critical phenomena, give rise to power-law distributions, where emergent patterns and structures become visible across vastly different scales. Recent observations reveal power-law distributions in the spatial organization of, e.g., tree clusters and forest patch sizes. Crucially, these patterns do not follow a spatially periodic order but rather a statistical one. Unlike the spatially periodic patterns elucidated by the Turing mechanism, the statistical order of these particular vegetation patterns suggests an incomplete understanding of the underlying mechanisms. Here, we present a self-segregation mechanism, driving the emergence of power-law scalings in pattern-forming systems. The model incorporates an Allee-logistic reaction term, responsible for the local growth, and a nonlinear diffusion process accounting for positive interactions and limited resources. According to a self-organized criticality (SOC) principle, after an initial decrease, the system mass reaches an analytically predictable threshold, beyond which it self-segregates into distinct clusters, due to local positive interactions that promote cooperation. Numerical investigations show that the distribution of cluster sizes obeys a power law with an exponential cutoff.

Early mother-infant interactions within the context of childbirth-related posttraumatic stress symptoms.

BACKGROUND: Childbirth may lead to perinatal mental health issues, such as childbirth-related posttraumatic stress symptoms (CB-PTSS), depression, and anxiety. Despite well explored mother-infant interactions in the context of maternal depression and anxiety, only limited studies investigated mother-infant interactions in the context of CB-PTSS, which is the aim of the present study. METHODS: One-hundred mother-infant dyads in the French speaking part of Switzerland were classified into three groups: birth-related symptoms (BRS, i.e., symptoms of re-experiencing and avoidance) (n = 20), general symptoms (GS, i.e., symptoms of negative cognition and mood and hyperarousal) (n = 46), and non-symptomatic (NS) (n = 34) based on maternal report on PTSD Checklist for DSM-5 (PCL-5). At six months postpartum, mother-infant interactions were video-recorded and their quality was assessed using the Global Rating Scale. Data was analyzed using ordinal logistic and negative binomial regressions. RESULTS: In the adjusted model, mothers in BRS group engaged in more frequent coercions compared to the NS group (B = -1.46, p = 0.01, 95%CI = -2.63, -0.36) and showed lower reciprocity in their interactions with their infants compared to the GS group (B = 1.21, p = 0.03, 95%CI = 0.05, 2.37). LIMITATIONS: The use of a cross-sectional design limited the exploration of how consistent these findings are regarding mother-infant interactions between groups over time. CONCLUSIONS: Mothers with higher BRS may need support to improve interactions with their infants. Future studies should consider longitudinal design to observe mother-infant interaction changes between CB-PTSS groups over time.

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes.

Reactive changes of glial cells during neuroinflammation impact brain disorders and disease progression. Elucidating the mechanisms that control reactive gliosis may help us to understand brain pathophysiology and improve outcomes. Here, we report that adult ablation of autism spectrum disorder (ASD)-associated CHD8 in astrocytes attenuates reactive gliosis via remodeling chromatin accessibility, changing gene expression. Conditional Chd8 deletion in astrocytes, but not microglia, suppresses reactive gliosis by impeding astrocyte proliferation and morphological elaboration. Astrocyte Chd8 ablation alleviates lipopolysaccharide-induced neuroinflammation and septic-associated hypothermia in mice. Astrocytic CHD8 plays an important role in neuroinflammation by altering the chromatin landscape, regulating metabolic and lipid-associated pathways, and astrocyte-microglia crosstalk. Moreover, we show that reactive gliosis can be directly mitigated in vivo using an adeno-associated virus (AAV)-mediated Chd8 gene editing strategy. These findings uncover a role of ASD-associated CHD8 in the adult brain, which may warrant future exploration of targeting chromatin remodelers in reactive gliosis and neuroinflammation in injury and neurological diseases.

Effects of a range of 6 prefabricated orthotic insole designs on plantar pressure in a healthy population: A randomized, open-label crossover investigation.

BACKGROUND: Prefabricated orthotic insoles are widely commercially available for self-selection to treat foot and lower-body musculoskeletal pain, without requiring advice from health care professionals. Although they are generally designed to mimic traditional design features of custom-made orthotics used in clinical practice, the effects of prefabricated insoles on plantar pressure distribution are poorly understood. OBJECTIVE: This investigation aimed to evaluate and directly compare the effects of a range of 6 different commercially available prefabricated orthotic insole designs on plantar pressure in healthy individuals. METHODS: This was a single-center, randomized, open-label, crossover investigation. In-shoe dynamic pressure (F-scan) was investigated in 24 healthy subjects with normal foot posture, wearing standard shoes alone and in combination with 6 different orthotic insoles, consecutively, measured on a single day. The biomechanical impact of each insole was determined by the statistical significance of changes from baseline measurements (standard shoe alone). RESULTS: Insoles with heel cups and medial arch geometries consistently increased contact area at medial arch and whole-foot regions and reduced both plantar peak pressure (PP) and pressure time integral at medial arch and heel regions. CONCLUSIONS: This investigation has aided in further understanding the mode of action of prefabricated insoles in a healthy population. The insoles in this study redistributed plantar pressure at key regions of the foot, based on design features common to prefabricated insoles. Prefabricated orthotic insoles represent an easily accessible means of reducing lower-body musculoskeletal stress for those who spend prolonged periods of time on their feet.

A finite volume approach to dosimetric calculations in diffusing alpha-emitters radiation therapy.

OBJECTIVE: In diffusing alpha-emitters radiation therapy (DaRT), the diffusion-leakage (DL) model is used to determine the spatial distributions of the emitters and the corresponding alpha dose, critical for a successful treatment. This work presents how variations over realistic ranges of the DL model parameters related to desorption, diffusion and leakage processes affect the alpha dose distribution and the position of the clinically significant alpha particle 10 Gy isodose. This work also presents the effects of three modeling approximations: two source geometry approximations (solid cylinder instead of hollow, pixelized cross section instead of circular), and the single-source dose superposition (instead of the multiple sources direct dose calculation). Approach. A finite volume approach was used to develop numerical schemes to simulate the DL model in one, two and three dimensions and obtain the spatial distributions of the emitters. The corresponding alpha dose distributions were calculated under the assumption of a local deposition of the alpha particles' energies. Variation ranges of the DL model parameters were based on previously published data. For each modeling approximation studied, the error and relative error on the alpha dose distribution were calculated and the displacement of the 10 Gy isodose was evaluated. Main results. Over realistic ranges, the desorption probabilities, diffusion lengths, and leakage probabilities respectively affect the position of the alpha particle 10 Gy isodose by ∼ 0.1 mm, ∼ 1.5 mm and ∼ 0.5 mm. The three modeling approximations studied have a negligible effect on the alpha particle 10 Gy isodose position, with displacements ≤ 0.01 mm. Significance. This work quantitatively evaluates the relative importance of different parameters and approximations in DaRT alpha dose calculations based on their impact not only on the dose variation at a given distance from the source but also on the displacement of clinically significant isodoses. .

Safety and Immunogenicity of Respiratory Syncytial Virus Prefusion F Protein Vaccine when Co-administered with Adjuvanted Seasonal Quadrivalent Influenza Vaccine in Older Adults: A Phase 3 Randomized Trial.

BACKGROUND: We evaluated co-administration of adjuvanted seasonal quadrivalent influenza vaccine (FLU-aQIV) and respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) in ≥65-year-olds. METHODS: This phase 3, open-label trial randomized ≥65-year-olds to receive FLU-aQIV and RSVPreF3 OA concomitantly (Co-Ad) or sequentially, 1 month apart (Control). Primary objectives were to demonstrate the non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration in terms of hemagglutination inhibition (HI) titers for each FLU-aQIV strain and RSV-A and RSV-B neutralization titers, 1 month post-vaccination. Reactogenicity and safety were also assessed. RESULTS: Overall, 1045 participants were vaccinated (Co-Ad: 523; Control: 522). Non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration was demonstrated in terms of HI titers for the A/Victoria(H1N1), B/Victoria, and B/Yamagata influenza strains and RSV-A neutralization titers (upper limits [ULs] of 95% confidence intervals [CIs] for adjusted geometric mean titer [GMT] ratios [Control/Co-Ad] ≤1.50) but not for A/Darwin(H3N2) HI titers (95% CI UL = 1.53). The immune response to A/Darwin(H3N2) was further assessed post-hoc using a microneutralization assay; the post-vaccination adjusted GMT ratio (Control/Co-Ad) was 1.23 (95% CI: 1.06-1.42, ie, UL ≤1.50), suggesting an adequate immune response to A/Darwin(H3N2) following co-administration. RSV-B neutralization titers were comparable between groups (95% CI UL for adjusted GMT ratio ≤1.50). Solicited adverse events were mostly mild or moderate and transient; unsolicited and serious adverse event rates were balanced between groups. CONCLUSIONS: Adjuvanted FLU-aQIV and RSVPreF3 OA had acceptable reactogenicity/safety profiles when co-administered in ≥65-year-olds, without clinically relevant interference with the immune responses to either vaccine. CLINICAL TRIALS REGISTRATION: NCT05568797.

Longitudinal Changes of Clinical, Imaging, and Fluid Biomarkers in Preataxic and Early Ataxic Spinocerebellar Ataxia Type 2 and 7 Carriers.

BACKGROUND AND OBJECTIVES: Brain MRI abnormalities and increases in neurofilament light chain (NfL) have mostly been observed in cross-sectional studies before ataxia onset in polyglutamine spinocerebellar ataxias. Our study aimed to identify longitudinal changes in biological, clinical, and/or imaging biomarkers in spinocerebellar ataxia (SCA) 2 and SCA7 carriers over 1 year. METHODS: We studied SCA2 and SCA7 carriers and controls (expansion-negative relatives) at the Paris Brain Institute. Inclusion criteria included Scale for the Assessment and Rating of Ataxia (SARA) scores between 0 and 15. Assessments at baseline, 6 months, and 12 months comprised neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations, along with gait and oculomotor recordings, brain MRI, CSF, and blood sampling. The primary outcome was the longitudinal change in these assessments over 1 year. RESULTS: We included 15 SCA2 carriers, 15 SCA7 carriers, and 10 controls between May 2020 and April 2021. At baseline, the ages were similar (41 [37, 46] for SCA2, 38 [28.5, 39.8] for SCA7, and 39.5 [31, 54.5] for controls, p = 0.78), as well the sex (p = 0.61); SARA scores were low but different (4 [1.25, 6.5] in SCA2, 2 [0, 11.5] in SCA7, and 0 in controls, p < 0.01). Pons and medulla volumes were smaller in SCAs (p < 0.05) and cerebellum volume only in SCA2 (p = 0.01). Plasma NfL levels were higher in SCA participants (SCA2: 14.2 pg/mL [11.52, 15.89], SCA7: 15.53 [13.27, 23.23]) than in controls (4.88 [3.56, 6.17], p < 0.001). After 1-year follow-up, in SCA2, there was significant pons (-144 ± 60 mm3) and cerebellum (-1,508 ± 580 mm3) volume loss and a worsening of gait assessment; in SCA7, SARA score significantly increased (+1.3 ± 0.4) and outer retinal nuclear layer thickness decreased (-15.4 ± 1.6 µm); for both SCA groups, the orofacial motor assessment significantly worsened. For preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7. DISCUSSION: Despite the limitation of the small sample size, we detected annual changes in preataxic and early ataxic SCA individuals across brain MRI imaging, clinical scores, gait parameters, and retinal thickness. These parameters could serve as potential end points for future therapeutic trials in the preataxic phase. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04288128.