Titanium Surface Characteristics Induce the Specific Reprogramming of Toll-like Receptor Signaling in Macrophages.

Most of the research on titanium-based dental implants (Ti-discs) is focused on how they are able to stimulate the formation of new tissue and/or cytotoxic studies, with very scarce data on their effects on functional responses by immunocompetent cells. In particular, the link between the rewiring of innate immune responses and surface biomaterials properties is poorly understood. To address this, we characterize the functional response of macrophage cultures to four different dental titanium surfaces (MA: mechanical abrasion; SB + AE: sandblasting plus etching; SB: sandblasting; AE: acid etching). We use different Toll-like receptor (TLR) ligands towards cell surface receptors (bacterial lipopolysaccharide LPS for TLR4; imiquimod for TLR7; synthetic bacterial triacylated lipoprotein for TLR2/TLR1) and endosomal membrane receptor (poly I:C for TLR3) to simulate bacterial (cell wall bacterial components) or viral infections (dsRNA and ssRNA). The extracellular and total LDH levels indicate that exposure to the different Ti-surfaces is not cytotoxic for macrophages under resting or TLR-stimulated conditions, although there is a tendency towards an impairment in macrophage proliferation, viability or adhesion under TLR4, TLR3 and TLR2/1 stimulations in SB discs cultures. The secreted IL-6 and IL-10 levels are not modified upon resting macrophage exposure to the Ti-surfaces studied as well as steady state levels of iNos or ArgI mRNA. However, macrophage exposure to MA Ti-surface do display an enhanced immune response to TLR4, TLR7 or TLR2/1 compared to other Ti-surfaces in terms of soluble immune mediators secreted and M1/M2 gene expression profiling. This change of characteristics in cellular phenotype might be related to changes in cellular morphology. Remarkably, the gene expression of Tlr3 is the only TLR that is differentially affected by distinct Ti-surface exposure. These results highlight the relevance of patterned substrates in dental implants to achieve a smart manipulation of the immune responses in the context of personalized medicine, cell-based therapies, preferential lineage commitment of precursor cells or control of tissue architecture in oral biology.

Application of Composite Spectrum in Agricultural Machines.

Composite spectrum (CS) is a data-fusion technique that reduces the number of spectra to be analyzed, simplifying the analysis process for machine monitoring and fault detection. In this work, vibration signals from five components of a combine harvester (thresher, chopper, straw walkers, sieve box, and engine) are obtained by placing four accelerometers along the combine-harvester chassis in non-optimal locations. Four individual spectra (one from each accelerometer) and three CS (non-coherent, coherent and poly-coherent spectra) from 18 cases are analyzed. The different cases result from the combination of three working conditions of the components-deactivated (off), balanced (healthy), and unbalanced (faulty)-and two speeds-idle and maximum revolutions per minute (RPM). The results showed that (i) the peaks can be identified in the four individual spectra that correspond to the rotational speeds of the five components in the analysis; (ii) the three formulations of the CS retain the relevant information from the individual spectra, thereby reducing the number of spectra required for monitoring and detecting rotating unbalances within a combine harvester; and, (iii) data noise reduction is observed in coherent and poly-coherent CS with respect to the non-coherent CS and the individual spectra. This study demonstrates that the rotating unbalances of various components within agricultural machines, can be detected with a reduced number of accelerometers located in non-optimal positions, and that it is feasible to simplify the monitoring with CS. Overall, the coherent CS may be the best composite spectra formulation in order to monitor and detect rotating unbalances in agricultural machines.

Spanish research in gender dysphoria: A review of more than 20 years of biomedical literature.

To provide a bibliometric and contents analyses of the Spanish research in the field of gender dysphoria based on a literature review.

Effect of Melatonin and Its Analogs on Tear Secretion.

Melatonin has been shown to enhance tear secretion associated with dinucleotide diadenosine tetraphosphate. This study investigated the isolated action of melatonin and its analogs, agomelatine, N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl) ethanamine (IIK7), and 5-methoxycarbonylamino-N-cetyltryptamine (5-MCA-NAT) (10 µl at 100 µM), on tear secretion when applied topically in the rabbit cornea and its relationship with the melatonin MT1, MT2, and MT3/quinone reductase QR2 receptors. The results showed a significant increase in tear secretion, with a maximal effect at 60 minutes for the agonists (138.9% ± 6.5%, 128.9% ± 6.4%, and 120.0% ± 5.2%, respectively; P < 0.05; 100% control) but not for melatonin (101.6% ± 7.9%; P > 0.05). Agonist action was tested combined with the antagonists DH97 (MT2 selective), prazosin (MT3/QR2 inhibitor), and luzindole (nonselective MT membrane receptor) (10 µl at 100 µM). DH97 reversed the effect of agomelatine, IIK7, and 5-MCA-NAT up to 30.85% ± 7.6%,108% ± 7.2%, and 87.01% ± 7.6%, respectively (P < 0.05; 100% control). Luzindole antagonized agomelatine and 5-MCA-NAT up to 67.35% ± 7.6% and 92.12% ± 8%, respectively (P < 0.05). Prazosin only reversed 5-MCA-NAT action up to 84.2% ± 7.7% (P < 0.05). These results suggest different pathways for the agonists to act through MT membrane receptors. Therefore, agomelatine, IIK7, and 5-MCA-NAT act through MT membrane receptors as secretagogues of tear secretion, and these analogs could be considered excellent therapeutic candidates for dry eye treatment. SIGNIFICANCE STATEMENT: Currently, dry eye with aqueous deficit is treated by adding artificial tears palliatively. This study shows that topical installation of three melatonin analogs (agomelatine, IIK7, and 5-MCA-NAT), but not melatonin, in therapeutic doses in the rabbit cornea significantly increases tear production, acting through different melatonin membrane receptor subtypes. Therefore, this study suggests that melatoninergic compounds could be considered excellent therapeutic candidates for dry eye treatment and ocular surface diseases occurring with a reduction in tear production.

In vitro cell response on CP-Ti surfaces functionalized with TGF-ß1 inhibitory peptides.

Osseointegration of implants is conversely related to the generation of a fibrous tissue capsule around the implant by the host environment. Although TGF-ß1 plays many roles in regeneration processes, it is the cytokine to be mostly associated to the production of fibrotic tissue and thus, its inhibition has demonstrated to be beneficial to prevent several fibrotic reactions. Surface biofunctionalization enables the immobilization of biologically active molecules on an implant surface to tailor the biological response of the host. Here, we studied in vitro biological effects of biofunctionalized CP-Ti surfaces with a TGF-ß1 inhibitor peptide, P144. A reliable biofunctionalization process that tethers P144 peptides to commercially pure titanium was developed. Differentiation of human mesenchymal stem cells, osteoblasts and fibroblasts on P144-functionalized and control surfaces was assessed at the gene expression and protein production levels. Results showed that P144-functionalized surfaces reduced expression and production of fibrotic differentiation markers and increased osteoblastic differentiation markers. Therefore, biofunctionalization of surfaces with TGF-ß1 inhibitor peptides are an alternative promising strategy for inducing osseointegration around medical devices and implants.

Modification of titanium surfaces by adding antibiotic-loaded PHB spheres and PEG for biomedical applications.

Novel researches are focused on the prevention and management of post-operative infections. To avoid this common complication of implant surgery, it is preferable to use new biomaterials with antibacterial properties. Therefore, the aim of this work is to develop a method of combining the antibacterial properties of antibiotic-loaded poly(3-hydroxybutyrate) (PHB) nano- and micro-spheres and poly(ethylene glycol) (PEG) as an antifouling agent, with titanium (Ti), as the base material for implants, in order to obtain surfaces with antibacterial activity. The Ti surfaces were linked to both PHB particles and PEG by a covalent bond. This attachment was carried out by firstly activating the surfaces with either Oxygen plasma or Sodium hydroxide. Further functionalization of the activated surfaces with different alkoxysilanes allows the reaction with PHB particles and PEG. The study confirms that the Ti surfaces achieved the antibacterial properties by combining the antibiotic-loaded PHB spheres, and PEG as an antifouling agent.

Bioactive macroporous titanium implants highly interconnected.

Intervertebral implants should be designed with low load requirements, high friction coefficient and low elastic modulus in order to avoid the stress shielding effect on bone. Furthermore, the presence of a highly interconnected porous structure allows stimulating bone in-growth and enhancing implant-bone fixation. The aim of this study was to obtain bioactive porous titanium implants with highly interconnected pores with a total porosity of approximately 57 %. Porous Titanium implants were produced by powder sintering route using the space holder technique with a binder phase and were then evaluated in an in vivo study. The size of the interconnection diameter between the macropores was about 210 µm in order to guarantee bone in-growth through osteblastic cell penetration. Surface roughness and mechanical properties were analyzed. Stiffness was reduced as a result of the powder sintering technique which allowed the formation of a porous network. Compression and fatigue tests exhibited suitable properties in order to guarantee a proper compromise between mechanical properties and pore interconnectivity. Bioactivity treatment effect in novel sintered porous titanium materials was studied by thermo-chemical treatments and were compared with the same material that had undergone different bioactive treatments. Bioactive thermo-chemical treatment was confirmed by the presence of sodium titanates on the surface of the implants as well as inside the porous network. Raman spectroscopy results suggested that the identified titanate structures would enhance in vivo apatite formation by promoting ion exchange for the apatite formation process. In vivo results demonstrated that the bioactive titanium achieved over 75 % tissue colonization compared to the 40 % value for the untreated titanium.

Roughness and wettability effect on histological and mechanical response of self-drilling orthodontic mini-implants.

OBJECTIVES: Self-drilling orthodontic mini-implants can be used as temporary devices for orthodontic treatments. Our main goal was to evaluate surface characteristics, roughness and wettability, of surface modified mini-implants to increase their stability during orthodontic treatment without inducing bone fracture and tissue destruction during unscrewing. MATERIALS AND METHODS: Modified mini-implants by acid etching, grit-blasting and its combination were implanted in 20 New Zealand rabbits during 10 weeks. After that, the bone-to-implant (BIC) parameter was determined and the torque during unscrewing was measured. The surface characteristics, roughness and wettability, were also measured, onto modified Ti c.p. discs. RESULTS: Acid-etched mini-implants (R a ≈ 1.7 µm, contact angle (CA) ≈ 66°) significantly improved the bone-to-implant parameter, 26 %, compared to as-machined mini-implants (R a ≈ 0.3 µm, CA ≈ 68°, BIC = 19 %) due to its roughness. Moreover, this surface treatment did not modify torque during unscrewing due to their statistically similar wettability (p > 0.05). Surface treatments with higher roughness and hydrophobicity (R a ≈ 4.5 µm, CA ≈ 74°) lead to a greater BIC and to a higher removal torque during unscrewing, causing bone fracture, compared to as-machined mini-implants. CONCLUSIONS: Based on these in vivo findings, we conclude that acid-etching surface treatment can support temporary anchoring of titanium mini-implants. CLINICAL RELEVANCE: This treatment represents a step forward in the direction of reducing the time prior to mini-implant loading by increasing their stability during orthodontic treatment, without inducing bone fracture and tissue destruction during unscrewing.

Advances in surfaces and osseointegration in implantology. Biomimetic surfaces.

The present work is a revision of the processes occurring in osseointegration of titanium dental implants according to different types of surfaces -namely, polished surfaces, rough surfaces obtained from subtraction methods, as well as the new hydroxyapatite biomimetic surfaces obtained from thermochemical processes. Hydroxyapatite's high plasma-projection temperatures have proven to prevent the formation of crystalline apatite on the titanium dental implant, but lead to the formation of amorphous calcium phosphate (i.e., with no crystal structure) instead. This layer produce some osseointegration yet the calcium phosphate layer will eventually dissolve and leave a gap between the bone and the dental implant, thus leading to osseointegration failure due to bacterial colonization. A new surface -recently obtained by thermochemical processes- produces, by crystallization, a layer of apatite with the same mineral content as human bone that is chemically bonded to the titanium surface. Osseointegration speed was tested by means of minipigs, showing bone formation after 3 to 4 weeks, with the security that a dental implant can be loaded. This surface can be an excellent candidate for immediate or early loading procedures.

Biomimetic treatment on dental implants for short-term bone regeneration.

OBJECTIVES: The main purpose of this work was to assess the short-term bone regenerative potential of new osteoconductive implants. The novelty of the study lies in the analysis of the effectiveness of a novel two-step treatment which combines shot-blasting with a thermo-chemical treatment, at very short times after implant placement in a minipig model. MATERIALS AND METHODS: Three hundred twenty implants with four different surface treatments, namely bioactivated surfaces, micro-rough grit-blasted, micro-rough acid-etched and smooth as-machined titanium implants were placed into the bone of 20 minipigs. The percent of bone-to-implant contact was determined 3 days, 1, 2, 3 and 10 weeks after implant placement by histomorphometric analysis. Surface composition, topography and wettability of the implant specimens were analysed. RESULTS: The combination of shot-blasting and thermo-chemical treatment accelerated bone regeneration at early stages in comparison with all other treatments between day 3 and week 3 (p < 0.05). The value of osseointegration attained at week 2 was maintained until the end of the experiment without any significant changes (percent direct contact ≈ 85 %). This was mostly attributed to the ability of these implants to form in vivo a layer of apatitic mineral that coated the implant and could rapidly stimulate bone nucleation and growth from the implant surface. CONCLUSIONS: The surface quality resulting from this treatment on cpTi provided dental implants with a unique ability of rapid bone regeneration and osseointegration. CLINICAL RELEVANCE: This treatment represents a step forward in the direction of reducing the time prior to implant loading.

The influence of tractor-seat height above the ground on lateral vibrations.

Farmers experience whole-body vibrations when they drive tractors. Among the various factors that influence the vibrations to which the driver is exposed are terrain roughness, tractor speed, tire type and pressure, rear axle width, and tractor seat height above the ground. In this paper the influence of tractor seat height above the ground on the lateral vibrations to which the tractor driver is exposed is studied by means of a geometrical and an experimental analysis. Both analyses show that: (i) lateral vibrations experienced by a tractor driver increase linearly with tractor-seat height above the ground; (ii) lateral vibrations to which the tractor driver is exposed can equal or exceed vertical vibrations; (iii) in medium-size tractors, a feasible 30 cm reduction in the height of the tractor seat, which represents only 15% of its current height, will reduce the lateral vibrations by around 20%; and (iv) vertical vibrations are scarcely influenced by tractor-seat height above the ground. The results suggest that manufacturers could increase the comfort of tractors by lowering tractor-seat height above the ground, which will reduce lateral vibrations.

An SVM-based classifier for estimating the state of various rotating components in agro-industrial machinery with a vibration signal acquired from a single point on the machine chassis.

The goal of this article is to assess the feasibility of estimating the state of various rotating components in agro-industrial machinery by employing just one vibration signal acquired from a single point on the machine chassis. To do so, a Support Vector Machine (SVM)-based system is employed. Experimental tests evaluated this system by acquiring vibration data from a single point of an agricultural harvester, while varying several of its working conditions. The whole process included two major steps. Initially, the vibration data were preprocessed through twelve feature extraction algorithms, after which the Exhaustive Search method selected the most suitable features. Secondly, the SVM-based system accuracy was evaluated by using Leave-One-Out cross-validation, with the selected features as the input data. The results of this study provide evidence that (i) accurate estimation of the status of various rotating components in agro-industrial machinery is possible by processing the vibration signal acquired from a single point on the machine structure; (ii) the vibration signal can be acquired with a uniaxial accelerometer, the orientation of which does not significantly affect the classification accuracy; and, (iii) when using an SVM classifier, an 85% mean cross-validation accuracy can be reached, which only requires a maximum of seven features as its input, and no significant improvements are noted between the use of either nonlinear or linear kernels.

Experimental study and geometrical method to design bio-inspired robotic kinematic chains of inching-locomotion caterpillars.

Inching-locomotion caterpillars (ILAR) show impressive environmental adaptation, having high dexterity and flexibility. To design robots that mimic these abilities, a novel bioinspired robotic design (BIROD) method is presented. The method is composed by an algorithm for geometrical kinematic analysis (GEKINS) to standardize the proportional dimensions according to the insect's anatomy and obtain the kinematic chains. The approach is experimentally applied to analyze the locomotion and kinematic chain of these specimens:Geometridae-two pair of prolegs (represents 35 000 species) andPlusiinae-three pair of prolegs (represents 400 species). The obtained data indicate that the application of the proposed method permits to locate the attachment mechanisms, joints, links, and to calculate angular displacement, angular average velocity, number of degrees of freedom, and thus the kinematic chain.Geometridaein contrast toPlusiinae, shows a longer walk-stride length, a lower number of single-rotational joints in 2D (3 DOF versus 4 DOF), and a lower number of dual-rotational joints in 3D (6 DOF versus 8 DOF). The application of BIROD and GEKINS provides the forward kinematics for 35 400 ILAR species and are expected to be useful as a preliminary phase for the design of bio-inspired arthropod robots.

Bio-inspired design of hard-bodied mobile robots based on arthropod morphologies: a 10-year systematic review and bibliometric analysis.

This research presents a 10-year systematic review based on bibliometric analysis of the bio-inspired design of hard-bodied mobile robot mechatronic systems considering the anatomy of arthropods. These are the most diverse group of animals whose flexible biomechanics and adaptable morphology, thus, it can inspire robot development. Papers were reviewed from two international databases (Scopus and Web of Science) and one platform (Aerospace Research Central), then they were classified according to: year of publication (January 2013 to April 2023), arthropod group, published journal, conference proceedings, editorial publisher, research teams, robot classification according to the name of arthropod, limb's locomotion support, number of legs/arms, number of legs/body segments, limb's degrees of freedom, mechanical actuation type, modular system, and environment adaptation. During the screening, more than 33000 works were analyzed. Finally, a total of 174 studies (90 journal-type, 84 conference-type) were selected for in-depth study: Insecta - hexapod (53,8%), Arachnida - octopods (20.7%), Crustacea - decapods (16,1%), and Myriapoda - centipedes and millipedes (9,2%). The study reveals that the most active editorials are the Institute of Electrical and Electronics Engineers Inc., Springer, MDPI, and Elsevier, while the most influential researchers are located in the USA, China, Singapore, and Japan. Most works pertained to spiders, crabs, caterpillars, cockroaches, and centipedes. We conclude that "arthrobotics" research, which merges arthropods and robotics, is constantly growing and includes a high number of relevant studies with findings that can inspire new methods to design biomechatronic systems.

A Kalman filter implementation for precision improvement in low-cost GPS positioning of tractors.

Low-cost GPS receivers provide geodetic positioning information using the NMEA protocol, usually with eight digits for latitude and nine digits for longitude. When these geodetic coordinates are converted into Cartesian coordinates, the positions fit in a quantization grid of some decimeters in size, the dimensions of which vary depending on the point of the terrestrial surface. The aim of this study is to reduce the quantization errors of some low-cost GPS receivers by using a Kalman filter. Kinematic tractor model equations were employed to particularize the filter, which was tuned by applying Monte Carlo techniques to eighteen straight trajectories, to select the covariance matrices that produced the lowest Root Mean Square Error in these trajectories. Filter performance was tested by using straight tractor paths, which were either simulated or real trajectories acquired by a GPS receiver. The results show that the filter can reduce the quantization error in distance by around 43%. Moreover, it reduces the standard deviation of the heading by 75%. Data suggest that the proposed filter can satisfactorily preprocess the low-cost GPS receiver data when used in an assistance guidance GPS system for tractors. It could also be useful to smooth tractor GPS trajectories that are sharpened when the tractor moves over rough terrain.

Titanium Boston keratoprosthesis with corneal cell adhesive and bactericidal dual coating.

The Boston keratoprosthesis (BKPro) is a medical device used to restore vision in complicated cases of corneal blindness. This device is composed by a front plate of polymethylmethacrylate (PMMA) and a backplate usually made of titanium (Ti). Ti is an excellent biomaterial with numerous applications, although there are not many studies that address its interaction with ocular cells. In this regard, despite the good retention rates of the BKPro, two main complications compromise patients' vision and the viability of the prosthesis: imperfect adhesion of the corneal tissue to the upside of the backplate and infections. Thus, in this work, two topographies (smooth and rough) were generated on Ti samples and tested with or without functionalization with a dual peptide platform. This molecule consists of a branched structure that links two peptide moieties to address the main complications associated with BKPro: the well-known RGD peptide in its cyclic version (cRGD) as cell pro-adherent motif and the first 11 residues of lactoferrin (LF1-11) as antibacterial motif. Samples were physicochemically characterized, and their biological response was evaluated in vitro with human corneal keratocytes (HCKs) and against the gram-negative bacterial strain Pseudomonas aeruginosa. The physicochemical characterization allowed to verify the functionalization in a qualitative and quantitative manner. A higher amount of peptide was anchored to the rough surfaces. The studies performed using HCKs showed increased long-term proliferation on the functionalized samples. Gene expression was affected by topography and peptide functionalization. Roughness promoted α-smooth muscle actin (α-SMA) overexpression, and the coating notably increased the expression of extracellular matrix components (ECM). Such changes may favour the development of unwanted fibrosis, and thus, corneal haze. In contrast, the combination of the coating with a rough topography decreased the expression of α-SMA and ECM components, which would be desirable for the long-term success of the prosthesis. Regarding the antibacterial activity, the functionalized smooth and rough surfaces promoted the death of bacteria, as well as a perturbation in their wall definition and cellular morphology. Bacterial killing values were 58 % for smooth functionalised and 68 % for rough functionalised samples. In summary, this study suggests that the use of the dual peptide platform with cRGD and LF1-11 could be a good strategy to improve the in vitro and in vivo performance of the rough topography used in the commercial BKPro.

Is the Increase in Record of Skin Wounds in Hospitalized Patients in Internal Medicine Units a Side Effect of the COVID-19 Pandemic?

Wound care is an important public health challenge that is present in all areas of the healthcare system, whether in hospitals, long term care institutions or in the community. We aimed to quantify the number of skin wounds reported after and during the COVID-19 pandemic. This descriptive longitudinal retrospective study compared of wound records in patients hospitalized in the internal medicine service during the first year of the COVID-19 pandemic (from 1 March 2020, to 28 February 2021) and previous-year to the outbreak (from 1 January 2019, to 31 December 2019). A sample of 1979 episodes was collected corresponding to 932 inpatients, 434 from the pre-pandemic year and 498 from the first year of COVID-19 pandemic; 147 inpatients were diagnosed with SARS-CoV-2 infection (3.2%). The percentage of wound episodes in the first year of the COVID-19 pandemic was higher than the pre-pandemic year, 17.9% (1092/6090) versus 15% (887/5906), with a significant increase in the months with the highest incidence of COVID cases. This study shows an increase in the burden of wound care during the COVID-19 pandemic, and it could be attributable to the increase in the number of patients hospitalized for SARS-CoV-2 infection in internal medicine units.

Contact Lenses Loaded with Melatonin Analogs: A Promising Therapeutic Tool against Dry Eye Disease.

Melatonin analogs topically administered evoke a potent tear secretagogue effect in rabbits. This route of drug administration requires high drug concentration and frequent dosing due to its reduced ocular surface retention. Therefore, contact lenses (CLs) have emerged as an alternative drug-delivery system that prolongs drug retention in the cornea, improving its therapeutic performance. This study explores the in vitro ability of five commercially available hydrogel CLs to act as a delivery system for melatonin analogs and the in vivo secretagogue effect of melatonin analog-loaded CLs. We soaked CLs with melatonin or melatonin analog solutions (1 mM) for 12 h. Spectroscopic assays showed that IIK7-loaded CLs led to the inadequate delivery of this compound. Conventional hydrogel lenses loaded with agomelatine released more agomelatine than silicone ones (16-33% more). In contrast, the CLs of silicone materials are more effective as a delivery system of 5-MCA-NAT than CLs of conventional materials (24-29%). The adaptation of CLs loaded with agomelatine or 5-MCA-NAT in rabbits triggered a higher tear secretion than the corresponding eye drops (78% and 59% more, respectively). These data suggest that CLs preloaded with melatonin analogs could be an adequate strategy to combat aqueous tear deficient dry eye disease.

ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850-4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.