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Juliana Nicolino,1 Dionei Ramos,1 Marceli Rocha Leite,1 Fernanda Maria Machado Rodrigues,1 Bruna Spolador de Alencar Silva,1 Guilherme Yassuyuki Tacao,1 Alessandra Choqueta de Toledo,2 Luiz Carlos Marques Vanderlei,1 Ercy Mara Cipulo Ramos1 1Department of Physiotherapy, Paulista State University (UNESP), Presidente Prudente, São Paulo, Brazil; 2Department of Pathology, School of Medicine of the University of São Paulo, São Paulo, Brazil Purpose: Physical exercises are employed as part of the treatment of patients with chronic obstructive pulmonary disease (COPD); however information regarding cardiac autonomic modulation after an acute session of resistance exercise (RE) is unknown. The aim of this study was to evaluate the cardiac autonomic modulation, via heart rate variability after an acute session of RE applied at different intensities in COPD patients. Patients and methods: Twelve COPD patients underwent an acute session of RE with an intensity of 60% and another of 90% of the one repetition maximum test. For analysis of autonomic modulation, heart rate was recorded beat-by-beat for 20 minutes at rest and after the training session. Heart rate variability indexes were obtained in the time and frequency domains for the assessment of autonomic modulation. Results: Regardless of exercise intensity, RE acute sessions influenced the autonomic modulation when the recovery period was compared with the baseline. An increase in standard deviation of normal to normal RR intervals was observed throughout recovery time after the RE, as compared to baseline in both protocols: 60% and 90% of the one repetition maximum test. The spectral component of low frequency index (ms) was higher throughout recovery when compared to baseline in both protocols. The same was also observed in the spectral component of high frequency index (ms) for the protocols of 60% and 90%. Conclusion: RE sessions impact on the autonomic modulation of COPD patients by promoting differences in the recovery period compared to baseline, regardless of the intensity of the exercise performed. Keywords: heart rate variability, autonomic nervous system, sympathetic nervous system, parasympathetic nervous system, physical exercise

IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

IntroductionLeisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsA total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.ResultsGreater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.DiscussionActive lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Isis Grigoletto,1 Fabiano Francisco de Lima,2 Daniele Akemi Eto,1 Natália Narumi Voltareli Suzuki,1 Juliana Souza Uzeloto,1 Ercy Mara Cipulo Ramos1 1Department of Physical Therapy, São Paulo State University (UNESP), Faculty of Science and Technology, Presidente Prudente, São Paulo, Brazil; 2Department of Physical Therapy, Speech and Occupational Therapy, School of Medicine, University of São Paulo (USP), São Paulo, São Paulo, BrazilCorrespondence: Isis Grigoletto, Department of Physical Therapy, São Paulo State University (UNESP), Faculty of Science and Technology, 305, Roberto Simonsen St, Presidente Prudente, SP, 19060-900, Brazil, Tel +55 18 3229 5821, Email isis.grigoletto@unesp.brPurpose: To verify, through quali-quantitative analysis, the satisfaction and adherence of patients with Chronic Obstructive Pulmonary Disease (COPD) to the insertion of functional circuit training into conventional training.Patients and Methods: 23 patients with COPD from a randomized clinical trial were invited to participate in a quali-quantitative analysis after the training finalization, divided into FTG (Functional Training Group) and CTG (Conventional Training Group). A total of 21 patients participated [(FTG: n=10; 65.80± 7.31 years; FEV1/FVC: 56.44± 12.67%) and CTG (n=11; 70.36± 7.02 years; FEV1/FVC: 55.89± 8.20)]. For the qualitative evaluation, focus groups were performed, using a previously developed script. Adherence was verified by the presence in the training sessions that were prescribed, and the quantitative analysis was performed using questionnaires with multiple-choice questions (evaluation of the aspects that can interfere in a training). The participants were asked to define a grade between zero and ten regarding the aspects of the training (satisfaction).Results: In both groups, there was similar adherence (p=0.965) and satisfaction (p=0.341). The qualitative analysis identified seven themes and 17 codes, representing factors related to satisfaction and negative aspects, as follows: factors associated with satisfaction: self-efficacy management, physical and psychosocial improvement, interpersonal relationships, and proposed exercises. Negative aspects: pains, comorbidities, beliefs, and personal demotivation. In the quantitative analysis, was verified that an increase in the symptoms, the distance between home and training center, and personal problems were not factors that interfered in the adherence of the participants (p< 0.05).Conclusion: Similar satisfaction and adherence of patients with COPD were observed in the FTG and CTG and patients from FTG reported higher fatigue.Keywords: Chronic Obstructive Pulmonary Disease, physical exercise, patient satisfaction, patient adherence, qualitative research, quantitative evaluation

Juliana Souza Uzeloto,1 Alessandra Choqueta de Toledo-Arruda,2 Bruna Spolador de Alencar Silva,1 Marjorie de Assis Golim,3 Aline Márcia Marques Braz,3 Fabiano Francisco de Lima,1 Isis Grigoletto,1 Ercy Mara Cipulo Ramos1 1São Paulo State University (UNESP), Faculty of Science and Technology, Department of Physiotherapy, Postgraduate Program in Physiotherapy, Presidente Prudente, São Paulo, Brazil; 2Department of Physiotherapy, Federal University of Rio de Janeiro, Rio De Janeiro, Brazil; 3São Paulo State University (UNESP), Botucatu Medical School, Postgraduate Program in Research & Development: Medical Biotechnology, Blood Center, Flow Cytometry Laboratory, Botucatu, São Paulo, BrazilCorrespondence: Juliana Souza Uzeloto Email juliana_uzeloto@hotmail.comAims: To evaluate the expressions of intracellular cytokines in CD4+ T lymphocytes and to investigate the correlation between biomarker expressions and clinical and functional characteristics of stable COPD patients.Patients and Methods: Peripheral blood was collected from 36 COPD patients, and the expression of cytokines (IL-8, IL-13, IL-17, IL-6, IL-2, IL-10, and TNF-α) in T lymphocytes CD4 + was investigated. In addition, lung function, dyspnea symptoms, quality of life, vital signs, body composition, level of physical activity, peripheral muscle strength, and functional capacity were assessed.Results: Individuals with greater bronchial obstruction present a higher proportion of CD4 + IL-2 + lymphocytes compared to individuals with less severe bronchial obstruction. We found a positive correlation between the expression of the cytokines IL-13, IL-17, IL-6, IL-2, IL-10, and TNF-α in CD4+ T lymphocytes. In addition, we found a positive correlation between CD4+ IL-10+ T lymphocytes and lower limb muscle strength and a negative correlation between CD4+ IL-8+ T lymphocytes and peripheral oxygen saturation and steps per day.Conclusion: Systemic CD4+IL-2+, IL-8+, and IL-10+ T lymphocytes presented a correlation with clinical characteristics and functional status in stable COPD.Keywords: chronic obstructive pulmonary disease, inflammation, phenotype, flow cytometry

The Clinical Genome Resource (ClinGen) is a National Institutes of Health (NIH)-funded collaborative program that brings together a variety of projects designed to provide high-quality, curated information on clinically relevant genes and variants. ClinGen's EHR (Electronic Health Record) Workgroup aims to ensure that ClinGen is accessible to providers and patients through EHR and related systems. This article describes the current scope of these efforts and progress to date. The ClinGen public portal can be accessed at . [ABSTRACT FROM AUTHOR]

Marceli Rocha Leite,1 Ercy Mara Cipulo Ramos,1 Carlos Augusto Kalva-Filho,2 Ana Paula Coelho Figueira Freire,1 Bruna Spolador de Alencar Silva,1 Juliana Nicolino,1 Alessandra Choqueta de Toledo-Arruda,3 Marcelo Papoti,4 Luiz Carlos Marques Vanderlei,1 Dionei Ramos1 1Department of Physiotherapy, São Paulo State University, Presidente Prudente, 2Program in Rehabilitation and Functional Performance, São Paulo University, Ribeirão Preto, 3Department of Medicine, São Paulo University, 4School of Physical Education and Sport of Ribeirão Preto, São Paulo University, Ribeirão Preto, São Paulo, Brazil Introduction: Patients with chronic obstructive pulmonary disease (COPD) exhibit aerobic function, autonomic nervous system, and mucociliary clearance alterations. These parameters can be attenuated by aerobic training, which can be applied with continuous or interval efforts. However, the possible effects of aerobic training, using progressively both continuous and interval sessions (ie, linear periodization), require further investigation.Aim: To analyze the effects of 12-week aerobic training using continuous and interval sessions on autonomic modulation, mucociliary clearance, and aerobic function in patients with COPD.Methods: Sixteen patients with COPD were divided into an aerobic (continuous and interval) training group (AT) (n=10) and a control group (CG) (n=6). An incremental test (initial speed of 2.0 km·h-1, constant slope of 3%, and increments of 0.5 km·h-1 every 2 minutes) was performed. The training group underwent training for 4 weeks at 60% of the peak velocity reached in the incremental test (vVO2peak) (50 minutes of continuous effort), followed by 4 weeks of sessions at 75% of vVO2peak (30 minutes of continuous effort), and 4 weeks of interval training (5×3-minute effort at vVO2peak, separated by 1 minute of passive recovery). Intensities were adjusted through an incremental test performed at the end of each period.Results: The AT presented an increase in the high frequency index (ms2) (P=0.04), peak oxygen uptake (VO2peak) (P=0.01), vVO2peak (P=0.04), and anaerobic threshold (P=0.02). No significant changes were observed in the CG (P>0.21) group. Neither of the groups presented changes in mucociliary clearance after 12 weeks (AT: P=0.94 and CG: P=0.69).Conclusion: Twelve weeks of aerobic training (continuous and interval sessions) positively influenced the autonomic modulation and aerobic parameters in patients with COPD. However, mucociliary clearance was not affected by aerobic training. Keywords: COPD, exercise, aerobic treatment, mucociliary clearance

Dionei Ramos,1 Giovana Navarro Bertolini,1 Marceli Rocha Leite,1 Luiz Carlos Soares Carvalho Junior,1 Paula Roberta da Silva Pestana,1 Vanessa Ribeiro dos Santos,2 Ana Claudia de Souza Fortaleza,2 Fernanda Maria Machado Rodrigues,1 Ercy Mara Cipulo Ramos1 1Department of Physiotherapy, São Paulo State University, Presidente Prudente, Brazil; 2Department of Motricity Sciences, São Paulo State University, Rio Claro, Brazil Introduction: Sarcopenia is characterized by a progressive and generalized decrease of strength and muscle mass. Muscle mass loss is prevalent in patients with chronic obstructive pulmonary disease (COPD) as a result of both the disease and aging. Some methods have been proposed to assess body composition (and therefore identify muscle mass loss) in this population. Despite the high accuracy of some methods, they require sophisticated and costly equipment.Aim: The purpose of this study was to infer the occurrence of muscle mass loss measured by a sophisticated method (dual energy X-ray absorptiometry [DEXA]) using a more simple and affordable equipment (dynamometer).Methods: Fifty-seven stable subjects with COPD were evaluated for anthropometric characteristics, lung function, functional exercise capacity, body composition, and peripheral muscle strength. A binary logistic regression model verified whether knee-extension strength (measured by dynamometry) could infer muscle mass loss (from DEXA).Results: Patients with decreased knee-extension strength were 5.93 times more likely to have muscle mass loss, regardless of sex, disease stage, and functional exercise capacity (P=0.045).Conclusion: Knee-extension dynamometry was able to infer muscle mass loss in patients with COPD. Keywords: COPD, sarcopenia, peripheral muscle strength

Introduction: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD)., Methods: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing., Results: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories., Discussion: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD., Highlights: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Frequencies of pharmacogenetic (PGx) variants are known to differ substantially across populations but much of the available PGx literature focuses on one or a few population groups, often defined in nonstandardized ways, or on a specific gene or variant. Guidelines produced by the Clinical Pharmacogenetic Implementation Consortium (CPIC) provide consistent methods of literature extraction, curation, and reporting, including comprehensive curation of allele frequency data across nine defined "biogeographic groups" from the PGx literature. We extracted data from 23 CPIC guidelines encompassing 19 genes to compare the sizes of the populations from each group and allele frequencies of altered function alleles across groups. The European group was the largest in the curated literature for 16 of the 19 genes, while the American and Oceanian groups were the smallest. Nearly 200 alleles were detected in nonreference groups that were not reported in the largest (reference) group. The genes CYP2B6 and CYP2C9 were more likely to have higher frequencies of altered function alleles in nonreference groups compared to the reference group, while the genes CYP4F2, DPYD, SLCO1B1, and UGT1A1 were less likely to have higher frequencies in nonreference groups. PGx allele frequencies and function differ substantially across nine biogeographic groups, all but two of which are underrepresented in available PGx data. Awareness of these differences and increased efforts to characterize the breadth of global PGx variation are needed to ensure that implementation of PGx-guided drug selection does not further widen existing health disparities among populations currently underrepresented in PGx data., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Sous vide meat is an emerging food category, the consumption of which has increased owing to greater convenience, sensory traits, elderly consumers acceptance, and low-cost cuts use. However, required prolonged thermal treatment to achieve desired tenderness, impact energy-consumption besides triggering lipid oxidation, undesired off-flavors, and cooked meat profiles. Using a response surface methodology (RSM), this study evaluated the effects of the vegetal proteolytic papain (0 to 20 mg/kg) and low-temperature sous vide cooking (SVC) time (1 to 8 h at 65°C) in low-value marinated M. semitendinosus beefsteaks on technological characteristics associated with tenderness, and lipid oxidation. Additionally, the sensory profile traits of the pre-selected treatments were described using check-all-that-apply (CATA) and preference mapping. Shear force (WBsSF) was reduced with greater papain addition, whereas higher cooking losses (CL) were observed with longer SVC cooking times. Both the released total collagen and TBARS values increased with increasing papain concentrations and SVC times. Combining high levels of papain (>10 mg/kg) and SVC time (>6 h) resulted in lower WBsSF values (<20 N) but higher CL (>27%) and the CATA descriptors "aftertaste" and "mushy." The optimized conditions (14 mg/kg papain; 2 h SVC) also reduced WBsSF values (<26 N) with lower CL (<20%) and were most preferred and described as "juicy" and "tender" by consumers. Observed results suggest that combined mild SVC and papain may potentiate tenderness, conjointly favor juiciness and oxidation, further representing a promising tool for reducing SVC time without compromising valued sous vide sensory traits., (© 2024 Wiley Periodicals LLC.)

Novel shelf-stable and high-protein meat products that are affordable, convenient, and healthy are hot topic in current food innovation trends. To offer technological databases for developing new functional lamb meat products, this study aimed to evaluate the technological and sensory aspects of dry-cured lamb meat snacks incorporated with the probiotic culture Lactobacillus paracasei and the prebiotic lactulose. Four formulations were analyzed: control (without prebiotic or probiotic); PREB (with 2% lactulose); PROB (with 10 7  CFU/g of L. paracasei); and SYMB (with 2% lactulose and 10 7  CFU/g of L. paracasei). Fitted curves revealed that weight-loss behavior during snack ripening was not affected (P > 0.05) by treatments. Snack moisture, water activity, pH, titratable acidity, lipid oxidation, and residual nitrite were affected (P < 0.05) only by ripening time. The target probiotic strain stood out against competitive flora and was detected at 10 7  CFU/g in the snack-supplemented formulations (PROB and SYMB). In snacks supplemented with prebiotics (PREB and SYMB), the lactulose content was maintained at 2.17%. Significant differences were not observed in the chemical composition, texture profiles, and CIE color indices between the proposed functional snacks and the control. In addition to texture, flavor, and overall impression evaluation, only color attributes were positively impacted (P < 0.05) in the acceptance and multiple comparison tests against the control. The proposed formulation and bench process parameters produced potential nutritionally and sensory-appreciated, microbiologically stable, and safe (multi-hurdle perspective) functional high-protein restructured lamb snacks., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown., Objective: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD., Methods: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age., Results: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases)., Conclusions: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change., (©Emily W Paolillo, Kaitlin B Casaletto, Annie L Clark, Jack C Taylor, Hilary W Heuer, Amy B Wise, Sreya Dhanam, Mark Sanderson-Cimino, Rowan Saloner, Joel H Kramer, John Kornak, Walter Kremers, Leah Forsberg, Brian Appleby, Ece Bayram, Andrea Bozoki, Danielle Brushaber, R Ryan Darby, Gregory S Day, Bradford C Dickerson, Kimiko Domoto-Reilly, Fanny Elahi, Julie A Fields, Nupur Ghoshal, Neill Graff-Radford, Matthew G H Hall, Lawrence S Honig, Edward D Huey, Maria I Lapid, Irene Litvan, Ian R Mackenzie, Joseph C Masdeu, Mario F Mendez, Carly Mester, Toji Miyagawa, Georges Naasan, Belen Pascual, Peter Pressman, Eliana Marisa Ramos, Katherine P Rankin, Jessica Rexach, Julio C Rojas, Lawren VandeVrede, Bonnie Wong, Zbigniew K Wszolek, Bradley F Boeve, Howard J Rosen, Adam L Boxer, Adam M Staffaroni, ALLFTD Consortium. Originally published in JMIR Aging (https://aging.jmir.org), 26.06.2024.)

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.

Competing Interests: The authors declare no conflicts of interest.

This study aimed to evaluate the use of freezing/thawing as a way of accelerating the aging processes of beef from Nellore animals. Non-frozen (NF) or freezing/thawing (FT) strip loins were aged (for 14 and 28 days) using two systems: bone-in dry-aging (DA); boneless wet-aging (WA). FT-treated samples had greater weight losses (P < 0.05) during aging than NF-treated samples, especially using the DA process. However, the weight loss of the FT 14-days DA beef samples was comparable to that of NF 28-days DA. FT beef had lower fragmentation index and shear force values (P < 0.05), as well as its maximum sensorial tenderness was achieved earlier (P < 0.05) than the NF counterpart. With 28 days of aging, DA beef showed higher (P < 0.05) tenderness and juiciness scores and lower lightness values than WA beef. The FT process decreased the reducing capacity of meat samples, generating more metmyoglobin and lower amounts of chroma than NF. The expected volatile profile of DA beef was achieved faster in FT-treated samples, but the freezing treatments did not compromise the microbial count for either aging system. Our findings indicate that accelerated DA by the FT process could improve the palatability of Nellore beef, allowing the desired tenderness and flavor profile to be achieved in a shorter time, without increasing costs with weight losses or adversely affecting physicochemical, chemical, and microbial characteristics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Increasing physical activity in daily life (PADL) in chronic obstructive pulmonary disease (COPD), mainly in short-term training programs, is still a challenge. The combination of functional exercises with aerobic and resistance training may be a strategy to improve PADL and limitations in activities of daily living (ADL) in COPD., Objective: To evaluated the short- and medium-term effects of the combination of functional exercises with aerobic and resistance training., Methods: Seventy-six patients were randomized into (1) functional training group who performed resistance and aerobic and functional exercises; (2) conventional training group (CTG) who performed resistance and aerobic exercise; or (3) usual care group who performed respiratory physiotherapy. Patients were evaluated for PADL (activity monitor), ADL limitations (London Chest Activity of Daily Living scale [LCADL]), functional exercise capacity (6-minute walk test [6MWT]), and peripheral muscle strength before and after eight weeks. Medium-term effects were evaluated 12 weeks after the training., Results: There were no changes or differences between groups in PADL and in 6MWT post-intervention and 12 weeks post-training. Only CTG showed a reduction in the total score on LCADL scale after the intervention and increase at follow-up (score: 20 ± 8; 17 ± 6; 19 ± 8, pre-intervention, post-intervention, and 12 weeks post-training, respectively, p = 0.001), without differences between groups ( p = 0.375). There were increases in the muscle strength of knee flexors ( p = 0.016) and extensors ( p < 0.001) after the intervention only in CTG., Conclusions: Combined aerobic and resistance training with functional exercises failed to improve PADL and ADL limitations in COPD. Eight weeks of conventional training improved ADL. This, however, was not superior to the results from the other groups and was not sustained at medium-term 12 weeks post-training.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD., Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations., Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes., Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests., Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy., Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (β = -0.14 [95% CI, -0.42 to 0.14]; P = .32)., Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

In this study, an active films of polyvinyl alcohol (PVA) films, incorporated with sodium nitrite were developed, characterized and applied to pork stored for six days at 25 °C. As for the film characterization by FTIR, no chemical interactions were observed between nitrite and PVA under the studied conditions. The physical properties of the PVA films were not altered by the presence of nitrite. PVA films incorporated with 100 ppm nitrite reduced TBARS values of refrigerated pork from 0.63 µmol MDA/g (control) to 0.49 µmol MDA/g (PVA 01). Color changes were observed in all meat samples packaged with the film. It is concluded that the presence of nitrite does not interfere in the physical properties of the PVA films and that the developed films have an active potential for application in pork in natura., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This study evaluated the use of the S-nitrosothiols, S-nitroso-N-acetylcysteine (NAC-SNO) and S-nitroso-N-acetylcysteine ethyl ester (NACET-SNO), at different concentrations (25-300 mg nitrite equivalent - NEq/kg) as sodium nitrite substitutes in restructured cooked hams. The pH value and instrumental cured color were not affected by the type or amount of curing agent used. Products with 25 and 50 mg/kg ingoing nitrite had lower thiobarbituric acid-reactive substance values than those with equimolar amounts of S-nitrosothiols. Products with >150 mg NEq/kg of S-nitrosothiols had residual nitrite similar to 50 mg/kg nitrite, and this resulted in the same volatile compound profile as nitrite added in equimolar amounts. A 300 mg NEq/kg of S-nitrosothiols was required to obtain a similar and minimally stable cured pink color perception as sliced samples with 50-150 mg/kg added nitrite. The results obtained reinforce the great potential of both alternative curing agents in the complete replacement of nitrite by equimolar amounts in restructured cooked products; however, differences in cured color stability should be considered., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We present a longitudinal description of a man with the TARDBP I383V variant of frontotemporal dementia (FTD). His progressive changes in behavior and language resulted in a diagnosis of the right temporal variant of FTD, also called the semantic behavioral variant (sbvFTD). We also present data from a small series of patients with the TARDBP I383V variant who were enrolled in a nationwide FTD research collaboration (ALLFTD). These data support slowly progressive loss of semantic function. While semantic dementia is infrequently considered genetic, the TARDBP I383V variant seems to be an exception. Longitudinal analyses in larger samples are warranted.

We assessed white matter (WM) integrity in MAPT mutation carriers (16 asymptomatic, 5 symptomatic) compared to 31 non-carrier family controls using diffusion tensor imaging (DTI) (fractional anisotropy; FA, mean diffusivity; MD) and neurite orientation dispersion and density imaging (NODDI) (neurite density index; NDI, orientation and dispersion index; ODI). Linear mixed-effects models accounting for age and family relatedness revealed alterations across DTI and NODDI metrics in all mutation carriers and in symptomatic carriers, with the most significant differences involving fronto-temporal WM tracts. Asymptomatic carriers showed higher entorhinal MD and lower cingulum FA and patterns of higher ODI mostly involving temporal areas and long association and projections fibers. Regression models between estimated time to or time from disease and DTI and NODDI metrics in key regions (amygdala, cingulum, entorhinal, inferior temporal, uncinate fasciculus) in all carriers showed increasing abnormalities with estimated time to or time from disease onset, with FA and NDI showing the strongest relationships. Neurite-based metrics, particularly ODI, appear to be particularly sensitive to early WM involvement in asymptomatic carriers., Competing Interests: Declaration of Competing Interest CRJ receives no personal compensation from any commercial entity. He receives research support from National Institute of Health (NIH), the GHR Foundation, and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. RCP consults for Roche, Inc., Merck, Inc., Biogen, Inc., Genentech, Inc., Eisai, Inc., and Nestle, Inc. but does not receive significant fees due to NIH limitations from the U24 AG057437 Co-PI role. BB receives honoraria for SAB activities for the Tau Consortium, and has received research grant support but no personal compensation for clinical trials from Alector, Biogen, Transposon, Cognition Therapeutics, GE Healthcare. VKR receives research funding from the NIH and the Mangurian Foundation for Lewy Body disease research, has provided educational content for Medscape, is co-PI for a clinical trial supported by the Alzheimer’s Association, and is a site clinician for clinical trials supported by Eisai, the Alzheimer's Treatment and Research Institute at USC, and Transposon Therapeutics, Inc. EMR has no disclosure and receives funding from the NIH. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157–206) and Vigil Neuroscience, Inc. (VGL101–01.002, VGL101–01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. KK consults Biogen, Inc.; receives research support from Avid Radiopharmaceuticals and Eli Lilly and receives funding from NIH and Alzheimer’s Drug Discovery Foundation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework., Methods: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated., Results: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both Sequence Ontology (SO) and Human Phenotype Ontology (HPO) ontologies. Gene Curation Coalition member groups intend to use or map to these terms in their respective resources., Conclusion: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation., Competing Interests: Conflict of Interest James S. Ware has received research support or consultancy fees from Myokardia, Bristol-Myers Squibb, Pfizer, and Foresite Labs. All other authors declare no conflicts of interest. For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease and several of spinocerebellar ataxias. In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of Huntington's disease corrected for individual HTT CAG repeat length (i.e. residual age-at-onset), is modified by repeat instability-related DNA maintenance/repair genes as demonstrated by recent genome-wide association studies. Modification of one polyglutamine disease (e.g. Huntington's disease) by the repeat length of another (e.g. ATXN3, CAG expansions in which cause spinocerebellar ataxia 3) has also been hypothesized. Consequently, we determined whether age-at-onset in Huntington's disease is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes that were polymorphic in Huntington's disease participants but did not influence Huntington's disease age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set ( n = 1388) confirmed the lack of association between Huntington's disease residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our Huntington's disease onset modifier genome-wide association studies single nucleotide polymorphism data nor imputed short tandem repeat data supported the involvement of other polyglutamine disease genes in modifying Huntington's disease. By contrast, our genome-wide association studies based on imputed short tandem repeats revealed significant modification signals for other genomic regions. Together, our short tandem repeat genome-wide association studies show that modification of Huntington's disease is associated with short tandem repeats that do not involve other polyglutamine disease-causing genes, refining the landscape of Huntington's disease modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers., Competing Interests: J.F.G. was a Scientific Advisory Board member and had a financial interest in Triplet Therapeutics, Inc. His NIH-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in Huntington disease. The company is developing new therapeutic approaches to address triplet repeat disorders such Huntington's disease, myotonic dystrophy and SCAs. His interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.F.G. has also been a consultant for Wave Life Sciences USA, Inc., Biogen, Inc. and Pfizer, Inc. Within the last five years D.G.M. has been a scientific consultant and/or received an honoraria/stock options from AMO Pharma, Dyne, F. Hoffman-La Roche, LoQus23, Novartis, Ono Pharmaceuticals, Rgenta Therapeutics, Sanofi, Sarepta Therapeutics Inc, Script Biosciences, Triplet Therapeutics, and Vertex Pharmaceuticals and held research contracts with AMO Pharma and Vertex Pharmaceuticals. J.D.L. is a paid Advisory Board member for F. Hoffmann-La Roche Ltd and uniQure biopharma B.V., and he is a paid consultant for Vaccinex Inc, Wave Life Sciences USA Inc, Genentech Inc, Triplet Inc, and PTC Therapeutics Inc. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics. L.J. was a member of the scientific advisory boards of LoQus23 Therapeutics and Triplet Therapeutics. V.C.W. was a Scientific Advisory Board member of Triplet Therapeutics, Inc., a company developing new therapeutic approaches to address triplet repeat disorders such Huntington's disease and myotonic dystrophy. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. She is a scientific advisory board member of LoQus23 Therapeutics and has provided paid consulting services to Alnylam, Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc. and Passage Bio. J.M.L consults for Life Edit Therapeutics and serves in the scientific advisory board of GenEdit, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The quest for healthiness has driven the meat industry to seek solutions to reduce or replace saturated animal fat. The replacement (partial or total) of animal fat by polyunsaturated vegetable oils rich in omega fatty acids has gained prominence in terms of making a product healthier. However, an obstacle to this strategy is the effects on the sensory characteristics of the products, which may be unfavorable to consumers. The objective of this study was to evaluate the lipid reformulation of hamburgers through the total replacement of pork fat with canola, sunflower, and corn oil emulsions. The physical-chemical, technological, and sensory properties analyses were performed. There were no significant changes ( P  > 0.05) in moisture content, protein content, ash content, pH, weight loss (%), moisture retention (%), or shrinkage (%). However, the lipid content was reduced ( P  < 0.05) and there was a significant improvement in the fatty acid profile with the application of gelled emulsions. The lipid peroxidation and oxidation also increased ( P  < 0.05) for the samples with the addition of gelled emulsions, and we observed the same behavior for lipid retention (%). In the sensory evaluation, the samples showed good overall acceptance, with hedonic scores ranging from "like slightly" to "like very much." In addition, through check-all-that-apply questions, we observed that the most positive scores given applied to the treatments were applied to the emulsions. The total replacement of animal fat by gelled emulsions is a promising strategy for producing healthier hamburgers., Competing Interests: DECLARATION OF CONFLICTING INTERESTSThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers., Methods: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles., Results: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline., Interpretation: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Social determinants are structures and conditions in the biological, physical, built, and social environments that affect health, social and physical functioning, health risk, quality of life, and health outcomes. The adoption of recommended, standard measurement protocols for social determinants of health will advance the science of minority health and health disparities research and provide standard social determinants of health protocols for inclusion in all studies with human participants., Methods: A PhenX (consensus measures for Phenotypes and eXposures) Working Group of social determinants of health experts was convened from October 2018 to May 2020 and followed a well-established consensus process to identify and recommend social determinants of health measurement protocols. The PhenX Toolkit contains data collection protocols suitable for inclusion in a wide range of research studies. The recommended social determinants of health protocols were shared with the broader scientific community to invite review and feedback before being added to the Toolkit., Results: Nineteen social determinants of health protocols were released in the PhenX Toolkit (https://www.phenxtoolkit.org) in May 2020 to provide measures at the individual and structural levels for built and natural environments, structural racism, economic resources, employment status, occupational health and safety, education, environmental exposures, food environment, health and health care, and sociocultural community context., Conclusions: Promoting the adoption of well-established social determinants of health protocols can enable consistent data collection and facilitate comparing and combining studies, with the potential to increase their scientific impact., (Published by Elsevier Inc.)

Introduction: Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress., Methods: Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51)., Results: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy., Discussion: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials., (© 2022 the Alzheimer's Association.)

Biochar is a carbonaceous and porous material with limited adsorption capacity, which increases by modifying its surface. Many of the biochars modified with magnetic nanoparticles reported previously were obtained in two steps: first, the biomass was pyrolyzed, and then the modification was performed. In this research, a biochar with Fe 3 O 4 particles was obtained during the pyrolysis process. Corn cob residues were used to obtain the biochar (i.e., BCM) and the magnetic one (i.e., BCM Fe ). The BCM Fe biochar was synthesized by a chemical coprecipitation technique prior to the pyrolysis process. The biochars obtained were characterized to determine their physicochemical, surface, and structural properties. The characterization revealed a porous surface with a 1013.52 m 2 /g area for BCM and 903.67 m 2 /g for BCM Fe . The pores were uniformly distributed, as observed in SEM images. BCM Fe showed Fe 3 O 4 particles on the surface with a spherical shape and a uniform distribution. According to FTIR analysis, the functional groups formed on the surface were aliphatic and carbonyl functional groups. Ash content in the biochar was 4.0% in BCM and 8.0% in BCM Fe ; the difference corresponded to the presence of inorganic elements. The TGA showed that BCM lost 93.8 wt% while BCM Fe was more thermally stable due to the inorganic species on the biochar surface, with a weight loss of 78.6%. Both biochars were tested as adsorbent materials for methylene blue. BCM and BCM Fe obtained a maximum adsorption capacity (q m ) of 23.17 mg/g and 39.66 mg/g, respectively. The obtained biochars are promising materials for the efficient removal of organic pollutants.

Importance: The neurological substrates of visual artistic creativity (VAC) are unknown. VAC is demonstrated here to occur early in frontotemporal dementia (FTD), and multimodal neuroimaging is used to generate a novel mechanistic hypothesis involving dorsomedial occipital cortex enhancement. These findings may illuminate a novel mechanism underlying human visual creativity., Objective: To determine the anatomical and physiological underpinnings of VAC in FTD., Design, Setting, and Participants: This case-control study analyzed records of 689 patients who met research criteria for an FTD spectrum disorder between 2002 and 2019. Individuals with FTD and emergence of visual artistic creativity (VAC-FTD) were matched to 2 control groups based on demographic and clinical parameters: (1) not visually artistic FTD (NVA-FTD) and (2) healthy controls (HC). Analysis took place between September 2019 to December 2021., Main Outcomes and Measures: Clinical, neuropsychological, genetic, and neuroimaging data were analyzed to characterize VAC-FTD and compare VAC-FTD with control groups., Results: Of 689 patients with FTD, 17 (2.5%) met VAC-FTD inclusion criteria (mean [SD] age, 65 [9.7] years; 10 [58.8%] female). NVA-FTD (n = 51; mean [SD] age, 64.8 [7] years; 25 [49.0%] female) and HC (n = 51; mean [SD] age, 64.5 [7.2] years; 25 [49%] female) groups were well matched to VAC-FTD demographically. Emergence of VAC occurred around the time of onset of symptoms and was disproportionately seen in patients with temporal lobe predominant degeneration (8 of 17 [47.1%]). Atrophy network mapping identified a dorsomedial occipital region whose activity inversely correlated, in healthy brains, with activity in regions found within the patient-specific atrophy patterns in VAC-FTD (17 of 17) and NVA-FTD (45 of 51 [88.2%]). Structural covariance analysis revealed that the volume of this dorsal occipital region was strongly correlated in VAC-FTD, but not in NVA-FTD or HC, with a volume in the primary motor cortex corresponding to the right-hand representation., Conclusions and Relevance: This study generated a novel hypothesis about the mechanisms underlying the emergence of VAC in FTD. These findings suggest that early lesion-induced activation of dorsal visual association areas may predispose some patients to the emergence of VAC under certain environmental or genetic conditions. This work sets the stage for further exploration of enhanced capacities arising early in the course of neurodegeneration.

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis ( n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity ( n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS , which predicted atrophy of FTD-relevant thalamic nuclei. SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information., (Copyright © 2023 Bonham et al.)

To describe the clinical progression and medical protocols applied in a 41 year old man who was bited by a bat three months before. The patient did not ask for medical care until acute tremor and pain in the right thoracic limb and hydro-phobia started. For a history of a wild animal bite associated with a unique clinical condition, we suspected of rabies encephalitis, confirming the diagnostic by pathology after his death. This case ocurred in Guadalajara, Jalisco, México, in April, 2022. The last case of human rabies reported in Jalisco secondary to bat bite was almost 30 years ago. As an uncomon disease, medical personnel and facilities should be prepared to attend this sort of cases after clinical suspicion. For the present case, the medical history was the key for diagnosis. Rabies is a disease caused by the neurotropic virus belonging to the Rhabdoviridae family whose prognosis is bleak, with mortality close to 100% and therapeutic options limited. This case emphasizes the high mortality of rabies virus infection and the importance of increasing awareness and education to the public in general, with regard to applying the vaccine as post-exposure prophylaxis.

Importance: Physical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown., Objective: To examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD., Design, Setting, and Participants: This cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms., Exposures: Baseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity., Main Outcomes and Measures: Annual plasma NfL concentrations were measured with single-molecule array technology., Results: Of 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, -22.7 to -4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, -52.2 to -8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, -43.4 to -7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training)., Conclusions and Relevance: In this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

Tuberous sclerosis complex (TSC) is a neurogenetic disorder leading to epilepsy, developmental delay, and neurobehavioral dysfunction. The syndrome is caused by pathogenic variants in TSC1 (coding for hamartin) or TSC2 (coding for tuberin). Recently, we reported a progressive frontotemporal dementia-like clinical syndrome in a patient with a mutation in TSC1, but the neuropathological changes seen in adults with TSC with or without dementia have yet to be systematically explored. Here, we examined neuropathological findings in adults with TSC (n = 11) aged 30-58 years and compared them to age-matched patients with epilepsy unrelated to TSC (n = 9) and non-neurological controls (n = 10). In 3 of 11 subjects with TSC, we observed a neurofibrillary tangle-predominant "TSC tauopathy" not seen in epilepsy or non-neurological controls. This tauopathy was observed in the absence of pathological amyloid beta, TDP-43, or alpha-synuclein deposition. The neurofibrillary tangles in TSC tauopathy showed a unique pattern of post-translational modifications, with apparent differences between TSC1 and TSC2 mutation carriers. Tau acetylation (K274, K343) was prominent in both TSC1 and TSC2, whereas tau phosphorylation at a common phospho-epitope (S202) was observed only in TSC2. TSC tauopathy was observed in selected neocortical, limbic, subcortical, and brainstem sites and showed a 3-repeat greater than 4-repeat tau isoform pattern in both TSC1 and TSC2 mutation carriers, but no tangles were immunolabeled with MC1 or p62 antibodies. The findings suggest that individuals with TSC are at risk for a unique tauopathy in mid-life and that tauopathy pathogenesis may involve TSC1, TSC2, and related molecular pathways., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)