Peripheral inflammatory hyperalgesia is exacerbated in rats with metabolic disorders induced by a fructose diet.

This study explored the effects of fructose-induced obesity and metabolic disorders on peripheral inflammatory hyperalgesia, employing quantitative sensory testing with the von Frey test and measuring paw edema to assess inflammatory responses. Wistar rats were administered water or 10% fructose solution ad libitum over a period of 5 weeks. After intraplantar administration of inflammatory agents such as carrageenan (1 mg/paw), lipopolysaccharide (LPS; 100 µg/paw), or prostaglandin E2 (PGE2, 100 ng/paw), we conducted mechanical hyperalgesia tests and paw edema evaluations. The fructose diet resulted in dyslipidemia, elevated insulin and leptin plasma levels, insulin resistance, and increased epididymal and retroperitoneal adiposity compared to control animals. In response to inflammatory agents, the fructose group displayed significantly enhanced peripheral hyperalgesia and more pronounced paw edema. Our results demonstrate that fructose not only contributes to the development of obesity and metabolic disorder but also exacerbates peripheral inflammatory pain responses by enhancing prostaglandin sensitivity.

An Individual Barrier Enclosure Actively Removing Aerosols for Airborne Isolation: A Vacuum Tent.

BACKGROUND: Aerosol barrier enclosure systems have been designed to prevent airborne contamination, but their safety has been questioned. A vacuum tent was designed with active continuous suctioning to minimize risks of aerosol dispersion. We tested its efficacy, risk of rebreathing, and usability on a bench, in healthy volunteers, and in an ergonomic clinical assessment study. METHODS: First, a manikin with airway connected to a breathing simulator was placed inside the vacuum tent to generate active breathing, cough, and CO2 production; high-flow nasal cannula (HFNC) was applied in the manikin's nares. Negative pressure was applied in the vacuum tent's apex port using wall suction. Fluorescent microparticles were aerosolized in the vacuum tent for qualitative assessment. To quantify particles inside and around vacuum tent (aerosol retention), an airtight aerosol chamber with aerosolized latex microparticles was used. The vacuum tent was tested on healthy volunteers breathing with and without HFNC. Last, its usability was assessed in 5 subjects by 5 different anesthesiologists for delivery of full anesthesia, including intubation and extubation. RESULTS: The vacuum tent was adjusted until no leak was visualized using fluorescent particles. The efficacy in retaining microparticles was confirmed quantitatively. CO2 accumulation inside the vacuum tent showed an inverse correlation with the suction flow in all conditions (normal breathing and HFNC 30 or 60 L/min) in bench and healthy volunteers. Particle removal efficacy and safe breathing conditions (CO2, temperature) were reached when suctioning was at least 60 L/min or 20 L/min > HFNC flow. Five subjects were successfully intubated and anesthetized without ergonomic difficulties and with minimal interference with workflow and an excellent overall assessment by the anesthesiologists. CONCLUSIONS: The vacuum tent effectively minimized aerosol dispersion. Its continuous suction system set at a high suction flow was crucial to avoid the spread of aerosol particles and CO2 rebreathing.

Neuromodulator hydrogen sulfide attenuates sickness behavior induced by lipopolysaccharide.

Sickness behavior reflects a state of altered physiology and central nervous system function that occurs during systemic infection or inflammation, serving as an adaptive response to illness. This study aims to elucidate the role of hydrogen sulfide (H2S) in regulating sickness behavior and neuroinflammatory responses in a rat model of systemic inflammation. Adult male Wistar rats were treated with lipopolysaccharide (LPS) to induce sickness behavior. Intracerebroventricular (i.c.v.) pretreatments included aminooxyacetic acid (AOAA), an inhibitor of H2S synthesis, and sodium sulfide (NaHS), an H2S donor. Behavioral assays were conducted, along with the assessment of astrocyte activation, as indicated by GFAP expression in the hypothalamus. Pretreatment with NaHS mitigated LPS-induced behavioral changes, including hypophagia, social and exploratory deficits, without affecting peripheral cytokine levels, indicating a central modulatory effect. AOAA, conversely, accentuated certain behavioral responses, suggesting a complex role of endogenous H2S in sickness behavior. These findings were reinforced by a lack of effect on plasma interleukin levels but significant reduction in GFAP expression. Our findings support the central role of H2S in modulating neuroinflammation and sickness behavior, highlighting the therapeutic potential of targeting H2S signaling in neuroinflammatory conditions.

Airway opening pressure maneuver to detect airway closure in mechanically ventilated pediatric patients.

Background: Airway closure, which refers to the complete collapse of the airway, has been described under mechanical ventilation during anesthesia and more recently in adult patients with acute respiratory distress syndrome (ARDS). A ventilator maneuver can be used to identify airway closure and measure the pressure required for the airway to reopen, known as the airway opening pressure (AOP). Without that maneuver, AOP is unknown to clinicians. Objective: This study aims to demonstrate the technical adaptation of the adult maneuver for children and illustrate its application in two cases of pediatric ARDS (p-ARDS). Methods: A bench study was performed to adapt the maneuver for 3-50 kg patients. Four maneuvers were performed for each simulated patient, with 1, 2, 3, and 4 s of insufflation time to deliver a tidal volume (Vt) of 6 ml/kg by a continuous flow. Results: Airway closure was simulated, and AOP was visible at 15 cmH2O with a clear inflection point, except for the 3 kg simulated patient. Regarding insufflation time, a 4 s maneuver exhibited a better performance in 30 and 50 kg simulated patients since shorter insufflation times had excessive flowrates (>10 L/min). Below 20 kg, the difference in resistive pressure between a 3 s and a 4 sec maneuver was negligible; therefore, prolonging the maneuver beyond 3 s was not useful. Airway closure was identified in two p-ARDS patients, with the pediatric maneuver being employed in the 28 kg patient. Conclusions: We propose a pediatric AOP maneuver delivering 6 ml/kg of Vt at a continuous low-flow inflation for 3 s for patients weighing up to 20 kg and for 4 s for patients weighing beyond 20 kg.

PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.

Influence of maternal immune activation on autism-like symptoms and coping strategies in male offspring.

Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of gestation increased susceptibility to neurodevelopmental disorders, including autism, in the offspring. In the present work, we aimed to provide characterization of the long-term consequences on anxiety-like behavior and cardiovascular stress response of MIA in the offspring. This study aimed to evaluate the effect of MIA by lipopolysaccharide (LPS) in adult male offspring. In our study, the animals were subjected to a range of behavioral and physiological tests, including the elevated plus maze, social interaction, cat odor response, open field behavior, contextual fear conditioning, and cardiovascular responses during restraint stress. In the offspring of MIA, our study unveiled distinct anxious behaviors. This was evident by fewer entries into the open arms of the maze, diminished anti-thigmotaxis in the open field, and a decrease in social interaction time. Moreover, these rats showed heightened sensitivity to cat odor, exhibited prolonged freezing during fear conditioning, and presented elevated 22 Hz ultrasonic vocalizations. Notably, during restraint stress, these animals manifested an augmented blood pressure response, and this was associated with an increase in c-fos expression in the locus coeruleus compared to the control group. These findings collectively underline the extensive behavioral and physiological alterations stemming from MIA. This study deepens our understanding of the significance of maternal health in predisposing offspring to neurobehavioral deficits and psychiatric disorders.

Analysis of anthropometric and physical performance variables in U-17 soccer players.

Introduction: Soccer is considered a multifaceted collective sport, and to reach an elevated level, players must have moderate to high power, good agility, joint flexibility and muscle development. Also, players must be able to generate high torques during fast movements, which implies the development of different capacities, understood as multifactorial preparation. The objective was to analyse the effects of training (aerobic and continuous) on the leg power, fatigue levels, speed, agility, body fat, muscle mass and bone mass of these players. Methods: Seventy-two soccer players, male and under 17, from 4 teams participated. The teams performed 3 times a week training sessions of about 60-90 min each. Informed consent requests were given to their parents for authorisation to participate in this investigation. Data was collected in two different time points, about ten months apart. Specific tests were performed for each variable: the vertical jump with Bosco System for leg power, the T-Test for agility, the linear sprint test for speed and the RAST test for fatigue levels. A precision Tanita scale was used for the anthropometric tests such as body fat, muscle mass and bone mass. Statistical procedures were applied through the Wilcoxon test to compare the two time points of evaluation. Results: Improvements were found between evaluations regarding the level of anthropometric and physical fitness variables. Conclusions: The implemented training improved all the analysed variables with significant statistical values for leg power, speed, bone mass, muscle mass and fat mass.

At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis causes degeneration of motor neurons, resulting in progressive muscle weakness and impairment in motor function. Promising drug development efforts have accelerated in amyotrophic lateral sclerosis, but are constrained by a lack of objective, sensitive, and accessible outcome measures. Here we investigate the use of wearable sensors, worn on four limbs at home during natural behavior, to quantify motor function and disease progression in 376 individuals with amyotrophic lateral sclerosis. We use an analysis approach that automatically detects and characterizes submovements from passively collected accelerometer data and produces a machine-learned severity score for each limb that is independent of clinical ratings. We show that this approach produces scores that progress faster than the gold standard Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (-0.86 ± 0.70 SD/year versus -0.73 ± 0.74 SD/year), resulting in smaller clinical trial sample size estimates (N = 76 versus N = 121). This method offers an ecologically valid and scalable measure for potential use in amyotrophic lateral sclerosis trials and clinical care.

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity.

Introduction: Intronic repeat expansions in the C9orf72 gene are the most frequent known single genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeat expansions are believed to result in both loss-of-function and toxic gain-of-function. Gain-of-function results in the production of toxic arginine-rich dipeptide repeat proteins (DPRs), namely polyGR and polyPR. Small-molecule inhibition of Type I protein arginine methyltransferases (PRMTs) has been shown to protect against toxicity resulting from polyGR and polyPR challenge in NSC-34 cells and primary mouse-derived spinal neurons, but the effect in human motor neurons (MNs) has not yet been explored. Methods: To study this, we generated a panel of C9orf72 homozygous and hemizygous knockout iPSCs to examine the contribution of C9orf72 loss-of-function toward disease pathogenesis. We differentiated these iPSCs into spinal motor neurons (sMNs). Results: We found that reduced levels of C9orf72 exacerbate polyGR15 toxicity in a dose-dependent manner. Type I PRMT inhibition was able to partially rescue polyGR15 toxicity in both wild-type and C9orf72-expanded sMNs. Discussion: This study explores the interplay of loss-of-function and gain-of-function toxicity in C9orf72 ALS. It also implicates type I PRMT inhibitors as a possible modulator of polyGR toxicity.

Associação entre área de secção transversa do reto femoral e excursão diafragmática com o desmame de pacientes com traqueostomia na unidade de terapia intensiva / Association between rectus femoris cross-sectional area and diaphragmatic excursion with weaning of tracheostomized patients in the intensive care unit

RESUMO Objetivo: Verificar a relação entre área de secção transversa do reto femoral e excursão diafragmática com sucesso no desmame da ventilação mecânica em pacientes críticos crônicos com traqueostomia. Métodos: Este foi um estudo de coorte observacional prospectivo. Incluímos pacientes críticos crônicos (aqueles submetidos à colocação de traqueostomia após 10 dias de ventilação mecânica). A área de secção transversa do reto femoral e a excursão diafragmática foram obtidas por ultrassonografia realizada dentro das primeiras 48 horas após a traqueostomia. Medimos a área de secção transversa do reto femoral e a excursão diafragmática para avaliar sua associação com o desmame da ventilação mecânica, incluindo sua capacidade de prever o sucesso no desmame e a sobrevida durante toda a internação na unidade de terapia intensiva. Resultados: Foram incluídos 81 pacientes. Quarenta e cinco pacientes (55%) foram desmamados da ventilação mecânica. A mortalidade foi de 42% e 61,7% na unidade de terapia intensiva e hospitalar, respectivamente. O grupo que falhou em relação ao grupo que obteve sucesso no desmame apresentou menor área transversa do reto femoral (1,4 [0,8] versus 1,84 [0,76]cm2, p = 0,014) e menor excursão diafragmática (1,29 ± 0,62 versus 1,62 ± 0,51cm, p = 0,019). Quando a área de secção transversa do reto femoral ≥ 1,80cm2 e a excursão diafragmática ≥ 1,25cm era uma condição combinada, apresentava forte associação com sucesso no desmame (RC ajustada de 20,81; IC95% 2,38 - 182,28; p = 0,006), mas não com sobrevida na unidade de terapia intensiva (RC ajustada de 0,19; IC95% 0,03 - 1,08; p = 0,061). Conclusão: O sucesso no desmame da ventilação mecânica em pacientes críticos crônicos foi associado a medidas maiores de área de secção transversa do reto femoral e da excursão diafragmática.

ABSTRACT Objective: To verify the relationship between the rectus femoris cross-sectional area and diaphragmatic excursion with successful weaning from mechanical ventilation in chronic critically tracheostomized patients. Methods: This was a prospective observational cohort study. We included chronic critically ill patients (those who underwent tracheostomy placement after 10 days under mechanical ventilation). The rectus femoris cross-sectional area and diaphragmatic excursion were obtained by ultrasonography performed within the first 48 hours after tracheostomy. We measured rectus femoris cross-sectional area and diaphragmatic excursion to assess their association with weaning from mechanical ventilation, including their potential to predict successful weaning and survival throughout the intensive care unit stay. Results: Eighty-one patients were included. Forty-five patients (55%) were weaned from mechanical ventilation. The mortality rates were 42% and 61.7% in the intensive care unit and hospital, respectively. The fail group in relation to the success group at weaning presented a lower rectus femoris cross-sectional area (1.4 [0.8] versus 1.84 [0.76]cm2, p = 0.014) and lower diaphragmatic excursion (1.29 ± 0.62 versus 1.62 ± 0.51cm, p = 0.019). When rectus femoris cross-sectional area ≥ 1.80cm2 and diaphragmatic excursion ≥ 1.25cm was a combined condition, it had a strong association with successful weaning (adjusted OR = 20.81, 95%CI 2.38 - 182.28; p = 0.006) but not with intensive care unit survival (adjusted OR = 0.19, 95%CI 0.03 - 1.08; p = 0.061). Conclusion: Successful weaning from mechanical ventilation in chronic critically ill patients was associated with higher measurements of rectus femoris cross-sectional area and diaphragmatic excursion.

The Benefits of Resistance Training in Obese Adolescents: A Systematic Review and Meta-analysis.

BACKGROUND: Physical activity is essential in acquiring healthy lifestyle behaviors in the early years of maturational development and preventing various diseases. Resistance training (RT) is fundamental for improving body composition and is increasingly recommended for obese adolescents. A systematic review and meta-analysis were performed to synthesize and analyze data on the effects of RT programs in this population, seeking to develop useful recommendations for health and sports professionals. METHODS: A search was performed using four databases (Web of Science, Scopus, PubMed, and ScienceDirect). According to specific inclusion criteria, twenty-one studies were selected to evaluate the impact of RT on body mass index (BMI), body fat, waist circumference, muscle strength, insulin sensitivity, lean mass and cardiorespiratory fitness. RESULTS: After the RT programs, the adolescents improved their muscle strength (SMD, 1.44; 95% CI: 0.76-2.12), cardiorespiratory fitness (SMD, 1.09; 95% CI: 0.15-2.04), BMI (SMD, 0.21; 95% CI: 0.07-0.35), waist circumference (SMD, 0.27; 95% CI: 0.06-0.47) and body fat (SMD, 0.20; 95% CI: 0.05-0.34). However, insulin sensitivity (SMD, 0.32; 95% CI: - 0.47 to 1.10) and lean mass (SMD, 0.12; 95% CI: - 0.06 to 0.31) did not reveal any changes. Different RT programs were used but it seems that 2-3 times/week ∼60 min/session of RT for 12 weeks should be recommended for positive changes. CONCLUSIONS: RT seems to be effective when the objective is to improve muscle strength, cardiorespiratory fitness and can be an efficient strategy to reduce obesity in adolescents by reducing body fat, waist circumference and body mass index. PROSPERO Registration number: CRD42022333411.

Curcumin attenuates LPS-induced sickness behavior and fever in rats by modulating Nrf2 activity.

Lipopolysaccharide (LPS) is a potent inducer of inflammation, triggering behavioral changes and fever. The present study aimed to evaluate whether pretreatment with curcumin prevents the behavioral changes and fever induced by LPS through the modulation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Male Wistar rats received either vehicle or LPS and after 2 h, the behavioral responses were assessed through open field test (OFT), social interaction test, forced swim test (FST), and food intake assessment. The febrile response was assessed by telemetry after vehicle or LPS injection to evaluate the effect of curcumin on the thermoregulatory response during the immunological challenge. The pretreatment with curcumin at doses of 50 and 100 mg/kg prevented the reduction of distance traveled on OFT, increased the immobility time of FST, impaired social withdrawal, decreased food intake, and induced fever. In addition, at these doses, it was possible to observe a significant decrease in the plasma levels of cytokines and an increase in Nrf2 translocation to the cell nucleus during the immunological challenge. Our data provide further evidence of curcumin's ability to prevent LPS-induced sickness behavior and fever possibly by a mechanism related to the modulation of Nrf2 translocation.

High Flow Nasal Cannula compared to Continuous Positive Airway Pressure: a bench and physiological study.

High-flow nasal cannula (HFNC) is extensively used for acute respiratory failure. However, questions remain regarding its physiological effects. We explored 1) whether HFNC produced similar effects to continuous positive airway pressure (CPAP); 2) possible explanations of respiratory rate changes; 3) the effects of mouth opening. Two studies were conducted: a bench study using a manikin's head with lungs connected to a breathing simulator while delivering HFNC flow rates from 0 to 60L/min; a physiological cross-over study in 10 healthy volunteers receiving HFNC (20 to 60L/min) with the mouth open or closed and CPAP 4cmH2O delivered through face-mask. Nasopharyngeal and esophageal pressures were measured; tidal volume and flow were estimated using calibrated electrical impedance tomography. In the bench study, nasopharyngeal pressure at end-expiration reached 4cmH2O with HFNC at 60L/min, while tidal volume decreased with increasing flow. In volunteers with HFNC at 60L/min, nasopharyngeal pressure reached 6.8cmH2O with mouth closed and 0.8cmH2O with mouth open; p<0.001. When increasing HFNC flow, respiratory rate decreased by lengthening expiratory time, tidal volume did not change, and effort decreased (pressure-time product of the respiratory muscles); at 40L/min, effort was equivalent between CPAP and HFNC40L/min and became lower at 60L/min (p=0.045). During HFNC with mouth closed, and not during CPAP, resistance to breathing was increased, mostly during expiration. In conclusion, mouth closure during HFNC induces a positive nasopharyngeal pressure proportional to flow rate and an increase in expiratory resistance that might explain the prolonged expiration and reduction in respiratory rate and effort, and contribute to physiological benefits.

Quality of life in a randomized trial comparing two neoadjuvant regimens for locally advanced rectal cancer-INCAGI004.

BACKGROUND: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC), but the emergence of different drug regimens may result in different response rates. Good clinical response translates into greater sphincter preservation, but quality of life (QOL) may be impaired after treatment due to chemoradiotherapy and surgical side effects. OBJECTIVE: To prospectively evaluate the impact of clinical response and surgical resection on QOL in a randomized trial comparing two different neoCRT regimens. METHODS: Stage II and III rectal cancer patients were randomized to receive neoCRT with either capecitabine (group 1) or 5-Fu and leucovorin (group 2) concomitant to long-course radiotherapy. Clinical downstaging was accessed using MRI 6-8 weeks after treatment. EORTCs QLQ-C30 and CR38 were applied before treatment (T0), after neoCRT (T1), after rectal resection (T2), early after adjuvant chemotherapy (T3), and 1 year after the end of treatment or stoma closure (T4). The Wexner scale was used for fecal incontinence evaluation at T4. A C30SummaryScore (Geisinger and cols.) was calculated to compare QOL results. RESULTS: Thirty-two patients were assigned to group 1 and 31 to group 2. Clinical downstaging occurred in 70.0% of group 1 and 53.3% of group 2 (p = 0.288), and sphincter preservation was 83.3% in group 1 and 80.0% in group 2 (p = 0.111). No significant difference in QOL was detected when comparing the two treatment groups after neoCRT using QLQ-C30. However, the CR38 module detected differences in micturition problems (15.3 points), gastrointestinal problems (15.3 points), defecation problems (11.8 points), and sexual satisfaction (13.3 points) favoring the capecitabine group. C30SummaryScore detected significant improvement comparing T0 to T1 and deterioration comparing T1 to T2 (p = 0.025). The mean Wexner scale score was 9.2, and a high score correlated with symptoms of diarrhea and defecation problems at T4. CONCLUSIONS: QOL was equivalent between groups after neoCRT except for micturition problems, gastrointestinal problems, defecation problems, and sexual satisfaction favoring the capecitabine arm after. The overall QOL using the C30SummaryScore was improved after neoCRT, but decreased following rectal resection, returning to basal levels at late evaluation. Fecal incontinence was high after sphincter preservation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03428529.

A machine-learning based objective measure for ALS disease severity.

Amyotrophic Lateral Sclerosis (ALS) disease severity is usually measured using the subjective, questionnaire-based revised ALS Functional Rating Scale (ALSFRS-R). Objective measures of disease severity would be powerful tools for evaluating real-world drug effectiveness, efficacy in clinical trials, and for identifying participants for cohort studies. We developed a machine learning (ML) based objective measure for ALS disease severity based on voice samples and accelerometer measurements from a four-year longitudinal dataset. 584 people living with ALS consented and carried out prescribed speaking and limb-based tasks. 542 participants contributed 5814 voice recordings, and 350 contributed 13,009 accelerometer samples, while simultaneously measuring ALSFRS-R scores. Using these data, we trained ML models to predict bulbar-related and limb-related ALSFRS-R scores. On the test set (n = 109 participants) the voice models achieved a multiclass AUC of 0.86 (95% CI, 0.85-0.88) on speech ALSFRS-R prediction, whereas the accelerometer models achieved a median multiclass AUC of 0.73 on 6 limb-related functions. The correlations across functions observed in self-reported ALSFRS-R scores were preserved in ML-derived scores. We used these models and self-reported ALSFRS-R scores to evaluate the real-world effects of edaravone, a drug approved for use in ALS. In the cohort of 54 test participants who received edaravone as part of their usual care, the ML-derived scores were consistent with the self-reported ALSFRS-R scores. At the individual level, the continuous ML-derived score can capture gradual changes that are absent in the integer ALSFRS-R scores. This demonstrates the value of these tools for assessing disease severity and, potentially, drug effects.