Developing a shortened spine functional index (SFI-10) for patients with sub-acute/chronic spinal disorders: a cross-sectional study.

BACKGROUND: Brief whole-spine patient-reported outcome measures (PROMs) provide regional solutions and future directions for quantifying functional status, evidence, and effective interventions. The whole-spine regional Spine Functional Index (SFI-25) is used internationally in clinical and scientific contexts to assess general sub-acute/chronic spine populations. However, to improve structural validity and practicality a shortened version is recommended. This study developed a shortened-SFI from the determined optimal number of item questions that: correlated with criteria PROMs being highly with whole-spine, moderately with regional-spine, condition-specific and patient-specific, and moderately-low with general-health and pain; retained one-dimensional structural validity and high internal consistency; and improved practicality to reduce administrative burden. METHODS: A cross-sectional study (n = 505, age = 18-87 yrs., average = 40.3 ± 10.1 yrs) of sub-acute/chronic spine physiotherapy outpatients from an international sample of convenience. Three shortened versions of the original SFI-25 were developed using 1) qualitative 'content-retention' methodology, 2) quantitative 'factorial' methodology, and 3) quantitative 'Rasch' methodology, with a fourth 'random' version produced as a comparative control. The clinimetric properties were established for structural validity with exploratory (EFA) and confirmatory (CFA) factorial analysis, and Rasch analysis. Criterion validity used the: whole-spine SFI-25 and Functional Rating Index (FRI); regional-spine Neck Disability Index (NDI), Oswestry Disability Index (ODI), and Roland Morris Questionnaire (RMQ), condition-specific Whiplash Disability Questionnaire (WDQ); and patient-specific functional scale (PSFS); and determined floor/ceiling effect. A post-hoc pooled international sub-acute/chronic spine sample (n = 1433, age = 18-91 yrs., average = 42.0 ± 15.7 yrs) clarified the findings and employed the general-health EuroQuol-Index (EQ-5D), and 11-point Pain Numerical Rating Scale (P-NRS) criteria. RESULTS: A 10-item SFI retained structural validity with optimal practicality requiring no computational aid. The SFI-10 concept-retention-version demonstrated preferred criterion validity with whole-spine criteria (SFI-25 = 0.967, FRI = 0.810) and exceeded cut-off minimums with regional-spine, condition-specific, and patient-specific measures. An unequivocal one-dimensional structure was determined. Internal consistency was satisfactory (α = 0.80) with no floor/ceiling effect. Post-hoc analysis of the international sample confirmed these findings. CONCLUSION: The SFI-10 qualitative concept-retention version was preferred to quantitative factorial and Rasch versions, demonstrated structural and criterion validity, and preferred correlation with criteria measures. Further longitudinal research is required for reliability, error, and responsiveness, plus an examination of the practical characteristics of readability and administrative burden.

Parameterization of Biomechanical Variables through Inertial Measurement Units (IMUs) in Occasional Healthy Runners.

Running is one of the most popular sports practiced today and biomechanical variables are fundamental to understanding it. The main objectives of this study are to describe kinetic, kinematic, and spatiotemporal variables measured using four inertial measurement units (IMUs) in runners during treadmill running, investigate the relationships between these variables, and describe differences associated with different data sampling and averaging strategies. A total of 22 healthy recreational runners (M age = 28 ± 5.57 yrs) participated in treadmill measurements, running at their preferred speed (M = 10.1 ± 1.9 km/h) with a set-up of four IMUs placed on tibias and the lumbar area. Raw data was processed and analysed over selections spanning 30 s, 30 steps and 1 step. Very strong positive associations were obtained between the same family variables in all selections. The temporal variables were inversely associated with the step rate variable in the selection of 30 s and 30 steps of data. There were moderate associations between kinetic (forces) and kinematic (displacement) variables. There were no significant differences between the biomechanics variables in any selection. Our results suggest that a 4-IMU set-up, as presented in this study, is a viable approach for parameterization of the biomechanical variables in running, and also that there are no significant differences in the biomechanical variables studied independently, if we select data from 30 s, 30 steps or 1 step for processing and analysis. These results can assist in the methodological aspects of protocol design in future running research.

Inhibition of Adult Neurogenesis in Male Mice after Repeated Exposure to Paracetamol Overdose.

Paracetamol, or acetaminophen (N-acetyl-para-aminophenol, APAP), is an analgesic and antipyretic drug that is commonly used worldwide, implicated in numerous intoxications due to overdose, and causes serious liver damage. APAP can cross the blood-brain barrier and affects brain function in numerous ways, including pain signals, temperature regulation, neuroimmune response, and emotional behavior; however, its effect on adult neurogenesis has not been thoroughly investigated. We analyze, in a mouse model of hepatotoxicity, the effect of APAP overdose (750 mg/kg/day) for 3 and 4 consecutive days and after the cessation of APAP administration for 6 and 15 days on cell proliferation and survival in two relevant neurogenic zones: the subgranular zone of the dentate gyrus and the hypothalamus. The involvement of liver damage (plasma transaminases), neuronal activity (c-Fos), and astroglia (glial fibrillar acidic protein, GFAP) were also evaluated. Our results indicated that repeated APAP overdoses are associated with the inhibition of adult neurogenesis in the context of elevated liver transaminase levels, neuronal hyperactivity, and astrogliosis. These effects were partially reversed after the cessation of APAP administration for 6 and 15 days. In conclusion, these results suggest that APAP overdose impairs adult neurogenesis in the hippocampus and hypothalamus, a fact that may contribute to the effects of APAP on brain function.

Three-arm clinical trial of improved flour targeting intestinal microbiota (MALINEA).

The main objective of this project was to compare in the field conditions two strategies of re-nutrition of children with moderate acute malnutrition (MAM) aged from 6 to 24 months, targeting the microbiota in comparison with a standard regimen. A three-arm, open-label, pragmatic randomised trial was conducted in four countries (Niger, CAR, Senegal and Madagascar). Children received for 12 weeks either fortified blended flour (FBF control) = arm 1, or FBF + azithromycin (oral suspension of 20 mg/kg/day daily given with a syringe) for the first 3 days at inclusion = arm 2 or mix FBF with inulin/fructo-oligosaccharides (6 g/day if age ≥12 months and 4 g if age <12 months) = arm 3. For each arm, children aged from 6 to 11 months received 100 g x 2 per day of flours and those aged from 12 to 24 months received 100 g × 3 per day of FBF. The primary endpoint was nutritional recovery, defined by reaching a weight-for-height z-score (WHZ) ≥ -1.5 within 12 weeks. Overall, 881 children were randomised (297, 290 and 294 in arm 1, arm 2 and arm 3, respectively). Three hundred and forty-four children were males (39%) and median/mean age were 14.6/14.4 months (SD = 4.9, IQR = 10.5-18.4). At inclusion, the three arms were comparable for all criteria, but differences were observed between countries. Overall, 44% (390/881) of the children recovered at week 12 from MAM, with no significant difference between the three arms (41.4%, 45.5% and 45.9%, in arm 1, arm 2 and arm 3, respectively, p = 0.47). This study did not support the true advantages of adding a prebiotic or antibiotic to flour. When using a threshold of WHZ ≥ -2 as an exploratory endpoint, significant differences were observed between the three arms, with higher success rates in arms with antibiotics or prebiotics compared to the control arm (66.9%, 66.0% and 55.2%, respectively, p = 0.005).

Effectiveness of Therapeutic Exercise for Children Undergoing Treatment for Cancer: A Systematic Review: Therapeutic Exercise Children Cancer.

PURPOSE: To evaluate the effectiveness of therapeutic physical exercise (TPE) interventions on the physical functioning, psychosocial well-being, and quality of life (QoL) of children undergoing treatment for cancer. METHOD: Systematic review: databases were searched in April 2023. Selection criteria: children (<18 years old) undergoing treatment for cancer or a malignant neoplasm, randomized controlled trial design, utilization of TPE, and including physical and psychosocial outcomes. Internal validity was measured with Physiotherapy Evidence Database scale. RESULTS: Seven randomized controlled trials were included. Most studies showed that strength, fatigue, and QoL improved after the intervention. Cardiorespiratory capacity through 6-minute walk test and physical activity levels were better in the experimental groups. No changes were noted in other variables. CONCLUSIONS: This review supports the importance of a TPE program during cancer treatment, with the aim of maintaining physical capacities and counteracting physical inactivity.

[Self-care education during Cardiac Rehabilitation programs for patients with Heart Failure with preserved Ejection Fraction: a Delphi Study]. / Educación en autocuidado durante programas de rehabilitación cardiaca para pacientes con insuficiencia cardiaca con fracción de eyección preservada: estudio Delphi.

OBJECTIVES: To develop a decalogue of self-care competencies to manage educational intervention during Cardiac Rehabilitation (CR) programs in Heart Failure with preserved Ejection Fraction (HFpEF) patients through multidisciplinary consensus. DESIGN: 3-round e-Delphi study using an initial questionnaire of 23 competencies based on the main recommendations of the CR and self-care guidelines. SITE: It was framed under the ethics of a randomised clinical trial developed at the Regional Hospital of Malaga. The survey was designed and disseminated as an online questionnaire. PARTICIPANTS: The expert panel comprised two patients with HFpEF and 13 healthcare professionals from Internal Medicine (n=3), Cardiology (n=2), Physiotherapy (n=3), Nursing (n=3) and Occupational Therapy (n=2). METHOD: The analysis of results included the content validity index, the percentage of agreement, and the concordance using Fleiss Kappa and Krippendorff's alpha. RESULTS: After the third round, 20 self-care competencies were identified, grouped into 12 domains, with sufficient consensus for their inclusion in the decalogue. CONCLUSIONS: The decalogue of self-care competencies generated from the multidisciplinary consensus guides education in patients with HFpEF, systematically addressing educational content tailored to patients for clinical practice in CR programs.

Transferring Substituents from Alkynes to Furans and Pyrroles through Heteronorbornadienes as Intermediates: Synthesis of ß-Substituted Pyrroles/Furans.

The use of 7-oxa/azanorbornadienes as synthetic intermediates for the preparation of 3/4-substituted (ß-substituted) furans/pyrroles is presented. The method lies in the inverse electron demand Diels-Alder (iEDDA) cycloaddition between a substituted heteronorbornadiene and an electron-poor tetrazine followed by spontaneous fragmentation of the resulting cycloadduct via two retro-Diels-Alder (rDA) reactions affording a ß-substituted furan/pyrrole. The scope of this tandem iEDDA/rDA/rDA reaction was explored in the preparation of 29 heterocycles. A one-pot procedure starting directly from the alkyne precursors of the heteronorbornadiene intermediates is also described.

Towards precision pain medicine for pain after cancer: the Cancer Pain Phenotyping Network multidisciplinary international guidelines for pain phenotyping using nociplastic pain criteria.

Pain after cancer remains underestimated and undertreated. Precision medicine is a recent concept that refers to the ability to classify patients into subgroups that differ in their susceptibility to, biology, or prognosis of a particular disease, or in their response to a specific treatment, and thus to tailor treatment to the individual patient characteristics. Applying this to pain after cancer, the ability to classify post-cancer pain into the three major pain phenotypes (i.e. nociceptive, neuropathic, and nociplastic pain) and tailor pain treatment accordingly, is an emerging issue. This is especially relevant because available evidence suggests that nociplastic pain is present in an important subgroup of those patients experiencing post-cancer pain. The 2021 International Association for the Study of Pain (IASP) clinical criteria and grading system for nociplastic pain account for the need to identify and correctly classify patients according to the pain phenotype early in their treatment. These criteria are an important step towards precision pain medicine with great potential for the field of clinical oncology. Within this framework, the Cancer Pain Phenotyping (CANPPHE) Network, an international and interdisciplinary group of oncology clinicians and researchers from seven countries, applied the 2021 IASP clinical criteria for nociplastic pain to the growing population of those experiencing post-cancer pain. A manual is provided to allow clinicians to differentiate between predominant nociceptive, neuropathic, or nociplastic pain after cancer. A seven-step diagnostic approach is presented and illustrated using cases to enhance understanding and encourage effective implementation of this approach in clinical practice.

Effectiveness of a cardiac rehabilitation program on biomechanical, imaging, and physiological biomarkers in elderly patients with heart failure with preserved ejection fraction (HFpEF): FUNNEL + study protocol.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) have a low functional status, which in turn is a risk factor for hospital admission and an important predictor of survival in HFpEF. HFpFE is a heterogeneous syndrome and recent studies have suggested an important role for careful, pathophysiological-based phenotyping to improve patient characterization. Cardiac rehabilitation has proven to be a useful tool in the framework of secondary prevention in patients with HFpEF. Facilitating decision-making and implementing cardiac rehabilitation programs is a challenge in public health systems for HFpEF management. The FUNNEL + study proposes to evaluate the efficacy of an exercise and education-based cardiac rehabilitation program on biomechanical, physiological, and imaging biomarkers in patients with HFpEF. METHODS: A randomised crossover clinical trial is presented among people older than 70 years with a diagnosis of HFpEF. The experimental group will receive a cardiac rehabilitation intervention for 12 weeks. Participants in the control group will receive one educational session per week for 12 weeks on HFpEF complications, functional decline, and healthy lifestyle habits. VO2peak is the primary outcome. Biomechanical, imaging and physiological biomarkers will be assessed as secondary outcomes. Outcomes will be assessed at baseline, 12 weeks, and 24 weeks. DISCUSSION: Identifying objective functional parameters indicative of HFpEF and the subsequent development of functional level stratification based on functional impairment ("biomechanical phenotypes") may help clinicians identify cardiac rehabilitation responders and non-responders and make future clinical decisions. In this way, future pharmacological and non-pharmacological interventions, such as exercise, could be improved and tailored to improve quality of life and prognosis and reducing patients' hospital readmissions, thereby reducing healthcare costs. TRIAL REGISTRATION: NCT05393362 (Clinicaltrials.gov).

Differences in wasting assessment through Middle-Upper Arm Circumference (MUAC) adjusted by sex, age and geographic origin for children aged 6-59 months: New reference based on anthropometric surveys from 22 low-and-middle-income countries.

OBJECTIVES: The Middle Upper Arm Circumference (MUAC) bracelet is a widely used instrument in public health assessments and humanitarian assistance projects. The WHO guidelines present a universal cut-off point of 115 mm to determine whether a child has severe acute malnutrition. The objective of this study is to analyze the existing differences in the MUAC for boys and girls aged between 6 and 59 months, from 22 countries distributed in three different continents, in contrast to the use of this single cut-off point. In addition, the creation of MUAC growth charts is presented for reference use. MATERIALS AND METHODS: This study was carried out with a database developed by Action Against Hunger, composed, after the data pre-processing phase, of 97 921 individuals without anthropometric failure from African, Asian, and American continents. MUAC measurements were compared between countries, dividing by sex and age groups. A k-means method was used to create country clusters to allow comparisons and the variability was resumed using a Principal Component Analysis. For each cluster, growth curves were created and smoothed using the LOESS method. RESULTS: Our research has revealed the existence of differences in the MUAC between countries in both, males and females, although with different trends. The evidence was confirmed with the creation of two clusters using the k-means method, which, when graphically represented by the Principal Component Analysis, showed that the MUAC was clearly different. There were also differences between males and females within each cluster, where growth curves did not overlap in any age group. CONCLUSIONS: All statistical analysis indicate that there are differences in the MUAC values for children without anthropometric failure between countries, but also between sexes. With this research, a new reference is proposed that consider the existing variability between human populations to improve the precision in the determination of severe acute malnutrition in children.

AI-Assisted Fatigue and Stamina Control for Performance Sports on IMU-Generated Multivariate Times Series Datasets.

BACKGROUND: Optimal sports performance requires a balance between intensive training and adequate rest. IMUs provide objective, quantifiable data to analyze performance dynamics, despite the challenges in quantifying athlete training loads. The ability of AI to analyze complex datasets brings innovation to the monitoring and optimization of athlete training cycles. Traditional techniques rely on subjective assessments to prevent overtraining, which can lead to injury and underperformance. IMUs provide objective, quantitative data on athletes' physical status during action. AI and machine learning can turn these data into useful insights, enabling data-driven athlete performance management. With IMU-generated multivariate time series data, this paper uses AI to construct a robust model for predicting fatigue and stamina. MATERIALS AND METHODS: IMUs linked to 19 athletes recorded triaxial acceleration, angular velocity, and magnetic orientation throughout repeated sessions. Standardized training included steady-pace runs and fatigue-inducing techniques. The raw time series data were used to train a supervised ML model based on frequency and time-domain characteristics. The performances of Random Forest, Gradient Boosting Machines, and LSTM networks were compared. A feedback loop adjusted the model in real time based on prediction error and bias estimation. RESULTS: The AI model demonstrated high predictive accuracy for fatigue, showing significant correlations between predicted fatigue levels and observed declines in performance. Stamina predictions enabled individualized training adjustments that were in sync with athletes' physiological thresholds. Bias correction mechanisms proved effective in minimizing systematic prediction errors. Moreover, real-time adaptations of the model led to enhanced training periodization strategies, reducing the risk of overtraining and improving overall athletic performance. CONCLUSIONS: In sports performance analytics, the AI-assisted model using IMU multivariate time series data is effective. Training can be tailored and constantly altered because the model accurately predicts fatigue and stamina. AI models can effectively forecast the beginning of weariness before any physical symptoms appear. This allows for timely interventions to prevent overtraining and potential accidents. The model shows an exceptional ability to customize training programs according to the physiological reactions of each athlete and enhance the overall training effectiveness. In addition, the study demonstrated the model's efficacy in real-time monitoring performance, improving the decision-making abilities of both coaches and athletes. The approach enables ongoing and thorough data analysis, supporting strategic planning for training and competition, resulting in optimized performance outcomes. These findings highlight the revolutionary capability of AI in sports science, offering a future where data-driven methods greatly enhance athlete training and performance management.

Differences in Tridimensional Shoulder Kinematics between Asymptomatic Subjects and Subjects Suffering from Rotator Cuff Tears by Means of Inertial Sensors: A Cross-Sectional Study.

Background: The aim of this study was to analyze differences in three-dimensional shoulder kinematics between asymptomatic subjects and patients who were diagnosed with rotator cuff tears. Methods: This cross-sectional study recruited 13 symptomatic subjects and 14 asymptomatic subjects. Data were obtained from three inertial sensors placed on the humerus, scapula and sternum. Kinematic data from the glenohumeral, scapulothoracic and thoracohumeral joints were also calculated. The participants performed shoulder abductions and flexions. The principal angles of movements and resultant vectors in each axis were studied. Results: The glenohumeral joint showed differences in abduction (p = 0.001) and flexion (p = 0.000), while differences in the scapulothoracic joint were only significant during flexion (p = 0.001). The asymptomatic group showed higher velocity values in all sensors for both movements, with the differences being significant (p < 0.007). Acceleration differences were found in the scapula during abduction (p = 0.001) and flexion (p = 0.014), as well as in the sternum only during shoulder abduction (p = 0.022). Conclusion: The results showed kinematic differences between the patients and asymptomatic subjects in terms of the mobility, velocity and acceleration variables, with lower values for the patients.

Machine Learning on Prediction of Relative Physical Activity Intensity Using Medical Radar Sensor and 3D Accelerometer.

BACKGROUND: One of the most critical topics in sports safety today is the reduction in injury risks through controlled fatigue using non-invasive athlete monitoring. Due to the risk of injuries, it is prohibited to use accelerometer-based smart trackers, activity measurement bracelets, and smart watches for recording health parameters during performance sports activities. This study analyzes the synergy feasibility of medical radar sensors and tri-axial acceleration sensor data to predict physical activity key performance indexes in performance sports by using machine learning (ML). The novelty of this method is that it uses a 24 GHz Doppler radar sensor to detect vital signs such as the heartbeat and breathing without touching the person and to predict the intensity of physical activity, combined with the acceleration data from 3D accelerometers. METHODS: This study is based on the data collected from professional athletes and freely available datasets created for research purposes. A combination of sensor data management was used: a medical radar sensor with no-contact remote sensing to measure the heart rate (HR) and 3D acceleration to measure the velocity of the activity. Various advanced ML methods and models were employed on the top of sensors to analyze the vital parameters and predict the health activity key performance indexes. three-axial acceleration, heart rate data, age, as well as activity level variances. RESULTS: The ML models recognized the physical activity intensity and estimated the energy expenditure on a realistic level. Leave-one-out (LOO) cross-validation (CV), as well as out-of-sample testing (OST) methods, have been used to evaluate the level of accuracy in activity intensity prediction. The energy expenditure prediction with three-axial accelerometer sensors by using linear regression provided 97-99% accuracy on selected sports (cycling, running, and soccer). The ML-based RPE results using medical radar sensors on a time-series heart rate (HR) dataset varied between 90 and 96% accuracy. The expected level of accuracy was examined with different models. The average accuracy for all the models (RPE and METs) and setups was higher than 90%. CONCLUSIONS: The ML models that classify the rating of the perceived exertion and the metabolic equivalent of tasks perform consistently.

Head-Mounted Display for Clinical Evaluation of Neck Movement Validation with Meta Quest 2.

Neck disorders have a significant impact on people because of their high incidence. The head-mounted display (HMD) systems, such as Meta Quest 2, grant access to immersive virtual reality (iRV) experiences. This study aims to validate the Meta Quest 2 HMD system as an alternative for screening neck movement in healthy people. The device provides data about the position and orientation of the head and, thus, the neck mobility around the three anatomical axes. The authors develop a VR application that solicits participants to perform six neck movements (rotation, flexion, and lateralization on both sides), which allows the collection of corresponding angles. An InertiaCube3 inertial measurement unit (IMU) is also attached to the HMD to compare the criterion to a standard. The mean absolute error (MAE), the percentage of error (%MAE), and the criterion validity and agreement are calculated. The study shows that the average absolute errors do not exceed 1° (average = 0.48 ± 0.09°). The rotational movement's average %MAE is 1.61 ± 0.82%. The head orientations obtain a correlation between 0.70 and 0.96. The Bland-Altman study reveals good agreement between the HMD and IMU systems. Overall, the study shows that the angles provided by the Meta Quest 2 HMD system are valid to calculate the rotational angles of the neck in each of the three axes. The obtained results demonstrate an acceptable error percentage and a very minimal absolute error when measuring the degrees of neck rotation; therefore, the sensor can be used for screening neck disorders in healthy people.

Sex-Dependent Altered Expression of Cannabinoid Signaling in Hippocampal Astrocytes of the Triple Transgenic Mouse Model of Alzheimer's Disease: Implications for Controlling Astroglial Activity.

Alzheimer's disease (AD) is a common neurodegenerative disease. In AD-associated neuroinflammation, astrocytes play a key role, finding glial activation both in patients and in animal models. The endocannabinoid system (ECS) is a neurolipid signaling system with anti-inflammatory and neuroprotective properties implicated in AD. Astrocytes respond to external cannabinoid signals and also have their own cannabinoid signaling. Our main objective is to describe the cannabinoid signaling machinery present in hippocampal astrocytes from 3×Tg-AD mice to determine if they are actively involved in the neurodegenerative process. Primary cultures of astrocytes from the hippocampus of 3×Tg-AD and non-Tg offspring were carried out. We analyzed the gene expression of astrogliosis markers, the main components of the ECS and Ca2+ signaling. 3×Tg-AD hippocampal astrocytes show low inflammatory activity (Il1b, Il6, and Gls) and Ca2+ flow (P2rx5 and Mcu), associated with low cannabinoid signaling (Cnr1 and Cnr2). These results were more evident in females. Our study corroborates glial involvement in AD pathology, in which cannabinoid signaling plays an important role. 3×Tg-AD mice born with hippocampal astrocytes with differential gene expression of the ECS associated with an innate attenuation of their activity. In addition, we show that there are sex differences from birth in this AD animal, which should be considered when investigating the pathogenesis of the disease.

Studies on the Regioselective Rearrangement of Azanorbornanic Aminyl Radicals into 2,8-Diazabicyclo[3.2.1]oct-2-ene Systems.

Aminyl radicals are nitrogen-centered radicals of interest in synthetic strategies involving C-N bond formation due to their high reactivity. These intermediate radicals are generated by the reaction of an organic azide with tributyltin hydride (Bu3SnH) in the presence of substoichiometric amounts of azobisisobutyronitrile (AIBN). In this work, we report the regioselective rearrangement of azanorbornanic ([2.2.1]azabicyclic) aminyl radicals into 2,8-diazabicyclo[3.2.1]oct-2-ene systems. With the aim to establish the structural requirements for this ring expansion, we have studied the effect of different bridgehead atoms of the [2.2.1]bicyclic system and the presence of an alkyl substituent at C4. Attempts to perform this ring expansion on a monocyclic analogue have been also explored to evaluate the influence of the bicyclic skeleton on the rearrangement. A detailed mechanistic proposal supported by computational studies is reported.

Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars.

Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of ß-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal ß-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic ß-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 × 104 times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A.

Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer's disease.

Concerned by the urgent need to explore new approaches for the treatment of Alzheimer's disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain. Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine. The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD; it turned out to be a strong inhibitor of BuChE (IC50 = 0.46 µM), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC50 = 2.2 µM). This compound exhibited a roughly 12-fold increase in activity compared to galantamine, one of the currently marketed drugs against AD, and a selective AChE inhibitor, and virtually the same activity as rivastigmine, a selective BuChE inhibitor. Furthermore, it was also endowed with a strong inhibitory activity against human OGA, within the nanomolar range (IC50 = 0.053 µM for hOGA, >100 µM for hHexB), and, thus, with an outstanding selectivity (IC50(hHexB)/IC50(hOGA) > 1887). The title compounds also exhibited an excellent selectivity against a panel of glycosidases and a negligible cytotoxicity against tumor and non-tumor cell lines. Docking simulations performed on the three target enzymes (AChE, BuChE, and OGA) revealed the key interactions to rationalize the biological data.

Design and implementation of a standard care programme of therapeutic exercise and education for breast cancer survivors.

BACKGROUND: Breast cancer survivors (BCS) face several symptoms and are at higher risk of weight gain following diagnosis. Current literature shows that both exercise and diet play a key role in recovery of BCS. However, there is a gap between current guidelines and the real-world context. The aim of this article is to describe the process behind a free, not-for-profit community-based therapeutic exercise and education programme (TEEP) for BCS in the clinical setting. METHODS: The "Onco-Health Club" (OHC) consists of therapeutic exercise (TE) intervention aimed at ameliorating cancer-related fatigue (CRF) and improving QoL and physical function. TE is supplemented with nutritional education, providing information about the Mediterranean diet. To this end, patients are recruited from an oncologist and are referred to a physiotherapist and a nutritionist for baseline assessment. TEEP consists of a 3-month intervention, delivered twice a week in a group format with 1 h of TE and 30 min of nutritional education. BCS then have a final assessment and are advised to continue with a healthy lifestyle. Data about referral, compliance and assessment were collected. RESULTS: From May 2017 to February of 2020, a total of 158 patients were recruited from 8 cohorts and 142 initially started the OHC. From 119 that joined the program, 96 patients were considered to have finished it with good adherence (assistance > 80%). BCS significantly improved their QoL, as well as upper and lower limb's function, and increased their level of physical activity. CRF tended to decrease (p = 0.005). CONCLUSIONS: This study obtained data on recruitment, compliance, and possible limitations of these kinds of programmes in a real-world context. Further research is needed in order to optimize patient engagement and compliance, as well as to determine the transferability of these programmes in the clinical setting. TRIAL REGISTRATION: NCT03879096, Registered 18th March 2019. Retrospectively registered.

Thirty-second sit-to-stand test as an alternative for estimating peak oxygen uptake and 6-min walking distance in women with breast cancer: a cross-sectional study.

PURPOSE: To determine whether the 30-s sit-to-stand (30STS) test can be a valid tool for estimating and stratifying peak oxygen uptake (VO2peak) and 6-min walking distance (6MWD) in women with breast cancer. METHODS: This cross-sectional study uses data from the ONCORE randomized controlled trial, including 120 women aged 18-70 years with early-stage breast cancer under treatment with anthracycline and/or anti-HER2 antibodies. Participant characteristics were collected at baseline and pooled data from functional assessment (30STS test, relative and absolute VO2peak, and 6MWD) were collected at baseline and post-intervention (comprehensive cardio-oncology rehabilitation program vs. usual care). Bivariate correlations and multivariate linear regression analyses were performed to study the relationship between functional test variables. RESULTS: The number of repetitions in the 30STS test showed (i) a moderate correlation with relative VO2peak (ml/kg/min) (r = 0.419; p < 0.001; n = 126), (ii) a weak correlation with absolute VO2peak (ml/min) (r = 0.241; p = 0.008; n = 120), and (iii) a moderate correlation with the 6MWD (r = 0.440; p < 0.001; n = 85). The ONCORE equations obtained from the multivariate regression models allowed the estimation of VO2peak and 6MWD (r2 = 0.390; r2 = 0.261, respectively) based on the 30STS test, and its stratification into tertiles (low, moderate, and high). CONCLUSION: The 30STS test was found to be a useful tool to estimate VO2peak and/or 6MWD in women with early-stage breast cancer. Its use may facilitate the assessment and stratification of functional capacity in this population for the implementation of therapeutic exercise programs if cardiopulmonary exercise testing (CPET) or 6MWT are not available. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03964142. Registered on 28 May 2019. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03964142.