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Abstract Background In the last years, the classical pattern of diabetic kidney disease (DKD) has been partially overcome, because of the uncovering of a new DKD phenotype with significant renal dysfunction without presence of albuminuria: the non-albuminuric DKD (NA-DKD). To date, the cardiovascular risk associated with this phenotype is still debated. We investigated the cardiovascular risk and renal injury profile of NA-DKD subjects in comparison with other DKD phenotypes. Methods Pulse wave velocity (PWV), intima-media thickness, presence of carotid atherosclerotic plaque, renal resistive index (RRI), and a panel of urinary biomarkers of kidney injury were evaluated in 160 subjects with type 2 diabetes, stratified according to estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR) into four groups: controls (UACR

Abstract In human movement augmentation, the number of controlled degrees of freedom could be enhanced by the simultaneous and independent use of supernumerary robotic limbs (SRL) and natural ones. However, this poses several challenges, that could be mitigated by encoding and relaying the SRL status. Here, we review the impact of supplementary sensory feedback on the control and embodiment of SRLs. We classify the main feedback features and analyse how they improve control performance. We report the feasibility of pushing body representation beyond natural human morphology and suggest that gradual SRL embodiment could make multisensory incongruencies less disruptive. We also highlight shared computational bases between SRL motor control and embodiment and suggest contextualizing them within the same theoretical framework. Finally, we argue that a shift towards long term experimental paradigms is necessary for successfully integrating motor control and embodiment.

Abstract Proprioception plays a key role in moving our body dexterously and effortlessly. Nevertheless, the majority of investigations evaluating the benefits of providing supplemental feedback to prosthetics users focus on delivering touch restitution. These studies evaluate the influence of touch sensation in an attempt to improve the controllability of current robotic devices. Contrarily, investigations evaluating the capabilities of proprioceptive supplemental feedback have yet to be comprehensively analyzed to the same extent, marking a major gap in knowledge within the current research climate. The non-invasive strategies employed so far to restitute proprioception are reviewed in this work. In the absence of a clearly superior strategy, approaches employing vibrotactile, electrotactile and skin-stretch stimulation achieved better and more consistent results, considering both kinesthetic and grip force information, compared with other strategies or any incidental feedback. Although emulating the richness of the physiological sensory return through artificial feedback is the primary hurdle, measuring its effects to eventually support the integration of cumbersome and energy intensive hardware into commercial prosthetic devices could represent an even greater challenge. Thus, we analyze the strengths and limitations of previous studies and discuss the possible benefits of coupling objective measures, like neurophysiological parameters, as well as measures of prosthesis embodiment and cognitive load with behavioral measures of performance. Such insights aim to provide additional and collateral outcomes to be considered in the experimental design of future investigations of proprioception restitution that could, in the end, allow researchers to gain a more detailed understanding of possibly similar behavioral results and, thus, support one strategy over another.

The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their association with thyroid disorders requires clarification due to the complex interplay between thyroid hormones and metabolic pathways. Thyroid dysfunction commonly co-occurs with metabolic conditions such as diabetes and obesity, suggesting a profound interconnection between these systems. This review aims to contribute to a deeper understanding of the interaction between GLP-1 RAs and thyroid dysfunction and to clarify the safety of GLP-1 RAs in diabetic patients with thyroid disorders. By synthesizing existing evidence, this review highlights that, despite various studies exploring this topic, current evidence is inconclusive, with conflicting results. It is important to note that these drugs are relatively recent, and longer-term studies with larger sample sizes are likely needed to draw clearer conclusions. Currently, no existing guidelines provide definitive directions on this clinical issue; however, it is advisable to include thyroid function tests in the routine screening of diabetic patients, particularly those treated with GLP-1 Ras, with the goal of optimizing patient care and management.

Background and aimsFH women are less likely to receive intensive statin treatment and to obtain a 50% reduction of LDL-C from baseline compared to men with FH. SLCO1B1 rs4149056 might influence statin therapy compliance and thus LDL-C target achievement. Our aim was to evaluate the impact of SLCO1B1 rs4149056 on LDL-C target achievement after lipid lowering therapy (LLT) optimization in men and women with FH.MethodsThis was a retrospective observational study involving 412 FH subjects with a probable or defined clinical diagnosis of FH who had had genetic analysis from June 2016 to September 2022. Biochemical analysis was obtained from all subjects at baseline and at the last follow-up after LLT optimization.ResultsAfter LLT optimization the percentage of FH subjects on high-intensity statins decreased from the M/SLCO1B1- group to the W/SLCO1B1+ group and the same was found in LDL-C target distribution (for both p for trend < 0.01). The prevalence of SASE fear increased from the M/SLCO1B1- group to the W/SLCO1B1+ group and the same was observed in reported myalgia distribution (for both p for trend < 0.01). Logistic regression analysis showed that the W/SCLO1B1-, M/SCLO1B1+ and W/SCLO1B1+ groups were inversely associated with LDL-C target achievement (p for trend < 0.001) and the W/SCLO1B1+ group exhibited the strongest association.ConclusionA low prevalence of FH women with SLCO1B1 rs4149056 were on high intensity statins and they rarely achieved LDL-C target. The genotype effect of SLCO1B1 rs4149056 could be more pronounced in FH women than men.

Magnetoencephalography and electroencephalography (M/EEG) seed-based connectivity analysis typically requires regions of interest (ROI)-based extraction of measures. M/EEG ROI-derived source activity can be treated in different ways. For instance, it is possible to average each ROI's time series prior to calculating connectivity measures. Alternatively one can compute connectivity maps for each element of the ROI, prior to dimensionality reduction to obtain a single map. The impact of these different strategies on connectivity estimation is still unclear.Here, we address this question within a large MEG resting state cohort (N=113) and simulated data. We consider 68 ROIs (Desikan-Kiliany atlas), two measures of connectivity (phase locking value-PLV, and its imaginary counterpart- ciPLV), and three frequency bands (theta 4-8 Hz, alpha 9-12 Hz, beta 15-30 Hz). We consider four extraction methods: (i) mean, or (ii) PCA of the activity within the ROI before computing connectivity, (iii) average, or (iv) maximum connectivity after computing connectivity for each element of the seed. Connectivity outputs from these extraction strategies are then compared with hierarchical clustering, followed by direct contrasts across extraction methods. Finally, the results are validated by using a set of realistic simulations.We show that ROI-based connectivity maps vary remarkably across strategies in both connectivity magnitude and spatial distribution. Dimensionality reduction procedures conducted after computing connectivity are more similar to each-other, while PCA before approach is the most dissimilar to other approaches. Although differences across methods are consistent across frequency bands, they are influenced by the connectivity metric and ROI size. Greater differences were observed for ciPLV than PLV, and in larger ROIs. Realistic simulations confirmed that after aggregation procedures are generally more accurate but have lower specificity (higher rate of false positive connections). Although computationally demanding, after dimensionality reduction strategies should be preferred when higher sensitivity is desired. Given the remarkable differences across aggregation procedures, caution is warranted in comparing results across studies applying different extraction methods.

“Crossmodal correspondences” are the consistent mappings between perceptual dimensions or stimuli from different sensory domains, which have been widely observed in the general population and investigated by experimental psychologists in recent years. At the same time, the emerging field of human movement augmentation (i.e., the enhancement of an individual’s motor abilities by means of artificial devices) has been struggling with the question of how to relay supplementary information concerning the state of the artificial device and its interaction with the environment to the user, which may help the latter to control the device more effectively. To date, this challenge has not been explicitly addressed by capitalizing on our emerging knowledge concerning crossmodal correspondences, despite these being tightly related to multisensory integration. In this perspective paper, we introduce some of the latest research findings on the crossmodal correspondences and their potential role in human augmentation. We then consider three ways in which the former might impact the latter, and the feasibility of this process. First, crossmodal correspondences, given the documented effect on attentional processing, might facilitate the integration of device status information (e.g., concerning position) coming from different sensory modalities (e.g., haptic and visual), thus increasing their usefulness for motor control and embodiment. Second, by capitalizing on their widespread and seemingly spontaneous nature, crossmodal correspondences might be exploited to reduce the cognitive burden caused by additional sensory inputs and the time required for the human brain to adapt the representation of the body to the presence of the artificial device. Third, to accomplish the first two points, the benefits of crossmodal correspondences should be maintained even after sensory substitution, a strategy commonly used when implementing supplementary feedback.

Abstract Auditory white noise (WN) is widely used in neuroscience to mask unwanted environmental noise and cues, e.g. TMS clicks. However, to date there is no research on the influence of WN on corticospinal excitability and potentially associated sensorimotor integration itself. Here we tested the hypothesis, if WN induces M1 excitability changes and improves sensorimotor performance. M1 excitability (spTMS, SICI, ICF, I/O curve) and sensorimotor reaction-time performance were quantified before, during and after WN stimulation in a set of experiments performed in a cohort of 61 healthy subjects. WN enhanced M1 corticospinal excitability, not just during exposure, but also during silence periods intermingled with WN, and up to several minutes after the end of exposure. Two independent behavioural experiments highlighted that WN improved multimodal sensorimotor performance. The enduring excitability modulation combined with the effects on behaviour suggest that WN might induce neural plasticity. WN is thus a relevant modulator of corticospinal function; its neurobiological effects should not be neglected and could in fact be exploited in research applications.

Supernumerary robotic limbs are mainly designed to augment the physical capabilities of able-bodied individuals, in a wide range of contexts from body support to surgery. When they are worn as wearable devices, they naturally provide inherent feedback due to the mechanical coupling with the human body. The user can, thus, perceive the interaction with the environment by relying on a combination of visual and inherent feedback. However, these can be inefficient in accomplishing complex tasks, particularly in the case of visual occlusion or variation in the environment stiffness. Here, we investigated whether, in a force-regulation task using a wearable supernumerary robotic arm (SRA), additional vibrotactile feedback can increase the control performance of participants compared to the inherent feedback. Additionally, to make the scenario more realistic, we introduced variations in the SRA’s kinematic posture and in the environment stiffness. Notably, our findings revealed a statistically significant improvement in user performance over all the evaluated metrics while receiving additional vibrotactile feedback. Compared to inherent feedback alone, the additional vibrotactile feedback allowed participants to exert the required force faster (p < 0.01), to maintain it for longer (p < 0.001), and with lower errors (p < 0.001). No discernible effects related to the SRA’s posture or environment stiffness were observed. These results proved the benefits of providing the user with additional vibrotactile feedback to convey the SRA’s force during interaction tasks.

In this Review, the authors discuss recent technological and neuroscientific advances in human body augmentation. They construct a movement augmentation taxonomy, discuss how it is achieved, and propose a vision for the field.

IntroductionRobotic therapy allow to propose sessions of controlled and identical exercises, customizing settings, and characteristics on the individual patient. The effectiveness of robotic assisted therapy is still under study and the use of robots in clinical practice is still limited. Moreover, the possibility of treatment at home allows to reduce the economic costs and time to be borne by the patient and the caregiver and is a valid tool during periods of pandemic such as covid. The aim of this study is to assess whether a robotic home-based treatment rehabilitation using the iCONE robotic device has effects on a stroke population, despite the chronic condition of patients involved and the absence of a therapist next to the patient while performing the exercises.Materials and methodsAll patients underwent an initial (T0) and final (T1) assessment with the iCONE robotic device and clinical scales. After T0 evaluation, the robot was delivered to the patient's home for 10 days of at-home treatment (5 days a week for 2 weeks).ResultsComparison between T0 and T1 evaluations revealed some significant improvements in robot-evaluated indices such as Independence and Size for the Circle Drawing exercise and Movement Duration for Point-to-Point exercise, but also in the MAS of the elbow. From the analysis of the acceptability questionnaire, a general appreciation of the robot emerged: patients spontaneously asked for the addition of further sessions and to continue therapy.DiscussionTelerehabilitation of patients suffering from a chronic stroke is an area that is still little explored. From our experience, this is one of the first studies to carry out a telerehabilitation with these characteristics. The use of robots can become a method to reduce the rehabilitation health costs, to ensure continuity of care, and to arrive in more distant places or where the availability of resources is limited.ConclusionFrom the data obtained, this rehabilitation seems to be promising for this population. Moreover, promoting the recovery of the upper limb, iCONE can improve patient's quality of life. It would be interesting to conduct RCT studies to compare a conventional treatment in structure with a robotic telematics treatment.

Somatosensation greatly increases the ability to control our natural body. This suggests that supplementing vision with haptic sensory feedback would also be helpful when a user aims at controlling a robotic arm proficiently. However, whether the position of the robot and its continuous update should be coded in a extrinsic or intrinsic reference frame is not known. Here we compared two different supplementary feedback contents concerning the status of a robotic limb in 2-DoFs configuration: one encoding the Cartesian coordinates of the end-effector of the robotic arm (i.e., Task-space feedback) and another and encoding the robot joints angles (i.e., Joint-space feedback). Feedback was delivered to blindfolded participants through vibrotactile stimulation applied on participants’ leg. After a 1.5-hour training with both feedbacks, participants were significantly more accurate with Task compared to Joint-space feedback, as shown by lower position and aiming errors, albeit not faster (i.e., similar onset delay). However, learning index during training was significantly higher in Joint space feedback compared to Task-space feedback. These results suggest that Task-space feedback is probably more intuitive and more suited for activities which require short training sessions, while Joint space feedback showed potential for long-term improvement. We speculate that the latter, despite performing worse in the present work, might be ultimately more suited for applications requiring long training, such as the control of supernumerary robotic limbs for surgical robotics, heavy industrial manufacturing, or more generally, in the context of human movement augmentation.

Anderson–Fabry disease (AFD) is a genetic lysosomal storage disorder caused by mutations in the α-galactosidase A gene, leading to impaired lysosomal function and resulting in both macrovascular and microvascular alterations. AFD patients often exhibit increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating non-atherosclerotic arterial thickening and the potential for cardiovascular events. Nailfold capillaroscopy, a non-invasive diagnostic tool, has shown potential in diagnosing and monitoring microcirculatory disorders in AFD, despite limited research. This study evaluates nailfold capillaroscopy findings in AFD patients, exploring correlations with GLA gene variant subgroups (associated with classical or late-onset phenotypes and variants of uncertain significance (VUSs)), and assessing morpho-functional differences between sexes. It aims to determine whether capillaroscopy can assist in the early identification of individuals with multiorgan vascular involvement. A retrospective observational study was conducted with 25 AFD patients from AOUP "G. Rodolico-San Marco" in Catania (2020–2023). Patients underwent genetic testing, enzyme activity evaluation, and nailfold capillaroscopy using Horus basic HS 200 videodermatoscopy. Parameters like angiotectonic disorder, vascular areas, capillary density, and intimal thickening were assessed. The study identified significant differences in capillaroscopy findings among patients with different GLA gene variant subgroups. Classic AFD variant patients showed reduced capillary length and signs of erythrocyte aggregation and dilated subpapillary plexus. No correlation was found between enzymatic activity and capillaroscopy parameters. However, Lyso-Gb3 levels were positively correlated with average capillary length (ῤ = 0.453; p = 0.059). Sex-specific differences in capillaroscopy findings were observed in neoangiogenesis and average capillary length, with distinct implications for men and women. This study highlights the potential of nailfold capillaroscopy in the diagnostic process and clinical management of AFD, particularly in relation to specific GLA gene mutations, as a valuable tool for the early diagnosis and monitoring of AFD. [ABSTRACT FROM AUTHOR]

Background and Aims: Cholemic nephropathy is a cause of acute kidney injury occurring in patients with jaundice. The aim of this study was to evaluate early renal function impairment in patients with mild acute hyperbilirubinemia in the absence of alterations of the common parameters used in clinical practice (serum creatinine or urea) and with normal renal morphology. We studied urinary biomarkers of tubular damage urinary neutrophil gelatinase‐associated lipocalin (u‐NGAL), urinary beta‐2‐microglobulin (u‐B2M), urinary osteopontin (u‐OPN), urinary trefoil factor 3 (u‐TFF3) and urinary Cystatin C (u‐Cys). Methods: This is a case‐control study investigating the following urinary biomarkers of tubular damage: u‐NGAL, u‐B2M, u‐OPN, u‐TFF3 and u‐Cys, in patients with mild acute hyperbilirubinemia. Seventy‐four patients were included in this study: 36 patients with jaundice and 38 patients without jaundice. Results: Subjects with jaundice (total bilirubin 12.4 ± 7.3 mg/dL) showed higher u‐NGAL, u‐B2M, u‐OPN, u‐TFF3 and u‐Cys compared with controls. After logistic regression analyses, including the following independent variables: age, estimated Glomerular Filtration Rate (eGFR), haemoglobin, diabetes, hypertension and jaundice, we observed a higher risk of elevated u‐NGAL values (OR = 3.8, 95% CI 1.07–13.5, p =.03) and u‐B2M (OR = 9.4, 95% CI 2.3–38.9, p =.0018) in jaundiced subjects. Moreover, urinary biomarkers had a direct correlation with serum cholestasis indexes. Conclusions: This study demonstrated increased urinary biomarkers of tubular damage (u‐NGAL, u‐B2M, u‐OPN, u‐TFF3, and u‐Cys) in patients with mild hyperbilirubinemia in comparison with a control group. These findings suggest early renal tubular damage in the absence of alterations of the normal parameters used in clinical practice (eGFR, serum urea and renal morphology). [ABSTRACT FROM AUTHOR]

Abstract The successful completion of complex tasks like hanging a picture or laparoscopic surgery requires coordinated motion of more than two limbs. User-controlled supernumerary robotic limbs (SL) have been proposed to bypass the need for coordination with a partner in such tasks. However, neither the capability to control multiple limbs alone relative to collaborative control with partners, nor how that capability varies across different tasks, is well understood. In this work, we present an investigation of tasks requiring three-hands where the foot was used as an additional source of motor commands. We considered: (1) how does simultaneous control of three hands compare to a cooperating dyad; (2) how this relative performance was altered by the existence of constraints emanating from real or virtual physical connections (mechanical constraints) or from cognitive limits (cognitive constraints). It was found that a cooperating dyad outperformed a single user in all scenarios in terms of task score, path efficiency and motion smoothness. However, while the participants were able to reach more targets with increasing mechanical constraints/decreasing number of simultaneous goals, the relative difference in performance between a dyad and a participant performing trimanual activities decreased, suggesting further potential for SLs in this class of scenario.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond regulating LDL cholesterol (LDL-c) plasma levels, exerts several pleiotropic effects by modulating lipid metabolism in extrahepatic cells such as macrophages. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (CEC) and the serum capacity to promote cell cholesterol loading (CLC). The aim of this observational study was to investigate the effect of PCSK9 inhibitors (PCSK9-i) treatment on HDL-CEC and serum CLC in patients with familial hypercholesterolemia (FH). 31 genetically confirmed FH patients were recruited. Blood was collected and serum isolated at baseline and after 6 months of PCSK9-i treatment. HDL-CEC was evaluated through the main pathways with a radioisotopic cell-based assay. Serum CLC was assessed fluorimetrically in human THP-1 monocyte-derived macrophages. After treatment with PCSK9-i, total cholesterol and LDL-c significantly decreased (−41.6%, p < 0.0001 and −56.7%, p < 0.0001, respectively). Total HDL-CEC was not different between patients before and after treatment. Conversely, despite no changes in HDL-c levels between the groups, ABCG1 HDL-CEC significantly increased after treatment (+22.2%, p < 0.0001) as well as HDL-CEC by aqueous diffusion (+7.8%, p = 0.0008). Only a trend towards reduction of ABCA1 HDL-CEC was observed after treatment. PCSK9-i significantly decreased serum CLC (−6.6%, p = 0.0272). This effect was only partly related to the reduction of LDL-c levels. In conclusion, PCSK9-i treatment significantly increased HDL-CEC through ABCG1 and aqueous diffusion pathways and reduced the serum CLC in FH patients. The favorable effect of PCSK9-i on functional lipid profile could contribute to the cardiovascular benefit of these drugs in FH patients.

El objetivo de este artículo es mapear los artículos más trascendentes relativos a las reformas introducidas a la Ley de Ejecución de la Pena Privativa de la Libertad (ley n° 24.660) entre 2004 y 2017. Estas decisiones legislativas las pondremos en diálogo con las decisiones más relevantes de la Corte Interamericana de Derechos Humanos en cuestiones referidas a estándares de ejecución de la pena y condiciones de detención. Finalmente, mostraremos que las reformas menoscaban el principio de progresividad de la pena y producen problemas en las condiciones materiales de la vida dentro de las prisiones.

Background: The autonomic nervous system is the main determinant of the blood flow directed towards a body part, and it is tightly connected to the representation of the body in the brain; would the experimental modulation of the sense of limb ownership affect its blood perfusion? Methods: In healthy participants, we employed the rubber hand illusion paradigm to modulate limb ownership while we monitored the brachial artery blood flow and resistance index within the investigated limb. Results: In all conditions with brush-stroking, we found an initial drop in the blood flow due to tactile stimulation. Subsequently, in the illusion condition (where both the rubber and real hand synchronous brush-stroking were present), the blood flow rose significantly faster and reached significantly higher values. Moreover, the increase in blood flow correlated with the extent of embodiment as measured by questionnaires and correlated negatively with the change of peripherical vascular resistance. Conclusions: These findings suggest that modulating the representation of a body part impacts its blood perfusion.

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m2, absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD.