Foot-Floor Contact Sequences: A Metric for Gait Assessment in Parkinson's Disease after Deep Brain Stimulation.

Digital gait monitoring is increasingly used to assess locomotion and fall risk. The aim of this work is to analyze the changes in the foot-floor contact sequences of Parkinson's Disease (PD) patients in the year following the implantation of Deep Brain Stimulation (DBS). During their best-ON condition, 30 PD patients underwent gait analysis at baseline (T0), at 3 months after subthalamic nucleus DBS neurosurgery (T1), and at 12 months (T2) after subthalamic nucleus DBS neurosurgery. Thirty age-matched controls underwent gait analysis once. Each subject was equipped with bilateral foot-switches and a 5 min walk was recorded, including both straight-line and turnings. The walking speed, turning time, stride time variability, percentage of atypical gait cycles, stance, swing, and double support duration were estimated. Overall, the gait performance of PD patients improved after DBS, as also confirmed by the decrease in their UPDRS-III scores from 19.4 ± 1.8 to 10.2 ± 1.0 (T0 vs. T2) (p < 0.001). In straight-line walking, the percentages of atypical cycles of PD on the more affected side were 11.1 ± 1.5% (at T0), 3.1 ± 1.5% (at T1), and 5.1 ± 2.4% (at T2), while in controls it was 3.1 ± 1.3% (p < 0.0005). In turnings, this percentage was 13.7 ± 1.1% (at T0), 7.8 ± 1.1% (at T1), and 10.9 ± 1.8% (at T2), while in controls it was 8.1 ± 1.0% (p < 0.001). Therefore, in straight-line walking, the atypical cycles decreased by 72% at T1, and by 54% at T2 (with respect to baseline), while, in turnings, atypical cycles decreased by 43% at T1, and by 20% at T2. The percentage of atypical gait cycles proved an informative digital biomarker for quantifying PD gait changes after DBS, both in straight-line paths and turnings.

The role of nutrition on Parkinson's disease: a systematic review.

BACKGROUND: Parkinson's disease (PD) in elderly patients is the second most prevalent neurodegenerative disease. The pathogenesis of PD is associated with dopaminergic neuron degeneration of the substantia nigra in the basal ganglia, causing classic motor symptoms. Oxidative stress, mitochondrial dysfunction, and neuroinflammation have been identified as possible pathways in laboratory investigations. Nutrition, a potentially versatile factor from all environmental factors affecting PD, has received intense research scrutiny. METHODS: A systematic search was conducted in the MEDLINE, EMBASE, and WEB OF SCIENCE databases from 2000 until the present. Only randomized clinical trials (RCTs), observational case-control studies, and follow-up studies were included. RESULTS: We retrieved fifty-two studies that met the inclusion criteria. Most selected studies investigated the effects of malnutrition and the Mediterranean diet (MeDiet) on PD incidence and progression. Other investigations contributed evidence on the critical role of microbiota, vitamins, polyphenols, dairy products, coffee, and alcohol intake. CONCLUSIONS: There are still many concerns regarding the association between PD and nutrition, possibly due to underlying genetic and environmental factors. However, there is a body of evidence revealing that correcting malnutrition, gut microbiota, and following the MeDiet reduced the onset of PD and reduced clinical progression. Other factors, such as polyphenols, polyunsaturated fatty acids, and coffee intake, can have a potential protective effect. Conversely, milk and its accessory products can increase PD risk. Nutritional intervention is essential for neurologists to improve clinical outcomes and reduce the disease progression of PD.

Protective Effects of Hexarelin and JMV2894 in a Human Neuroblastoma Cell Line Expressing the SOD1-G93A Mutated Protein.

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease whose etiology remains unresolved; nonetheless, mutations of superoxide dismutase 1 (SOD1) have been associated with several variants of ALS. Currently available pharmacologic interventions are only symptomatic and palliative in effect; therefore, there is a pressing demand for more effective drugs. This study examined potential therapeutic effects of growth hormone secretagogues (GHSs), a large family of synthetic compounds, as possible candidates for the treatment of ALS. Human neuroblastoma cells expressing the SOD1-G93A mutated protein (SH-SY5Y SOD1G93A cells) were incubated for 24 h with H2O2 (150 µM) in the absence, or presence, of GHS (1 µM), in order to study the protective effect of GHS against increased oxidative stress. The two GHSs examined in this study, hexarelin and JMV2894, protected cells from H2O2-induced cytotoxicity by activating molecules that regulate apoptosis and promote cell survival processes. These findings suggest the possibility of developing new GHS-based anti-oxidant and neuroprotective drugs with improved therapeutic potential. Further investigations are required for the following: (i) to clarify GHS molecular mechanisms of action, and (ii) to envisage the development of new GHSs that may be useful in ALS therapy.

miRNA Expression Profiling in Subcutaneous Adipose Tissue of Monozygotic Twins Discordant for HIV Infection: Validation of Differentially Expressed miRNA and Bioinformatic Analysis.

Combined AntiRetroviral Treatments (cARTs) used for HIV infection may result in varied metabolic complications, which in some cases, may be related to patient genetic factors, particularly microRNAs. The use of monozygotic twins, differing only for HIV infection, presents a unique and powerful model for the controlled analysis of potential alterations of miRNAs regulation consequent to cART treatment. Profiling of 2578 mature miRNA in the subcutaneous (SC) adipose tissue and plasma of monozygotic twins was investigated by the GeneChip® miRNA 4.1 array. Real-time PCR and ddPCR experiments were performed in order to validate differentially expressed miRNAs. Target genes of deregulated miRNAs were predicted by the miRDB database (prediction score > 70) and enrichment analysis was carried out with g:Profiler. Processes in SC adipose tissue most greatly affected by miRNA up-regulation included (i) macromolecular metabolic processes, (ii) regulation of neurogenesis, and (iii) protein phosphorylation. Furthermore, KEGG analysis revealed miRNA up-regulation involvement in (i) insulin signaling pathways, (ii) neurotrophin signaling pathways, and (iii) pancreatic cancer. By contrast, miRNA up-regulation in plasma was involved in (i) melanoma, (ii) p53 signaling pathways, and (iii) focal adhesion. Our findings suggest a mechanism that may increase the predisposition of HIV+ patients to insulin resistance and cancer.

The role of androgens in women's health and wellbeing.

Androgens in women, as well as in men, are intrinsic to maintenance of (i) reproductive competency, (ii) cardiac health, (iii) appropriate bone remodeling and mass retention, (iii) muscle tone and mass, and (iv) brain function, in part, through their mitigation of neurodegenerative disease effects. In recognition of the pluripotency of endogenous androgens, exogenous androgens, and selected congeners, have been prescribed off-label for several decades to treat low libido and sexual dysfunction in menopausal women, as well as, to improve physical performance. However, long-term safety and efficacy of androgen administration has yet to be fully elucidated. Side effects often observed include (i) hirsutism, (ii) acne, (iii) deepening of the voice, and (iv) weight gain but are associated most frequently with supra-physiological doses. By contrast, short-term clinical trials suggest that the use of low-dose testosterone therapy in women appears to be effective, safe and economical. There are, however, few clinical studies, which have focused on effects of androgen therapy on pre- and post-menopausal women; moreover, androgen mechanisms of action have not yet been thoroughly explained in these subjects. This review considers clinical effects of androgens on women's health in order to prevent chronic diseases and reduce cancer risk in gynecological tissues.

Atypical Gait Cycles in Parkinson's Disease.

It is important to find objective biomarkers for evaluating gait in Parkinson's Disease (PD), especially related to the foot and lower leg segments. Foot-switch signals, analyzed through Statistical Gait Analysis (SGA), allow the foot-floor contact sequence to be characterized during a walking session lasting five-minutes, which includes turnings. Gait parameters were compared between 20 PD patients and 20 age-matched controls. PDs showed similar straight-line speed, cadence, and double-support compared to controls, as well as typical gait-phase durations, except for a small decrease in the flat-foot contact duration (-4% of the gait cycle, p = 0.04). However, they showed a significant increase in atypical gait cycles (+42%, p = 0.006), during both walking straight and turning. A forefoot strike, instead of a "normal" heel strike, characterized the large majority of PD's atypical cycles, whose total percentage was 25.4% on the most-affected and 15.5% on the least-affected side. Moreover, we found a strong correlation between the atypical cycles and the motor clinical score UPDRS-III (r = 0.91, p = 0.002), in the subset of PD patients showing an abnormal number of atypical cycles, while we found a moderate correlation (r = 0.60, p = 0.005), considering the whole PD population. Atypical cycles have proved to be a valid biomarker to quantify subtle gait dysfunctions in PD patients.

Palmitoylethanolamide Modulation of Microglia Activation: Characterization of Mechanisms of Action and Implication for Its Neuroprotective Effects.

Palmitoylethanolamide (PEA) is an endogenous lipid produced on demand by neurons and glial cells that displays neuroprotective properties. It is well known that inflammation and neuronal damage are strictly related processes and that microglia play a pivotal role in their regulation. The aim of the present work was to assess whether PEA could exert its neuroprotective and anti-inflammatory effects through the modulation of microglia reactive phenotypes. In N9 microglial cells, the pre-incubation with PEA blunted the increase of M1 pro-inflammatory markers induced by lipopolysaccharide (LPS), concomitantly increasing those M2 anti-inflammatory markers. Images of microglial cells were processed to obtain a set of morphological parameters that highlighted the ability of PEA to inhibit the LPS-induced M1 polarization and suggested that PEA might induce the anti-inflammatory M2a phenotype. Functionally, PEA prevented Ca2+ transients in both N9 cells and primary microglia and antagonized the neuronal hyperexcitability induced by LPS, as revealed by multi-electrode array (MEA) measurements on primary cortical cultures of neurons, microglia, and astrocyte. Finally, the investigation of the molecular pathway indicated that PEA effects are not mediated by toll-like receptor 4 (TLR4); on the contrary, a partial involvement of cannabinoid type 2 receptor (CB2R) was shown by using a selective receptor inverse agonist.

JMV5656, a short synthetic derivative of TLQP-21, alleviates acid-induced lung injury and fibrosis in mice.

TLQP-21, a peptide encoded by the prohormone VGF, is expressed in neuroendocrine cells and can modulate inflammatory processes. Since TLQP-21 can bind the complement 3a receptor 1 on macrophages, interest has risen in this peptide as a potential drug for the treatment of Acute Respiratory Distress Syndrome (ARDS), whose hospital mortality can reach 35-46%. Since no effective pharmacologic therapies are available, our aim was to exploit the potential of a short analog of TLQP-21(JMV5656) in order to modulate the inflammatory process in ARDS and the progression to pulmonary fibrosis in an experimental model of unilateral acid aspiration in mice. Mice were divided in 2 treatment groups. In the acute protocol, mice received intra-peritoneal injection of either vehicle or 0.6 mg/kg JMV5656 on experimental days 1 and 2, and ARDS was induced on day 3 under deep anesthesia by instillation of HCl (1.5 ml/kg of 0.1 M HCl in 0.9% NaCl) into the right lung; all measurements were performed 24 h later. In the subacute protocol, mice were treated as previously, but treatment with vehicle or JMV5656 was repeated also on day 4 and measurements were made 2 weeks later. Twenty-four hours after acid instillation, the total number of immune cell in the BAL rose sharply due primarily to an increase in the PMN population which increased from 1% up to 58% of total cell numbers. JMV5656 significantly reduced PMN recruitment into the alveolar space, but had no effects on cytokine levels in BAL. Two weeks after acid injury, static compliance of the right lung was significantly higher in the JMV5656-treated group compared to vehicle-treated group. Treatment with JMV5656 also blunted the acid-induced collagen deposition in the right lung. These results suggest that JMV5656 can ameliorate mechanical compliance, and reduce collagen deposition in acid-injured lungs in mice. This effect was likely due to the ability of JMV5656 to inhibit PMN recruitment in the injured lung.

Characterization of Synovial Cytokine Patterns in Bucket-Handle and Posterior Horn Meniscal Tears.

The specific etiology of meniscal tears, including the mechanism of lesion, location, and orientation, is considered for its contribution to subsequent joint cytokine responsiveness, healing outcomes, and by extension, appropriate lesion-specific surgical remediation. Meniscal repair is desirable to reduce the probability of development of posttraumatic osteoarthritis (PTOA) which is strongly influenced by the coordinate generation of pro- and anti-inflammatory cytokines by the injured cartilage. We now present biochemical data on variation in cytokine levels arising from two particular meniscal tears: bucket-handle (BH) and posterior horn (PH) isolated meniscal tears. We selected these two groups due to the different clinical presentations. We measured the concentrations of TNF-α, IL-1ß, IL-6, IL-8, and IL-10 in knee synovial fluid of 45 patients with isolated meniscal lesions (BH tear, n = 12; PH tear, n = 33). TNF-α levels were significantly (p < 0.05) greater in the BH group compared with the PH group, whereas IL-1ß levels were significantly greater (p < 0.05) in the PH group compared with the BH group. Both BH and PH groups were consistent in presenting a positive correlation between concentrations of IL-6 and IL-1ß. A fundamental difference in IL-10 responsiveness between the two groups was noted; specifically, levels of IL-10 were positively correlated with IL-6 in the BH group, whereas in the PH group, levels of IL-10 were positively correlated with IL-1ß. Collectively, our data suggest a possible influence of the meniscal tear pattern to the articular cytokine responsiveness. This differential expression of inflammatory cytokines may influence the risk of developing PTOA in the long term.

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies.

Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function.

Clinical, demographical characteristics and hospitalisation of 3,010 patients with Covid-19 in Friuli Venezia Giulia Region (Northern Italy). A multivariate, population-based, statistical analysis.

OBJECTIVES: to describe the clinical and demographical characteristics of COVID-19 infected people in the Friuli Venezia Giulia Region (FVG, Northern Italy). DESIGN: retrospective cohort study with an individual level record linkage procedure of different administrative databases. SETTING AND PARTICIPANTS: the cohort included 3,010 patients residing in FVG who tested positive for COVID-19 between 1 March and 15 May 2020, 2020. Regional hospital admissions and deaths without hospital admissions up to June 1st, 2020 were analysed. Determinants of the probability of a highly severe illness were investigated in terms of hospitalisations or death without hospital admission. MAIN OUTCOME MEASURES: COVID-19 patients were identified from regional epidemiological data warehouse. Demographical and clinical variables such as gender, age, patient's comorbidities, vaccinations, ARBs/sartans prescriptions, and geographical residence variables were collected by linking different databases. Descriptive analyses were performed. Logistic multivariate regressions were used to estimate the probability of hospitalisation or death, whichever came first. Model coefficients and odds ratios (OR) were reported. RESULTS: COVID-19 population in FVG had a mean age of 60 years and 59% were females. The study found that 37% had hypertension while patients with cardiologic diseases, diabetes, and cancer were around 15%; 22% of the cases were residing in retirement homes. Approximately 30% received flu or pneumococcal vaccination and a similar proportion of patients had at least one prescription of ARBs /sartans in the previous 6 months. Statistical models showed a higher probability of a worst course of disease for males, elderly, highly complicated (in terms of resource use) subjects, in the presence of cardiologic diseases, diabetes, and pneumococcal vaccination. People living in retirement homes had a lower probability of hospitalisation/death without hospital admission. The cohort was divided into two groups: COVID-19 patients infected in the territory and infected in retirement homes. Among COVID-19 patients infected in the territory, the probability of hospitalisation/death was higher for males, for older individuals, and for those with comorbidities. Diabetes resulted to be a risk factor (OR 1.79; 95%CI 1.23-2.62), as well as pneumococcal vaccination (OR 1.64; 95%CI: 1.18-2.29), which is a likely proxy of fragile patients with pulmonary disease. The flu vaccination showed a potential protective effect with a 40% lower probability of hospitalisation or death (OR 0.62; 95%CI 0.44-0.85). Among the retirement homes cohort group, a higher probability of a bad course of disease emerged for males and for more complex patients. CONCLUSIONS: the greatest risk of hospitalisation/death as a measure of more severe illness was confirmed for males, elderly, and for individuals with comorbidities. Flu vaccination seemed to have had a protective effect while pneumococcal vaccination likely identified a group of high-risk patients to be actively monitored. For patients infected in the territory, different hospitalisation strategies were implemented by the regional health districts.

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle.

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia-reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.

TLQP-21, A VGF-Derived Peptide Endowed of Endocrine and Extraendocrine Properties: Focus on In Vitro Calcium Signaling.

VGF gene encodes for a neuropeptide precursor of 68 kDa composed by 615 (human) and 617 (rat, mice) residues, expressed prevalently in the central nervous system (CNS), but also in the peripheral nervous system (PNS) and in various endocrine cells. This precursor undergoes proteolytic cleavage, generating a family of peptides different in length and biological activity. Among them, TLQP-21, a peptide of 21 amino acids, has been widely investigated for its relevant endocrine and extraendocrine activities. The complement complement C3a receptor-1 (C3aR1) has been suggested as the TLQP-21 receptor and, in different cell lines, its activation by TLQP-21 induces an increase of intracellular Ca2+. This effect relies both on Ca2+ release from the endoplasmic reticulum (ER) and extracellular Ca2+ entry. The latter depends on stromal interaction molecules (STIM)-Orai1 interaction or transient receptor potential channel (TRPC) involvement. After Ca2+ entry, the activation of outward K+-Ca2+-dependent currents, mainly the KCa3.1 currents, provides a membrane polarizing influence which offset the depolarizing action of Ca2+ elevation and indirectly maintains the driving force for optimal Ca2+ increase in the cytosol. In this review, we address the main endocrine and extraendocrine actions displayed by TLQP-21, highlighting recent findings on its mechanism of action and its potential in different pathological conditions.

Correction to: Parma consensus statement on metabolic disruptors.

CORRECTION: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".

Neurotrophic and Neuroregenerative Effects of GH/IGF1.

INTRODUCTION: Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects. METHODS: In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: "GH/IGF-1" associated with "neuroregeneration", "amyotrophic lateral sclerosis", "Alzheimer disease", "Parkinson's disease", "brain", and "neuron". RESULTS: Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results. CONCLUSIONS: Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone.

Medical therapy and subthalamic deep brain stimulation in advanced Parkinson's disease: a different long-term outcome?

OBJECTIVES: Few clinical trials reported the comparative short-term efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) versus medical therapy in advanced Parkinson's disease (PD). However, the comparative efficacy, safety and the potential disease-modifying effect of these treatments have not been investigated over a longer follow-up period. METHODS: In this study, we organised a 'retrospective control group' to compare medical and surgical therapies over a long-term period. We assessed a group of PD patients suitable for STN-DBS but successively treated with medical therapies for reasons not related to PD, and a group of similar consecutive STN-DBS patients. We thus obtained two groups comparable at baseline, which were re-evaluated after an average follow-up of 6 years (range 4-11). RESULTS: Patients treated with STN-DBS showed a long-lasting superior clinical efficacy on motor fluctuations, with a significant reduction in the average percentage of the waking day spent in 'OFF' and in the duration and disability of dyskinesia. Moreover, operated patients showed a better outcome in the activities of daily living in 'Medication-OFF' condition. On the other hand, a similar progression of motor score and cognitive/behavioural alterations was observed between the two groups, apart from phonemic verbal fluency, which significantly worsened in STN-DBS patients. CONCLUSIONS: To our knowledge, this is the first long-term comparison between medical and surgical therapies; a superior efficacy of STN-DBS was observed on motor disability, while no significant differences were observed in the progression of motor symptoms and, apart from phonemic verbal fluency, of neuropsychological alterations.

A nationwide prospective study on prescribing pattern of antidepressant drugs in Italian primary care.

PURPOSE: Our purpose was to explore antidepressant drug (AD) prescribing patterns in Italian primary care. METHODS: Overall, 276 Italian general practitioners (GPs) participated in this prospective study, recruiting patients >18 years who started AD therapy during the enrolment period (January 2007 to June 2008). During visits at baseline and 3, 6, and 12 months, data about patients' characteristics and AD treatments were collected by the GPs. Discontinuation rate among new users of AD classes [i.e., selective serotonin reuptake inhibitors (SSRI); tricyclics (TCAs); other ADs) were compared. Logistic regression analyses were performed to identify predictors of AD discontinuation. RESULTS: SSRIs were the most frequently prescribed ADs (N = 1,037; 75.3 %), especially paroxetine and escitalopram. SSRIs were more likely to be prescribed because of depressive disorders (80 %), and by GPs (51.1 %) rather than psychiatrists (31.8 %). Overall, 27.5 % (N = 378) of AD users discontinued therapy during the first year, mostly in the first 3 months (N = 242; 17.6 %), whereas 185 (13.4 %) were lost to follow-up. SSRI users showed the highest discontinuation rate (29 %). In patients with depressive disorders, younger age, psychiatrist-based diagnosis, and treatment started by GPs were independent predictors of SSRI discontinuation. CONCLUSIONS: In Italy, ADs-especially SSRIs-are widely prescribed by GPs because of depressive/anxiety disorders. Active monitoring of AD users in general practice might reduce the AD discontinuation rate.

Cascading wafer-scale integrated graphene complementary inverters under ambient conditions.

The fundamental building blocks of digital electronics are logic gates which must be capable of cascading such that more complex logic functions can be realized. Here we demonstrate integrated graphene complementary inverters which operate with the same input and output voltage logic levels, thus allowing cascading. We obtain signal matching under ambient conditions with inverters fabricated from wafer-scale graphene grown by chemical vapor deposition (CVD). Monolayer graphene was incorporated in self-aligned field-effect transistors in which the top gate overlaps with the source and drain contacts. This results in full-channel gating and leads to the highest low-frequency voltage gain reported so far in top-gated CVD graphene devices operating in air ambient, A(v) ∼ -5. Such gain enabled logic inverters with the same voltage swing of 0.56 V at their input and output. Graphene inverters could find their way in realistic applications where high-speed operation is desired but power dissipation is not a concern, similar to emitter-coupled logic.

Under-spending, over-spending or substitution among services? Spatial patterns of unexplained shares of health care expenditures.

Using individual-level administrative data, we investigate the spatial patterns of unexplained shares of health care expenditures (HCE) at the municipality level. The focus is on the elderly population in the Italian Region Friuli-Venezia Giulia observed over the period 2017-2019. The empirical analysis comprises two steps. First, random-effects two-part models are estimated to analyze the effect of age, morbidity, and death on the probability and amount of positive individual total HCE and its components. Second, the unexplained shares of HCE at the municipality level are examined to identify areas with under- or over-spending and substitution among services. Results confirm the existing findings on the determinants of HCE and reveal geographic patterns in the unexplained shares of expenditures. We identify clusters of municipalities with observed HCE higher than predicted for each type of service and clusters with substitution between home care and all other services. These findings are associated with the degree of urbanization of these areas and, consequently, with the ease of access to health care. This is crucial from a policy perspective, as it indicates specific policy targets for public health intervention.

Muscle synergies in Parkinson's disease before and after the deep brain stimulation of the bilateral subthalamic nucleus.

The aim of this study is to quantitatively assess motor control changes in Parkinson's disease (PD) patients after bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS), based on a novel muscle synergy evaluation approach. A group of 20 PD patients evaluated at baseline (before surgery, T0), at 3 months (T1), and at 12 months (T2) after STN-DBS surgery, as well as a group of 20 age-matched healthy control subjects, underwent an instrumented gait analysis, including surface electromyography recordings from 12 muscles. A smaller number of muscle synergies was found in PD patients (4 muscle synergies, at each time point) compared to control subjects (5 muscle synergies). The neuromuscular robustness of PD patients-that at T0 was smaller with respect to controls (PD T0: 69.3 ± 2.2% vs. Controls: 77.6 ± 1.8%, p = 0.004)-increased at T1 (75.8 ± 1.8%), becoming not different from that of controls at T2 (77.5 ± 1.9%). The muscle synergies analysis may offer clinicians new knowledge on the neuromuscular structure underlying PD motor types of behavior and how they can improve after electroceutical STN-DBS therapy.