REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma.

BACKGROUND: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting. PATIENTS AND METHODS: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs). RESULTS: From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs. CONCLUSIONS: This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.

3D volume growth rate evaluation in the EORTC-BTG-1320 clinical trial for recurrent WHO grade 2 and 3 meningiomas.

BACKGROUND: We previously reported that tumor 3D volume growth rate (3DVGR) classification could help in the assessment of drug activity in patients with meningioma using three main classes and a total of five subclasses: class 1: decrease; 2: stabilization or severe slowdown; 3: progression. The EORTC-BTG-1320 clinical trial was a randomized phase II trial evaluating the efficacy of trabectedin for recurrent WHO 2 or 3 meningioma. Our objective was to evaluate the discriminative value of 3DVGR classification in the EORTC-BTG-1320. METHODS: All patients with at least one available MRI before trial inclusion were included. 3D volume was evaluated on consecutive MRI until progression. 2D imaging response was centrally assessed by MRI modified Macdonald criteria. Clinical benefit was defined as neurological or functional status improvement or steroid decrease or discontinuation. RESULTS: Sixteen patients with a median age of 58.5 years were included. Best 3DVGR classes were: 1, 2A, 3A and 3B in 2 (16.7%), 4 (33.3%), 2 (16.7%) and 4 (33.3%) patients, respectively. All patients with progression-free survival longer than 6 months had best 3DVGR class 1 or 2. 3DVGR classes 1 and 2 (combined) had a median overall survival of 34.7 months versus 7.2 months for class 3 (p=0.061). All class 1 patients (2/2), 75% of class 2 patients (3/4) and only 10% of class 3 patients (1/10) had clinical benefit. CONCLUSIONS: Tumor 3DVGR classification may be helpful to identify early signals of treatment activity in meningioma clinical trials.

Humanoid facial expressions as a tool to study human behaviour.

Besides action vitality forms, facial expressions represent another fundamental social cue which enables to infer the affective state of others. In the present study, we proposed the iCub robot as an interactive and controllable agent to investigate whether and how different facial expressions, associated to different action vitality forms, could modulate the motor behaviour of participants. To this purpose, we carried out a kinematic experiment in which 18 healthy participants observed video-clips of the iCub robot performing a rude or gentle request with a happy or angry facial expression. After this request, they were asked to grasp an object and pass it towards the iCub robot. Results showed that the iCub facial expressions significantly modulated participants motor response. Particularly, the observation of a happy facial expression, associated to a rude action, decreased specific kinematic parameters such as velocity, acceleration and maximum height of movement. In contrast, the observation of an angry facial expression, associated to a gentle action, increased the same kinematic parameters. Moreover, a behavioural study corroborated these findings, showing that the perception of the same action vitality form was modified when associated to a positive or negative facial expression.

Prognostic role and interaction of TERT promoter status, telomere length and MGMT promoter methylation in newly diagnosed IDH wild-type glioblastoma patients.

BACKGROUND: The clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients. PATIENTS AND METHODS: We included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and -146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients. RESULTS: Median overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P = 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant. CONCLUSIONS: Our findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.

Can regulatory T cells improve outcomes of sensitised patients after HLA-Ab incompatible renal transplantation: study protocol for the Phase IIa GAMECHANgER-1 trial.

BACKGROUND: Kidney transplantation is the gold-standard treatment for patients with kidney failure. However, one-third of patients awaiting a kidney transplant are highly sensitized to human leukocyte antigens (HLA), resulting in an increased waiting time for a suitable kidney, more acute and chronic rejection, and a shorter graft survival compared to non-highly sensitised patients. Current standard immunosuppression protocols do not adequately suppress memory responses, and so alternative strategies are needed. Autologous polyclonally expanded regulatory T cells (Tregs) have been demonstrated to be safe in transplant settings and could be a potential alternative to modulate memory immune alloresponses. METHODS: The aim of this trial is to determine whether adoptive transfer of autologous Tregs into HLA sensitised patients can suppress memory T and B cell responses against specific HLA antigens. This is a two-part, multi-centre, prospective clinical trial, comprising an observational phase (Part 1) aiming to identify patients with unregulated cellular memory responses to HLA (Pure HLA Proteins) followed by an interventional phase (Part 2). The first 9 patients identified as being eligible in Part 1 will undergo baseline immune monitoring for 2 months to inform statistical analysis of the primary endpoint. Part 2 is an adaptive, open labelled trial based on Simon's two-stage design, with 21 patients receiving Good Manufacturing Practice (GMP)-grade polyclonally expanded Tregs to a dose of 5-10 × 106 cells/kg body weight. The primary EP is suppression of in vitro memory responses for 2 months post-infusion. 12 patients will receive treatment in stage 1 of Part 2, and 9 patients will receive treatment in stage 2 of Part 2 if ≥ 50% patients pass the primary EP in stage 1. DISCUSSION: This is a prospective study aiming to identify patients with unregulated cellular memory responses to Pure HLA Proteins and determine baseline variation in these patterns of response. Part 2 will be an adaptive phase IIa clinical trial with 21 patients receiving a single infusion of GMP-grade polyclonally expanded Tregs in two stages. It remains to be demonstrated that modulating memory alloresponses clinically using Treg therapy is achievable. TRIAL REGISTRATION: EudraCT Number: 2021-001,664-23. REC Number: 21/SC/0253. Trial registration number ISRCTN14582152.

Metronomic Temozolomide in Heavily Pretreated Patients With Recurrent Isocitrate Dehydrogenase Wild-type Glioblastoma: A Large Real-Life Mono-Institutional Study.

AIMS: Glioblastoma (GBM) is the most common primary malignant brain tumour in adults and frequently relapses. The aim of this study was to assess the efficacy and safety of metronomic temozolomide (TMZ) in the recurrent GBM population. MATERIALS AND METHODS: All patients treated at our centre between September 2013 and March 2021 were retrospectively reviewed. The main inclusion criteria were first-line therapy with the Stupp protocol, relapse after the first or subsequent line of therapy, treatment with a metronomic TMZ schedule (50 mg/m2 continuously) and histological diagnosis of isocitrate dehydrogenase wild-type GBM according to World Health Organization 2016 classification. RESULTS: In total, 120 patients were enrolled. The median follow-up was 15.6 months, the median age was 59 years, Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0-2 in 107 patients (89%). O6-methylguanine-DNA-methyltransferase (MGMT) was methylated in 66 of 105 (62%) evaluable patients. The median number of prior lines of treatment was 2 (range 1-7). Three (2%) patients showed a partial response; 48 (40%) had stable disease; 69 (57%) had progressive disease. The median overall survival from the start of metronomic TMZ was 5.4 months (95% confidence interval 4.3-6.4), whereas the median progression-free survival (PFS) was 2.6 months (95% confidence interval 2.3-2.8). At univariate analysis, MGMT methylated and unmethylated patients had a median PFS of 2.9 and 2.1 months (P = 0.001) and a median overall survival of 5.6 and 4.4 months (P = 0.03), respectively. At multivariate analysis, the absence of MGMT methylation (hazard ratio = 2.3, 95% confidence interval 1.3-3.9, P = 0.004) and ECOG-PS ≤ 2 (hazard ratio = 0.5, 95% confidence interval 0.3-0.9, P = 0.017) remained significantly associated with PFS, whereas ECOG-PS ≤ 2 (hazard ratio = 0.4, 95% confidence interval 0.3-07, P = 0.001) was the only factor associated with overall survival. The most common grade 3-4 toxicities were haematological (lymphopenia 10%, thrombocytopenia 3%). CONCLUSIONS: Rechallenge with metronomic TMZ is a well-tolerated option for recurrent GBM, even in pretreated patients. Patients with methylated MGMT disease and good ECOG-PS seem to benefit the most from this treatment.

Treatment of severe infections caused by ESBL or carbapenemases-producing Enterobacteriaceae / Tratamiento de las infecciones severas causadas por enterobacterias productoras de beta lactamasas de espectro extendido (BLEE) y carbapenemasas

Enterobacteriaceae are the most frequent pathogens in the Intensive Care Unit. Due to their safety and activity, β-Lactams (BL) and carbapenems represented the most common strategy adopted against these germs. The increasing exposure to these molecules led to the development of several types of antimicrobial resistance as the expression of extended-spectrum β-lactamases (ESBLs) and carbapenemases. Great molecular variability exists among these enzymes, with significant clinical impact. To limit morbidity and mortality, old antibiotics were tested and represent viable alternatives for specific types of infections, or once the spectrum of susceptibility of each germ has been determined. Alongside, new molecules have been specifically designed but enzyme molecular variability prevents the existence of one single antibiotic which fits for all. Therefore, a quicker identification of the molecular identity of each germ, together with the knowledge of the activity spectrum of each antibiotic is crucial to tailor the therapy and make it effective. (AU)

Las enterobacterias son patógenos cada vez más frecuentes en las unidades de cuidados intensivos. Los antibióticos beta lactámicos y carbapenémicos representan las estrategias más comunes contra estos gérmenes, debido a sus mecanismos de acción y seguridad clínica. La exposición cada vez mayor de los patógenos a dichas moléculas ha llevado al desarrollo de nuevas diferentes resistencias a los antibióticos, representadas por la expresión de las beta lactamasas de espectro extendido y de las carbapenemasas. Esas enzimas manifiestan mucha variabilidad molecular, que resulta en un sustancial impacto clínico. Una opción disponible y válida para limitar la morbilidad y la mortalidad de estas infecciones es volver a utilizar los viejos antibióticos, una vez que se haya averiguado el espectro de sensibilidad de los gérmenes. Además, nuevos antibióticos han sido específicamente diseñados para solucionar el problema de las resistencias. Sin embargo, la variabilidad molecular de las enzimas hace que sea muy difícil encontrar una única molécula que funcione para todas. Por lo tanto, una rápida identificación de la identidad molecular de los gérmenes, junto a la comprensión detallada del espectro de actividad de cada antibiótico, es de vital importancia para adaptar el tratamiento y hacerlo más efectivo (AU)

Treatment of severe infections caused by ESBL or carbapenemases-producing Enterobacteriaceae.

Enterobacteriaceae are the most frequent pathogens in the Intensive Care Unit. Due to their safety and activity, ß-Lactams (BL) and carbapenems represented the most common strategy adopted against these germs. The increasing exposure to these molecules led to the development of several types of antimicrobial resistance as the expression of extended-spectrum ß-lactamases (ESBLs) and carbapenemases. Great molecular variability exists among these enzymes, with significant clinical impact. To limit morbidity and mortality, old antibiotics were tested and represent viable alternatives for specific types of infections, or once the spectrum of susceptibility of each germ has been determined. Alongside, new molecules have been specifically designed but enzyme molecular variability prevents the existence of one single antibiotic which fits for all. Therefore, a quicker identification of the molecular identity of each germ, together with the knowledge of the activity spectrum of each antibiotic is crucial to tailor the therapy and make it effective.

Investigating the Origin of Mycobacterium chimaera Contamination in Heater-Cooler Units: Integrated Analysis with Fourier Transform Infrared Spectroscopy and Whole-Genome Sequencing.

Mycobacterium chimaera is ubiquitously spread in the environment, including factory and hospital water systems. Invasive cases of M. chimaera infection have been associated with aerosols produced by the use of heater-cooler units (HCU) during cardiac surgery. The aim of this study was to evaluate for the first time the performance of IR-Biotyper system on a large number of M. chimaera isolates collected from longitudinal environmental HCUs samples and water sources from hospitals located in three Italian provinces. In addition, IR-Biotyper results were compared with whole-genome sequencing (WGS) analysis, the reference method for molecular epidemiology, to investigate the origin of M. chimaera contamination of HCUs. From November 2018 to May 2021, 417 water samples from 52 HCUs (Stockert 3T, n = 41 and HCU40, n = 11) and 23 hospital taps (used to fill the HCU tanks) were concentrated, decontaminated, and cultured for M. chimaera. Positive cultures (n = 53) were purified by agar plate subcultures and analyzed by IR-Biotyper platform and Ion Torrent sequencing system. IR-Biotyper spectra results were analyzed using a statistical approach of dimensionality reduction by linear discriminant analysis (LDA), generating three separate clusters of M. chimaera, ascribable to each hospital. Furthermore, the only M. chimaera-positive sample from tap water clustered with the isolates from the HCUs of the same hospital, confirming that the plumbing system could represent the source of HCU contamination and, potentially, of patient infection. According to the genome-based phylogenies and following the classification proposed by van Ingen and collaborators in 2017, three distinct M. chimaera groups appear to have contaminated the HCU water systems: subgroups 1.1, 2.1, and branch 2. Most of the strains isolated from HCUs at the same hospital share a highly similar genetic profile. The nonrandom distribution obtained with WGS and IR-Biotyper leads to the hypothesis that M. chimaera subtypes circulating in the local plumbing colonize HCUs through the absolute filter, in addition with the current hypothesis that contamination occurs at the HCU production site. This opens the possibility that other medical equipment, such as endoscope reprocessing device or hemodialysis systems, could be contaminated by M. chimaera. IMPORTANCE Our manuscript focuses on interventions to reduce waterborne disease transmission, improve sanitation, and control infection. Sanitary water can be contaminated by nontuberculous Mycobacteria, including M. chimaera, a causative agent of invasive infections in immunocompromised patients. We found highly similar genetic and phenotypic profiles of M. chimaera isolated from heater-cooler units (HCU) used during surgery to thermo-regulate patients' body temperature, and from the same hospital tap water. These results lead to the hypothesis that M. chimaera subtypes circulating in the local plumbing colonize HCUs through the absolute filter, adding to the current hypothesis that contamination occurs at the HCU production site. In addition, this opens the possibility that other medical equipment using sanitized water, such as endoscope reprocessing devices or hemodialysis systems, could be contaminated by nontuberculous Mycobacteria, suggesting the need for environmental surveillance and associated control measures.

Acute changes in free and extracellular vesicle-associated circulating miRNAs and myokine profile in professional sky-runners during the Gran Sasso d'Italia vertical run.

The modification of gene expression profile, a first step in adaptation to exercise, leads to changes in the level of molecules associated with skeletal muscle activity and energy metabolism-such as myokines-as well as those involved in their transcriptional regulation, like microRNA. This study aimed to investigate the influence of strenuous exercise on circulating microRNAs and their possible association with myokine response. Pre-competition and post-competition plasma samples were collected from 14 male athletes participating in a vertical run (+1,000 m gain, 3,600 m length). Circulating total (t-miRNA) and extracellular vesicle-associated (EV-miRNA) miRNAs were extracted from the pooled plasma. Nanoparticle tracking analysis was performed to investigate pre- and post-competition EV concentration and size distribution. A panel of 179 miRNAs was assayed by qPCR and analyzed by Exiqon GenEx v6 normalized on the global mean. t-miRNA and EV-miRNAs whose level was ≥5-fold up- or down-regulated were validated for each single subject. Target prediction on MirWalk v3.0, Gene-Ontology, and pathway enrichment analysis on Panther v17.0 were performed to define the potential biological role of the identified miRNAs. A panel of 14 myokines was assayed in each sample by a multiplex immunoassay. In whole plasma, five miRNAs were upregulated and two were downregulated; in the EV fraction, five miRNAs were upregulated and three were downregulated. Nanoparticle tracking analysis revealed a similar EV size distribution in pre- and post-competition samples and a decreased concentration in post-competition samples related to pre-competition samples. Gene-Ontology and pathway enrichment analysis revealed that the identified t-miRNAs and EV-miRNAs were potentially involved in metabolism regulation in response to exercise. Correlation between fold-change of the post-competition relative to pre-competition plasma level of both t-miRNAs and EV-miRNAs and myokines further confirmed these results. This study provides an example of a systemic response to acute endurance exercise, in which circulating miRNAs play a pivotal role.

Long-term use of pharmacological treatment in Alzheimer's disease: a retrospective cohort study in real-world clinical practice.

PURPOSE: To assess the impact of long-term use of different drugs commonly prescribed in Alzheimer's disease (AD) on its clinical course and to identify clinical and therapeutic factors associated with a delay in AD progression. METHODS: We retrospectively enrolled 50 patients visited at the Neurology Unit, Careggi University Hospital (Florence), followed for at least 24 months. AD diagnosis was made according to clinical diagnostic criteria for probable/possible AD dementia, always supported at least by one biomarker. Clinical features, MMSE scores evaluated at diagnosis and every 6 months, and AD drugs used for at least 6 months, were recorded. Cox regression analysis was performed to estimate the hazard ratio (HR) for AD progression, assuming as the "final event," the progression to a more severe disease stage, defined as the achievement of an MMSE score less than 10. RESULTS: At baseline, the median MMSE score was 22. During follow-up (median of 41 months), 56% of patients progressed to a more severe disease stage. The use of memantine, either alone (HR 0.24; 95% CI 0.09-0.60) or combined with acetylcholinesterase inhibitors (HR 0.35; 95% CI 0.14-0.88) and a higher MMSE score at baseline (HR 0.82; 95% CI 0.70-0.96) were associated with a significantly lower risk of AD progression. CONCLUSION: Nowadays, effective disease-modifying therapy for AD is missing. Nevertheless, when the diagnosis is established, our results support the advantage of long-term use of available pharmacological treatments, especially in combination, in delaying AD progression to its more severe disease stage.

Modification of the Patient Competency Rating Scale to Measure Anosodiaphoria after Severe Acquired Brain Injury: Preliminary Findings.

OBJECTIVE: Impaired self-awareness (ISA) of altered functional capacities is a common sequelae of severe acquired brain injury that can severely hamper neuro-rehabilitation in this clinical population. ISA is frequently associated with anosodiaphoria and/or apathy. Although several scales are available to measure apathy, no tools have been published to specifically assess anosodiaphoria after acquired brain injury. In this paper, we reported an initial effort to develop an anosodiaphoria subscale in a commonly used measure of ISA, that is, the Patient Competency Rating scale-neurorehabilitation form (PCRS-NR). METHOD: A sample of 46 participants with severe acquired brain injury completed a functional, ISA, apathy, and anosodiaphoria assessment. One informal caregiver of each patient participated in the study. Thus, we were able to obtain external data on his/her level of functional competencies, and self-awareness, which allowed separating patients with low self-awareness (LSA) from those with high self-awareness (HSA). Finally, the patients were compared with 44 healthy age-gender-years of formal education matched control participants (HCs). RESULTS: Compared to both patients with HSA and HCs, patients with LSA demonstrated greater anosodiapvhoria and lower levels of functioning than both HSA patients and HCs. A stronger relationship emerged between ISA and anosodiaphoria rather than with apathy. CONCLUSIONS: These initial findings provide support that PCRS scale can be adapted to measure anosodiaphoria as well as ISA. The findings reveal a stronger correlation between this measure of anosodiaphoria and ISA compared with the correlation of apathy to ISA. The present method for measuring anosodiaphoria takes into account the actual levels of patients' functioning.

The influence of vitality forms on action perception and motor response.

During the interaction with others, action, speech, and touches can communicate positive, neutral, or negative attitudes. Offering an apple can be gentle or rude, a caress can be kind or rushed. These subtle aspects of social communication have been named vitality forms by Daniel Stern. Although they characterize all human interactions, to date it is not clear whether vitality forms expressed by an agent may affect the action perception and the motor response of the receiver. To this purpose, we carried out a psychophysics study aiming to investigate how perceiving different vitality forms can influence cognitive and motor tasks performed by participants. In particular, participants were stimulated with requests made through a physical contact or vocally and conveying rude or gentle vitality forms, and then they were asked to estimate the end of a passing action observed in a monitor (action estimation task) or to perform an action in front of it (action execution task) with the intention to pass an object to the other person presented in the video. Results of the action estimation task indicated that the perception of a gentle request increased the duration of a rude action subsequently observed, while the perception of a rude request decreased the duration of the same action performed gently. Additionally, during the action execution task, accordingly with the perceived vitality form, participants modulated their motor response.

The middle cingulate cortex and dorso-central insula: A mirror circuit encoding observation and execution of vitality forms.

Actions with identical goals can be executed in different ways (gentle, rude, vigorous, etc.), which D. N. Stern called vitality forms [D. N. Stern, Forms of Vitality Exploring Dynamic Experience in Psychology, Arts, Psychotherapy, and Development (2010)]. Vitality forms express the agent's attitudes toward others. In a series of fMRI studies, we found that the dorso-central insula (DCI) is the region that is selectively active during both vitality form observation and execution. In one previous experiment, however, the middle cingulate gyrus also exhibited activation. In the present study, in order to assess the role of the cingulate cortex in vitality form processing, we adopted a classical vitality form paradigm, but making the control condition devoid of vitality forms using jerky movements. Participants performed two different tasks: Observation of actions performed gently or rudely and execution of the same actions. The results showed that in addition to the insula, the middle cingulate cortex (MCC) was strongly activated during both action observation and execution. Using a voxel-based analysis, voxels showing a similar trend of the blood-oxygen-level-dependent (BOLD) signal in both action observation and execution were found in the DCI and in the MCC. Finally, using a multifiber tractography analysis, we showed that the active sites in MCC and DCI are reciprocally connected.

The generalized Wiener-Hopf equations for wave motion in angular regions: electromagnetic application.

In this work, we introduce a general method to deduce spectral functional equations and, thus, the generalized Wiener-Hopf equations (GWHEs) for wave motion in angular regions filled by arbitrary linear homogeneous media and illuminated by sources localized at infinity with application to electromagnetics. The functional equations are obtained by solving vector differential equations of first order that model the problem. The application of the boundary conditions to the functional equations yields GWHEs for practical problems. This paper shows the general theory and the validity of GWHEs in the context of electromagnetic applications with respect to the current literature. Extension to scattering problems by wedges in arbitrarily linear media in different physics will be presented in future works.

Psychological status and role of caregivers in the neuro-rehabilitation of patients with severe Acquired Brain Injury (ABI).

OBJECTIVE: To investigate the relationships between (a) the psychological status of the caregiver, (b) the specific features of caregiving as perceived by the cognitive therapist in neuro-rehabilitation, (c) the caregivers' subjective approach to neuro-rehabilitation, and (d) the functional outcome of the patient. METHODS: Twenty-four patients with severe acquired brain injury and their 24 caregivers participated in this observational study. Caregivers underwent a psychological assessment examining emotional distress, burden and family strain; their subjective approach to neuro-rehabilitation has been evaluated by two specific answers. The patients' cognitive therapists responded to an ad-hoc questionnaire, namely the "Caregiving Impact on Neuro-Rehabilitation Scale" (CINRS), evaluating the features (i.e., amount and quality) of caregiving. Finally, the functional outcome of the patient was assessed through standardized scales of disability and cognitive functioning. RESULTS: The caregivers' psychological well-being was associated to the features of caregiving, to the subjective approach to neuro-rehabilitation, and to the functional recovery of their loved ones. A better caregivers' approach to neuro-rehabilitation was also associated to an overall positive impact of caregiving in neuro-rehabilitation and to a better functional outcome of the patients. CONCLUSIONS: We posited a virtuous circle involving caregivers within the neuro-rehabilitation process, according to which the caregivers' psychological well-being could be strictly associated to a better level of caregiving and to a better functional outcome of the patients that, in turn, could positively influence the caregivers' psychological well-being. Although preliminary, these results suggest a specific psycho-educational intervention, aimed at improving the caregivers' psychological well-being and at facilitating their caring of the loved one.

Circulating fractures-related microRNAs distinguish primary hyperparathyroidism-related from estrogen withdrawal-related osteoporosis in postmenopausal osteoporotic women: A pilot study.

Primary hyperparathyroidism (PHPT) represents a common cause of secondary osteoporosis in postmenopausal women, where the negative effect of estrogen withdrawal and that of hyperparathyroidism on bone mineralization coexist. Circulating microRNAs (miRNAs) expression profile has been correlated to both osteoporosis and fragility fractures. The study aimed to profile a set of miRNAs associated with osteoporotic fractures, namely miR-21-5p, miR-23a-5p, miR-24-2-5p, miR-24-3p, miR-93-5p, miR-100-5p, miR-122-5p, miR-124-3p, miR-125b-5p and miR-148-3p, in the plasma of 20 postmenopausal PHPT women. PHPT miRNAs profiles were compared with those detected in 10 age-matched postmenopausal non-PHPT osteoporotic women (OP). All the 10 miRNAs were detected in the plasma samples of both PHPT and OP women. The miRNA profiles clearly distinguished PHPT from OP samples, and identified within the PHPT group, two clusters differing for the PHPT severity, in term of ionized calcium and bone mineralization. In particular, miR-93-5p was significantly downregulated in PHPT samples, while miR-24-3p negatively correlated with the T-score at lumbar, femur neck and total hip sites. PHPT women who experienced osteoporotic fractures had plasma miR-24-3p levels higher than those detected in unfractured PHPT women. In conclusion, PHPT may modulate circulating fractures-related miRNAs, in particular, miR-93-5p, which may distinguish estrogen-related from PHPT-related osteoporosis.

Author Correction: Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.