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Glucose is the most important substrate for proper brain functioning and development, with an increased glucose consumption in relation to the need of creating new brain structures and connections. Therefore, alterations in glucose homeostasis will inevitably be associated with changes in the development of the Nervous System. Several studies demonstrated how the alteration of glucose homeostasis - both hyper and hypoglycemia- may interfere with the development of brain structures and cognitivity, including deficits in intelligence quotient, anomalies in learning and memory, as well as differences in the executive functions. Importantly, differences in brain structure and functionality were found after a single episode of diabetic ketoacidosis suggesting the importance of glycemic control and stressing the need of screening programs for type 1 diabetes to protect children from this dramatic condition. The exciting progresses of the neuroimaging techniques such as diffusion tensor imaging, has helped to improve the understanding of the effects, outcomes and mechanisms underlying brain changes following dysglycemia, and will lead to more insights on the physio-pathological mechanisms and related neurological consequences about hyper and hypoglycemia.

IntroductionBone marrow (BM) Vγ9Vδ2 T cells are intrinsically predisposed to sense the immune fitness of the tumor microenvironment (TME) in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).MethodsIn this work, we have used BM Vγ9Vδ2 T cells to interrogate the role of the immune checkpoint/immune checkpoint-ligand (ICP/ICP-L) network in the immune suppressive TME of MM patients.ResultsPD-1+ BM MM Vγ9Vδ2 T cells combine phenotypic, functional, and TCR-associated alterations consistent with chronic exhaustion and immune senescence. When challenged by zoledronic acid (ZA) as a surrogate assay to interrogate the reactivity to their natural ligands, BM MM Vγ9Vδ2 T cells further up-regulate PD-1 and TIM-3 and worsen TCR-associated alterations. BM MM Vγ9Vδ2 T cells up-regulate TIM-3 after stimulation with ZA in combination with αPD-1, whereas PD-1 is not up-regulated after ZA stimulation with αTIM-3, indicating a hierarchical regulation of inducible ICP expression. Dual αPD-1/αTIM-3 blockade improves the immune functions of BM Vγ9Vδ2 T cells in MM at diagnosis (MM-dia), whereas single PD-1 blockade is sufficient to rescue BM Vγ9Vδ2 T cells in MM in remission (MM-rem). By contrast, ZA stimulation induces LAG-3 up-regulation in BM Vγ9Vδ2 T cells from MM in relapse (MM-rel) and dual PD-1/LAG-3 blockade is the most effective combination in this setting.DiscussionThese data indicate that: 1) inappropriate immune interventions can exacerbate Vγ9Vδ2 T-cell dysfunction 2) ICP blockade should be tailored to the disease status to get the most of its beneficial effect.

This study aimed to investigate the effect of different sport environments (open-and closed-skill sports) on proactive and reactive inhibitory processes as two distinct components of motor inhibition. A mouse-tracking procedure was employed to compare behavioral performance among three groups of participants (tennis players, swimmers and non-athletes) in non-sport-specific cued Go/No-Go (GNG) and Stop Signal Task (SST), which mainly engage proactive and reactive inhibitory control, respectively. Reaction times (RTs), inhibitory failures, and Stop Signal Reaction Times (SSRTs) were measured. To investigate dynamic aspects of inhibitory control, movement trajectories classified as one-shot (absence of trajectory alteration reflected in a steep slope) or non-one-shot (non-linear/multipeaked trajectory, with one or multiple corrections) were analyzed and compared among groups. Results showed no group differences in RTs in Go/No-Go and Stop conditions. SSRTs were significant shorter for the athletes than non-athletes in SST, but no differences emerged for inhibitory failures in cued GNG. During inhibitory failures athletes showed higher proportion of non-one-shot movements than non-athletes. Higher proportion of non-one-shot profiles was observed in cued GNG compared to SST. Finally, no differences between open-and closed-skilled athletes were found in both tasks. Our findings suggest that both proactive and reactive inhibitory controls do benefit from sport practice, but open-and closed-skill sports do not differ in influencing inhibitory processes. Movement profile analysis could be a promising, complementary behavioral analysis to integrate for more fine-grained evaluation and differentiation of inhibitory motor control in athletes, specifically when using GNG tasks.

Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats.

Recently, the development of learning-based algorithms has shown a crucial role to extract features of vital importance from multi-spectral photoacoustic imaging. In particular, advances in spectral photoacoustic unmixing algorithms can identify tissue biomarkers without a priori information. This has the potential to enhance the diagnosis and treatment of a large number of diseases. Here, we investigated the latest progress within spectral photoacoustic unmixing approaches. We evaluated the sensitivity of different unsupervised Blind Source Separation (BSS) techniques such as Principal Component Analysis (PCA), Independent Component Analysis (ICA), and Non-negative Matrix Factorization (NNMF) to distinguish absorbers from spectral photoacoustic imaging. Besides, the performance of a recently developed superpixel photoacoustic unmixing (SPAX) framework has been also examined in detail. Near-infrared spectroscopy (NIRS) has been used to validate the performance of the different unmixing algorithms. Although the NNMF has shown superior unmixing performance than PCA and ICA in terms of correlation and processing time, this is still prone to unmixing misinterpretation due to spectral coloring artifact. Thus, the SPAX framework, which also compensates for the spectral coloring effect, has shown improved sensitivity and specificity of the unmixed components. In addition, the SPAX also reveals the most and less prominent tissue components from sPAI at a volumetric scale in a data-driven way. Phantom experimental measurements and in vivo studies have been conducted to benchmark the performance of the BSS algorithms and the SPAX framework.

Numerosity perception is a key ability for human and non-human species, probably mediated by dedicated brain mechanisms. Electrophysiological studies revealed the existence of both early and mid-latency components of the Electrophysiological (EEG) signal sensitive to numerosity changes. However, it is still unknown whether these components respond to physical or perceived variation in numerical attributes. We here tackled this point by recording electrophysiological signal while participants performed a numerosity adaptation task, a robust psychophysical method yielding changes in perceived numerosity judgments despite physical numerosity invariance. Behavioral measures confirmed that the test stimulus was consistently underestimated when presented after a high numerous adaptor while perceived as veridical when presented after a neutral adaptor. Congruently, EEG results revealed a potential at around 200 ms (P2p) which was reduced when the test stimulus was presented after the high numerous adaptor. This result was much prominent over the left posterior cluster of electrodes and correlated significantly with the amount of adaptation. No earlier modulations were retrievable when changes in numerosity were illusory while both early and mid-latency modulations occurred for physical changes. Taken together, our results reveal that mid-latency P2p mainly reflects perceived changes in numerical attributes, while earlier components are likely to be bounded to the physical characteristics of the stimuli. These results suggest that short-term plastic mechanisms induced by numerosity adaptation may involve a relatively late processing stage of the visual hierarchy likely engaging cortical areas beyond the primary visual cortex. Furthermore, these results also indicate mid-latency electrophysiological correlates as a signature of the internal representation of numerical information.

A Galactic cosmic-ray transport model featuring non-homogeneous transport has been developed over the latest years. This setup is aimed at reproducing γ-ray observations in different regions of the Galaxy (with particular focus on the progressive hardening of the hadronic spectrum in the inner Galaxy) and was shown to be compatible with the very-high-energy γ-ray diffuse emission recently detected up to PeV energies. In this work, we extend the results previously presented to test the reliability of that model throughout the whole sky. To this aim, we compare our predictions with detailed longitude and latitude profiles of the diffuse γ-ray emission measured by Fermi-LAT for different energies and compute the expected Galactic ν diffuse emission, comparing it with current limits from the ANTARES collaboration. We emphasize that the possible detection of a Galactic ν component will allow us to break the degeneracy between our model and other scenarios featuring prominent contributions from unresolved sources and TeV halos.

The aim of the present study is to investigate the relation between self-reported aberrant behaviors as measured by using the Italian version of the Manchester Driver Behavior Questionnaire (DBQ) and actual driving performance during a virtual simulation, focusing particularly on over-speeding. Individual variables are considered based on participants’ behavior, and driving styles are derived from both the self-report questionnaire and the kinematic variables obtained through a moped simulator after the simulated driving task. The experiment was carried out on an Italian sample of 79 individuals aged between 18 and 35 who had to drive throughout virtual road environments. A cluster analysis of the kinematic variables provided by the simulator was used to individuate two different groups of drivers: 45 fell into the cluster named “Prudent” and 34 participants fell into the “Imprudent” cluster. The Prudent participants were characterized by lower acceleration, lower speed, better overall evaluations, and a smaller number of accidents. Correlations showed that self-report responses correlated positively with performance variables in terms of acceleration, speed, and over-speeding. Furthermore, the results from a MANOVA supported and complemented this evidence by emphasizing the usefulness of the integrated approach employed. Overall, these results reflect the suitability of experimental sample-splitting into two clusters, pointing out the appropriateness and relevance of self-report DBQ use with particular emphasis on Ordinary Violations and Lapses. The integrated use of the driving simulator and the self-report DBQ instrument with reference to driving behavior made it possible to support previous theoretical considerations regarding the relations between on-road aberrant behaviors and over-speeding behaviors. It also enabled the addition of evidence on the effectiveness of the simulator in detecting drivers’ actual performance. These results are relevant to allow the integration of useful information to expand intervention and training designs that can be used to reduce risky behavior and promote road safety.

Well-being inequalities arising from different healthcare expenditure public policies is currently a hot topic at a national scale, but especially so at a sub-national level because the inequalities in question are among citizens of the same country. Spain is an optimal study area to carry out research on this topic because it is considered to have one of the best health systems in the world, it is one of the top-ranking countries in terms of life expectancy rates (the indicators we use for well-being), and it has a decentralized public health system with significantly different regional healthcare expenditure public policies. Given that the factors involved in the complex direct, indirect, and second-order relationships between well-being and health spending are latent in nature, and that there are more hypotheses than certainties regarding these relationships, we propose a partial least squares structural equation modeling specification to test the research hypotheses and to estimate the corresponding impacts. These constructs are proxied by a set of 26 indicators, for which annual values at a regional scale were used for the period 2005–2018. From the estimation of this model, it can be concluded that mortality, expenditure and resources are the factors that have the greatest impact on well-being. In addition, a cluster analysis of the indicators for the constructs included in this research reveals the existence of three clearly differentiated groups of autonomous communities: the northern part of the country plus Extremadura (characterized by the lowest well-being and the highest mortality rates), Madrid (with the best results in well-being and mortality, the lowest public health expenditure per inhabitant and percentage of pharmaceutical spending, and the highest percentage in specialty care services and medical staff spending), and the rest of the country (south-eastern regions, with similar well-being values to those of the first group but with less health expenditure). Finally, a principal component analysis reveals that “healthiness” and “basic spending” are the optimal factors for mapping well-being and health spending in Spain.

Although primary degenerative diseases are the main cause of dementia, a non-negligible proportion of patients is affected by a secondary and potentially treatable cognitive disorder. Therefore, diagnostic tools able to early identify and monitor them and to predict the response to treatment are needed. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological technique capable of evaluating in vivo and in “real time” the motor areas, the cortico-spinal tract, and the neurotransmission pathways in several neurological and neuropsychiatric disorders, including cognitive impairment and dementia. While consistent evidence has been accumulated for Alzheimer’s disease, other degenerative cognitive disorders, and vascular dementia, to date a comprehensive review of TMS studies available in other secondary dementias is lacking. These conditions include, among others, normal-pressure hydrocephalus, multiple sclerosis, celiac disease and other immunologically mediated diseases, as well as a number of inflammatory, infective, metabolic, toxic, nutritional, endocrine, sleep-related, and rare genetic disorders. Overall, we observed that, while in degenerative dementia neurophysiological alterations might mirror specific, and possibly primary, neuropathological changes (and hence be used as early biomarkers), this pathogenic link appears to be weaker for most secondary forms of dementia, in which neurotransmitter dysfunction is more likely related to a systemic or diffuse neural damage. In these cases, therefore, an effort toward the understanding of pathological mechanisms of cognitive impairment should be made, also by investigating the relationship between functional alterations of brain circuits and the specific mechanisms of neuronal damage triggered by the causative disease. Neurophysiologically, although no distinctive TMS pattern can be identified that might be used to predict the occurrence or progression of cognitive decline in a specific condition, some TMS-associated measures of cortical function and plasticity (such as the short-latency afferent inhibition, the short-interval intracortical inhibition, and the cortical silent period) might add useful information in most of secondary dementia, especially in combination with suggestive clinical features and other diagnostic tests. The possibility to detect dysfunctional cortical circuits, to monitor the disease course, to probe the response to treatment, and to design novel neuromodulatory interventions in secondary dementia still represents a gap in the literature that needs to be explored.

Low moisture foods (LMFs) have traditionally been recognized as safe for consumption, as most bacteria require higher water content to grow. However, outbreaks due to LMF foods are increasing, and the microbial pathogen Salmonella enterica is frequently implicated. S. enterica can survive in LMFs for years, but few serovars have been studied, and the mechanisms which underlie this longevity are not well understood. Here, we determine that S. enterica serovars S. Tennessee, S. Anatum, and S. Reading but not S. Oranienburg can survive in the ground black pepper for 6 years. S. Reading was not previously associated with any LMF. Using both Illumina and Pacific Biosciences sequencing technologies, we also document changes in the genomes and methylomes of the surviving serovars over this 6-year period. The three serovars acquired a small number of single nucleotide polymorphisms (SNPs) including seven substitutions (four synonymous, two non-synonymous, and one substitution in a non-coding region), and two insertion-deletions. Nine distinct N6-methyladenine (m6A) methylated motifs across the three serovars were identified including five which were previously known, Gm6ATC, CAGm6AG, BATGCm6AT, CRTm6AYN6CTC, and CCm6AN7TGAG, and four novel serovar-specific motifs, GRTm6AN8TTYG, GAm6ACN7GTA, GAA m6ACY, and CAAm6ANCC. Interestingly, the BATGCAT motif was incompletely methylated (35–64% sites across the genome methylated), suggesting a possible role in gene regulation. Furthermore, the number of methylated BATGCm6AT motifs increased after storage in ground black pepper for 6 years from 475 to 657 (S. Tennessee), 366 to 608 (S. Anatum), and 525 to 570 (S. Reading), thus warranting further study as an adaptive mechanism. This is the first long-term assessment of genomic changes in S. enterica in a low moisture environment, and the first study to examine the methylome of any bacteria over a period of years, to our knowledge. These data contribute to our understanding of S. enterica survival in LMFs, and coupled with further studies, will provide the information necessary to design effective interventions which reduce S. enterica in LMFs and maintain a healthy, safe food supply.

ObjectivesThe aim of this study was to compare the effects of a sustained inflation alveolar recruiting maneuver (ARM) followed by 5 cmH2O of PEEP and a stepwise ARM, in dogs undergoing laparoscopic surgery.Materials and methodsTwenty adult dogs were enrolled in this prospective randomized clinical study. Dogs were premedicated with methadone intramuscularly (IM); anesthesia was induced with propofol intravenously (IV) and maintained with inhaled isoflurane in pure oxygen. The baseline ventilatory setting (BVS) was as follows: tidal volume of 15 mL/kg, inspiratory pause of 25%, inspiratory to expiratory ratio of 1:2, and the respiratory rate to maintain the end-tidal carbon dioxide between 45 and 55 mmHg. 10 min after pneumoperitoneum, randomly, 10 dogs underwent sustained inflation ARM followed by 5 cmH2O of PEEP (ARMi), while 10 dogs underwent a stepwise recruitment maneuver followed by the setting of the “best PEEP” (ARMc). Gas exchange, respiratory system mechanics, and hemodynamic were evaluated before the pneumoperitoneum induction (BASE), 10 min after the pneumoperitoneum (PP), 10 min after the recruitment (ARM), and 10 min after the pneumoperitoneum resolution (PostPP). Statistical analysis was performed with the ANOVA test (p < 0.05).ResultsStatic compliance decreased in both groups at PP (ARMc = 1.35 ± 0.21; ARMi = 1.16 ± 0.26 mL/cmH2O/kg) compared to BASE (ARMc = 1.78 ± 0.60; ARMi = 1.66 ± 0.66 mL/cmH2O/kg) and at ARM (ARMc = 1.71 ± 0.41; ARMi = 1.44 ± 0.84 mL/cmH2O/kg) and PostPP (ARMc = 1.75 ± 0.45; ARMi = 1.89 ± 0.59 mL/cmH2O/kg), and it was higher compared to PP and similar to BASE. The PaO2/FiO2, in both groups, was higher at ARM (ARMc = 455.11 ± 85.90; ARMi = 505.40 ± 31.70) and PostPP (ARMc = 521.30 ± 66.20; ARMi = 450.90 ± 70.60) compared to PP (ARMc = 369.53 ± 49.31; ARMi = 394.32 ± 37.72).Conclusion and clinical relevanceThe two ARMs improve lung function in dogs undergoing laparoscopic surgery similarly. Application of PEEP at the end of the ARMs prolonged the effects of the open-lung strategy.

Brain-computer interface (BCI) can provide people with motor disabilities with an alternative channel to access assistive technology (AT) software for communication and environmental interaction. Multiple sclerosis (MS) is a chronic disease of the central nervous system that mostly starts in young adulthood and often leads to a long-term disability, possibly exacerbated by the presence of fatigue. Patients with MS have been rarely considered as potential BCI end-users. In this pilot study, we evaluated the usability of a hybrid BCI (h-BCI) system that enables both a P300-based BCI and conventional input devices (i.e., muscular dependent) to access mainstream applications through the widely used AT software for communication “Grid 3.” The evaluation was performed according to the principles of the user-centered design (UCD) with the aim of providing patients with MS with an alternative control channel (i.e., BCI), potentially less sensitive to fatigue. A total of 13 patients with MS were enrolled. In session I, participants were presented with a widely validated P300-based BCI (P3-speller); in session II, they had to operate Grid 3 to access three mainstream applications with (1) an AT conventional input device and (2) the h-BCI. Eight patients completed the protocol. Five out of eight patients with MS were successfully able to access the Grid 3 via the BCI, with a mean online accuracy of 83.3% (± 14.6). Effectiveness (online accuracy), satisfaction, and workload were comparable between the conventional AT inputs and the BCI channel in controlling the Grid 3. As expected, the efficiency (time for correct selection) resulted to be significantly lower for the BCI with respect to the AT conventional channels (Z = 0.2, p < 0.05). Although cautious due to the limited sample size, these preliminary findings indicated that the BCI control channel did not have a detrimental effect with respect to conventional AT channels on the ability to operate an AT software (Grid 3). Therefore, we inferred that the usability of the two access modalities was comparable. The integration of BCI with commercial AT input devices to access a widely used AT software represents an important step toward the introduction of BCIs into the AT centers’ daily practice.

In this review, the current understanding of leptin’s role in energy balance, glycemic regulation, and cognitive function is examined, and its involvement in maintaining the homeostatic “harmony” of these physiologies is explored. The effects of exercise on circulating leptin levels are summarized, and the results of clinical application of leptin to metabolic disease and neurologic dysfunction are reviewed. Finally, pre-clinical evidence is presented which suggests that synthetic peptide leptin mimetics may be useful in resolving not only the leptin resistance associated with common obesity and other elements of metabolic syndrome, but also the peripheral insulin resistance characterizing type 2 diabetes mellitus, and the central insulin resistance associated with certain neurologic deficits in humans.

Reelin is a secreted extracellular matrix protein playing pivotal roles in neuronal migration and cortical stratification during embryonal brain development. In the adult brain, its activity is crucial for synaptic plasticity, memory processing, and cognition. Genetic alterations in RELN have been variably reported as possible contributors to the pathogenesis of autism spectrum disorders (ASD). In particular, GCCs repeats in the 5′UTR, and single nucleotide polymorphysms (SNPs) in RELN have been suggested to affect brain development and predispose to autism. We reviewed pertinent literature on RELN expression and haplotypes transmission in children with ASD, critically analyzing available evidence in support of the pathophysiological association between Reelin deficiency and ASD.

Temporal networks are graphs where each edge is linked with a timestamp, denoting when an interaction between two nodes happens. According to the most recently proposed definitions of the problem, motif search in temporal networks consists in finding and counting all connected temporal graphs Q (called motifs) occurring in a larger temporal network T, such that matched target edges follow the same chronological order imposed by edges in Q. In the last few years, several algorithms have been proposed to solve motif search, but most of them are limited to very small or specific motifs due to the computational complexity of the problem. In this paper, we present MODIT (MOtif DIscovery in Temporal Networks), an algorithm for counting motifs of any size in temporal networks, inspired by a very recent algorithm for subgraph isomorphism in temporal networks, called TemporalRI. Experiments show that for big motifs (more than 3 nodes and 3 edges) MODIT can efficiently retrieve them in reasonable time (up to few hours) in many networks of medium and large size and outperforms state-of-the art algorithms.

Background: The radiographic assessment for lung edema (RALE) score has an association with mortality in patients with acute respiratory distress syndrome (ARDS). It is uncertain whether the RALE scores at the start of invasive ventilation or changes thereof in the next days have prognostic capacities in patients with COVID-19 ARDS.Aims and Objectives: To determine the prognostic capacity of the RALE score for mortality and duration of invasive ventilation in patients with COVID-19 ARDS.Methods: An international multicenter observational study included consecutive patients from 6 ICUs. Trained observers scored the first available chest X-ray (CXR) obtained within 48 h after the start of invasive ventilation (“baseline CXR”) and each CXRs thereafter up to day 14 (“follow-up CXR”). The primary endpoint was mortality at day 90. The secondary endpoint was the number of days free from the ventilator and alive at day 28 (VFD-28).Results: A total of 350 CXRs were scored in 139 patients with COVID-19 ARDS. The RALE score of the baseline CXR was high and was not different between survivors and non-survivors (33 [24–38] vs. 30 [25–38], P = 0.602). The RALE score of the baseline CXR had no association with mortality (hazard ratio [HR], 1.24 [95% CI 0.88–1.76]; P = 0.222; area under the receiver operating characteristic curve (AUROC) 0.50 [0.40–0.60]). A change in the RALE score over the first 14 days of invasive ventilation, however, had an independent association with mortality (HR, 1.03 [95% CI 1.01–1.05]; P < 0.001). When the event of death was considered, there was no significant association between the RALE score of the baseline CXR and the probability of being liberated from the ventilator (HR 1.02 [95% CI 0.99–1.04]; P = 0.08).Conclusion: In this cohort of patients with COVID-19 ARDS, with high RALE scores of the baseline CXR, the RALE score of the baseline CXR had no prognostic capacity, but an increase in the RALE score in the next days had an association with higher mortality.

Background: Patients with acute respiratory failure (ARF) may need mechanical ventilation (MV), which can lead to diaphragmatic dysfunction and muscle wasting, thus making difficult the weaning from the ventilator. Currently, there are no biomarkers specific for respiratory muscle and their function can only be assessed trough ultrasound or other invasive methods. Previously, the fast and slow isoform of the skeletal troponin I (fsTnI and ssTnI, respectively) have shown to be specific markers of muscle damage in healthy volunteers. We aimed therefore at describing the trend of skeletal troponin in mixed population of ICU patients undergoing weaning from mechanical ventilation and compared the value of fsTnI and ssTnI with diaphragmatic ultrasound derived parameters.Methods: In this prospective observational study we enrolled consecutive patients recovering from acute hypoxemic respiratory failure (AHRF) within 24 h from the start of weaning. Every day an arterial blood sample was collected to measure fsTnI, ssTnI, and global markers of muscle damage, such as ALT, AST, and CPK. Moreover, thickening fraction (TF) and diaphragmatic displacement (DE) were assessed by diaphragmatic ultrasound. The trend of fsTnI and ssTnI was evaluated during the first 3 days of weaning.Results: We enrolled 62 consecutive patients in the study, with a mean age of 67 ± 13 years and 43 of them (69%) were male. We did not find significant variations in the ssTnI trend (p = 0.623), but fsTnI significantly decreased over time by 30% from Day 1 to Day 2 and by 20% from Day 2 to Day 3 (p < 0.05). There was a significant interaction effect between baseline ssTnI and DE [F(2) = 4.396, p = 0.015], with high basal levels of ssTnI being associated to a higher decrease in DE. On the contrary, the high basal levels of fsTnI at day 1 were characterized by significant higher DE at each time point.Conclusions: Skeletal muscle proteins have a distinctive pattern of variation during weaning from mechanical ventilation. At day 1, a high basal value of ssTnI were associated to a higher decrease over time of diaphragmatic function while high values of fsTnI were associated to a higher displacement at each time point.

Depression is a risk factor for the development of Alzheimer’s disease (AD). A neurobiological and clinical continuum exists between AD and depression, with neuroinflammation and oxidative stress being involved in both diseases. Second-generation antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are currently investigated as neuroprotective drugs in AD. By employing a non-transgenic AD model, obtained by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ) oligomers in 2-month-old C57BL/6 mice, we recently demonstrated that the SSRI fluoxetine (FLX) and the multimodal antidepressant vortioxetine (VTX) reversed the depressive-like phenotype and memory deficits induced by Aβ oligomers rescuing the levels of transforming growth factor-β1 (TGF-β1). Aim of our study was to test FLX and VTX for their ability to prevent oxidative stress in the hippocampus of Aβ-injected mice, a brain area strongly affected in both depression and AD. The long-term intraperitoneal (i.p.) administration of FLX (10 mg/kg) or VTX (5 and 10 mg/kg) for 24 days, starting 7 days before Aβ injection, was able to prevent the over-expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (Nox2) induced by Aβ oligomers. Antidepressant pre-treatment was also able to rescue the mRNA expression of glutathione peroxidase 1 (Gpx1) antioxidant enzyme. FLX and VTX also prevented Aβ-induced neurodegeneration in mixed neuronal cultures treated with Aβ oligomers. Our data represent the first evidence that the long-term treatment with the antidepressants FLX or VTX can prevent the oxidative stress phenomena related to the cognitive deficits and depressive-like phenotype observed in a non-transgenic animal model of AD.

We describe the respiratory mechanics and lung aeration in anesthetized obese dogs ventilated with tidal volumes (VT) based on ideal (VTi) vs. current (VTc) body weight. Six dogs with body condition scores ≥ 8/9 were included. End-expiratory respiratory mechanics and end-expiratory CT-scan were obtained at baseline for each dog. Thereafter, dogs were ventilated with VT 15 ml kg−1 based on VTi and VTc, applied randomly. Respiratory mechanics and CT-scan were repeated at end-inspiration during VTi and VTc. Data analyzed with linear mixed models and reported as mean ± SD or median [range]. Statistical significance p < 0.05. The elastance of the lung, chest wall and respiratory system indexed by ideal body weight (IBW) were positively correlated with body fat percentage, whereas the functional residual capacity indexed by IBW was negatively correlated with body fat percentage. At end-expiration, aeration (%) was: hyperaeration 0.03 [0.00–3.35], normoaeration 69.7 [44.6–82.2], hypoaeration 29.3 [13.6–49.4] and nonaeration (1.06% [0.37–6.02]). Next to the diaphragm, normoaeration dropped to 12 ± 11% and hypoaeration increased to 90 ± 8%. No differences in aeration between groups were found at end-inspiration. Airway driving pressure (cm H2O) was higher (p = 0.002) during VTc (9.8 ± 0.7) compared with VTi (7.6 ± 0.4). Lung strain was higher (p = 0.014) during VTc (55 ± 21%) than VTi (38 ± 10%). The stress index was higher (p = 0.012) during VTc (SI = 1.07 [0.14]) compared with VTi (SI = 0.93 [0.18]). This study indicates that body fat percentage influences the magnitude of lung, chest wall, and total respiratory system elastance and resistance, as well as functional residual capacity. Further, these results indicate that obese dogs have extensive areas of hypoaerated lungs, especially in caudodorsal regions. Finally, lung strain and airway driving pressure, surrogates of lung deformation, are higher during VTc than during VTi, suggesting that in obese anesthetized dogs, ventilation protocols based on IBW may be advantageous.

Neuropathic pain is one of the most disabling forms of chronic pain and it is characterized by hyperalgesia and allodynia linked to an aberrant processing of pain transmission and to neuroinflammation. Transforming growth factor-β1 (TGF-β1) is an anti-inflammatory cytokine, which protects against neuroinflammation. It has been demonstrated that TGF-β1 and opioid receptors signalling crosstalk results in an improvement of endogenous opioid analgesia, but it is not known whether mu opioid peptide receptor (MOPr) or delta opioid peptide receptor (DOPr) agonists can positively modulate TGF-β1 pathway. In the present study, we examined the correlation between anti-allodynic effect of LP2, a dual-target MOPr/DOPr agonist, and TGF-β1 signalling in the chronic constriction injury (CCI) model. We detected a significant decrease of active TGF-β1 and of its type II receptor TGFβ-R2 levels in the spinal cord from CCI rats and a selective deficit of TGF-β1 in microglia cells both at days 11 and 21 post-ligature, as assessed by immunofluorescence analysis. LP2, when administered from the 11 days post-ligature to 21 days, was able to reduce CCI-induced mechanical allodynia by rescue of TGF-β1 and TGFβ-R2 levels. Our data suggest that the rescue of TGF-β1 signalling by dual-target MOPr/DOPr agonist LP2 could be mediated by DOPr activation in spinal microglia, thus the dual-target approach could represent a novel pharmacological approach to increase the analgesic efficacy of MOPr agonists.

Background: Cancer patients are now facing a double distinctive challenge of survival against both the disease and fear of contracting COVID-19. This challenge has resulted in the forced adoption of social distancing measures and reorganization of the delivery of medical and psychological treatments. The perceived loneliness and uncertainty increased distress and symptoms burden. In the current period, eHealth interventions might provide valuable benefits in the field of cancer care.Objective: The overall goal of the study protocol will be to provide an innovative intervention for cancer patients based on an online platform, to help them manage and prevent psychological problems related to social isolation. Specifically, the efficacy of two web-based interventions aimed at lowering stress in cancer patients will be tested and compared.Methods: One hundred and fifty participants (75 per group) will be enrolled in a two-group randomized trial. The two interventions will be composed either by exercises on relaxation and meditation practices, presented in both automated online content and interactive group sessions or by fixed psychoeducational online content. Stress, anxiety, and depressive symptoms, distress, resilience, and perceived social isolation will be measured before the start of the interventions (T0), 2 weeks (T1), 4 weeks (T2), and 2 months (T3) after the beginning of the interventions in both groups. A repeated measures ANOVA will be performed to test differences in the questionnaires' scores between groups across the four-time points.Expected Results: We hypothesized greater improvement in the specific domain of stress symptoms (IES-R) assessed in the group receiving the interactive intervention, compared to the group which will receive only fully automated psychoeducational content. Secondarily, we expect the same trend of improvement across all the psychological variables in the blended intervention group.Conclusions: Implementing these practices on people who are forced into mandatory social isolation may help them become more aware of their mind-body condition and reduce negative effects. Moreover, relaxation techniques help individuals in achieving a greater state of well-being, increasing the ability to cope with stressful situations (resilience), and strengthening the immune system.

In recent years, veno-venous extracorporeal membrane oxygenation (V-V ECMO) has allowed complex lung and airways resections in patients with a compromised perioperative respiratory function. In the following report, we present a case of successful weaning from V-V ECMO in a patient who underwent an inferior bilobectomy for lung cancer.

Case investigation (CI) and contact tracing (CT) are key to containing the COVID-19 pandemic. Widespread community transmission necessitates a large, diverse workforce with specialized knowledge and skills. The University of California, San Francisco and Los Angeles partnered with the California Department of Public Health to rapidly mobilize and train a CI/CT workforce. In April through August 2020, a team of public health practitioners and health educators constructed a training program to enable learners from diverse backgrounds to quickly acquire the competencies necessary to function effectively as CIs and CTs. Between April 27 and May 5, the team undertook a curriculum design sprint by performing a needs assessment, determining relevant goals and objectives, and developing content. The initial four-day curriculum consisted of 13 hours of synchronous live web meetings and 7 hours of asynchronous, self-directed study. Educational content emphasized the principles of COVID-19 exposure, infectious period, isolation and quarantine guidelines and the importance of prevention and control interventions. A priority was equipping learners with skills in rapport building and health coaching through facilitated web-based small group skill development sessions. The training was piloted among 31 learners and subsequently expanded to an average weekly audience of 520 persons statewide starting May 7, reaching 7,499 unique enrollees by August 31. Capacity to scale and sustain the training program was afforded by the UCLA Extension Canvas learning management system. Repeated iteration of content and format was undertaken based on feedback from learners, facilitators, and public health and community-based partners. It is feasible to rapidly train and deploy a large workforce to perform CI and CT. Interactive skills-based training with opportunity for practice and feedback are essential to develop independent, high-performing CIs and CTs. Rigorous evaluation will continue to monitor quality measures to improve the training experience and outcomes.

Short stature is a frequent disorder in the pediatric population and can be caused by multiple factors. In the last few years, the introduction of Next Generation Sequencing (NGS) in the molecular diagnostic workflow led to the discovery of mutations in novel genes causing short stature including heterozygous mutations in ACAN gene. It encodes for aggrecan, a primary proteoglycan component specific for the structure of the cartilage growth plate, articular and intervertebral disc. We report a novel ACAN heterozygous pathogenic variant in a family with idiopathic short stature, early-onset osteoarthritis and osteoarthritis dissecans (SSOAOD). We also performed a literature review summarizing the clinical characteristic of ACAN's patients. The probands are two Caucasian sisters with a family history of short stature and osteoarthritis dissecans. They showed dysmorphic features such as mild midface hypoplasia, brachydactyly and broad thumbs, especially the great toes. The same phenotype was presented in the mother who had had short stature and suffered from intervertebral disc disease. DNA sequencing identified a heterozygous pathogenic variation (c.4390delG p.Val1464Ter) in the sisters, with a maternal inheritance. The nonsense mutation, located on exon 12, results in premature truncation and presumed loss of protein function. In terms of treatment, our patients underwent recombinant human growth hormone replacement therapy, associated with gonadotropin releasing hormone therapy, in order to block early growth cessation and therefore reach a better final height. Our case suggests that SSOAOD ACAN related should be considered in the differential diagnosis of children with autosomal dominant short stature and family history of joints disease.

IntroductionAnorexia nervosa (AN) promotes psychological distress in caregivers who adopt different coping strategies. Dysfunctional caregiving styles exacerbate further distress in the patient promoting the maintenance of the illness. We aimed to assess the possible contribution of personality traits of caregivers to the adoption of different coping strategies to deal with the affected relative.MethodsAbout 87 adolescents with AN were recruited. Their parents completed the Family Coping Questionnaire for Eating Disorders (FCQ-EDs) and the Temperament and Character Inventory-Revised (TCI-R). Differences between mothers and fathers were assessed through the independent sample t-test. Multivariate regression analyses were run to assess if personality traits, the occurrence of psychiatry conditions in the parents, the marital status, and the duration of the illness predicted parental coping strategies.ResultsThe group of mothers showed higher levels of avoidance and seeking for information coping strategies than the sample of fathers. Lower illness duration predicted higher collusion with the illness in both parents. Harm avoidance, cooperativeness, and self-directedness positively predicted parental coercion, collusion, and seeking for information strategies with some differences between mothers and fathers.DiscussionIllness duration and personality traits of parents affect the type of parental coping strategies developed to face AN in adolescents. These variables should be considered in the assessment of families of adolescents with AN and may be addressed to promote more fine-tuned clinical interventions for caregivers.

Background: Intestinal dysbiosis might play a pathogenetic role in subjects with symptomatic uncomplicated diverticular disease (SUDD), but the effect of rifaximin therapy has been scantly explored with regard to gut microbiota variations in patients with SUDD.Aims: To verify to which extent rifaximin treatment affects the gut microbiota and whether an electronic multisensorial assessment of stools and breath has the potential for detecting these changes.Methods: Breath and stool samples were collected from consecutive patients with SUDD before and after a 7 days' therapy with rifaximin. Stool microbiota was assessed, and the electronic multisensorial assessment was carried out by means of the BIONOTE electronic (e-)tongue in stools and (e-)nose in breath.Results: Forty-three subjects (female 60%, median age 66 years) were included, and 20 (47%) reported clinical improvement after rifaximin therapy. Alpha and beta diversity of stool microbiota did not significantly change after treatment, while a significant variation of selected taxa was shown (i.e., Citrobacter, Coprococcus, Anaerotruncus, Blautia, Eggerthella lenta, Dehalobacterium, SMB53, and Haemophilus parainfluenzae). Overall, the electronic multisensorial system suboptimally mirrored microbiota changes, but it was able to efficiently predict patients' clinical improvement after rifaximin with accuracies ranging from 0.81 to 0.98.Conclusions: In patients with SUDD, rifaximin administration is associated with significant variation of selected taxa. While inaccurate in predicting gut microbiota change, an electronic multisensorial system, made up of e-tongue and e-nose, was able to predict clinical improvement, thus potentially qualifying as an easy and cheap tool to forecast subjects taking most likely benefit from rifaximin therapy.

The perception of putative pheromones or social odors (PPSO) in humans is a widely debated topic because the published results seem ambiguous. Our research aimed to evaluate how cross-modal processing of PPSO and gender voice can affect the behavioral and psychophysiological states of the subject during a listening task with a bodily contact medium, and how these effects could be gender related. Before the experimental session, three embodied media, were exposed to volatilized estratetraenol (Estr), 5α-androst-16-en-3 α-ol (Andr), and Vaseline oil. The experimental session consisted in listening to a story that were transmitted, with a male or female voice, by the communicative medium via a Bluetooth system during a listening task, recorded through 64-active channel electroencephalography (EEG). The sense of co-presence and social presence, elicited by the medium, showed how the established relationship with the medium was gender dependent and modulated by the PPSO. In particular, Andr induced greater responses related to co-presence. The gender of the participants was related to the co-presence desire, where women imagined higher medium co-presence than men. EEG findings seemed to be more responsive to the PPSO–gender voice interaction, than behavioral results. The mismatch between female PPSO and male voice elicited the greatest cortical flow of information. In the case of the Andr–male voice condition, the trained model appeared to assign more relevance to the flow of information to the right frontotemporal regions (involved in odor recognition memory and social behavior). The Estr–male voice condition showed activation of the bilateral frontoparietal network, which is linked to cognitive control, cognitive flexibility, and auditory consciousness. The model appears to distinguish the dissonance condition linked to Andr matched with a female voice: it highlights a flow of information to the right occipital lobe and to the frontal pole. The PPSO could influence the co-presence judgements and EEG response. The results seem suggest that could be an implicit pattern linked to PPSO-related gender differences and gender voice.

Aims: The aim was to analyse the psychiatric consultations in nine Italian hospital emergency departments, by comparing the lockdown and post-lockdown periods of 2020 with the equivalent periods of 2019.Methods: Characteristics of psychiatric consultations, patients, and drug prescriptions were analyzed. Joinpoint models were used to identify changes in the weekly trend of consultations.Results: A 37.5% decrease in the number of consultations was seen during the lockdown period and 17.9% after the lockdown. The number of individual patients seen decreased by 34.9% during the lockdown and 11.2% after the lockdown. A significant change in the number of consultations from week 11 to week 18 occurred, followed by a gradual increase. There was a higher percentage of patients with previous psychiatric hospitalizations during the lockdown period (61.1 vs. 56.3%) and a lower percentage after the lockdown (59.7 vs. 64.7%). During the lockdown there was a large increase in psychiatric consultations for substance use disorders, whereas more consultations for manic episodes occurred after the lockdown. A 3.4% decrease was observed in consultations for suicidal ideation and planning during the lockdown, followed by an upward rebound after the lockdown, along with an increase in consultations for suicide attempts. During lockdown antipsychotic and benzodiazepine prescriptions increased by 5.2 and 4.1%, respectively. After the lockdown, the number of compulsory hospitalizations was higher than in 2019.Conclusions: We observed a decrease of psychiatric consultations during and after the lockdown. There was an increase in consultations for manic episodes and suicidality after the lockdown. The focus of psychiatric services must remain high particularly in this latter period.

Background: Bilateral opacities on chest radiographs are part of the Berlin Definition for Acute Respiratory Distress Syndrome (ARDS) but have poor interobserver reliability. The “Radiographic Assessment of Lung Edema” (RALE) score was recently proposed for evaluation of the extent and density of alveolar opacities on chest radiographs of ARDS patients. The current study determined the accuracy of the RALE score for the diagnosis and the prognosis of ARDS.Methods:Post-hoc analysis of a cohort of invasively ventilated intensive care unit (ICU) patients expected to need invasive ventilation for >24 h. The Berlin Definition was used as the gold standard. The RALE score was calculated for the first available chest radiograph after start of ventilation in the ICU. The primary endpoint was the diagnostic accuracy for ARDS of the RALE score. Secondary endpoints included the prognostic value of the RALE score for ICU and hospital mortality, and the association with ARDS severity, and the PaO2/FiO2. Receiver operating characteristic (ROC) curves were constructed, and the optimal cutoff was used to determine sensitivity, specificity and the negative and positive predictive value of the RALE score for ARDS.Results: The study included 131 patients, of whom 30 had ARDS (11 mild, 15 moderate, and 4 severe ARDS). The first available chest radiograph was obtained median 0 [0 to 1] days after start of invasive ventilation in ICU. Compared to patients without ARDS, a higher RALE score was found in patients with ARDS (24 [interquartile range (IQR) 16–30] vs. 6 [IQR 3–11]; P < 0.001), with RALE scores of 20 [IQR 14–24], 26 [IQR 16–32], and 32 [IQR 19–36] for mild, moderate and severe ARDS, respectively, (P = 0.166). The area under the ROC for ARDS was excellent (0.91 [0.86–0.96]). The best cutoff for ARDS diagnosis was 10 with 100% sensitivity, 71% specificity, 51% positive predictive value and 100% negative predictive value. The RALE score was not associated with ICU or hospital mortality, and weakly correlated with the PaO2/FiO2.Conclusion: In this cohort of invasively ventilated ICU patients, the RALE score had excellent diagnostic accuracy for ARDS.

Duckweeds (Lemnaceae) are the smallest and fastest-growing angiosperms. This feature, together with high starch production and good nutritional properties, makes them suitable for several applications, including wastewater treatment, bioenergy production, or feed and food supplement. Due to their reduced morphology and great similarity between diverse species, taxonomic identification of duckweeds is a challenging issue even for experts. Among molecular genotyping methods, DNA barcoding is the most useful tool for species identification without a need for cluster analysis. The combination of two plastid barcoding loci is now considered the gold standard for duckweed classification. However, not all species can be defined with confidence by these markers, and a fast identification method able to solve doubtful cases is missing. Here we show the potential of tubulin-based polymorphism (TBP), a molecular marker based on the intron length polymorphisms of β-tubulin loci, in the genomic profiling of the genera Spirodela, Landoltia, and Lemna. Ninety-four clones were analyzed, including at least two representatives of each species of the three genera, with a special focus on the very heterogeneous species Lemna minor. We showed that a single PCR amplification with universal primers, followed by agarose gel analysis, was able to provide distinctive fingerprinting profiles for 10 out of 15 species. Cluster analysis of capillary electrophoresis–TBP data provided good separation for the remaining species, although the relationship between L. minor and Lemna japonica was not fully resolved. However, an accurate comparison of TBP profiles provided evidence for the unexpected existence of intraspecific hybrids between Lemna turionifera and L. minor, as further confirmed by amplified fragment length polymorphism and sequence analysis of a specific β-tubulin locus. Such hybrids could possibly correspond to L. japonica, as originally suggested by E. Landolt. The discovery of interspecific hybrids opens a new perspective to understand the speciation mechanisms in the family of duckweeds.

Background: Binge eating disorder (BED) is clinically relevant by virtue of the global impairment, poor quality of life, and increased overall medical morbidity. The high comorbidity with psychiatric disorders, particularly depression, has received attention as a possible mediator of the poor outcome. Further, BED and depression share cognitive dysfunctions. This naturalistic and uncontrolled pilot study aimed at evaluating the efficacy of vortioxetine (VTX) on depressive symptoms in patients with BED, secondly the efficacy in improving a broad array of executive functions, and third to explore the effect on eating behavior and body weight.Methods: This pilot study involved 30 patients with BED and comorbid MDD, treated with VTX for 24 weeks. Assessments were run at baseline (t0), 4 (t1), 8 (t2), 12 (t3), and 24 (t4) weeks. Changes in depressive symptoms (HDRS and BDI), executive functions, eating behaviors (binge frequency and severity, night eating, food addiction), and body weight were estimated after treatment with VTX through GLM.Results: Significant improvements emerged after treatment with VTX in: depression (HDRS p < 0.001; BDI p = 0.002) regardless the dose of VTX and first diagnosis (BED/MDD), working memory (RAVLT acquisition p = 0.01, delay recall p < 0.001, RCFT percentage of recall p = 0.01, and Attentional Matrices p = 0.05), binge days frequency (p < 0.001), binge eating severity (BES p < 0.001), night eating (p = 0.001), food addiction (YFAS 2.0 p = 0.039), and body weight (p = 0.039). The improvement in depressive symptoms was associated with the concurrent improvement in night eating as assessed by the I-NEQ.Conclusions: VTX can be a valid therapeutic choice for patients with BED with comorbid depression in controlling the depressive symptoms, working memory, and eating behavior. Indeed, by acting on affective symptoms, neurocognitive functioning, and eating behaviors, it confirms the results already obtained with VTX in other disorders, expanding them to BED.

Mitophagy and zymophagy are selective autophagy pathways early induced in acute pancreatitis that may explain the mild, auto limited, and more frequent clinical presentation of this disease. Adequate mitochondrial bioenergetics is necessary for cellular restoration mechanisms that are triggered during the mild disease. However, mitochondria and zymogen contents are direct targets of damage in acute pancreatitis. Cellular survival depends on the recovering possibility of mitochondrial function and efficient clearance of damaged mitochondria. This work aimed to analyze mitochondrial dynamics and function during selective autophagy in pancreatic acinar cells during mild experimental pancreatitis in rats. Also, using a cell model under the hyperstimulation of the G-coupled receptor for CCK (CCK-R), we aimed to investigate the mechanisms involved in these processes in the context of zymophagy. We found that during acute pancreatitis, mitochondrial O2 consumption and ATP production significantly decreased early after induction of acute pancreatitis, with a consequent decrease in the ATP/O ratio. Mitochondrial dysfunction was accompanied by changes in mitochondrial dynamics evidenced by optic atrophy 1 (OPA-1) and dynamin-related protein 1 (DRP-1) differential expression and ultrastructural features of mitochondrial fission, mitochondrial elongation, and mitophagy during the acute phase of experimental mild pancreatitis in rats. Mitophagy was also evaluated by confocal assay after transfection with the pMITO-RFP-GFP plasmid that specifically labels autophagic degradation of mitochondria and the expression and redistribution of the ubiquitin ligase Parkin1. Moreover, we report for the first time that vacuole membrane protein-1 (VMP1) is involved and required in the mitophagy process during acute pancreatitis, observable not only by repositioning around specific mitochondrial populations, but also by detection of mitochondria in autophagosomes specifically isolated with anti-VMP1 antibodies as well. Also, VMP1 downregulation avoided mitochondrial degradation confirming that VMP1 expression is required for mitophagy during acute pancreatitis. In conclusion, we identified a novel DRP1-Parkin1-VMP1 selective autophagy pathway, which mediates the selective degradation of damaged mitochondria by mitophagy in acute pancreatitis. The understanding of the molecular mechanisms involved to restore mitochondrial function, such as mitochondrial dynamics and mitophagy, could be relevant in the development of novel therapeutic strategies in acute pancreatitis.

Viruses play an important role in the development of certain human cancers. They are estimated to contribute 16% to all human cancers. Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus to be discovered and is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive T-cell malignancy with poor prognosis. HTLV-1 viral proteins interact with mechanisms and proteins present in host cells for their own benefit, evading the immune system and promoting the establishment of disease. Several viruses manipulate the autophagy pathway to achieve their infective goals, and HTLV-1 is not the exception. HTLV-1 Tax viral protein engages NF-κB and autophagy pathways prone favoring viral replication and T cell transformation. In this review we focus on describing the relationship of HTLV-1 with the autophagy machinery and its implication in the development of ATLL.

The clinical effects of the Covid-19 pandemic are now the subject of numerous studies worldwide. But what are the effects of the quarantine imposed by the states that implemented the measures of lockdown? The present research aims to explore, in a preliminary way, the major stress-related symptoms during the lockdown, due to Covid-19, in the Italian population. Subjects were asked to fill out a survey, that traced a line identifying the most relevant psychophysiological symptoms that took into account factors such as perceived stress, body perception, perceived pain, quality of sleep, perceptive variations (i.e., olfactory, gustatory, visual, acoustic, and haptic perception). A network approach formulating a hypothesis-generating exploratory analysis was adopted. Main results of the network analysis showed that the beliefs of having had the Covid-19 was related to individual variables (i.e., gender, working in presence, sleep quality, anxiety symptoms), while the familiarity of Covid-19 disease was related to contextual factors (e.g., number of recorded cases in the Region, working in presence). The self-perception of olfactory and perceptive alterations highlighted a great sensorial cross-modality, additionally, the olfactory impairment was related to the belief of having had the Covid-19. Compared to general network data, BAI, perceived stress, anxiety and chronic pain were in relation to daily sleep disturbance. Main study's results show how the management of the Covid-19 stressful representation, in its cognitive aspects, can modulate the psychophysiological responses.

Pancreas ductal adenocarcinoma is a highly aggressive cancer with an incredible poor lifespan. Different chemotherapeutic agents’ schemes have been tested along the years without significant success. Furthermore, immunotherapy also fails to cope with the disease, even in combination with other standard approaches. Autophagy stands out as a chemoresistance mechanism and is also becoming relevant as responsible for the inefficacy of immunotherapy. In this complex scenario, exosomes have emerged as a new key player in tumor environment. Exosomes act as messengers among tumor cells, including tumor microenvironment immune cells. For instance, tumor-derived exosomes are capable of generating a tolerogenic microenvironment, which in turns conditions the immune system behavior. But also, immune cells-derived exosomes, under non-tolerogenic conditions, induce tumor suppression, although they are able to promote chemoresistance. In that way, NK cells are well known key regulators of carcinogenesis and the inhibition of their function is detrimental for tumor suppression. Additionally, increasing evidence suggests a crosstalk between exosome biogenesis and the autophagy pathway. This mini review has the intention to summarize the available data in the complex relationships between the autophagy pathway and the broad spectrum of exosomes subpopulations in pancreatic cancer, with focus on the NK cells response.

Interleukin-23 (IL-23) is a pro-inflammatory cytokine composed of two subunits, IL-23A (p19) and IL-12/23B (p40), the latter shared with Interleukin-12 (IL-12). IL-23 is mainly produced by macrophages and dendritic cells, in response to exogenous or endogenous signals, and drives the differentiation and activation of T helper 17 (Th17) cells with subsequent production of IL-17A, IL-17F, IL-6, IL-22, and tumor necrosis factor α (TNF-α). Although IL-23 plays a pivotal role in the protective immune response to bacterial and fungal infections, its dysregulation has been shown to exacerbate chronic immune-mediated inflammation. Well-established experimental data support the concept that IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as PsA, Psoriasis, Psoriatic Arthritis; AS, Ankylosing Spondylitis; IBD, Inflammatory Bowel Disease; RA, Rheumatoid Arthritis; SS, Sjogren Syndrome; MS, Multiple Sclerosis. As a result, emerging clinical studies have focused on the blockade of this pathogenic axis as a promising therapeutic target in several autoimmune disorders; nevertheless, a greater understanding of its contribution still requires further investigation. This review aims to elucidate the most recent studies and literature data on the pathogenetic role of IL-23 and Th17 cells in inflammatory rheumatic diseases.

Cancer is considered an age-related disease that, over the next 10 years, will become the most prevalent health problem worldwide. Although cancer therapy has remarkably improved in the last few decades, novel treatment concepts are needed to defeat this disease. Photodynamic Therapy (PDT) signalize a pathway to treat and manage several types of cancer. Over the past three decades, new light sources and photosensitizers (PS) have been developed to be applied in PDT. Nevertheless, there is a lack of knowledge to explain the main biochemical routes needed to trigger regulated cell death mechanisms, affecting, considerably, the scope of the PDT. Although autophagy modulation is being raised as an interesting strategy to be used in cancer therapy, the main aspects referring to the autophagy role over cell succumbing PDT-photoinduced damage remain elusive. Several reports emphasize cytoprotective autophagy, as an ultimate attempt of cells to cope with the photo-induced stress and to survive. Moreover, other underlying molecular mechanisms that evoke PDT-resistance of tumor cells were considered. We reviewed the paradigm about the PDT-regulated cell death mechanisms that involve autophagic impairment or boosted activation. To comprise the autophagy-targeted PDT-protocols to treat cancer, it was underlined those that alleviate or intensify PDT-resistance of tumor cells. Thereby, this review provides insights into the mechanisms by which PDT can be used to modulate autophagy and emphasizes how this field represents a promising therapeutic strategy for cancer treatment.

Various in vivo experimental works carried out on different animals and organs have shown that it is possible to reduce the damage caused to healthy tissue still preserving the therapeutic efficacy on the tumor tissue, by drastically reducing the total time of dose delivery (

Automated flow cytometry (FCM) adapted to real-time quality surveillance provides high-temporal-resolution data about the microbial communities in a water system. The cell concentration calculated from FCM measurements indicates sudden increases in the number of bacteria, but can fluctuate significantly due to man-made and natural dynamics; it can thus obscure the presence of microbial anomalies. Cytometric fingerprinting tools enable a detailed analysis of the aquatic microbial communities, and could distinguish between normal and abnormal community changes. However, the vast majority of current cytometric fingerprinting tools use offline statistical computations which cannot detect anomalies immediately. Here, we present a computational model, entitled Microbial Community Change Detection (MCCD), which transforms microbial community characteristics into an online process control signal (herein called outlier score) that remains close to zero if the microbial community remains stable and increases with fluctuations in the community. The model is based on fingerprints and distance-based outlier calculations. We tested it in silico and in vitro by simulating acute contaminations to real-world water systems with large inherent microbial fluctuations. We showed that the outlier score was robust against these dynamic variations, while reliably detecting intentional contaminations. This model can be used with automated FCM to quickly detect potential microbiological contamination, and this especially when the time between treatment and distribution is very short.

Tumor cells without mitochondrial (mt) DNA (ρ0 cells) are auxotrophic for uridine, and their growth is supported by pyruvate. While ATP synthesis in ρ0 cells relies on glycolysis, they fail to form tumors unless they acquire mitochondria from stromal cells. Mitochondrial acquisition restores respiration that is essential for de novo pyrimidine biosynthesis and for mitochondrial ATP production. The physiological processes that underpin intercellular mitochondrial transfer to tumor cells lacking mtDNA and the metabolic remodeling and restored tumorigenic properties of cells that acquire mitochondria are not well understood. Here, we investigated the changes in mitochondrial and nuclear gene expression that accompany mtDNA deletion and acquisition in metastatic murine 4T1 breast cancer cells. Loss of mitochondrial gene expression in 4T1ρ0 cells was restored in cells recovered from subcutaneous tumors that grew from 4T1ρ0 cells following acquisition of mtDNA from host cells. In contrast, the expression of most nuclear genes that encode respiratory complex subunits and mitochondrial ribosomal subunits was not greatly affected by loss of mtDNA, indicating ineffective mitochondria-to-nucleus communication systems for these nuclear genes. Further, analysis of nuclear genes whose expression was compromised in 4T1ρ0 cells showed that immune- and stress-related genes were the most highly differentially expressed, representing over 70% of those with greater than 16-fold higher expression in 4T1 compared with 4T1ρ0 cells. The monocyte recruiting chemokine, Ccl2, and Psmb8, a subunit of the immunoproteasome that generates MHCI-binding peptides, were the most highly differentially expressed. Early monocyte/macrophage recruitment into the tumor mass was compromised in 4T1ρ0 cells but recovered before mtDNA could be detected. Taken together, our results show that mitochondrial acquisition by tumor cells without mtDNA results in bioenergetic remodeling and re-expression of genes involved in immune function and stress adaptation.

Objective: The aim of the present observational study is to report on the data from a large sample of inpatients, clinical staff and other workers at an Italian neurorehabilitation hospital dealing with SARS-CoV-2 infections, in order to analyze how it might have affected the management and the effectiveness of neurorehabilitation.Methods: The data on infection monitoring, obtained by 2,192 swabs, were reported and compared among 253 patients, 722 clinical professionals and 232 other hospital workers. The number of admissions and neurorehabilitation sessions performed in the period from March-May 2020 was compared with those of the same period in 2019.Results: Four patients and three clinical professionals were positive for COVID-19 infection. Six out of these seven people were from the same ward. Several measures were taken to handle the infection, putting in place many restrictions, with a significant reduction in new admissions to the hospital (p < 0.001). However, neither the amount of neurorehabilitation for inpatients (p = 0.681) nor the effectiveness of treatments (p = 0.464) were reduced when compared to the data from 2019.Conclusions: Our data show that the number of infections was contained in our hospital, probably thanks to the protocols adopted for reducing contagion and the environmental features of our wards. This allowed inpatients to continue to safely spend more than 3 hours per day in neurorehabilitation, effectively improving their independence in the activities of daily living.

Since Favaudon's paper of 2014, there has been an increasing interest in FLASH radiotherapy. The FLASH modality could represent a breakthrough in radiation oncology; nevertheless, it brings new scientific and technological challenges. Currently, one of the main limits the scientific community has to cope with is the lack of a common technological platform to experiment with. Considering this framework, the possibility of readapting existing linac platforms to produce a FLASH beam is particularly attractive and different attempts have been already made. The purpose of this article is to illustrate how it is possible to transform a dedicated Intra Operative Radio Therapy (IORT) mobile linac into a FLASH research machine. Compared to the modification required by a standard medical linac, such transformation is easier, does not affect the machine settings and can be rapidly performed by the final user. NOVAC 7 is an IORT linac which can reach a maximum dose-per-pulse up to 13 cGy/pulse (average dose rate 39 Gy/min); such dose rate can be significantly increased by modifying the collimation system.Four different Source Surface Distance (SSD) can be obtained: - Clinical reference configuration;- Upper applicator only (SSD 50 cm);- Monitor chambers housing only (SSD 7 cm);- Dismounted monitor chambers (SSD 1.6 cm).The fourth configuration allows reaching values of dose-per-pulse up to around 18 Gy/pulse and dose rates up to around 500 Gy/s, at a Pulse Repetition Frequency (PRF) of 30 Hz. The other three configurations can be obtained without using any tool and without changing NOVAC settings, until reaching a FLASH dose rate in the third configuration. For FLASH configurations, relative and absolute dosimetric characterization of the beam were performed using radiochromic films EBT3. NOVAC7 transformed in FLASH mode can be used both for dosimetric testing and characterization of detectors and for radiobiological studies on cells and organoids, offering a wide range of dose-per-pulse, from 3 cGy/pulse up to 18 Gy/pulse; dose rates correspondingly change from 3 cGy/s up to 540 Gy/s.

Decidualization is a process that involves phenotypic and functional changes of endometrial stromal cells to sustain endometrial receptivity and the participation of immunoregulatory factors to maintain immune homeostasis. In this context, tolerogenic dendritic cells (DCs) can induce regulatory T cells, which are essential to manage the pro- to anti-inflammatory transition during embryo implantation. Recently, Myeloid Regulatory Cells (MRCs) were proposed as immunosuppressants and tolerance-inducer cells, including the DC-10 subset. This novel and distinctive subset has the ability to produce IL-10 and to induce type 1 regulatory T cells (Tr1) through an HLA-G pathway. Here we focus on the impact of the decidualization process in conditioning peripheral monocytes to MRCs and the DC-10 subset, and their ability to induce regulatory T cells. An in vitro model of decidualization with the human endometrial stromal cell line (HESC), decidualized by medroxyprogesterone and dibutyryl-cAMP was used. Monocytes isolated from peripheral blood mononuclear cells from healthy women were cultured with rhGM-CSF + rhIL-4 and then, the effect of conditioned media from decidualized (Dec-CM) and non-decidualized cells (Non-dec-CM) was tested on monocyte cultures. We found that Dec-CM inhibited the differentiation to the CD1a+CD14– immature DC profile in a concentration-dependent manner. Dec-CM also significantly increased the frequency of CD83+CD86low and HLA-DR+ cells in the monocyte-derived culture. These markers, associated with the increased production of IL-10, are consistent with a MRCs tolerogenic profile. Interestingly, Dec-CM treatment displayed a higher expression of the characteristic markers of the tolerogenic DC-10 subset, HLA-G and ILT2/CD85j; while this modulation was not observed in cultures treated with Non-dec-CM. Moreover, when monocyte cultures with Dec-CM were challenged with LPS, they sustained a higher IL-10 production and prevented the increase of CD83, CD86, IL-12p70, and TNF-α expression. Finally, the DC-10 subset was able to induce a CD4+HLA-G+ regulatory T cells subset. These results suggest that the decidualization process might induce different subsets of MRCs, like DC-10, able to induce regulatory T cells as a novel CD4+HLA-G+ subset which might play an immunoregulatory role in embryo implantation.

Laboratory studies of empirically supported treatments (ESTs) for mental health problems achieve much higher rates of clinical improvement than has been observed following treatment in the community. This discrepancy is likely to due to limited reliance on ESTs by therapists outside of academia. Concerns about the generalizability of ESTs to patients in the community, who may have comorbid problems, likely limit rates of adoption. The present study examined the impact of ESTs delivered in the real-world for 1,256 adults who received services through an employee assistance program specializing in the delivery of ESTs. Rates of anxiety and depression decreased significantly, following treatment with an EST, and 898 (71.5%) patients demonstrated reliable improvement. Even among patients comorbid for depression and anxiety at baseline, over half reported reliable improvement in both disorders. Findings suggest ESTs can be effectively delivered outside of academic RCTs. However, additional research is needed to understand and overcome barriers to disseminating ESTs to the broader community.