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The electrospinning process is an effective technique for creating micro- and nanofibers from synthetic and natural polymers, with significant potential for biomedical applications and drug delivery systems due to their high drug-loading capacity, large surface area, and tunable release times. Poly(L-lactic acid) (PLLA) stands out for its excellent thermo-mechanical properties, biodegradability, and bioabsorbability. Electrospun PLLA nanofibrous structures have been extensively investigated as wound dressings, sutures, drug delivery carriers, and tissue engineering scaffolds. This study aims to create and characterize electrospun PLLA membranes loaded with spironolactone (SP), mimicking active compounds of Ganoderma lucidum (GL), to develop a biodegradable patch for topical wound-healing applications. GL, a medicinal mushroom, enhances dermal wound healing with its bioactive compounds, such as polysaccharides and ganoderic acids. Focusing on GL extracts-obtained through green extraction methods-and innovative drug delivery, we created new fibers for wound-healing potential applications. To integrate complex mixtures of bioactive compounds into the fibers, we developed a prototype using a single pure substance representing the extract mixture. This painstaking work presents the results of the fabricating, wetting, moisture properties, material resilience, and full characterization of the product, providing a robust rationale for the fabrication of fibers imbued with more complex extracts.

This narrative review aims to summarize the use of alternative treatments (e.g., relaxation training, meditation, written intervention) for emotional expression, processing, control, or management in patients with migraine and tension-type headaches, which the previous literature has shown to be related to migraine pain perception and headache symptoms. Online databases including PubMed, Scopus, Web of Science, PsycINFO, and Medline were searched to identify studies published between 2000 and 2023. A descriptive synthesis of the included studies was conducted. We included seven articles after screening 1.173 records. A total of 610 patients with a diagnosis of migraine or tension-type headache, and an average age of 19-45.5 years (68-90.4% females) were recruited in the selected studies. Overall, the results show that alternative approaches to headache treatment contribute to the management, reduction, or control of negative emotions and at the same time have a positive impact on pain perception and headache symptoms. However, in some cases, the effects are more promising than others, depending on the peculiarities or limitations of each approach considered. This review provides useful insights from a methodological point of view for future studies on the management or control of negative emotions in patients with migraine and tension-type headache.

Antibodies are the macromolecules of choice to ensure specific recognition of biomarkers in biological assays. However, they present a range of shortfalls including a relatively high production cost and limited tissue penetration. Peptides are relatively small molecules able to reproduce sequences of highly specific paratopes and, although they have less biospecificity than antibodies, they offer advantages like ease of synthesis, modifications of their amino acid sequences and tagging with fluorophores and other molecules required for detection. This work presents a strategy to design peptide sequences able to recognize the CD44 hyaluronic acid receptor present in the plasmalemma of a range of cells including human bone marrow stromal mesenchymal cells. The protocol of identification of the optimal amino acid sequence was based on the combination of rational design and in silico methodologies. This protocol led to the identification of two peptide sequences which were synthesized and tested on human bone marrow mesenchymal stromal cells (hBM-MSCs) for their ability to ensure specific binding to the CD44 receptor. Of the two peptides, one binds CD44 with sensitivity and selectivity, thus proving its potential to be used as a suitable alternative to this antibody in conventional immunostaining. In the context of regenerative medicine, the availability of this peptide could be harnessed to functionalize tissue engineering scaffolds to anchor stem cells as well as to be integrated into systems such as cell sorters to efficiently isolate MSCs from biological samples including various cell subpopulations. The data here reported can represent a model for developing peptide sequences able to recognize hBM-MSCs and other types of cells and for their integration in a range of biomedical applications.

Films and fibers of syndiotactic polystyrene (sPS), being amorphous or exhibiting nanoporous crystalline (NC) or dense crystalline phases, were loaded with salicylic acid (SA), a relevant non-volatile antimicrobial molecule. In the first section of the paper, sPS/SA co-crystalline (CC) δ form is characterized, mainly by wide angle X-ray diffraction (WAXD) patterns and polarized Fourier transform infrared (FTIR) spectra. The formation of sPS/SA δ CC phases allows the preparation of sPS fibers even with a high content of the antibacterial guest, which is also retained after repeated washing procedures at 65 °C. A preparation procedure starting from amorphous fibers is particularly appropriate because involves a direct formation of the CC δ form and a simultaneous axial orientation. The possibility of tuning drug amount and release kinetics, by simply selecting suitable crystalline phases of a commercially available polymer, makes sPS fibers possibly useful for many applications. In particular, fibers with δ CC forms, which retain SA molecules in their crystalline phases, could be useful for antimicrobial textiles and fabrics. Fibers with the dense γ form which easily release SA molecules, because they are only included in their amorphous phases, could be used for promising SA-based preparations for antibacterial purposes in food processing and preservation and public health. Finally, using a cell-based assay system and antibacterial tests, we investigated the cellular activity, toxicity and antimicrobial properties of amorphous, δ CC forms and dense γ form of sPS fibers loaded with different contents of SA.

Introduction: The empirical study about the negative impact of economic difficulties due to Covid- 19 on the psychological well-being of Italian women by considering perceived stress and marital satisfaction is an area worthy of investigation. The study explored these variables by hypothesizing that marital satisfaction (DAS) could moderate or mediate the links between economic difficulties, perceived stress (PSS), and psychological maladjustment (PGWBI)., Methods: A total of 320 Italian women completed an online survey about the study's variables during the lockdown period. Women's perceptions of economic difficulties due to COVID- 19 restrictions were detected through an ad-hoc specific question. Perceived stress, marital satisfaction and psychological maladjustment were assessed by standardized questionnaires (Perceived Stress Scale 10, Dyadic Satisfaction Scale and Psychological General Well-being Inventory)., Results: 39.7% of women who answered the online survey said that the Covid-19 significantly impacted their family income. Results indicated that marital satisfaction did not moderate the associations investigated. Conversely, data showed how economic difficulties (X) predicted lower psychological maladjustment through the mediation of perceived Stress (M1), which, in turn, was associated with higher levels of marital dissatisfaction (M2)., Conclusion: The results of the present study confirm the significant role of marital dissatisfaction in explaining the indirect effects of economic difficulties on psychological maladjustment in women. In particular, they indicated a significant spillover effect which transmitted strains experienced in one domain (economic difficulties) to another (the dissatisfaction of the couple), which in turn affected the psychological maladjustment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Camisasca, Covelli, Cafagna, Manzoni, Cantoia, Bavagnoli, Crescenzo, Marsicovetere, Pesce and Visco.)

Background: Since the COVID-19 pandemic and the subsequent measures of containment, multiple studies have been conducted aimed at assessing the impacts on people's psychophysical well-being; however, few studies have investigated the general population's perceptions, experiences, and effects by adopting a mixed-method approach., Methods: A total of 855 Italian participants completed an online survey, conducted in the period following the first lockdown in Italy. Psychological well-being, perceived stress and COVID-19-related fears were assessed by standardized questionnaires ( Psychological General Well-Being Index-Short version , Perceived Stress Scale 10 , and Multidimensional Assessment of COVID-19-Related Fears ). The process of sense-making of the experience during the lockdown period was also evaluated by means of an open-ended question., Results: Participants reported a lower level of general well-being, and a higher level of both perceived stress and COVID-19-related fear during the lockdown period compared to the time of the survey (1 month after the resumption of activities). The thematic analysis of responses to the open-ended question revealed two factors and five clusters, which explain the thematic variance among the narratives: the first factor refers to the type of experience (emotional states and feelings vs. objective descriptions of daily activities), while the second concerns positive or negative connotations of the experiences reported., Conclusions: This study explored the psychological impact of the first lockdown on people's well-being, and described the process of making sense of the experience during the lockdown 1 month after going back to previous habits. Results highlighted the effectiveness of the mixed-method approach for an in-depth and exhaustive investigation of people's psychological condition during and after the first lockdown., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Covelli, Camisasca, Manzoni, Crescenzo, Marelli, Visco, Cafagna, Marsicovetere, Pesce and Cantoia.)

The COVID-19 pandemic imposed changes on day-to-day activities and had a detrimental psychological effect on the population, especially among vulnerable individuals, such as adolescents and young adults. The current study aimed to explore variables associated with anxiety, depressive and somatic symptoms in a sample of 608 Italian young adults aged 18 to 25. Data were collected using an online questionnaire administered two months into the COVID-19 lockdown, which explored several areas including sociodemographic information, pre-pandemic and current psychological distress, pre-pandemic and current levels of loneliness, and the traits of intolerance of uncertainty and boredom susceptibility. Results highlighted that having pre-existing mental health issues, being female, and the personality traits of intolerance to uncertainty and boredom susceptibility all played a role in the psychological distress experienced during the pandemic. COVID-19 contributed to negative impacts on young adults' mental health, highlighting the necessity to develop protective psychological intervention tailored for this vulnerable population.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus identified as the cause of the coronavirus outbreak in December 2019 (COVID-19). Like all the RNA viruses, SARS-CoV-2 constantly evolves through mutations in its genome, accumulating 1-2 nucleotide changes every month, giving the virus a selective advantage through enhanced transmissibility, greater pathogenicity, and the possibility of circumventing immunity previously acquired by an individual either by natural infection or by vaccination. Several SARS-CoV-2 variants of concern (VoC) have been identified, among which we find Alpha (Lineage B.1.1.7), Beta (Lineage B.1.351), and Gamma (Lineage P.1) variants. Most of the mutations occur in the spike (S) protein, a surface glycoprotein that plays a crucial role in viral infection; the S protein binds the host cell receptor, the angiotensin-converting enzyme of type 2 (ACE2) via the receptor binding domain (RBD) and catalyzes the fusion of the viral membrane with the host cell. In this work, we present the development of a simplified system that would afford to study the change in the SARS-CoV-2 S RBD/ACE2 binding related to the frequent mutations. In particular, we synthesized and studied the structure of short amino acid sequences, mimicking the two proteins' critical portions. Variations in the residues were easily managed through the one-point alteration of the sequences. Nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopies provide insights into ACE2 and SARS-CoV-2 S RBD structure with its related three variants (Alpha, Beta, and Gamma). Spectroscopy data supported by molecular dynamics lead to the description of an ACE2/RBD binding model in which the effect of a single amino acid mutation in changing the binding of S protein to the ACE2 receptor is predictable., Competing Interests: The authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd.)

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N6-Isopentenyladenosine ( i6A ) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we demonstrated that i6A targeted farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway and prenylation of downstream proteins, which are aberrant in several cancers. Following our interest in the anticancer effects of FPPS inhibition, we developed a panel of i6A derivatives bearing bulky aromatic moieties in the N6 position of adenosine. With the aim of clarifying molecular action of N6-benzyladenosine analogs on the FPPS enzyme inhibition and cellular toxicity and proliferation, herein we report the evaluation of the N6-benzyladenosine derivatives' (compounds 2a-m ) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer cells (CRC). We found that compounds 2 , 2a and 2c showed a persistent antiproliferative effect on human CRC lines and compound 2f exerted a significant effect in impairing the prenylation of RAS and Rap-1A proteins, confirming that the antitumor activity of 2f was related to the ability to inhibit FPPS activity.

Background: The COVID-19 pandemic contributes to the burden of living with different diseases, including Systemic Lupus Erythematosus (SLE). We described, from a narrative point of view, the experiences and perspectives of Italian SLE adults during the COVID-19 emergency, by distinguishing the illness experience before and after the lockdown., Methods: Fifteen patients were invited to participate. Illness narratives were collected between 22 and 29 March 2020 using a written modality to capture patients' perspectives before and after the COVID-19 lockdown. We performed a two-fold analysis of collected data by distinguishing three narrative types and a qualitative analysis of content to identify the relevant themes and sub-themes reported., Results: Eight narratives included in the final analysis (mean length 436.9 words) have been written by eight females (mean age 43.3 ± 9.9 years, mean disease duration 13.1 ± 7.4 years). Six patients provided a quest narrative, one a chaos and the remaining one a restitution narrative. By text content analysis, we identified specific themes, temporally distinct before and after the lockdown. Before COVID-19, all the patients referred to a good control of disease, however the unexpected arrival of the COVID-19 emergency broke a balance, and patients perceived the loss of health status control, with anxiety and stress., Conclusions: We provided unique insight into the experiences of people with SLE at the time of COVID-19, underlining the perspective of patients in relation to the pandemic.

Ganoderma lucidum or Reishi is recognized as the most potent adaptogen present in nature, and its anti-inflammatory, antioxidant, immunomodulatory and anticancer activities are well known. Moreover, lately, there has been an increasing interest from pharmaceutical companies in antiaging G. lucidum -extract-based formulations. Nevertheless, the pharmacological mechanisms of such adaptogenic and regenerative actions remain unclear. The present investigation aimed to explore its molecular and cellular effects in vitro in epidermal keratinocyte cultures by applying liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LCMS-IT-TOF) for analysis of ethanol extracts using ganoderic acid-A as a reference compound. The G. lucidum extract showed a keratinocyte proliferation induction accompanied by an increase of cyclic kinase protein expressions, such as CDK2 and CDK6. Furthermore, a noteworthy migration rate increase and activation of tissue remodelling factors, such as matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), were observed. Finally, the extract showed an antioxidant effect, protecting from H 2 O 2 -induced cytotoxicity; preventing activation of AKT (protein kinase B), ERK (extracellular signal-regulated kinase), p53 and p21; and reducing the number of apoptotic cells. Our study paves the path for elucidating pharmacological properties of G. lucidum and its potential development as cosmeceutical skin products, providing the first evidence of its capability to accelerate the healing processes enhancing re-epithelialization and to protect cells from free-radical action.

Farnesyl pyrophosphate synthase (FPPS) is a crucial enzyme for the synthesis of isoprenoids and the key target of nitrogen-containing bisphosphonates (N-BPs). N-BPs are potent and selective FPPS inhibitors that are used in the treatment of bone-related diseases, but have poor pharmacokinetic properties. Given the key role played by FPPS in many cancer-related pathways and the pharmacokinetic limits of N-BPs, hundreds of molecules have been screened to identify new FPPS inhibitors characterized by improved drug-like properties that are useful for broader therapeutic applications in solid, non-skeletal tumours. We have previously shown that N6-isopentenyladenosine (i6A) and its related compound N6-benzyladenosine (2) exert anti-glioma activity by interfering with the mevalonate pathway and inhibiting FPPS. Here, we report the design and synthesis of a panel of N6-benzyladenosine derivatives (compounds 2a-m) incorporating different chemical moieties on the benzyl ring. Compounds 2a-m show in vitro antiproliferative activity in U87MG glioma cells and, analogous to the bisphosphonate FPPS inhibitors, exhibit immunogenic properties in ex vivo γδ T cells from stimulated peripheral blood mononuclear cells (PBMCs). Using saturation transfer difference (STD) and quantitative 1 H nuclear magnetic resonance (NMR) experiments, we found that 2f, the N6-benzyladenosine analogue that includes a tertbutyl moiety in the para position of the benzyl ring, is endowed with increased FPPS binding and inhibition compared to the parent compounds i6A and 2. N6-benzyladenosine derivatives, characterized by structural features that are significantly different from those of N-BPs, have been confirmed to be promising chemical scaffolds for the development of non N-BP FPPS inhibitors, exerting combined cytotoxic and immunostimulatory activities., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests. Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Deep Brain Stimulation (DBS) is increasingly used in pediatric patients affected by isolated dystonia, with excellent results. Despite well documented long-term effects on motor functioning, information on quality of life and social adaptation is almost lacking., Objectives: The present study aims to explore the experience of illness and the relation with the device in adult patients suffering from dystonia who underwent DBS surgery in pediatric age., Methods: A narrative inquiry approach was used to collect patients' narratives of their experience with dystonia and DBS stimulator. A written interview was administered to 8 patients over 18 years old with generalized isolated dystonia who had undergone pallidal DBS implantation in childhood. A thematic analysis was realized to examine the narratives collected., Results: Five main themes emerged: "relationship with the disease", "experience related to DBS procedure", "relationship with one's own body", "fears", "thoughts about future". Despite a general satisfaction in relation to DBS intervention, some patients expressed difficulties, such as the acceptance of changes in one's own body, concerns and fears regarding the device and the future, also considering the critical phase of transition from childhood to adulthood., Conclusions: These results suggest that further research is needed to understand the contribution of psychological, as much as medical, aspects to the overall outcome of the intervention. The present explorative study encourages a deeper investigations of psychological aspects of patients, in order to plan a tailored care path and to decide whether to suggest a psychological support, both before and after the intervention., Competing Interests: Declaration of competing interest The authors declare no conflict of interest concerning the research related to the manuscript., (Copyright © 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Pain assessment in patients with disorders of consciousness (DoC) is a controversial issue for clinicians, who require tools and standardised procedures for testing nociception in non-communicative patients. The aims of the present study were, first, to analyse the psychometric properties of the Italian version of the Nociception Coma Scale and, second, to evaluate pressure pain thresholds in a group of patients with DoC. The authors conducted a multi-centre study on 40 healthy participants and 60 DoC patients enrolled from six hospitals in Italy. For each group an electronic algometer was used to apply all nociceptive pressure stimuli. Our results show that the Italian version of the NCS retains the good psychometric properties of the original version and is therefore suitable for standardised pain assessment in clinical practice. In our study, pressure pain thresholds measured in a group of patients in vegetative and minimally conscious state were relatively lower than pain threshold values found in a group of healthy participants. Such findings motivate additional investigation on possible pain sensitisation in patients with severe brain injury and multiple co-morbidities, and on application of tailored therapeutic approaches useful for pain management in patients unable verbally to communicate their feelings.

Objectives: To address the way in which primary caregivers of people over 45 with Down syndrome describe daily life activities and context and foresee their future., Methods: Thirteen family members and 15 health professionals participated to four focus groups. Meaningful concepts were identified and linked to the International Classification of Functioning, Disability and Health using established linking rules., Results: A total of 258 relevant concepts were identified and linked to 75 categories of the classification: 38 were from activity and participation and 17 from environmental factors domains. The most commonly reported issues were mental functions (b117-intellectual functions and b152-emotional functions), community life activities (d910-community life and d920-recreation and leisure) and environmental factors (e310-support of immediate family, e355-support from health professionals and e555-associations and organizational services)., Conclusions: Information on the daily life and health of ageing people with Down syndrome is important to plan social and health care interventions tailored to deal with problems that they may encounter in older age. Considering the interaction between health and environment and maintaining a continuity of daily routines were reported as the most relevant topics for managing daily lives of persons with Down syndrome in older ages. Implications for rehabilitation Pay more attention to the interaction between environmental factors and health condition in ageing people with Down syndrome. Information about the life contest are important in order to plan present and future social-health care interventions. Future planning for people with Down syndrome is a great concern for family members.

Background: It is common clinical experience that, after structured withdrawal, some patients with chronic migraine and medication overuse headache (CM with MOH) are more prone than others to relapse and to be in need of further structured treatments. Our aim was to explore similarities and differences between frequent relapsers (FRs) and non-frequent relapsers (NFRs) by considering their point of view, perceptions, and perspective of their subjective experience with relapse into CM with MOH., Methods: Patients were consecutively recruited on occasion of a structured withdrawal treatment and were interviewed individually about their headache experience and their perspectives on relapse into CM with MOH. We considered FR those patients requiring 2 or more structured withdrawals for MOH within 3 years. A narrative approach with no preconceived coding schemes was employed. To facilitate coding, categorization and organization of data the software QRS NVivo 11.0 was used: themes were defined as common to FR and NFR, or peculiar (by frequency or content) to one of the 2 groups., Results: Sixteen patients (13 women; mean age of 53) were interviewed: 7 were classified as FRs. A total of 22 themes emerged from 552 single quotations (the 10 most relevant covered 82% of the entire body of quotations). Four themes were commonly reported by both FR and NFR patients, and 6 were peculiar to one group only. Common aspects included issues connected to the dilemma between disclosing, concealing and the feelings of isolation around MOH, the idea of being addicted to medication, presence of anxiety, and the attempt to use non-pharmacological therapies as an alternative to medication. Peculiar aspects included causal attribution (FRs attributed headache to uncontrollable factors); future expectations at the time point of withdrawal (FRs were generally resigned); high-performance functioning (FRs believed they are "forced" to reach high levels of performance as a consequence of others' inability); coping strategies (FRs tended to "passively accept" problems and showed avoidance-related behaviors). Moreover, FRs were less frequently aware of their problems and described more frequently depressive symptoms., Conclusions: Our results highlight that some differences between FR and NFR patients with CM and MOH exist. Frequent relapsers among patients with CM and MOH reported some important peculiarities of the lived experience of having chronic migraine; clinicians should recognize these psychosocial aspects such as social relationships, future expectations, the experience of illness, medication management, and how the withdrawal experience is regarded, as they may be associated with frequent relapse into MOH., (© 2018 American Headache Society.)

Background: The degree to which work-related difficulties are recognized in headache research is poor and often carried out with inadequate information such as "reduced ability to work as usual", which do not capture at all the variety of difficulties and the factors that impact over them. The aim of this paper is to present the validation of the HEADWORK questionnaire, which addresses the amount and severity of difficulties in work-related tasks and the factors that impact over them., Methods: We developed a set of items based on a previous literature review and patients' focus groups and tested it on a wide set of patients with episodic and chronic migraine attending eight different Italian headache centers. HEADWORK factor structure was assessed with exploratory and confirmatory factor analysis; internal consistency and construct validity were addressed as well., Results: The validation sample (N = 373) was mostly composed of patients with episodic migraine without aura (64.3%) and of females (81%). Factor analysis retrieved two different scales: "Work-related difficulties", composed of eleven items which explain 67.1% of the total variance, and "Factors contributing to work difficulties", composed of six items which explain 52.1% of the total variance. Both HEADWORK subscales have good measurement properties, with higher scores being associated to higher disability, lower quality of life, lower productivity, higher headache frequency and pain intensity., Conclusions: HEADWORK is a 17-item, two-scale questionnaire addressing the impact of migraine on work-related difficulties in terms of difficulties in general or specific skills, and the factors contributing to these difficulties, defined as negative impact on work tasks. It can be used to address disability weights for the purpose of calculating the burden of migraine, and to assess the balance between therapeutic and side effects of medication on productivity.

Metabolomics is increasingly popular for the study of pathogens. For the malaria parasite Plasmodium falciparum , both targeted and untargeted metabolomics have improved our understanding of pathogenesis, host-parasite interactions, and antimalarial drug treatment and resistance. However, purification and analysis procedures for performing metabolomics on intracellular pathogens have not been explored. Here, we purified in vitro -grown ring-stage intraerythrocytic P. falciparum parasites for untargeted metabolomics studies; the small size of this developmental stage amplifies the challenges associated with metabolomics studies as the ratio between host and parasite biomass is maximized. Following metabolite identification and data preprocessing, we explored multiple confounding factors that influence data interpretation, including host contamination and normalization approaches (including double-stranded DNA, total protein, and parasite numbers). We conclude that normalization parameters have large effects on differential abundance analysis and recommend the thoughtful selection of these parameters. However, normalization does not remove the contribution from the parasite's extracellular environment (culture media and host erythrocyte). In fact, we found that extraparasite material is as influential on the metabolome as treatment with a potent antimalarial drug with known metabolic effects (artemisinin). Because of this influence, we could not detect significant changes associated with drug treatment. Instead, we identified metabolites predictive of host and medium contamination that could be used to assess sample purification. Our analysis provides the first quantitative exploration of the effects of these factors on metabolomics data analysis; these findings provide a basis for development of improved experimental and analytical methods for future metabolomics studies of intracellular organisms. IMPORTANCE Molecular characterization of pathogens such as the malaria parasite can lead to improved biological understanding and novel treatment strategies. However, the distinctive biology of the Plasmodium parasite, including its repetitive genome and the requirement for growth within a host cell, hinders progress toward these goals. Untargeted metabolomics is a promising approach to learn about pathogen biology. By measuring many small molecules in the parasite at once, we gain a better understanding of important pathways that contribute to the parasite's response to perturbations such as drug treatment. Although increasingly popular, approaches for intracellular parasite metabolomics and subsequent analysis are not well explored. The findings presented in this report emphasize the critical need for improvements in these areas to limit misinterpretation due to host metabolites and to standardize biological interpretation. Such improvements will aid both basic biological investigations and clinical efforts to understand important pathogens., (Copyright © 2018 Carey et al.)

Objective: The study compared the metric characteristics (discriminant capacity and factorial structure) of two different methods for scoring the items of the Coma Recovery Scale-Revised and it analysed scale scores collected using the standard assessment procedure and a new proposed method., Design: Cross sectional design/methodological study., Setting: Inpatient, neurological unit., Participants: A total of 153 patients with disorders of consciousness were consecutively enrolled between 2011 and 2013., Intervention: All patients were assessed with the Coma Recovery Scale-Revised using standard (rater 1) and inverted (rater 2) procedures., Main Outcome Measures: Coma Recovery Scale-Revised score, number of cognitive and reflex behaviours and diagnosis., Results: Regarding patient assessment, rater 1 using standard and rater 2 using inverted procedures obtained the same best scores for each subscale of the Coma Recovery Scale-Revised for all patients, so no clinical (and statistical) difference was found between the two procedures. In 11 patients (7.7%), rater 2 noted that some Coma Recovery Scale-Revised codified behavioural responses were not found during assessment, although higher response categories were present. A total of 51 (36%) patients presented the same Coma Recovery Scale-Revised scores of 7 or 8 using a standard score, whereas no overlap was found using the modified score. Unidimensionality was confirmed for both score systems., Conclusion: The Coma Recovery Scale Modified Score showed a higher discriminant capacity than the standard score and a monofactorial structure was also supported. The inverted assessment procedure could be a useful evaluation method for the assessment of patients with disorder of consciousness diagnosis.

The aim of this study was to report the most frequent psychosocial difficulties (PSDs) in patients with Parkinson disease (PD), to explore the relationship between PSDs, disability and quality of life (QoL), and to address the predictors of PSDs. Patients with PD were interviewed using a protocol composed of a questionnaire investigating PSDs (PARADISE 24), QoL, disability, comorbidity, and social support questionnaires, scales on resilience, personality traits, and empathy in physician. Most frequent PSDs were reported. Spearman's correlation was used to address the relationship between PARADISE 24 and QoL and disability measures. Multiple linear regression was performed to investigate predictors of PARADISE 24. Eighty patients were enrolled: 40% women, mean age 61.2 years. The most frequent PSDs were related to cognitive and motor slowness, tiredness, sleeping, facing all things to do, depressive mood, and anxiety. PARADISE 24 were correlated with disability (ρ=0.831) and QoL (ρ=-0.685). Lower QoL, higher disability, early age at onset, and shorter disease duration were significant predictors of PSDs (adjusted R=0.762). PARADISE 24 is an easy to use questionnaire that could contribute toward describing the impact of PD on patients' life more extensively, thus helping to define more tailored interventions.

To explore the relationships between psychosocial difficulties (PSDs), quality of life (QoL), and disability and to explore the degree to which PSDs can be predicted by demographic variables, clinical variables, and risk and protective factors. Patients with episodic migraine completed a protocol inclusive of PARADISE 24 questionnaire (the 24-item Psychosocial Difficulties Relevant to Brain Disorders questionnaire), a new questionnaire that captures PSDs relevant to brain disorders, and assessments of disability, QoL, disease severity, presence of comorbidities, social support, and clinical and risk factors (i.e., smoking and body mass index). Spearman's correlation was used to address the relationship between PARADISE 24, and the assessments of disability and QoL; multivariable linear regression analysis was carried out to address PARADISE 24 predictors. Eighty patients were enrolled (86.3 % females, mean age 44.5). PARADISE 24 was well correlated with disability (ρ = 0.787) and moderately with QoL (ρ = -0.526). The regression analysis shows that younger age, higher migraine frequency, higher comorbidities index and being a smoker were predictors of PARADISE 24 (R 2 : 0.470). Addressing the burden associated with PSDs in migraineurs is important as these might be the reason why patients look for specialists in headache disorders. PARADISE 24 represents a viable way to address patients' difficulties in daily practice.

Aim: The aim of this observational study was to test the effectiveness of the PARADISE 24 instrument in describing the psychosocial difficulties (PSDs) reported by people with epilepsy, their relation with disability, and quality-of-life (QoL) levels and, overall, to explore a horizontal epidemiology methodology applied to a sample of patients with epilepsy., Methods: A convenience sample of 80 adult patients with epilepsy was included in this cross-sectional study. Patients were interviewed using a structured protocol composed of demographic, clinical, and patient-reported outcome measures to collect PSDs associated with epilepsy., Results: There were 80 patients, 40 females; mean age was 41.2years; mean disease duration was 18.7years; and mean number of AED was 2.09. Moderate severity rating according to clinicians' rating scale, low impact of comorbidities (mean: 2.36, SD: 2.97), high levels of QoL (mean: 30.00, SD: 4.4), medium levels of resilience (mean: 13.56, SD: 2.66), high levels of perceived empathy (mean: 15.05, SD: 4.74), poor or moderate perceived social support, and low levels of disability (mean: 10.85, SD: 10.05) were observed. The most frequently reported PSDs were related to tiredness (80%), emotional problems (73.75%), anxiety (68.75%), depressive mood (66.25%), and driving problems (61.25%). The EUROHIS-QOL (p=.003) had a negative significant relationship with PARADISE 24 while WHODAS-12 (p=.000) and CRS (p=.027) had a positive significant relationship with PARADISE 24., Conclusions: The PARADISE 24 permits data comparison and the creation of a complete description of a person's functioning and of all of his/her PSDs and allows better and more tailored interventions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To study the changes in the burden of informal caregivers of patients with disorders of consciousness (DOC) over time., Materials and Methods: Short Form-12, Family Strain Questionnaire, Beck Depression Inventory and Coping Orientations to Problem Experiences were administered., Results: Data collected on 216 informal caregivers of patients with DOC (59.6% females, mean age 53.4 ± 12.7 years old) were analysed at two time-points (mean distance is 2.7 years). Results of the national study revealed that caregivers' mental health improved (T0: M = 41.1, SD = 11.8; T1: M = 45.8, SD = 11.7), whereas the emotional burden (T0: M = 7.4, SD = 3.6; T1: M = 6.6, SD = 3.9) and the presence of depressive symptoms (T0: M = 14.3, SD = 9.3; T1: M = 11.7, SD = 10.2) as well as the need for information about the disease (T0: M = 2.7, SD = 1.2; T1: M = 2.2, SD = 1.4), thoughts of death (T0: M = 3.6, SD = 1.5; T1: M = 3.1, SD = 1.6) and the use of avoiding coping strategy (T0: M = 7.8, SD = 1.0; T1: M = 6.0, SD = 1.3) decreased at T1. Furthermore, depressive symptoms positively correlated with the emotional burden (0.580) and negatively with the mental health component of caregivers' self-perceived health condition (-0.473). Physical (-0.308) and mental health (-0.444) negatively correlated with emotional burden. Finally, the acute event and patients' health condition still have a deep impact on the economic situation of the family., Conclusion: Although high level of burden was observed, it tends to decrease over time, except for financial burden. Hence, this study suggests the importance to plan strategies or targeted interventions in order to reduce the psychosocial and financial burden associated with caregiving., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Multiple Sclerosis (MS) mainly affects people of working age. The Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job) was designed to measure difficulties in work-related tasks. Our aim is to define cut-off score of MSQ-Job to identify potential critical situations that might require specific attention. A sample of patients with MS completed the MSQ-Job, WHODAS 2.0 and MSQOL-54 respectively for work difficulties, disability and health-related quality of life (HRQoL) evaluation. K-means Cluster Analysis was used to divide the sample in three groups on the basis of HRQoL and disability. ANOVA test was performed to compare the response pattern between these groups. The cut-off score was defined using the receiver operating characteristic (ROC) curve analyses for MSQ-Job total and count of MSQ-Job items scores ≥3: a score value corresponding to the maximum of the sensitivity-to-specificity ratio was chosen as the cut-off. Out of 180 patients enrolled, twenty were clustered in the higher severity group. The area under the ROC curve was 0.845 for the MSQ-Job total and 0.859 for the count of MSQ-Job items scores ≥3 while the cut-off score was 15.8 for MSQ-Job total and 8 for count of items scored ≥3. We recommend the use of MSQ-Job with this calculation as cut-off for identifying critical situations, e.g. in vocational rehabilitation services, where work-related difficulties have a significant impact in terms of lower quality of life and higher disability.

Unlabelled: Penicillin encephalopathy is a rare, potentially reversible phenomenon of drug-induced neurotoxicity., Case: A 65-year-old female with a history of HIV was admitted with a three-day history of worsening headache, confusion, and lethargy. On examination she was awake but confused. Cerebrospinal fluid (CSF) and serum venereal disease research laboratory (VDRL) test returned positive and the patient was started on intravenous penicillin G with probenecid. On the second day of therapy, she developed myoclonic jerking, consistent with penicillin neurotoxicity. Repeat labs also showed new onset renal failure. Penicillin and probenecid therapy were stopped with a resolution of symptoms. Subsequently, therapy without probenecid was reinstituted uneventfully., Discussion: Herein, we describe a female who developed penicillin neurotoxicity after initiation of intravenous penicillin therapy with probenecid for neurosyphilis. It is important that penicillin-induced toxicity be considered if characteristic myoclonic movements accompany encephalopathy. The presence of coexistent renal compromise should heighten the vigilance of clinicians.

Life expectancy of people with Down's syndrome (DS) has increased considerably, now exceeding 60 years. People with DS start to get old around the age of 45. By referring to the WHO's International Classification of Functioning, Disability and Health (ICF) biopsychosocial perspective, this study aimed to present an up-to-date review of the past 14 years of literature concerning the ageing of people with DS. PUBMED, PsycInfo and the Social Sciences Citation Index were searched for studies published between 2000 and 2014. Studies were selected if they were written in English, focused on people more than 45 years of age with DS, and if terms related to DS and ageing appeared in either the title or the abstract. A total of 30 studies were retrieved and their meaningful concepts were linked to the ICF. In total, 38 ICF categories were identified that were mainly related to intellectual functions (b117) (19%), general metabolic functions (b540) (7.4%), mobility of joint functions (b710), muscle power functions (b730) (4.2%), gait pattern functions (b770) (4.2%) and structure of the brain (s110) (4.3%). Only two studies considered environmental factors, and only one considered the joint analysis of health condition and environmental factors. Data about the ageing of people with DS are predominantly based on medical evaluations and descriptions of their physical impairments. Few attempts have been made towards a comprehensive assessment of elderly people with DS with a joint analysis of their health condition and its interaction with environmental factors.

Objective: Depression, anxiety, disease severity, and cognitive functions impact on the quality of life of people with MS. However, the majority of studies were not based on multivariate models and did not target employed patients. The aim of this study was to investigate predictors of HRQoL in persons with MS in the workforce considering cognitive, psychological, disease severity, and disability-related variables., Methods: Cross-sectional study. Hierarchical block regression analyses were conducted to identify predictors of physical and mental components of HRQoL, measured with the MSQOL-54. Candidate predictors included cognitive functioning (a selection of Rao's BRB-NT), sample features (age, education, MS duration), depressive symptoms (BDI-II), anxiety (STAI-Y), disability (WHODAS 2.0), and MS severity (EDSS): those that correlated with PCS and MCS with p < .250 and those that correlated with other predictors with coefficients >.800 were excluded from regression analyses., Results: In total, 181 patients (60.8% females, mean age 39.6, median EDSS 1.5) were included. In both models, cognitive variables had a poor explicative power. The models improved significantly when psychological, as well as, disease severity and disability variables were added. R(2) of complete models was 0.732 for the physical component, 0.697 for the mental one: BDI-II, STAI-State and, some WHODAS 2.0 scales were significant predictors of HRQoL., Conclusions: Monitoring anxiety, depressive symptoms, and level of disability through self-reported questionnaires may provide useful suggestions to improve the HRQoL of persons with MS in the workforce, permitting to address possible problems in the work context and plan corrective actions.

Purpose: To explore which variables are associated to or determinants of work-related difficulties or unemployment in persons with multiple sclerosis (MS)., Method: Papers published between 1993 and February 2015 were included. Quality was judged as poor, acceptable, good or excellent. Determinants were extracted from prospective and retrospective data, associated variables from cross-sectional data; variables were grouped by similarity. Evidence was judged as strong if there were at least two good studies reporting the same results; limited if there was only one good and some acceptable studies., Results: Forty-two papers were selected, for a total of 31,192 patients (75% females). Work-related difficulties were referred as unemployment, lower amount of worked hours or job cessation. Strong evidence of impact over work-related difficulties was found for a core set of variables, i.e., expanded disability status scale, MS duration, patients' age, fatigue and walking problems. Little evidence exists on the impact of contextual factors., Discussion: Most of the variables identified as associated to or determinants of work-related difficulties can be treated through rehabilitative interventions. It is important that future research addresses not only unemployment issues in MS, but also the amount and severity of problems affecting work-related tasks relying on specific assessment instruments., Implications for Rehabilitation: Multiple sclerosis (MS) affects young persons of working age and limitation in work activities is part of MS-related disability, but they are not consistently addressed in MS research: EDSS, MS duration, patients' age, fatigue, walking problems, cognitive and neuropsychological impairments were the factors most commonly found as associated to or determinant of difficulties with work. Evidence exists that rehabilitation interventions are effective for fatigue, cognitive impairment, mobility and walking difficulties. However, research did not address the impact of rehabilitation programmes on vocational outcomes. Rehabilitation researchers should include MS-specific assessment instruments for work-related difficulties to standardised clinical protocols, so that the benefits of rehabilitation on persons' ability to work can be demonstrated directly: in this way, cost-benefit balance analyses can be added to the evaluation of treatment effectiveness.

Background: Persons with brain disorders experience significant psychosocial difficulties (PSD) in daily life, e.g. problems with managing daily routine or emotional lability, and the level of the PSD depends on social, physical and political environments, and psychologic-personal determinants. Our objective is to determine a brief set of environmental and psychologic-personal factors that are shared determinants of PSD among persons with different brain disorders., Methods: Cross-sectional study, convenience sample of persons with either dementia, stroke, multiple sclerosis, epilepsy, migraine, depression, schizophrenia, substance dependence or Parkinson's disease. Random forest regression and classical linear regression were used in the analyses., Results: 722 subjects were interviewed in four European countries. The brief set of determinants encompasses presence of comorbidities, health status appraisal, stressful life events, personality changes, adaptation, self-esteem, self-worth, built environment, weather, and health problems in the family., Conclusions: The identified brief set of common determinants of PSD can be used to support the implementation of cross-cutting interventions, social actions and policy tools to lower PSD experienced by persons with brain disorders. This set complements a recently proposed reliable and valid direct metric of PSD for brain disorders called PARADISE24.

The differential diagnosis between vegetative state and minimally conscious state is still complex and the development of an evaluation systems is one of the challenging tasks for researchers and professionals. The Coma Recovery Scale-revised is considered the gold standard for clinical/behavioral assessment and for the differential diagnosis of patients with disorder of consciousness. However, the scale presents some limitations in that (i) scores may partially overlap between different diagnoses and (ii) there is an underlying assumption that if a patient is able to show higher-level behaviors, he/she is also able to show lower-level responses. In the present study, a procedure to calculate a modified Coma Recovery Scale-revised score is presented that attempts to avoid these problems. To exemplify this new scoring approach, 60 patients with disorder of consciousness were studied and the results showed the usefulness of the Modified Score.

Objective: Multiple sclerosis (MS) affects young adults of working age. Difficulties in work-related activities are usually ascribed to MS symptoms, while the impact of workplace features is underestimated. This article presents the Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job), designed to assess working difficulties due to MS symptoms and workplace features., Methods: A sample of employed MS patients completed the MSQ-Job, the WHO-Disability Assessment Schedule (WHODAS 2.0) and the 54-items MS Quality of Life Questionnaires (MSQOL-54); the expanded disability status scale (EDSS) was used to define MS severity. Factor structure was evaluated using principal component extraction and Oblimin rotation; internal consistency was assessed with Cronbach's alpha; construct and discriminant validity using t-test (EDSS 0-2 vs >2; patients self-reporting need for support vs patients reporting no needs; full-time vs part-time employees); and Pearson's correlation with WHODAS 2.0 and MSQOL-54., Results: The MSQ-Job is a 42-item questionnaire with six scales and an overall factor. Scores range on a 0-100 scale (higher scores indicate more and more severe difficulties); patients with EDSS>2 and self-reporting support needs had worse scores than those with EDSS 0-2 and without needs. Correlations with WHODAS 2.0 and MSQOL-54 were generally significant (P < 0.0007) and below 0.70., Conclusions: The MSQ-Job jointly measures the impact of respondents' symptoms and workplace features on work activities and enables to assess the effects of clinical and occupational interventions and better describe the impact of MS indirect costs., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To evaluate quality of life (QoL) and its predictors, psychological burden and level of perceived social support in caregivers of patients with disorder of consciousness., Materials & Methods: World Health Organization Quality of Life-Bref (WHOQOL-BREF), State Trait Anxiety Inventory-Y (STAI-Y), Beck Depression Inventory (BDI-II), Prolonged Grief Disorder Questionnaire, Coping Orientations to Problem Experiences, State-Trait Anger Expression Inventory-2 (STAXI-2), and the Medical Outcome Study Social Support Survey (MOS-SSS) were administered. One-sample t-tests were performed to compare WHOQOL-BREF, STAI-Y and STAXI-2 mean scores to the respective normative sample (NS). Pearson correlation was calculated between time dedicated to patient's care, WHOQOL-BREF, BDI-II, STAI-Y and MOS-SSS scores. Hierarchical multiple regression analyses were performed to evaluate which variables have predictive power on QoL., Results: A total of 129 caregivers, 68.2% female, mean age 52.8 years, were enrolled. Three WHOQOL-BREF domains were significantly lower. Anxiety and anger were in line with NS. 28.7% of the sample reported high level of depressive symptoms; 20.9% satisfied the prolonged grief disorder criteria. No differences emerged between caregivers and chronic ill patients' scores at MOS-SSS. STAI-Y, BDI-II and WHOQOL-BREF scores positively correlated. MOS-SSS domains inversely correlate with BDI-II scores. BDI-II results the most relevant predictor of QoL., Conclusions: Study results provided innovative information about caregivers' poor QoL, difficulties in social support and high levels of burden. Time dedicated to care is not strictly related to burden, while social support perceived is highly associated with caregivers' depressive symptoms that are strong predictor of poor QoL. Supportive intervention able to integrate psychological, social and environmental levels is needed., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Primary Objective: This study aimed at better understanding of the complex psychological process underlying the demanding situation of taking care of a relative with disorder of consciousness (DOCs)., Research Design: This is a qualitative study based on the grounded theory constant comparative method., Methods and Procedures: Narratives of informal caregivers were collected through in-depth interviews with a psychologist. A three-step coding scheme was applied: coding of narratives to label the specific contents; organization of codes into sub-categories and categories; and theoretical coding to describe the relation between categories., Main Outcomes and Results: Twenty informal caregivers participated in one in-depth interview between December 2011 and May 2012. Four major themes emerged: Another person with past in common; Losing and finding myself; Old and new ways of being in relationship; and Dealing with concerns. These themes represent caregivers' efforts to deal with the situation in which their relative is at the same time present and absent. The core salient feature emerging from all these themes is the experience of ambiguous loss., Conclusions: Features of ambiguous loss that emerged in this study could guide clinicians' interventions to support adjustment of caregivers of patients with DOCs.

Introduction: Neurological conditions are associated with high levels of disability., Objectives: The aim of this study was to describe, using the International Classification of Functioning, Disability and Health (ICF), the most relevant aspects of disability in patients with neurological conditions. We collated data from previous studies on myasthenia gravis, migraine, Parkinson's disease, multiple sclerosis, traumatic brain injury, stroke, epilepsy, vegetative state and minimally conscious state, and identified as relevant those ICF categories reported by at least 50% of patients in each condition., Conclusions: Records from 1310 patients were available. A total of 97 ICF categories were reported, and 21 were commonly addressed in more than five conditions. Approximately half of the categories in body functions were related to mental and movement-related functions and more than 25% of the activities-related categories involved activities that require the support from a caregiver. Environmental factors were mostly reported as facilitators. Our data indicate a residual mind-body dichotomy, the relevance of disability not only for the patients but also for their caregivers, and the difficulties in addressing barriers in the environment.

Introduction: The aim of this study was to explore the most relevant determinants of severe disability in a heterogeneous sample of patients with neurological conditions., Objectives: We used data from previous studies on patients with myasthenia gravis (MG), migraine, Parkinson's disease (PD), multiple sclerosis, traumatic brain injury (TBI), stroke and epilepsy (349 patients, aged 18-74 years; mean 48.0, SD 11.7). We calculated count-based extension indexes to address severe disability, and hierarchical logistic regression to assess the association between severe disability, sociodemographic and health status information., Conclusions: Results show that sociodemographic variables played a minor role, while health state information was a stronger determinant of severe disability. Compared to the reference value of TBI patients, those with MG, PD and epilepsy had higher odds to have severe difficulties undertaking daily activities despite the presence of environmental factors. Our results contrast with those of previous studies, mostly derived from general populations, showing the different impact of clinical and sociodemographic variables.

Differential diagnosis between Vegetative State and Minimally Conscious State is a challenging task that requires specific assessment scales, involvement of expert neuropsychologists or physicians and use of tailored stimuli for eliciting behavioural responses. Although misdiagnosis rate as high as 40% has been reported, no clear guidelines are available in literature on the optimal setting for assessment. The present study aims to analyse score differences in behavioural assessments of persons with disorders of consciousness (DOC) with or without family members and to determine whether the presence of caregivers could improve clinical accuracy in diagnostic evaluation. The research was conducted on 92 adults with DOC among 153 consecutive patients enrolled in the Coma Research Centre of the Neurological Institute C. Besta of Milan between January 2011 and May 2013. The results indicate that in almost half of the sample the scoring, thus the performance, observed with caregivers was better than without them. Furthermore, in 16% of the sample, when assessment was performed with caregivers there was a change in diagnosis, from Vegetative to Minimally Conscious State or from that to Severe Disability. Finally, statistical differences were found in relation to diagnosis between mean scores in the "visual function" Coma Recovery Scale revised's subscale obtained by raters plus caregiver and rates only assessment. This study demonstrates how the presence of caregivers can positively affect behavioural assessments of persons with DOC, thus contributing to the definition of the optimal setting for behavioural evaluation of patients, to decrease misdiagnosis rates.