Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies.

Spinal muscular atrophy (SMA) linked to 5q is a recessive motor neuron disease characterized by progressive and diffuse weakness and muscular atrophy. SMA is the most common neurodegenerative disease in childhood with an incidence of approximately 1 in 6000-10,000 live births, being long considered a leading cause of hereditary mortality in infancy, worldwide. The classification of SMA is based on the natural history of the disease, with a wide clinical spectrum of onset and severity. We are currently in a new therapeutic era, that, thanks to the widespread use of the newly approved disease-modifying therapies and the possibility of an early administration, should lead to a deep change in the clinical scenario and, thus, in the history of SMA. With the aim to achieve a new view of SMA, in this review we consider different aspects of this neuromuscular disease: the historical perspective, the clinical features, the diagnostic process, the psychological outcome, innovation in treatments and therapies, the possibility of an early identification of affected infants in the pre-symptomatic phase through newborn screening programs.

Differential sensing with arrays of de novo designed peptide assemblies.

Differential sensing attempts to mimic the mammalian senses of smell and taste to identify analytes and complex mixtures. In place of hundreds of complex, membrane-bound G-protein coupled receptors, differential sensors employ arrays of small molecules. Here we show that arrays of computationally designed de novo peptides provide alternative synthetic receptors for differential sensing. We use self-assembling α-helical barrels (αHBs) with central channels that can be altered predictably to vary their sizes, shapes and chemistries. The channels accommodate environment-sensitive dyes that fluoresce upon binding. Challenging arrays of dye-loaded barrels with analytes causes differential fluorophore displacement. The resulting fluorimetric fingerprints are used to train machine-learning models that relate the patterns to the analytes. We show that this system discriminates between a range of biomolecules, drink, and diagnostically relevant biological samples. As αHBs are robust and chemically diverse, the system has potential to sense many analytes in various settings.

Needle Insertion Difficulty Algorithm (NIDA): A novel pilot study to predict Huber needle insertion difficulty in totally implanted devices.

Safeguarding of venous assets in cancer patients provides for positioning vascular devices. In totally implanted central venous access devices, hereinafter referred as TIVADs, it's necessary introducing Huber needle, into subcutaneous port, to use it. This procedure is not easy for all implanted devices. The procedural difficulty is to be attributed both to the type of the implanted port and to the skill of the clinician. The degree of patient satisfaction is variable and related with the clinician performing the maneuver. It follows a professional dissatisfaction of the clinician and a hesitation of the patient. Moreover, the incorrect positioning of the Huber needle into the port, could lead to the infusion of antiblastic drugs into the subcutaneous tissue with the consequent tissue damage due to extravasation of the drugs. Evaluation of different characteristics of TIVADs, allowed grouping them, in different types, setting up the S.P.I.A. method (Subcutaneous Port Investigator Assessment). Collected data from medical records concerning: primary pathology, port's permanence and using, Huber needle insertion failed events, if a vascular access expert/specialist clinician has been called, weight gain or loss were recruited. These data made it possible to determine the types of implanted ports that were most difficult to insert the Huber needle, creating the N.I.D.A. (Needle Inserting Difficulty Algorithm) as a prognostic index of Huber needle inserting into the port. In particular, the type of implanted port, that is, if it was a brachial or thoracic implant (p < 0.001), the SPIA type, if type 1, 2, or 3 (p < 0.001) and the experience of the clinician (p < 0.001) were considered as predictors of a successful first attempt and then can perform the NIDA. The relevant aspects in the success of the procedure are therefore the type of port (thoracic or brachial), the SPIA type, and the experience of the clinician in the successful insertion of the Huber needle into the port at the first attempt.

Mothers' and Children's Mental Health During the COVID-19 Pandemic Lockdown: The Mediating Role of Parenting Stress.

The present study, carried out during the first peak of the COVID-19 outbreak in Italy, aimed at investigating the mental health of mothers and children during the nationwide lockdown. More specifically, the study investigated children's depression and mothers' individual distress and parenting stress, in comparison with normative samples. The mediating effect of mothers' parenting stress on the relationship between mothers' individual distress and children's depression was also explored. Finally, the study analyzed whether children's biological sex and age moderated the structural paths of the proposed model. A sample of 206 Italian mothers and their children completed an online survey. Mothers were administered self-report questionnaires investigating individual distress and parenting stress; children completed a standardized measure of depression. Mothers' individual distress and parenting stress and children's depression were higher than those recorded for the normative samples. Mothers' parenting stress was found to mediate the association between mothers' individual distress and children's depression. With respect to children, neither biological sex nor age emerged as significant moderators of this association, highlighting that the proposed model was robust and invariant. During the current and future pandemics, public health services should support parents-and particularly mothers-in reducing individual distress and parenting stress, as these are associated with children's depression.

Successful synthesis of a glial-specific blood-brain barrier shuttle peptide following a fragment condensation approach on a solid-phase resin.

Successful manual synthesis of the TD2.2 peptide acting as a blood-brain barrier shuttle was achieved. TD2.2 was successfully synthesised by sequential condensation of four protected peptide fragments on solid-phase settings, after several unsuccessful attempts using the stepwise approach. These fragments were chosen to minimise the number of demanding amino acids (in terms of coupling, Fmoc removal) in each fragment that are expected to hamper the overall synthetic process. Thus, the hydrophobic amino acids as well as Arg(Pbf) were strategically spread over multiple fragments rather than having them congested in one fragment. This study shows how a peptide that shows big challenges in the synthesis using the common stepwise elongation methodology can be synthesised with an acceptable purity. It also emphasises that choosing the right fragment with certain amino acid constituents is key for a successful synthesis. It is worth highlighting that lower amounts of reagents were required to synthesise the final peptide with an identical purity to that obtained by the automatic synthesiser.

Strategies for Improving Peptide Stability and Delivery.

Peptides play an important role in many fields, including immunology, medical diagnostics, and drug discovery, due to their high specificity and positive safety profile. However, for their delivery as active pharmaceutical ingredients, delivery vectors, or diagnostic imaging molecules, they suffer from two serious shortcomings: their poor metabolic stability and short half-life. Major research efforts are being invested to tackle those drawbacks, where structural modifications and novel delivery tactics have been developed to boost their ability to reach their targets as fully functional species. The benefit of selected technologies for enhancing the resistance of peptides against enzymatic degradation pathways and maximizing their therapeutic impact are also reviewed. Special note of cell-penetrating peptides as delivery vectors, as well as stapled modified peptides, which have demonstrated superior stability from their parent peptides, are reported.

Pemigatinib in Intrahepatic Cholangiocarcinoma: A Work in Progress.

Cholangiocarcinoma (CCA) is the second most frequent primary liver cancer, following hepatocellular carcinoma (HCC). Progress in the molecular understanding of CCA has led to the development of several agents, including FGFR inhibitors, such as pemigatinib, whose approval has marked a new era in this hepatobiliary malignancy. However, a number of questions remain unanswered, including the development of secondary resistance and the role of combination therapies, including FGFR inhibitors. Herein, we specifically focus on the current challenges and future research directions of pemigatinib use in CCA patients.

BRCA1/2 pathogenetic variant carriers and reproductive decisions: Gender differences and factors associated with the choice of preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND).

PURPOSE: To investigate the way carriers of a BRCA1/2 pathogenetic variant make their reproductive decisions and to examine the factors associated with the choice of preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND). METHODS: We conducted a comprehensive literature search in PubMed, Scopus, and Web of Science in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. RESULTS: A total of 16 articles published from 2000 to 2021 were included in this review. Data were overall collected from 3564 participants (86% females). Three important themes were identified across studies: changes in family planning, factors associated with family plans, and with acceptance or regret of PGD and PND. CONCLUSION: This review may contribute to the knowledge of the experience of those who have a BRCA1/2 mutation and want a child. These results may help genetic counselors and healthcare professionals that support people with a BRCA pathogenetic variant with reproductive issues.

COVID-19 and home confinement: A study on fathers, father-child relationships and child adjustment.

BACKGROUND: The purpose of this study was to explore fathers' adjustment and father-child relationships during the first peak of the coronavirus disease 2019 (COVID-19) outbreak (April 2020). More particularly, the study analysed paternal perceptions of changes concerning familial economic conditions and children's psychological difficulties (viz., emotional problems and hyperactivity) during the lockdown produced by the current pandemic. Furthermore, we investigated the following correlates of fathers' parenting stress: socio-demographic condition, paternal individual stress, anxiety, depression and changes in the father-child relationship during the outbreak. METHODS: A total of 102 fathers (mean age = 41.60 years; SD = 11.54) with minor children were recruited through an online survey and reported data about their socio-economic condition, anxiety, and depressive levels, parenting stress, offspring's adjustment, and changes in their relationship with their children. RESULTS: As for the economic conditions, participants were equally distributed between those who did not perceive changes and those who perceived a worsening. With regard to changes in the child's psychological difficulties, results showed that levels of children's emotional problems and inattention/hyperactivity had significantly increased during the lockdown period. A multiple linear regression analysis highlighted that the principal predictor of paternal parenting stress was living in the regions most affected by the COVID-19 pandemic, followed by high levels of paternal anxiety symptomatology and high levels of worsening of the relationship with the child during the pandemic. CONCLUSIONS: Overall, our study suggests to consider the effects of COVID-19 on fathers as well, as they have been rather overlooked by previous research that has mainly focused on mothers, and to plan specific interventions able to also take them into account.

Immune-based combinations for metastatic triple negative breast cancer in clinical trials: current knowledge and therapeutic prospects.

INTRODUCTION: Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated. AREAS COVERED: The authors present a synopsis of current, state-of-art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed. EXPERT OPINION: Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.

Ampullary Carcinoma: An Overview of a Rare Entity and Discussion of Current and Future Therapeutic Challenges.

Ampullary carcinomas (ACs) represent a rare entity, accounting for approximately 0.2% of all gastrointestinal solid tumors and 20% of all periampullary cancers (PACs). Unfortunately, few data are available regarding the optimal therapeutic strategy for ACs due to their rarity, and physicians frequently encounter significant difficulties in the management of these malignancies. In this review, we will provide an overview of current evidence on AC, especially focusing on biological features, histological characteristics, and available data guiding present and future therapeutic strategies for these rare, and still barely known, tumors.

COVID-19 and chronic disease patients: Perceived stress, worry, and emotional regulation strategies.

OBJECTIVE: The current study aimed at investigating the perceived impact of the COVID-19 pandemic on Italian individuals with a preexisting medical condition. Specifically, the study analyzed: (a) if different conditions were associated with different levels of distress, different levels of worry, and different emotion regulation strategies (i.e., cognitive reappraisal, expressive suppression); and (b) if distress levels were associated with levels of worry about COVID-19, emotion regulation strategies, and changes to medical treatment due to the pandemic. METHOD: This cross-sectional study involved 124 individuals (79.8% female; mean age = 48.88 years; SD = 14.95) with a diagnosis of chronic disease. The questionnaires, administered during the peak of the first wave of the COVID-19 pandemic in Italy (April-May 2020), comprised the Perceived Stress Scale, the Emotion Regulation Questionnaire, a COVID-19 worry questionnaire, and a questionnaire designed to collect anamnestic and sociodemographic data. RESULTS: Higher levels of expressive suppression and worries related to COVID-19, and changes to medical treatment due to the pandemic, were associated with higher perceived stress in patients with a preexisting chronic disease. No differences emerged in the study variables according to the type of chronic disease. CONCLUSIONS: The results highlight the importance of considering expressive suppression, levels of worry about COVID-19, and changes to scheduled medical treatment. Screening procedures based on these factors may be useful for identifying individuals with a preexisting medical condition at higher risk of distress, in order to offer them specific and remotely delivered psychological support. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Uncertainty following an inconclusive result from the BRCA1/2 genetic test: A review about psychological outcomes.

BACKGROUND: An inconclusive result from BRCA1/2 genetic testing indicates that a genetic variant of uncertain significance is detected. This case constitutes the majority of genetic test results, but studies specifically addressing the psychological adjustment of people with inconclusive results are scarce. AIM: To examine psychological outcomes of receiving an uninformative BRCA1/2 test result. METHODS: PubMed, PsychInfo, and Cochrane Central Register of Controlled Trials were screened for studies focusing on distress, anxiety, and depression levels in individuals with inconclusive genetic test results. This review is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method. RESULTS: Studies on psychological outcomes of inconclusive BRCA1/2 focused on general and specific distress, anxiety, and depression. Overall, they produced mixed results. These inconsistent findings are probably due to the uncertainty caused by this type of result, that may also influence the decisions of individuals about surveillance and prophylactic options, reducing their compliance. In addition, this review highlights specific risk and protective factors that affect psychological adjustment in individuals with an inconclusive genetic testing result. CONCLUSION: Individuals with inconclusive genetic test results need specific educational programs and support to better understand the meaning of their results in order to be able to make decisions about surveillance and prophylactic options.

Metaplastic breast cancer: an old histotype but a current therapeutic problem.

Metaplastic breast cancer (MPBC) is a rare and aggressive tumor type in great need of satisfactory therapies. Although most cases of MPBC are 'triple negative', they are nonetheless related to worse outcomes compared with other triple-negative invasive tumors. MPBC presents high levels of genetic and molecular heterogeneity, suggesting that novel targeted therapies can be exploited. Overexpression of PD-L1 and high levels of tumor-infiltrating lymphocytes have also been observed in these tumors, suggesting a role for immunotherapy. We present an updated literature revision on clinical, histopathological and molecular features of MPBC and their significance to prognosis and therapy options. We discuss emerging efforts to improve and personalize prognostic and therapeutic approaches, exploiting the molecular signature of MPBC with targeted therapies and immunotherapies.

Covalently interconnected transition metal dichalcogenide networks via defect engineering for high-performance electronic devices.

Solution-processed semiconducting transition metal dichalcogenides are at the centre of an ever-increasing research effort in printed (opto)electronics. However, device performance is limited by structural defects resulting from the exfoliation process and poor inter-flake electronic connectivity. Here, we report a new molecular strategy to boost the electrical performance of transition metal dichalcogenide-based devices via the use of dithiolated conjugated molecules, to simultaneously heal sulfur vacancies in solution-processed transition metal disulfides and covalently bridge adjacent flakes, thereby promoting percolation pathways for the charge transport. We achieve a reproducible increase by one order of magnitude in field-effect mobility (µFE), current ratio (ION/IOFF) and switching time (τS) for liquid-gated transistors, reaching 10-2 cm2 V-1 s-1, 104 and 18 ms, respectively. Our functionalization strategy is a universal route to simultaneously enhance the electronic connectivity in transition metal disulfide networks and tailor on demand their physicochemical properties according to the envisioned applications.

Psychological Adjustment of Healthcare Workers in Italy during the COVID-19 Pandemic: Differences in Stress, Anxiety, Depression, Burnout, Secondary Trauma, and Compassion Satisfaction between Frontline and Non-Frontline Professionals.

Emergency situations have been associated with negative psychological adjustment outcomes in healthcare professionals, although studies on the impact of the Coronavirus Disease 2019 (COVID-19) pandemic amongst Italian health workers are limited. The main aim of this study was to investigate the psychological adjustment of healthcare professionals during the peak of the COVID-19 pandemic, evaluating differences according to working or not with patients affected by COVID-19 and in areas with a more severe spread of this pandemic. Healthcare professionals' attitudes toward psychological support were analyzed. The levels of anxiety, depression, psychological stress, and professional quality of life (compassion satisfaction, burnout, and compassion fatigue) and attitudes toward psychological support were measured among 627 Italian healthcare workers (mean age = 40.55 years; SD = 11.49; range: 27-72). Significantly higher levels of stress, burnout, secondary trauma, anxiety, and depression were observed among professionals working with COVID-19 patients. Higher levels of stress and burnout and lower levels of compassion satisfaction were detected in professionals working in areas with higher rates of contagion. No interaction effects were found between working (or not) with patients affected by COVID-19 and working (or not) in areas with a more severe diffusion of this pandemic. Finally, in the group of professionals who worked with COVID-19 patients, the percentage of professionals who thought to ask for psychological support was twice that of the group that did not work with COVID-19 patients. The overall findings indicate that the mental health of frontline healthcare workers requires further consideration and that targeted prevention and intervention programs are necessary.

Psychological effects of the COVID-2019 pandemic: Perceived stress and coping strategies among healthcare professionals.

Starting from China, the coronavirus disease (COVID-19) contagion spread unexpectedly and quickly all over the world, particularly affecting Italy. In the early stages of the epidemic, healthcare professionals have been in the front-line to manage the infection. The current study aimed to analyse the impact of COVID-19 outbreak on healthcare professionals and to detect some risk and protective factors of their distress levels, with regard to socio-demographic variables, direct exposure to COVID-19 and the coping strategies used to deal with stress. The data were collected during the peak of the infection. A total of 595 healthcare professionals enrolled in the study and completed the measures of socio-demographical and professional data, perceived stress (PSS) and coping strategies (COPE- NVI-25). Overall, we found that a positive attitude towards the stressful situation was the main protective factor, while female gender, seeking social support, avoidance strategies and working with COVID-19 patients were risk factors. Economic status, problem solving ability and turning to religion were not associated with stress levels. This study, one of the first on this topic, highlighted the main coping strategies used by healthcare professionals in facing the highly stressful situation caused by the pandemic.

The world of cell penetrating: the future of medical applications.

Cell-penetrating peptides present huge biomedical applications in a variety of pathologies, thanks to their ability to penetrate membranes and carry a variety of cargoes inside cells. Progress in peptide synthesis has produced a greater availability of virtually any synthetic peptide, increasing their attractiveness. Most molecules when associated to a cell-penetrating peptides can be delivered into a cell, however, understanding of the critical factors influencing the uptake mechanism is of paramount importance to construct nanoplatforms for effective delivery in vitro and in vivo in medical applications. Focus is now on the state-of-art of the mechanisms enabling therapeutics/diagnostics to reach the site target of their activities, and in support of scientists developing platforms for drug delivery and personalized therapies.

A boost to the antiviral activity: Cholesterol tagged peptides derived from glycoprotein B of Herpes Simplex virus type I.

Conformational changes of viral glycoproteins govern the fusion of viral and cellular membranes in the entry of enveloped viruses. Peptides mimicking domains of viral glycoproteins are apt to interfere with the fusion event, likely hampering the conformational rearrangements from the pre- to the post-fusion structures. We previously developed a peptide sequence with a high potential to inhibit the entry of herpes simplex type 1, which was able to trap glycoprotein B at an intermediate stage, arresting fusion. We propose that similarly to other viruses, membrane targeting through cholesterol conjugation may potently block fusion. The peptide conjugated to polyethylenglycol and cholesterol interacts with viral and cell membranes thanks to the presence of cholesterol and blocks the conformational rearrangements of the glycoprotein B. Here, we also probed the effect of the linker (polyethylenglycol) length on the activity. By targeting the peptide gBh1m to the membranes where fusion occurs and by engineering sequences with increased binding affinity for gB we have enhanced the antiviral potency of our prototype inhibitors. Our results provide proof of concept for the application of cholesterol tagging to develop inhibitors of HSV-1.

Eradication of Candida albicans persister cell biofilm by the membranotropic peptide gH625.

Biofilm formation poses an important clinical trouble due to resistance to antimicrobial agents; therefore, there is an urgent demand for new antibiofilm strategies that focus on the use of alternative compounds also in combination with conventional drugs. Drug-tolerant persisters are present in Candida albicans biofilms and are detected following treatment with high doses of amphotericin B. In this study, persisters were found in biofilms treated with amphotericin B of two clinical isolate strains, and were capable to form a new biofilm in situ. We investigated the possibility of eradicating persister-derived biofilms from these two Candida albicans strains, using the peptide gH625 analogue (gH625-M). Confocal microscopy studies allowed us to characterize the persister-derived biofilm and understand the mechanism of interaction of gH625-M with the biofilm. These findings confirm that persisters may be responsible for Candida biofilm survival, and prove that gH625-M was very effective in eradicating persister-derived biofilms both alone and in combination with conventional antifungals, mainly strengthening the antibiofilm activity of fluconazole and 5-flucytosine. Our strategy advances our insights into the development of effective antibiofilm therapeutic approaches.