Search

New training approaches have emerged advocating for the implementation of compensatory physical training. This approach aims to provide additional training that balances the load typically experienced by non-starters during a match. This may help maintain their readiness and ensures that their physical fitness is not compromised by the reduced exposure to match loads. Thus, this narrative review aims to describe the differences in external loads between starting and non-starting players and describe the studies conducted in compensatory training. Studies examining external load metrics such as total distances covered, high-speed running, and sprinting suggest that, adjusted for playing time, values are often higher in non-starting players. Although not standardized, there is an obvious decrease in exposure for these critical variables in non-starters. Additionally, internal load parameters such as perceived exertion and heart rate tend to be higher in starting players. Regarding the physical fitness impacts, evidence suggests differences observed between starters and non-starters in some aspects of physical performance, although the extent and significance of these differences can vary. The studies on compensatory training are limited, and the typical approach usually centres on running-based exercises and small-sided games, offering differing approaches to address the physical needs. The gap in research underscores the necessity for improved study designs that can shed light on the real impact of compensatory training. Presently, the practice of compensatory training has been adopted, yet a definitive understanding of its genuine influence, particularly in terms of enhancing physical fitness and mitigating injury risks, remains elusive., Competing Interests: The authors declare no conflict of interest., (Copyright © Institute of Sport – National Research Instutite.)

Background: An equal distribution of hospital structures represents an important factor to achieve Universal Health Coverage. Generally, the most diffused approach to measure the potential availability to healthcare is the provider-to-population ratio based on the number of beds or professionals. However, this approach considers only the availability of resources provided at regional or local level ignoring the spatial accessibility of interregional facilities that are particularly accessed by patients living at the borders. Aim of this study is to outline the distribution of the intra and interregional services in Italy to capture the level of equity across the country. Moreover, it explores the impact of the accessibility to these resources on interregional patient's mobility to receive care., Methods: To compute spatial accessibility, we propose an alternative approach that applies the enhanced two-step floating catchment area (ESFCA) to capture the level of attraction of intra and interregional hospitals to a given population. Moreover, the adoption of process and outcome indices captured to what extent the quality of structures influenced patients in choosing services located inside or outside their region of residence., Results: The study confirms that there is an unequal distribution of high-quality resources at regional and national level with a high level of inequality in the availability and accessibility of quality resources between the north and south part of Italy. This is particularly true considering the accessibility of intraregional resources in the southern part of the country that clearly influences patient choice and contribute to a significant cross border passive mobility to northern regions. This is confirmed by an econometric model that showed a significant effect of spatial accessibility with the propensity of patients of travel from the region of residence to receive care., Conclusions: The analysis of intra and interregional components of spatial accessibility may contribute to identify to what extent patients are willing to travel outside their region of residence to access to care services. Moreover, it can contribute to gain a deeper understanding of the allocation of health resources providing input for policy makers on the basis of the principles of service accessibility in order to contain patient mobility., (© 2024. The Author(s).)

SQM-ISS is a detector that will search from the International Space Station for massive particles possibly present among the cosmic rays. Among them, we mention strange quark matter, Q-Balls, lumps of fermionic exotic compact stars, Primordial Black Holes, mirror matter, Fermi balls, etc. These compact, dense objects would be much heavier than normal nuclei, have velocities of galaxy-bound systems, and would be deeply penetrating. The detector is based on a stack of scintillator and piezoelectric elements which can provide information on both the charge state and mass, with the additional timing information allowing to determine the speed of the particle, searching for particles with velocities of the order of galactic rotation speed (v ≲ 250 km/s). In this work, we describe the apparatus and its observational capabilities.

A remarkable enhancer of human glucocerebrosidase enzyme (GCase) was identified among a set of dihydroazulene-tagged iminosugars. An unprecedented 3.9-fold increase in GCase activity was detected on fibroblasts bearing the homozygous L444P mutation, which is frequently associated with neuronopathic Gaucher forms, and which commonly results refractory to chaperone-induced refolding., (© 2024 The Author(s). Chemistry & Biodiversity published by Wiley-VHCA AG.)

Not available.

Background: This study aimed to investigate the effects of different volumes of aerobic training (AT) and resistance training (RT) during a concurrent exercise training program on selected indicators of physical fitness and pulmonary function in women with spinal cord injury (SCI)., Methods: Twenty-three inactive females with complete or incomplete SCI from T6 to L5 were divided into three groups: concurrent training with a focus on AT (CTAT; two weekly sessions of AT and one of RT), concurrent training with a focus on RT (CTRT; two weekly sessions of RT and one of AT), and control (CON). Tests were performed before and after an 8-week experimental period for indicators of pulmonary function, aerobic power, endurance performance, muscular strength and endurance, speed, and change of direction., Results: Markers of both aerobic and muscular fitness increased in the CTAT and CTRT groups, but not in CON. There were significant differences in aerobic power and endurance performance between the CTAT and CTRT groups, with greater changes in CTAT. Both CTAT and CTRT improved respiratory functions, with no differences between them (p > 0.05)., Conclusions: CTAT and CTRT improved most of the indicators of physical fitness. However, CTAT should be used to achieve higher aerobic power and endurance without compromising muscle strength., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Paulo Gentil is an Assistant Editor for Heliyon If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Despite advances in wearable robots across various fields, there is no consensus definition or design framework for the application of this technology in rehabilitation or musculoskeletal (MSK) injury prevention. This paper aims to define wearable robots and explore their applications and challenges for military rehabilitation and force protection for MSK injury prevention. We conducted a modified Delphi method, including a steering group and 14 panelists with 10+ years of expertise in wearable robots. Panelists presented current wearable robots currently in use or in development for rehabilitation or assistance use in the military workforce and healthcare. The steering group and panelists met to obtain a consensus on the wearable robot definition applicable for rehabilitation or primary injury prevention. Panelists unanimously agreed that wearable robots can be grouped into three main applications, as follows: (1) primary and secondary MSK injury prevention, (2) enhancement of military activities and tasks, and (3) rehabilitation and reintegration. Each application was presented within the context of its target population and state-of-the-art technology currently in use or under development. Capturing expert opinions, this study defines wearable robots for military rehabilitation and MSK injury prevention, identifies health outcomes and assessment tools, and outlines design requirements for future advancements., Competing Interests: Conflicts of Interest: The opinions and assertions expressed herein are those of the author(s) and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences, the Department of Defense, the views of the Department of Veterans Affairs, or the United States Government. Nicola Vitiello has commercial interests in IUVO S.r.l., a spin-off company of Scuola Superiore Sant’Anna; IUVO is the exclusive licensee of the APO technology. The rest of the authors claim no conflicts of interest. Neither the authors, except for Nicola Vitiello, nor their family members have a financial interest in any commercial product, service, or organization providing financial support for this research.

The objectives of the study were to examine the incident rate (IR), characteristics, and mechanisms of muscle injuries of 121 men amateur soccer players that voluntarily participated in this project. Sixty-five muscle injuries with an overall IR of 3.62/1000 h, 95% CI 2.7-4.5, were reported. The most frequently injured muscle groups were the hamstrings (IR 1.78/1000 h, 95% CI 1.1-2.3), followed by the adductors (IR 1.5/1000 h, 95% CI 0.93-2.06). Most muscle injuries were characterized as mild (IR 2.3/1000 h, 95% CI 1.53-2.92) or minimal (IR 1.28/1000 h, 95% CI 1.16-2.39. Higher incidence of injury sustained during matches (IR 14.09 injuries/1000 h, 95% CI 9.49-18.7), than in training (IR 1.88 injuries/1000 h, 95% CI 1.19-2.56). The most frequent injury mechanisms were high-speed running (84.4%) and change of direction (44.4%), for hamstring and adductors-related groin injuries, respectively. Players aged over 24 years had a 7-fold increased risk to sustain a hamstring injury but a lower risk to sustain an adductor-related groin injury. Injury prevention and rehabilitation management strategies may reduce muscle injury rates in amateur soccer.

This study aimed to investigate an acute effect of foam rolling and tissue flossing of the Triceps Surae muscle on Achilles tendon stiffness, jump height and sprint performance at different time points. The participants were academic athletes (n = 32) aged between 22 and 24 years; randomly allocated into two groups: foam rolling (ROLL) and tissue flossing (FLOSS). The participants were tested at baseline and 5-min, 15-min, 30-min, 45-min, and 60-min after ROLL and FLOSS for Achilles tendon stiffness (AT stiffeness ) at three reference locations: (1) tendon's origin, (2) ankle joint height and (3) intermuscular septum of the gastronomies muscle; countermovement jump (CMJ); and sprint performance at 15-m (SPRINT 15 m ). The analysis of stiffness revealed a significant decrease in AT stiffness from baseline to Post-60 (p ≤ 0.001) for three locations in the FLOSS group (p ≤ 0.001). In FLOSS, a significant increase was observed from Post-15 to Post-60 (all p≤0.001) in CMJ. We found also a significant decrease in SPRINT 15 m in FLOSS in all-time points (p ≤ 0.001), however, SPRINT 15 m decreased in Post-5 min, Post-15 min, and Post-30 min (p ≤ 0.001 for all) in ROLL. The current study suggested that both groups enhanced performance up to 60 min after the intervention, caused by mitigating excessive stiffness.

Multiple vaccines have been approved to control COVID-19 pandemic, with Pfizer/BioNTech (BNT162b2) being widely used. We conducted a longitudinal analysis of the immune response elicited after three doses of the BNT162b2 vaccine in individuals who have previously experienced SARS-CoV-2 infection and in unexperienced ones. We conducted immunological analyses and single-cell transcriptomics of circulating T and B lymphocytes, combined to CITE-seq or LIBRA-seq, and VDJ-seq. We found that antibody levels against SARS-CoV-2 Spike, NTD and RBD from wild-type, delta and omicron VoCs show comparable dynamics in both vaccination groups, with a peak after the second dose, a decline after six months and a restoration after the booster dose. The antibody neutralization activity was maintained, with lower titers against the omicron variant. Spike-specific memory B cell response was sustained over the vaccination schedule. Clonal analysis revealed that Spike-specific B cells were polyclonal, with a partial clone conservation from natural infection to vaccination. Spike-specific T cell responses were oriented towards effector and effector memory phenotypes, with similar trends in unexperienced and experienced individuals. The CD8 T cell compartment showed a higher clonal expansion and persistence than CD4 T cells. The first two vaccinations doses tended to induce new clones rather than promoting expansion of pre-existing clones. However, we identified a fraction of Spike-specific CD8 T cell clones persisting from natural infection that were boosted by vaccination and clones specifically induced by vaccination. Collectively, our observations revealed a moderate effect of the second dose in enhancing the immune responses elicited after the first vaccination. Differently, we found that a third dose was necessary to restore comparable levels of neutralizing antibodies and Spike-specific T and B cell responses in individuals who experienced a natural SARS-CoV-2 infection., Competing Interests: Declaration of competing interest Author Renata Grifantini is currently employed by CheckmAb Srl. The remaining 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 © 2024. Published by Elsevier Inc.)

Human CD4 + EOMES + T cells are heterogeneous and contain Th1-cells, Tr1-cells, and CD4 + CTL. Tr1- cells and non-classical EOMES + Th1-cells displayed, respectively, anti- and pro-inflammatory cytokine profiles, but both expressed granzyme-K, produced IFN-γ, and suppressed T-cell proliferation. Diffusion map suggested a progressive CD4 + T-cell differentiation from naïve to cytotoxic cells and identified EOMES + Th1-cells as putative Tr1-cell precursors (pre-Tr1)., (© 2024 Wiley‐VCH GmbH.)

Electrical impedance spectroscopy (EIS) stands as a widely employed characterization technique for studying muscular tissue in both physio/pathological conditions. This methodology commonly involves modeling tissues through equivalent electrical circuits, facilitating a correlation between electrical parameters and physiological properties. Within existing literature, diverse equivalent electrical circuits have been proposed, varying in complexity and fitting properties. However, to date, none have definitively proven to be the most suiTable for tissue impedance measurements. This study aims to outline a systematic methodology for EIS measurements and to compare the performances of three widely used electrical circuits in characterizing both physiological and pathological muscle tissue conditions. Results highlight that, for optimal fitting with electrical parameters relevant to tissue characterization, the choice of the circuit to be fitted closely hinges on the specific measurement objectives, including measurement parameters and associated physiological features. Naturally, this necessitates a balance between simplicity and fitting accuracy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Castleman disease (CD) is a group of lymphoproliferative disorders that share common histopathological features yet have widely different aetiologies, clinical features and grades of severity as well as treatments and outcomes. Siltuximab is currently the only therapy approved by the FDA and EMA for idiopathic multicentric CD and is recommended as first-line therapy in treatment guidelines. Despite the extensive characterization of siltuximab treatment in clinical trials, available evidence from real-world practice is still scant. This collection of clinical experiences focuses on patients treated with siltuximab therapy, particularly regarding the idiopathic multicentric CD diagnostic work-up, and on treatment administration in patients with complex disease entering differential diagnosis with CD or concomitant diseases. Thus, these data help further characterize and improve the use of siltuximab in real practice in terms of effectiveness and safety of long-term administration as well as consequences of treatment interruption., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2024/02/dic.2023-9-4-COI.pdf, (Copyright © 2024 Rossini B, Cecchi N, Clemente F, De Paolis MR, Hohaus S, Innao V, Lucignano M, Massaiu R, Palumbo G, Rigolin GM, Rossi FG, Verga L, Guarini A.)

Gaucher disease (GD) is a rare genetic metabolic disorder characterized by a dysfunction of the lysosomal glycoside hydrolase glucocerebrosidase (GCase) due to mutations in the gene GBA1, leading to the cellular accumulation of glucosylceramide (GlcCer). While most of the current research focuses on the primary accumulated material, lesser attention has been paid to secondary storage materials and their reciprocal intertwining. By using a novel approach based on flow cytometry and fluorescent labelling, we monitored changes in storage materials directly in fibroblasts derived from GD patients carrying N370S/RecNcil and homozygous L444P or R131C mutations with respect to wild type. In L444P and R131C fibroblasts, we detected not only the primary accumulation of GlcCer accumulation but also a considerable secondary increase in GM1 storage, comparable with the one observed in infantile patients affected by GM1 gangliosidosis. In addition, the ability of a trivalent trihydroxypiperidine iminosugar compound (CV82), which previously showed good pharmacological chaperone activity on GCase enzyme, to reduce the levels of storage materials in L444P and R131C fibroblasts was tested. Interestingly, treatment with different concentrations of CV82 led to a significant reduction in GM1 accumulation only in L444P fibroblasts, without significantly affecting GlcCer levels. The compound CV82 was selective against the GCase enzyme with respect to the β-Galactosidase enzyme, which was responsible for the catabolism of GM1 ganglioside. The reduction in GM1-ganglioside level cannot be therefore ascribed to a direct action of CV82 on β-Galactosidase enzyme, suggesting that GM1 decrease is rather related to other unknown mechanisms that follow the direct action of CV82 on GCase. In conclusion, this work indicates that the tracking of secondary storages can represent a key step for a better understanding of the pathways involved in the severity of GD, also underlying the importance of developing drugs able to reduce both primary and secondary storage-material accumulations in GD.

The regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism would be a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control would require RBC lifespan to be variable and tightly regulated. We suggest that EPO may control RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP-α expression in sinusoidal macrophages. EPO could also regulate the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms would continuously modulate the rate of RBC destruction depending on oxygen availability. The control of RBC lifespan by EPO and autoimmunity emerges as a key mechanism in the homeostasis of RBCs., (© 2024. The Author(s).)

Engineering bioactive iminosugars with pH-responsive groups is an emerging approach to develop pharmacological chaperones (PCs) able to improve lysosomal trafficking and enzymatic activity rescue of mutated enzymes. The use of inexpensive l-malic acid allowed introduction of orthoester units into the lipophilic chain of an enantiomerically pure iminosugar affording only two diastereoisomers contrary to previous related studies. The iminosugar was prepared stereoselectively from the chiral pool (d-mannose) and chosen as the lead bioactive compound, to develop novel candidates for restoring the lysosomal enzyme glucocerebrosidase (GCase) activity. The stability of orthoester-appended iminosugars was studied by 1 H NMR spectroscopy both in neutral and acidic environments, and the loss of inhibitory activity with time in acid medium was demonstrated on cell lysates. Moreover, the ability to rescue GCase activity in the lysosomes as the result of a chaperoning effect was explored. A remarkable pharmacological chaperone activity was measured in fibroblasts hosting the homozygous L444P/L444P mutation, a cell line resistant to most PCs, besides the more commonly responding N370S mutation., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Background: The role of hormonal replacement therapy in menopause is under debate. The premature closure of the Women's Health Initiative (WHI) study in 2002 is still a source of concern among treating physicians., Objectives: The interest in alternatives to conventional hormone therapy has significantly increased. The adoption of personalized steroid hormone galenic preparations, formulated by compounding pharmacies, has recently spread., Methods: In June 2023, an extensive literature search was conducted by different authors to identify relevant studies in various databases (MEDLINE, Embase, PubMed, and Cochrane). The studies that met the inclusion and exclusion criteria were further analyzed, and relevant data were extracted and analyzed for each paper. Any discrepancies between the investigators were resolved through a consensus approach., Outcomes: The primary outcomes observed included the clinical utility of CBHT. This study reviewed the current evidence on the utility of compounded bioidentical hormones, concluding that improving knowledge and awareness of bioidentical hormones is necessary to consider their use in clinical practice., Conclusion and Outlook: These formulations might provide effective options to best tailor therapies to each patient., (© 2023 S. Karger AG, Basel.)

Introduction: The present scoping review focused on: i) which apps were previously studied; ii) what is the most common frequency for implementing cognitive training; and iii) what cognitive functions the interventions most focus on., Methods: PRISMA guidelines were followed, and the search was conducted on Web of Science, PsycInfo, Cochrane, and Pubmed. From 1733 studies found, 34 were included., Results: it was highlighted the necessity for forthcoming investigations to tackle the methodical restrictions and disparities in the domain., Discussion: great diversity in intervention protocols was found. Incorporating evaluations of physical fitness in conjunction with cognitive evaluations can offer a more all-encompassing comprehension of the impacts of combined interventions. Furthermore, exploring the efficacy of cognitive training applications requires additional scrutiny, considering individual variances and practical outcomes in real-life settings., Competing Interests: All authors declare that they have no conflicts of interest.

Purpose: To develop, implement and assess the results of psychoeducation to improve the QoL of parents with CHD newborns., Methods: Participants were parents of inpatient newborns with the diagnosis of non-syndromic CHD. We conducted a parallel RCT with an allocation ratio of 1:1 (intervention vs. control), considering the newborns, using mixed methods research. The intervention group received psychoeducation (Parental Psychoeducation in CHD [PPeCHD]) and the usual routines, and the control group received just the regular practices. The allocation concealment was assured. PI was involved in enrolling participants, developing and implementing the intervention, data collection and data analysis. We followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines., Results: Parents of eight newborns were allocated to the intervention group (n = 15 parents) and eight to the control group (n = 13 parents). It was performed as an intention-to-treat (ITT) analysis. In M2 (4 weeks), the intervention group presented better QoL levels in the physical, psychological, and environmental domains of World Health Organization Quality of Life instrument (WHOQOL-Bref). In M3 (16 weeks), scores in physical and psychological domains maintained a statistically significant difference between the groups., Conclusions: The PPeCHD, the psychoeducational intervention we developed, positively impacted parental QoL. These results support the initial hypothesis. This study is a fundamental milestone in this research field, adding new essential information to the literature., (© 2023 John Wiley & Sons Ltd.)

IFNγ-producing ex-Th17 cells ['Th1/17'] were shown to play a key pathogenic role in experimental colitis and are abundant in the intestine. Here, we identified and characterised a novel, potentially colitogenic subset of Th17 cells in the intestine of patients with Crohn's disease [CD]. Human Th17 cells expressing CCR5 ['pTh17'] co-expressed T-bet and RORC/γt and produced very high levels of IL-17, together with IFN-γ. They had a gene signature of Th17 effector cells and were distinct from established Th1/17 cells. pTh17 cells, but not Th1/17 cells, were associated with intestinal inflammation in CD, and decreased upon successful anti-TNF therapy with infliximab. Conventional CCR5[-]Th17 cells differentiated to pTh17 cells with IL-23 in vitro. Moreover, anti-IL-23 therapy with risankizumab strongly reduced pTh17 cells in the intestine. Importantly, intestinal pTh17 cells were selectively activated by adherent-invasive Escherichia coli [AIEC], but not by a commensal/probiotic E. coli strain. AIEC induced high levels of IL-23 and RANTES from dendritic cells [DC]. Intestinal CCR5+Th1/17 cells responded instead to cytomegalovirus and were reduced in ulcerative colitis [UC], suggesting an unexpected protective role. In conclusion, we identified an IL-23-inducible subset of human intestinal Th17 cells. pTh17 cells produced high levels of pro-inflammatory cytokines, were selectively associated with intestinal inflammation in CD, and responded to CD-associated AIEC, suggesting a key colitogenic role., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

N -Acetylgalactosamine-6-sulfatase (GALNS) is an enzyme whose deficiency is related to the lysosomal storage disease Morquio A. For the development of effective therapeutic approaches against this disease, the design of suitable enzyme enhancers ( i.e. pharmacological chaperones) is fundamental. The natural substrates of GALNS are the glycosaminoglycans keratan sulfate and chondroitin 6-sulfate, which mainly display repeating units of sulfated carbohydrates. With a biomimetic approach, gold nanoparticles (AuNPs) decorated with simple monosaccharides, sulfated ligands (homoligand AuNPs), or both monosaccharides and sulfated ligands (mixed-ligand AuNPs) were designed here as multivalent inhibitors of GALNS. Among the homoligand AuNPs, the most effective inhibitors of GALNS activity are the β-D-galactoside-coated AuNPs. In the case of mixed-ligand AuNPs, β-D-galactosides/sulfated ligands do not show better inhibition than the β-D-galactoside-coated AuNPs. However, a synergistic effect is observed for α-D-mannosides in a mixed-ligand coating with sulfated ligands that reduced IC 50 by one order of magnitude with respect to the homoligand α-D-mannoside-coated AuNPs. SAXS experiments corroborated the association of GALNS with β-D-galactoside AuNPs. These AuNPs are able to restore the enzyme activity by almost 2-fold after thermal denaturation, indicating a potential chaperoning activity towards GALNS. This information could be exploited for future development of nanomedicines for Morquio A. The recent implications of GALNS in cancer and neuropathic pain make these kinds of multivalent bionanomaterials of great interest towards multiple therapies.

Specific physical qualities such as sprint running, change-of-direction or jump height are determinants of sports performance. Photocell systems are practical and easy to use systems to assess the time from point A to point B. In addition, these photoelectric systems are also used to obtain the time of vertically displaced movements. Knowing the accuracy and precision of photocell timing can be a determinant of ensuring a higher quality interpretation of results and of selecting the most appropriate devices for specific objectives. This systematic review aimed to identify and summarize studies that have examined the validity and reliability of photocells in sport sciences. A systematic review of PubMed, SPORTDiscus, and Web of Science databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. From the 164 studies initially identified, 16 were fully reviewed, and their outcome measures were extracted and analyzed. Photocells appear to have a strong agreement with force plates (gold standard), but are not interchangeable to measure the vertical jump. For monitoring horizontal displacement, double beam systems, compared to single beam systems, are more valid and reliable when it comes to avoiding false triggers caused by swinging arms or legs., Competing Interests: The authors declare no conflict of interest., (Copyright: © Academy of Physical Education in Katowice.)

Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells are relevant immunoregulators in cancer, and often correlate with better survival. How the Th2-skewed microenvironment in PDAC modulates the differentiation of Tfh cells and their immunoregulatory function is unknown., Methods: We carried out high-dimensional flow cytometry and T-cell receptor- and RNA-sequencing, as well as bioinformatics, immunohistochemistry and in vitro mechanistic studies., Findings: We identified Tfh1-, Tfh2-, and Tfh17-like cell clusters in the blood, tumors and tumor-draining lymph-nodes (TDLNs) of chemo-naïve PDAC patients and showed that high percentages of Tfh2 cells within the tumor tissue and TDLNs correlated with reduced patient survival. Moreover, only Tfh2 cells were highly activated and were reduced in frequency in patients who responded to neoadjuvant chemotherapy. RNA-sequencing analysis of immunoglobulin expression showed that tumor and TDLN samples expressed all immunoglobulin (IGH) isotypes apart from IGHE. Consistent with these findings, Tfh2 cells differentiated in vitro by tumor microenvironment-conditioned dendritic cells promoted the production of anti-inflammatory IgG4 antibodies by co-cultured B cells, dependent on IL-13. Moreover, unexpectedly, Tfh2 cells inhibited the secretion of pro-inflammatory IgE, dependent on prostaglandin E 2 ., Interpretation: Our results indicate that in PDAC, highly activated pro-tumor Tfh2 favor anti-inflammatory IgG4 production, while inhibit pro-inflammatory IgE. Thus, targeting the circuits that drive Tfh2 cells, in combination with chemotherapy, may re-establish beneficial anti-tumor Tfh-B cell interactions and facilitate more effective treatment., Funding: Research grants from the Italian Association for Cancer Research (AIRC) IG-19119 to MPP and the AIRC Special Program in Metastatic disease: the key unmet need in oncology, 5 per Mille no. 22737 to CB, MF, CD, MR and MPP; the ERA-NET EuroNanoMed III (a collaborative european grant financed by the Italian Ministry of Health, Italy) project PANIPAC (JTC2018/041) to MPP; the Fondazione Valsecchi to SC., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Restoration of sensorimotor function after amputation has remained challenging because of the lack of human-machine interfaces that provide reliable control, feedback, and attachment. Here, we present the clinical implementation of a transradial neuromusculoskeletal prosthesis-a bionic hand connected directly to the user's nervous and skeletal systems. In one person with unilateral below-elbow amputation, titanium implants were placed intramedullary in the radius and ulna bones, and electromuscular constructs were created surgically by transferring the severed nerves to free muscle grafts. The native muscles, free muscle grafts, and ulnar nerve were implanted with electrodes. Percutaneous extensions from the titanium implants provided direct skeletal attachment and bidirectional communication between the implanted electrodes and a prosthetic hand. Operation of the bionic hand in daily life resulted in improved prosthetic function, reduced postamputation, and increased quality of life. Sensations elicited via direct neural stimulation were consistently perceived on the phantom hand throughout the study. To date, the patient continues using the prosthesis in daily life. The functionality of conventional artificial limbs is hindered by discomfort and limited and unreliable control. Neuromusculoskeletal interfaces can overcome these hurdles and provide the means for the everyday use of a prosthesis with reliable neural control fixated into the skeleton.

Plastic waste management is a pressing ecological, social, and economic challenge. The saliva of the lepidopteran Galleria mellonella larvae is capable of oxidizing and depolymerizing polyethylene in hours at room temperature. Here, we analyze by cryo-electron microscopy (cryo-EM) G. mellonella 's saliva directly from the native source. The three-dimensional reconstructions reveal that the buccal secretion is mainly composed of four hexamerins belonging to the hemocyanin/phenoloxidase family, renamed Demetra, Cibeles, Ceres, and a previously unidentified factor termed Cora. Functional assays show that this factor, as its counterparts Demetra and Ceres, is also able to oxidize and degrade polyethylene. The cryo-EM data and the x-ray analysis from purified fractions show that they self-assemble primarily into three macromolecular complexes with striking structural differences that likely modulate their activity. Overall, these results establish the ground to further explore the hexamerins' functionalities, their role in vivo, and their eventual biotechnological application.

High rates of lung failure have been reported in haematological patients after SARS-CoV2 infection. An early administration of monoclonal antibodies or anti-virals may improve the prognosis. Oral anti-virals may have a wider use independently of the genetic variations of the virus. Prospective data on anti-virals in haematological malignancies (HMs) are still lacking. Outpatients diagnosed with HM and early COVID-19 infection were prospectively treated with the oral anti-virals nirmatrelvir/ritonavir and molnupiravir. Incidence of lung failure, deaths and adverse events was analysed. Long-term outcome at third month was evaluated. Eighty-two outpatients were evaluable for the study objectives. All patients had been treated for their HM within 12 months. COVID-19-related lung failure was 23.1%. Active HM (aOR = 4.42; p = 0.038) and prolonged viral shedding (aOR = 1.04; p = 0.022) resulted independent predictors of severe infection. The vaccination with three to four doses (aOR = 0.02; p = 0.001) and with two doses (aOR = 0.06; p = 0.006) resulted protective. COVID-19-related deaths at 28 days were 6.1%. All-cause mortality at 90-day follow-up was 13.4% (n. 11) and included opportunistic infections and cardiovascular events. In conclusion, this approach reduced the incidence of lung failure and specific mortality compared to previous cohorts, but patients remain at high risk of further complications., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: SARS-CoV-2 infections have been associated with the onset of thyroid disorders like classic subacute thyroiditis (SAT) or atypical SAT upon severe COVID disease (COV-A-SAT). Little is known about thyroid anti-viral immune responses., Objectives: To define the role of T-cells in COV-A-SAT., Methods: T-cells from COV-A-SAT patients were analyzed by multi-dimensional flow cytometry, UMAP and DiffusionMap dimensionality reduction and FlowSOM clustering. T-cells from COVID-naïve healthy donors, patients with autoimmune thyroiditis (ATD) and with SAT following COVID vaccination were analyzed as controls. T-cells were analyzed four and eight months post-infection in peripheral blood and in thyroid specimen obtained by ultrasound-guided fine needle aspiration. SARS-COV2-specific T-cells were identified by cytokine production induced by SARS-COV2-derived peptides and with COVID peptide-loaded HLA multimers after HLA haplotyping., Results: COV-A-SAT was associated with HLA-DRB1*13 and HLA-B*57. COV-A-SAT patients contained activated Th1- and cytotoxic CD4+ and CD8+ effector cells four months post-infection, which acquired a quiescent memory phenotype after eight months. Anti-SARS-CoV-2-specific T-cell responses were readily detectable in peripheral blood four months post-infection, but were reduced after eight months. CD4+ and CD8+ tissue-resident memory cells (TRM) were present in the thyroid, and circulating CXCR3+T-cells identified as their putative precursors. SARS-CoV-2-specific T-cells were enriched in the thyroid, and acquired a TRM phenotype eight months post-infection., Conclusions: The association of COV-A-SAT with specific HLA haplotypes suggests a genetic predisposition and a key role for T-cells. COV-A-SAT is characterized by a prolonged systemic anti-viral effector T-cell response and the late generation of COVID-specific TRM in the thyroid target tissue., Competing Interests: Declaration of Competing Interest We declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A novel stereoselective synthetic approach to pentahydroxyazepane iminosugars is described. The strategy relies on a key osmium-catalyzed aminohydroxylation reaction of allylic alcohols obtained via addition of vinylmagnesium bromide to a d-mannose-derived aldehyde, which forms the new C-N bond with complete regio- and stereocontrol according to the tethering approach. Subsequent intramolecular reductive amination afforded the desired azepanes. This method represents the first application of the osmium-catalyzed tethered aminohydroxylation reaction to the synthesis of iminosugars.

(1) Background: Transition is a planned movement of paediatric patients to adult healthcare systems, and its implementation is not yet established in all inflammatory bowel disease (IBD) units. The aim of the study was to evaluate the impact of transition on IBD outcomes. (2) Methods: Multicentre, retrospective and observational study of IBD paediatric patients transferred to an adult IBD unit between 2017-2020. Two groups were compared: transition (≥1 joint visit involving the gastroenterologist, the paediatrician, a programme coordinator, the parents and the patient) and no-transition. Outcomes within one year after transfer were analysed. The main variable was poor clinical outcome (IBD flare, hospitalisation, surgery or any change in the treatment because of a flare). Predictive factors of poor clinical outcome were identified with multivariable analysis. (3) Results: A total of 278 patients from 34 Spanish hospitals were included. One hundred eighty-five patients (67%) from twenty-two hospitals (65%) performed a structured transition. Eighty-nine patients had poor clinical outcome at one year after transfer: 27% in the transition and 43% in the no-transition group ( p = 0.005). One year after transfer, no-transition patients were more likely to have a flare (36% vs. 22%; p = 0.018) and reported more hospitalisations (10% vs. 3%; p = 0.025). The lack of transition, as well as parameters at transfer, including IBD activity, body mass index < 18.5 and corticosteroid treatment, were associated with poor clinical outcome. One patient in the transition group (0.4%) was lost to follow-up. (4) Conclusion: Transition care programmes improve patients' outcomes after the transfer from paediatric to adult IBD units. Active IBD at transfer impairs outcomes.

Immunological consequences of endoscopic ultrasound (EUS)-local thermal ablation (LTA) for pancreatic ductal adenocarcinoma (PDAC) have not been extensively assessed. We aimed to explore EUS-LTA effects on the systemic immune response in PDAC. Peripheral blood was collected from 10 treatment-naïve patients with borderline resectable and locally advanced PDAC, randomly allocated to Nab-paclitaxel plus Gemcitabine chemotherapy (CT-arm, n = 5) or EUS-LTA with HybridTherm Probe plus CT (HTP + CT-arm, n = 5). Twenty healthy donors were included as controls. Flow-cytometry and multiplex assays were used to profile immune cell subsets and measure serum cytokines/chemokines, respectively. At baseline, PDAC patients showed increased circulating monocytes and lower circulating lymphocytes and CD19+ B cells counts compared to healthy controls. After 4 months, CT induced decrease of B regulatory cells, CD4+ cytotoxic T cells and IL-1β. The addition of EUS-HTP to CT selectively decreased the serum levels of APRIL/TNFSF13 as well as T regulatory cells, total, classic and inflammatory monocytes. Serum levels of APRIL/TNFSF13 and total, classic and inflammatory monocytes counts at baseline were associated with worse overall survival. EUS-HTP has the potential to selectively impact on immune cells and cytokines associated with poor outcomes in PDAC.

This study compared the sensitivity of peak running speed (PRS) measured during a submaximal run test (SRT) with a countermovement jump (CMJ) test to provide an alternate method of measuring neuromuscular fatigue (NMF). The study involved 20 semi-professional academy soccer players who performed a SRT and CMJ test, 24-hours pre-match, 24-, 48-, 72- and 96-hours post-match. Moderate decreases (effect-size (ES) ± 90% confidence intervals) were observed 24-hours post-match for CMJ H ; ES -0.70 ± 0.19, CMJ PV ; ES -0.92 ± 0.27 and PRS; ES -0.58 ± 0.11 with small decreases in CMJ H ; ES -0.36 ± 0.13 and PRS; ES -0.27 ± 0.23 still evident 48-hours post-match before returning to baseline 72-hours post-match. The results confirm PRS as an inexpensive alternate method of measuring NMF which, allows instantaneous real-time feedback on NMF. This can allow changes to be made immediately on-field within the post-match recovery phase without the need for further analysis or equipment.

Type 1 regulatory (Tr1) T cells are currently defined all T cells with regulatory functions that lack FOXP3 expression and produce IL-10. Tr1 cells are heterogeneous, and the different reported properties of Tr1-cell populations have caused some confusion in the field. Moreover, understanding the role of Tr1 cells in immune-mediated diseases has been hampered by the lack of a lineage-defining transcription factor. Several independent studies indicated recently that the transcription factor Eomesodermin (EOMES) could act as a lineage-defining transcription factor in a population of IL-10 and IFN-γ co-producing Tr1-like cells, since EOMES directly induces IFN-γ and cytotoxicity, enhances IL-10, and antagonizes alternative T-cell fates. Here, we review the known properties of EOMES + Tr1-like cells. They share several key characteristics with other Tr1 cells (i.e., "Tr1-like"), namely high IL-10 production, cytotoxicity, and suppressive capabilities. Notably, they also share some features with FOXP3 + Tregs, like downregulation of IL-7R and CD40L. In addition, they possess several unique, EOMES-dependent features, that is, expression of GzmK and IFN-γ, and downregulation of type-17 cytokines. Published evidence indicates that EOMES + Tr1-like cells play key roles in graft-versus-host disease, colitis, systemic autoimmunity and in tumors. Thus, EOMES + Tr1-like cells are key players of the adaptive immune system that are involved in several different immune-mediated diseases., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Competing Interests: The authors have no conflicts of interest to disclose.

Piperidine-based photoswitchable derivatives have been developed as putative pharmacological chaperones for glucocerebrosidase (GCase), the defective enzyme in Gaucher disease (GD). The structure-activity study revealed that both the iminosugar and the light-sensitive azobenzene are essential features to exert inhibitory activity towards human GCase and a system with the correct inhibition trend (IC 50 of the light-activated form lower than IC 50 of the dark form) was identified. Kinetic analyses showed that all compounds are non-competitive inhibitors (mixed or pure) of GCase and the enzyme allosteric site involved in the interaction was identified by means of MD simulations. A moderate activity enhancement of mutant GCase assessed in GD patients' fibroblasts (ex vivo experiments) carrying the most common mutation was recorded. This promising observation paves the way for further studies to improve the benefit of the light-to-dark thermal conversion for chaperoning activity., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The invention of fossil fuel-derived plastics changed and reshaped society for the better; however, their mass production has created an unprecedented accumulation of waste and an environmental crisis. Scientists are searching for better ways to reduce plastic waste than the current methods of mechanical recycling and incineration, which are only partial solutions. Biological means of breaking down plastics have been investigated as alternatives, with studies mostly focusing on using microorganisms to biologically degrade sturdy plastics like polyethylene (PE). Unfortunately, after a few decades of research, biodegradation by microorganisms has not provided the hoped-for results. Recent studies suggest that insects could provide a new avenue for investigation into biotechnological tools, with the discovery of enzymes that can oxidize untreated PE. But how can insects provide a solution that could potentially make a difference? And how can biotechnology revolutionize the plastic industry to stop ongoing/increasing contamination?, Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bertocchini, Arias. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Today, complete blood count (CBC) analyses are highly automated and allow for high throughput and accurate and reliable results. However, new analytical tools are in great demand to provide simple, rapid and cost-effective management of hematological indices in home care patients. Chronic disease monitoring at home has become a benefit for patients who are finding cost savings in programs designed to monitor/treat patients in offsite locations. This review reports the latest trends in point-of-care (POC) diagnostics useful for home testing of key hematological counts that may be affected during home therapy treatment.

Microbiomes have been the focus of a substantial research effort in the last decades. The composition of microbial populations is normally determined by comparing DNA sequences sampled from those populations with the sequences stored in genomic databases. Therefore, the amount of information available in databanks should be expected to constrain the accuracy of microbiome analyses. Albeit normally ignored in microbiome studies, this constraint could severely compromise the reliability of microbiome data. To test this hypothesis, we generated virtual bacterial populations that exhibit the ecological structure of real-world microbiomes. Confronting the analyses of virtual microbiomes with their original composition revealed critical issues in the current approach to characterizing microbiomes, issues that were empirically confirmed by analyzing the microbiome of Galleria mellonella larvae. To reduce the uncertainty of microbiome data, the effort in the field must be channeled towards significantly increasing the amount of available genomic information and optimizing the use of this information., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Serrano-Antón et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Checkpoint inhibitors have significantly changed the prognosis of patients with relapsing refractory classical Hodgkin's lymphoma (cHL), demonstrating excellent results in heavily pretreated patients. However, there is still limited data on the real-world experience with PD-1 inhibitors in cHL. Within the context of the Apulian hematological network (Rete Ematologica Pugliese, REP), we performed a retrospective, multicenter analysis of 66 patients with relapsing refractory cHL who had received PD-1 inhibitors in the non-trial setting. Forty-three patients (65%) were treated with nivolumab and 23 (35%) with pembrolizumab. Thirty-one (47%) and 8 (12%) patients underwent autologous or allogeneic stem cell transplantation prior to checkpoint inhibitor therapy, respectively. The median number of lines of treatment attempted prior to PD-1 inhibitor therapy was 4 (range, 3 to 7). All patients had received brentuximab vedotin prior to checkpoint inhibitor therapy. The overall response rate to PD-1 inhibitors therapy was 70% (47% complete remission (CR) and 23% partial remission (PR)). Twenty-four immune-related adverse events (19 (80%) grades 1-2; 5 (20%) grades 3-4) were documented (4 gastrointestinal, 4 hepatic, 6 fever, 4 hematological, 3 dermatological, 3 allergic rhinitis). Toxicity resolved in all patients, and there were no deaths attributed to checkpoint inhibitor therapy. After a median follow-up of 26 months (range 3-72 months), 54 patients (82%) are alive, and 12 (18%) died. The cause of death was attributed to disease progression in 9 patients and sepsis in 3 patients. After PD-1 inhibitor therapy, 22 patients (33%) relapsed or progressed. The overall survival and progression-free survival at 5 years were 65% and 54%, respectively. This study confirms the efficacy and tolerability of PD-1 inhibitor therapy in relapsed refractory cHL in a real-world setting, demonstrating similar clinical outcomes and toxicity profiles compared to clinical studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Anemia is a condition in which the oxygen-carrying capacity of red blood cells is insufficient to meet the body's physiological needs. It affects billions of people worldwide. An early diagnosis of this disease could prevent the advancement of other disorders. Traditional methods used to detect anemia consist of venipuncture, which requires a patient to frequently undergo laboratory tests. Therefore, anemia diagnosis using noninvasive and cost-effective methods is an open challenge. The pallor of the fingertips, palms, nail beds, and eye conjunctiva can be observed to establish whether a patient suffers from anemia. This article addresses the above challenges by presenting a novel intelligent system, based on machine learning, that supports the automated diagnosis of anemia. This system is innovative from different points of view. Specifically, it has been trained on a dataset that contains eye conjunctiva photos of Indian and Italian patients. This dataset, which was created using a very strict experimental set, is now made available to the Scientific Community. Moreover, compared to previous systems in the literature, the proposed system uses a low-cost device, which makes it suitable for widespread use. The performance of the learning algorithms utilizing two different areas of the mucous membrane of the eye is discussed. In particular, the RUSBoost algorithm, when appropriately trained on palpebral conjunctiva images, shows good performance in classifying anemic and nonanemic patients. The results are very robust, even when considering different ethnicities., Competing Interests: Conflict of interest The authors declare the absence of any potential competing interests in a person or entity of a financial, non-financial, professional or personal nature, or interests that may be perceived as such, in connection with the research. We declare the absence of competing potential to the best of our knowledge and belief., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Incident reporting is an important method to identify risks because learning from the reports is crucial in developing and implementing effective improvements. A medical malpractice claims analysis is an important tool in any case. Both incident reports and claims show cases of damage caused to patients, despite incident reporting comprising near misses, cases where no event occurred and no-harm events. We therefore compare the two worlds to assess whether they are similar or definitively different. From 1 January 2014 to 31 December 2021, the claims database of Policlinico Universitario A. Gemelli IRCCS collected 843 claims. From 1 January 2020 to 31 December 2021, the incident-reporting database collected 1919 events. In order to compare the two, we used IBNR calculation, usually adopted by the insurance industry to determine loss to a company and to evaluate the real number of adverse events that occurred. Indeed, the number of reported adverse events almost overlapped with the total number of events, which is indicative that incurred-but-not-reported events are practically irrelevant. The distribution of damage events reported as claims in the period from 1 January 2020 to 31 December 2021 and related to incidents that occurred in the months of the same period, grouped by quarter, was then compared with the distribution of damage events reported as adverse events and sentinel events in the same period, grouped by quarter. The analysis of the claims database showed that the claims trend is slightly decreasing. However, the analysis of the reports database showed that, in the period 2020-2021, the reports trend was increasing. In our study, the comparison of the two, malpractice claims and incident reporting, documented many differences and weak areas of overlap. Nevertheless, this contribution represents the first attempt to compare the two and new studies focusing on single types of adverse events are, therefore, desirable.

The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3 high patients displayed longer survival compared with NR1H3 low cases and a high-resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo-related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes., (© 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Bacterial cells are equipped with a variety of immune strategies to fight bacteriophage infections. Such strategies include unspecific mechanisms directed against any phage infecting the cell, ranging from the identification and cleavage of the viral DNA by restriction nucleases (restriction-modification systems) to the suicidal death of infected host cells (abortive infection, Abi). In addition, CRISPR-Cas systems generate an immune memory that targets specific phages in case of reinfection. However, the timing and coordination of different antiviral systems in bacterial cells are poorly understood. Here, we use simple mathematical models of immune responses in individual bacterial cells to propose that the intracellular dynamics of phage infections are key to addressing these questions. Our models suggest that the rates of viral DNA replication and cleavage inside host cells define functional categories of phages that differ in their susceptibility to bacterial anti-phage mechanisms, which could give raise to alternative phage strategies to escape bacterial immunity. From this viewpoint, the combined action of diverse bacterial defenses would be necessary to reduce the chances of phage immune evasion. The decision of individual infected cells to undergo suicidal cell death or to incorporate new phage sequences into their immune memory would be determined by dynamic interactions between the host's immune mechanisms and the phage DNA. Our work highlights the importance of within-cell dynamics to understand bacterial immunity, and formulates hypotheses that may inspire future research in this area., (© 2022. The Author(s).)

Introduction/purpose: Since a significant proportion of SARS-CoV-2 infections occur within healthcare facilities, a multidisciplinary approach is required for careful and timely assessment of the risk of infection in asymptomatic patients or those whose COVID-19 diagnosis has not yet been made. The aim of this study was to investigate whether an adaptative model based on microbiological testing can represent a valid risk management strategy., Material and Methods: We collected data from the risk management unit database of a 1,550-bed tertiary hospital (Fondazione Policlinico Gemelli IRCCS, Rome, Italy) concerning pediatric admissions to the Emergency Department (ED) from 1 March 2020 to 31 December 2021. The study period was subdivided in period A and period B according to the technique used for the microbiological screening, respectively reverse-transcription polymerase chain reaction (RT-PCR) and antigen-detection test., Results: In Period A, 426 children (mean age: 6 years) underwent microbiological screening at the ED. The total number of molecular tests performed was 463. 459/463 tested negative at the molecular test. In Period B, 887 children (mean age: 6 years) underwent microbiological screening in the ED. The total number of molecular tests performed was 1,154. 1,117/1,154 tested negative at the molecular test. Neither in Period A nor in Period B hospital-acquired SARS-CoV-2 infections were reported., Discussion and Conclusion: Despite high volumes, no cases of hospital-acquired SARS-CoV-2 infection have been reported. SARS-CoV-2 antigen-based tests can be used as a first-line option as they provide rapid results compared to RT-PCR, reducing the risk of infection in ED waiting rooms., 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 © 2022 Vetrugno, Grassi, Clemente, Cazzato, Rossi, Grassi, Buonsenso, Filograna, Sanguinetti, Focardi, Valentini, Ozonoff, Pinchi and Oliva.)

Pharmaceutical chaperones (PCs) are small compounds able to bind and stabilize misfolded proteins, allowing them to recover their native folding and thus their biological activity. In particular, lysosomal storage disorders (LSDs), a class of metabolic disorders due to genetic mutations that result in misfolded lysosomal enzymes, can strongly benefit from the use of PCs able to facilitate their translocation to the lysosomes. This results in a recovery of their catalytic activity. No PC for the GCase enzyme (lysosomal acid-β-glucosidase, or glucocerebrosidase) has reached the market yet, despite the importance of this enzyme not only for Gaucher disease, the most common LSD, but also for neurological disorders, such as Parkinson's disease. This review aims to describe the efforts made by the scientific community in the last 7 years (since 2015) in order to identify new PCs for the GCase enzyme, which have been mainly identified among glycomimetic-based compounds.

GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1 ; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N -pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable β-Gal inhibitors, namely compounds 10 and 12 . Among these, compound 12 showed chaperoning properties since it enhanced β-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations.

(1) Background: new generations of rFVIII products offered the possibility to improve personalized therapeutic approaches, reducing the number of infusions or increasing the protection against bleeding risk. The aim of this study was to assess the effectiveness of prophylaxis with BAY 81-8973 (octocog alfa, Kovaltry ® , Bayer Pharma AG) in the real-world setting and its impact on FVIII consumption compared to previous standard half-life treatments. (2) Methods: a retrospective observational study was conducted in five Italian Haemophilia Centers. Patients with haemophilia A under prophylactic treatment with BAY 81-8973 for at least one year, and previously on prophylaxis with a different product were included in the study. Annual bleeding rate (ABR) and annual FVIII consumption were compared. (3) Results: forty-four patients were included in the study. After switching to BAY 81-8973, ABR was significantly reduced (1.76 vs. 0.23; p = 0.015), the percentage of patients with zero bleeds increased from 54.6% to 84.1% ( p = 0.003), and the overall FVIII consumption decreased by 25,542 (-7.2%, p = 0.046) IU per patient-year. Patients treated every 3 days or 2 times per week increased from 0% to 27.3%. (4) Conclusion: our results suggest that prophylaxis with BAY 81-8973 can improve clinical outcomes and reduce FVIII consumption, in the real-world practice, compared with the previous prophylaxis regimen with standard half-life products.

We describe a multi-step high-dimensional (HD) flow cytometry workflow for the deep phenotypic characterization of T cells infiltrating metastatic tumor lesions in the liver, particularly derived from colorectal cancer (CRC-LM). First, we applied a novel flow cytometer setting approach based on single positive cells rather than fluorescent beads, resulting in optimal sensitivity when compared with previously published protocols. Second, we set up a 26-color based antibody panel designed to assess the functional state of both conventional T-cell subsets and unconventional invariant natural killer T, mucosal associated invariant T, and gamma delta T (γδT)-cell populations, which are abundant in the liver. Third, the dissociation of the CRC-LM samples was accurately tuned to preserve both the viability and antigenic integrity of the stained cells. This combined procedure permitted the optimal capturing of the phenotypic complexity of T cells infiltrating CRC-LM. Hence, this study provides a robust tool for high-dimensional flow cytometry analysis of complex T-cell populations, which could be adapted to characterize other relevant pathological tissues., (© 2022 Faccani et al.)