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Loop Gain (LG), a concept borrowed from engineering used to describe the stability of electrical circuits under negative feedback, has emerged as a crucial pathophysiological trait in sleep respiratory disorders. In simple terms, LG measures how the respiratory control system reacts to changes in breathing. A high LG suggests that minor disturbances in breathing prompt exaggerated responses, potentially leading to instability and oscillations in respiratory patterns. Conversely, a low LG implies that the system responds more gently to disturbances, resulting in stable and well-regulated breathing. However, understanding the concept of loop gain presents challenges due to its dynamic nature across various sleep respiratory disorders, sleep stages, positions, and interactions with other pathophysiological traits. Recent efforts have aimed to identify a non-invasive method for assessing LG, with some evidence suggesting that information regarding pathophysiological traits can be extracted from polysomnography. There exists a clinical imperative for physician to unravel the intricacies of LG when managing Obstructive Sleep Apnea (OSA) patients, because LG abnormalities delineate a distinct pathophysiological phenotype of OSA. Specifically, certain patients exhibit a high LG as the primary factor driving sleep apnea, influencing treatment outcomes. For instance, individuals with high LG may respond differently to therapies such as continuous positive airway pressure (CPAP) or oral appliances compared to those with normal LG, or they can be treated with specific drugs or combination therapies. Thus, understanding LG becomes paramount for precise assessment of OSA patients and is fundamental for optimizing a personalized and effective treatment approach., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Dysregulated systemic inflammation is the primary driver of mortality in severe coronavirus disease 2019 (COVID-19) pneumonia. Current guidelines favour a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg daily. A comparative randomised controlled trial (RCT) with a higher dose and a longer duration of intervention was lacking., Methods: We conducted a multicentre, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg once daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. The primary outcome was reduction in 28-day mortality. Secondary outcomes were mechanical ventilation-free days at 28 days, need for intensive care unit (ICU) referral, length of hospitalisation, need for tracheostomy, and changes in C-reactive protein (CRP) levels, arterial oxygen tension/inspiratory oxygen fraction ( P aO 2 / F IO 2 ) ratio and World Health Organization Clinical Progression Scale at days 3, 7 and 14., Results: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35 (10.4%) versus 41 (12.1%); p=0.49) nor in median mechanical ventilation-free days (median (interquartile range (IQR)) 23 (14) versus 24 (16) days; p=0.49). ICU referral was necessary in 41 (12.2%) versus 45 (13.2%) (p=0.68) and tracheostomy in 8 (2.4%) versus 9 (2.6%) (p=0.82). Survivors in the methylprednisolone group required a longer median (IQR) hospitalisation (15 (11) versus 14 (11) days; p=0.005) and experienced an improvement in CRP levels, but not in P aO 2 / F IO 2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified time-points., Conclusion: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared with conventional dexamethasone in COVID-19 pneumonia., Competing Interests: Conflict of interest: F. Salton, P. Confalonieri, S. Centanni, M. Mondoni, N. Petrosillo, D. Lacedonia, A. Voza, N. Carpenè, M. Montico, N. Reccardini, G.U. Meduri, B. Ruaro and M. Confalonieri have no conflicts of interest to disclose. P. Bonfanti received personal fees from ViiV Healthcare, Gilead, Janssen, Merck and Pfizer, not related to this work. G. Lapadula received personal fees from ViiV Healthcare and Pfizer, not related to this work., (Copyright ©The authors 2023.)

To control capillary bleeding, surgeons may use absorbable hemostatic agents, such as Surgicel® and TachoSil®. Due to their slow resorption, their persistence in situ can have a negative impact on tissue repair in the resected organ. To avoid complications and obtain a hemostatic agent that promotes tissue repair, a zinc-supplemented calcium alginate compress was developed: HEMO-IONIC®. This compress is non-absorbable and is therefore removed once hemostasis has been achieved. After demonstrating the hemostatic efficacy and stability of the blood clot obtained with HEMO-IONIC, the impact of Surgicel, TachoSil, and HEMO-IONIC on cell activation and tissue repair were compared (i) in vitro on endothelial cells, which are essential to tissue repair, and (ii) in vivo in a mouse skin excision model. In vitro , only HEMO-IONIC maintained the phenotypic and functional properties of endothelial cells and induced their migration. In comparison, Surgicel was found to be highly cytotoxic, and TachoSil inhibited endothelial cell migration. In vivo , only HEMO-IONIC increased angiogenesis, the recruitment of cells essential to tissue repair (macrophages, fibroblasts, and epithelial cells), and accelerated maturation of the extracellular matrix. These results demonstrate that a zinc-supplemented calcium alginate, HEMO-IONIC, applied for 10 min at the end of surgery and then removed has a long-term positive effect on all phases of tissue repair., Competing Interests: Anne-Charlotte Ponsen was employed at BROTHIER during her PhD. The other authors have not indicated any potential conflict of interest., (© 2022 The Authors.)

Purpose: Sinusoidal obstruction syndrome (SOS) is one of the most serious complications post haematopoietic stem cell transplantation (HSCT). The diagnosis of SOS is clinical, but nurses should be involved in the pre-transplant risk assessment period and play a crucial role in the early detection of signs and symptoms during and after hospitalization. The aim of this work is to achieve a consensus on nurses' behaviour in caring for SOS., Methods: On behalf of the Italian Group for Bone and Marrow Transplantation (GITMO), a promoter committee was established to put in place a consensus conference approach. A multidisciplinary group of GITMO together with four nurses, three haematology physicians and one patient representative acted as jury, who reviewed the reports and wrote recommendations and suggestions. Recommendations gaining 100% of consensus were considered 'Golden Points of Care'; if a consensus was achieved by ≥ 75% of the jury's members, those recommendations were defined as 'Good Practices'., Results: Eighteen papers written by nurses as first authors have been identified. Golden Points of Care and Good Practices were worked out for the following topics: nurses' role in general, nurses' role in pre-transplant assessment, pre-transplant risk assessment and risk stratification, baseline monitoring, suspected mild or moderate SOS, suspected severe or very severe SOS and late-onset cases., Conclusion: SOS is relatively rare; therefore, a holistic approach to the patients' needs considering nursing role as essential may result in better care outcomes.

Targeting chemoresistant malignant cells is one of the current major challenges in oncology. Therefore, it is mandatory to refine the characteristics of these cells to monitor their survival and develop adapted therapies. This is of particular interest in acute myeloid leukemia (AML), for which the 5-year survival rate only reaches 30%, regardless of the prognosis. The role of the microenvironment is increasingly reported to be a key regulator for blast survival. In this context, we demonstrate that contact with mesenchymal stromal cells promotes a better survival of blasts in culture in the presence of anthracycline through the activation of ABC transporters. Stroma-dependent ABC transporter activation leads to the induction of a Side Population (SP) phenotype in a subpopulation of primary leukemia blasts through alpha (α)4 engagement. The stroma-promoting effect is reversible and is observed with stromal cells isolated from either healthy donors or leukemia patients. Blasts expressing an SP phenotype are mostly quiescent and are chemoresistant in vitro and in vivo in patient-derived xenograft mouse models. At the transcriptomic level, blasts from the SP are specifically enriched in the drug metabolism program. This detoxification signature engaged in contact with mesenchymal stromal cells represents promising ways to target stroma-induced chemoresistance of AML cells., (Copyright© 2020 Ferrata Storti Foundation.)

Objectives: To identify which factors can influence the patients' perception of protective isolation following Haematopoietic Stem Cell Transplantation (HSCT)., Methods: This is a prospective study conducted in 10 Italian centres, members of the Italian Group of stem cell transplant (GITMO). Patients' perception of protective isolation was assessed using the ISOLA scale between 7 and 9 days post-transplant. Statistical linear regression analysis was performed., Results: The participants were 182 adult patients receiving autologous (48%) or allogeneic (52%) HSCT in protective isolation. Male sex (β = .152), education level (β = -.245), double room (β = .186), satisfaction with visiting hours (β = -.174) and emotional support from nurses (β = -.169) were independently associated with isolation-related suffering. Significant predictors of the relationship with oneself included body temperature (β = -.179), fatigue (β = -.192) and emotional support from nurses (β = -.292). Factors independently associated with the relationship with others were education (β = -.230), chemotherapy cycles (β = -.218), pain (β = .150) and satisfaction with visiting hours (β = -.162)., Conclusion: Healthcare providers should pay greater attention in caring for those patients who are at risk for a negative isolation experience. Nurses should provide emotional support., (© 2019 John Wiley & Sons Ltd.)

The aim of this study was to develop and psychometrically test a questionnaire assessing patients' perception of protective isolation following haematopoietic stem cell transplantation (HSCT). The conceptual framework for developing the questionnaire was a three-dimensional model that emerged from a metasynthesis: isolation-related suffering, relationship with oneself and relationship with others. Item selection was performed through a focus group, comparison with the findings of two phenomenological studies, and content validity with 22 experts. Cognitive interviews with five patients were used to verify face validity. A validation study was conducted in 10 Italian centres, all members of the Italian Group of stem cell transplant (GITMO). Patients completed the questionnaires between 7 and 9 days post-transplant. Dimensionality was tested through exploratory factor analysis (EFA). A total of 17 items yielded a content validity index (CVI) of 0.88. Participants included 186 adult patients receiving autologous (48%) or allogeneic (52%) HSCT in protective isolation. The EFA yielded a three-factor solution, explaining 55% of the variance. The scale showed adequate psychometric properties, with the exception of three items, which were eliminated. Future studies should test the psychometric properties of the questionnaire through confirmatory factor analysis and verify its transcultural validity., (© 2018 John Wiley & Sons Ltd.)

Smut disease caused by the fungal pathogen Thecaphora frezii Carranza & Lindquist is threatening the peanut production in Argentina. Fungicides commonly used in the peanut crop have shown little or no effect controlling the disease, making it a priority to obtain peanut varieties resistant to smut. In this study, recombinant inbred lines (RILs) were developed from three crosses between three susceptible peanut elite cultivars (Arachis hypogaea L. subsp. hypogaea) and two resistant landraces (Arachis hypogaea L. subsp. fastigiata Waldron). Parents and RILs were evaluated under high inoculum pressure (12000 teliospores g-1 of soil) over three years. Disease resistance parameters showed a broad range of variation with incidence mean values ranging from 1.0 to 35.0% and disease severity index ranging from 0.01 to 0.30. Average heritability (h2) estimates of 0.61 to 0.73 indicated that resistance in the RILs was heritable, with several lines (4 to 7 from each cross) showing a high degree of resistance and stability over three years. Evidence of genetic transfer between genetically distinguishable germplasm (introgression in a broad sense) was further supported by simple-sequence repeats (SSRs) and Insertion/Deletion (InDel) marker genotyping. This is the first report of smut genetic resistance identified in peanut landraces and its introgression into elite peanut cultivars., Competing Interests: The authors have declared that no competing interests exist.

Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles surrounding joints following spinal cord or brain injury. We investigated the mechanisms of NHO formation in 64 patients and a mouse model of spinal cord injury-induced NHO. We show that marrow from human NHOs contains hematopoietic stem cell (HSC) niches, in which mesenchymal stromal cells (MSCs) and endothelial cells provide an environment supporting HSC maintenance, proliferation, and differentiation. The transcriptomic signature of MSCs from NHOs shows a neuronal imprinting associated with a molecular network required for HSC support. We demonstrate that oncostatin M (OSM) produced by activated macrophages promotes osteoblastic differentiation and mineralization of human muscle-derived stromal cells surrounding NHOs. The key role of OSM was confirmed using an experimental model of NHO in mice defective for the OSM receptor (OSMR). Our results provide strong evidence that macrophages contribute to NHO formation through the osteogenic action of OSM on muscle cells within an inflammatory context and suggest that OSM/OSMR could be a suitable therapeutic target. Altogether, the evidence of HSCs in ectopic bones growing at the expense of soft tissue in spinal cord/brain-injured patients indicates that inflammation and muscle contribute to HSC regulation by the brain-bone-blood triad.

Skeletal muscle regeneration after injury follows a remarkable sequence of synchronized events. However, the mechanisms regulating the typical organization of the regenerating muscle at different stages remain largely unknown. Here we show that muscle regeneration in mice lacking either CD9 or CD81 is abnormal and characterized by the formation of discrete giant dystrophic myofibres, which form more quickly in the absence of both tetraspanins. We also show that, in myoblasts, these two tetraspanins associate with the immunoglobulin domain molecule CD9P-1 (EWI-F/FPRP), and that grafting of CD9P-1-depleted myoblasts in regenerating muscles also leads to abnormal regeneration. In vitro myotubes lacking CD9P-1 or both CD9 and CD81 fuse with a higher frequency than normal myotubes. Our study unveils a mechanism preventing inappropriate fusion of myotubes that has an important role in the restitution of normal muscle architecture during muscle regeneration.

Tetraspanins are integral membrane proteins involved in a variety of physiological and pathological processes. They associate with each other in multimolecular complexes containing numerous membrane proteins. As a first step towards the study of the supramolecular organization of tetraspanin complexes, we have implemented a proteomic approach based on in situ protein cross-linking on living cells followed by affinity purification of tetraspanin complexes. This allowed observing the presence of high molecular weight protein complexes that were characterized as containing CD9P-1/CD315 using LC-MS/MS. Western blot analyses and the use of different tags demonstrated the presence of CD9P-1 oligomer in cis-association at cell surface. A significant amount of CD9P-1 oligomer was observed on various cell types. We have shown that CD9P-1 self-associates independently from its association with tetraspanins. However, the expression level of CD9 or CD81 that associate directly and specifically with CD9P-1, positively modulates the cross-linking efficiency of CD9P-1. Thus, tetraspanins can play a role on CD9P-1 oligomerization status.

Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons and caused by mutations of the SMN1 gene. SMN1 is duplicated in a homologous gene called SMN2, which remains present in patients. SMN has an essential role in RNA metabolism, but its role in SMA pathogenesis remains unknown. Previous studies suggested that in neurons the protein lacking the C terminus (SMN(Delta7)), the major product of the SMN2 gene, had a dominant-negative effect. We generated antibodies specific to SMN(FL) or SMN(Delta7). In transfected cells, the stability of the SMN(Delta7) protein was regulated in a cell-dependent manner. Importantly, whatever the human tissues examined, SMN(Delta7) protein was undetectable because of the instability of the protein, thus excluding a dominant effect of SMN(Delta7) in SMA. A similar decreased level of SMN(FL) was observed in brain and spinal cord samples from human SMA, suggesting that SMN(FL) may have specific targets in motor neurons. Moreover, these data indicate that the vulnerability of motor neurons cannot simply be ascribed to the differential expression or a more dramatic reduction of SMN(FL) in spinal cord when compared with brain tissue. Improving the stability of SMN(Delta7) protein might be envisaged as a new therapeutic strategy in SMA.

In the present study we investigated the effects of K and other univalent cations on [3H]InsP3 [[3H]Ins(1,4,5)P3] binding to sheep cerebellar microsomes. In equilibrium binding experiments performed over 4 s at pH 7.1 and 20 degrees C, the addition of K to the binding medium decreased the affinity and increased the total number of binding sites for InsP3 in a dose-dependent manner. At low InsP3 concentration (0.5 nM) these effects resulted in a biphasic dose-response curve, with maximal binding at about 75 mM K. In contrast, the dose-response curve calculated for InsP3 at the physiological concentration of 5 mM, was linear up to 200 mM K. Univalent inorganic cations stimulated [3H]InsP3 binding to various extents, with the following descending order of efficiency at 75 mM: Cs approximately Rb approximately K>Na>Li. The effect of K on InsP3R affinity was rapidly reversed upon cation removal. We were therefore also able to demonstrate that K increased Bmax (maximal specific binding) by pre-treating microsomes with K before measuring [3H]InsP3 binding in the absence of that cation. The increase in Bmax was reversible, but this reversal occurred less rapidly than the change in affinity. These results are consistent with a process by which K reversibly converted very low-affinity sites into sites with higher affinity, making them detectable in competitive binding experiments. They suggest that interconversion between these two affinity states constitutes the basis of a K-controlled regulatory mechanism for cerebellar InsP3R.