Intranasal “painless” Human Nerve Growth Factors Slows Amyloid Neurodegeneration and Prevents Memory Deficits in App X PS1 Mice

Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease (AD) treatment but the clinical application is hindered by its potent pro-nociceptive activity. Thus, to reduce systemic exposure that would induce pain, in recent clinical studies NGF was administered through an invasive intracerebral gene-therapy approach. Our group demonstrated the feasibility of a non-invasive intranasal delivery of NGF in a mouse model of neurodegeneration. NGF therapeutic window could be further increased if its nociceptive effects could be avoided altogether. In this study we exploit forms of NGF, mutated at residue R100, inspired by the human genetic disease HSAN V (Hereditary Sensory Autonomic Neuropathy Type V), which would allow increasing the dose of NGF without triggering pain. We show that “painless” hNGF displays full neurotrophic and anti-amyloidogenic activities in neuronal cultures, and a reduced nociceptive activity in vivo. When administered intranasally to APPxPS1 mice ( n = 8), hNGFP61S/R100E prevents the progress of neurodegeneration and of behavioral deficits. These results demonstrate the in vivo neuroprotective and anti-amyloidogenic properties of hNGFR100 mutants and provide a rational basis for the development of “painless” hNGF variants as a new generation of therapeutics for neurodegenerative diseases

Laparoscopic right hemicolectomy: a SICE (Società Italiana di Chirurgia Endoscopica e Nuove tecnologie) network prospective study on the approach to right colon lymphadenectomy in Italy: is there a standard?—CoDIG 2 (ColonDx Italian Group)

Background: Colon cancer is a disease with a worldwide spread. Surgery is the best option for the treatment of advanced colon cancer, but some aspects are still debated, such as the extent of lymphadenectomy. In Japanese guidelines, the gold standard was D3 dissection to remove the central lymph nodes (203, 213, and 223), but in 2009, Hoenberger et al. introduced the concept of complete mesocolic excision, in which surgical dissection follows the embryological planes to remove the mesentery entirely to prevent leakage of cancer cells and collect more lymph nodes. Our study describes how lymphadenectomy is currently performed in major Italian centers with an unclear indication on the type of lymphadenectomy that should be performed during right hemicolectomy (RH). Methods: CoDIG 2 is an observational multicenter national study that involves 76 Italian general surgery wards highly specialized in colorectal surgery. Each center was asked not to modify their usual surgical and clinical practices. The aim of the study was to assess the preference of Italian surgeons on the type of lymphadenectomy to perform during RH and the rise of any new trends or modifications in habits compared to the findings of the CoDIG 1 study conducted 4 years ago. Results: A total of 788 patients were enrolled. The most commonly used surgical technique was laparoscopic (82.1%) with intracorporeal (73.4%), side-to-side (98.7%), or isoperistaltic (96.0%) anastomosis. The lymph nodes at the origin of the vessels were harvested in an inferior number of cases (203, 213, and 223: 42.4%, 31.1%, and 20.3%, respectively). A comparison between CoDIG 1 and CoDIG 2 showed a stable trend in surgical techniques and complications, with an increase in the robotic approach (7.7% vs. 12.3%). Conclusions: This analysis shows how lymphadenectomy is performed in Italy to achieve oncological outcomes in RH, although the technique to achieve a higher lymph node count has not yet been standardized. Trial registration (ClinicalTrials.gov) ID: NCT05943951

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Epidemiology of intensive care unit-acquired sepsis in Italy: results of the SPIN-UTI network

none139BACKGROUND: Sepsis is the major cause of mortality from any infectious disease worldwide. Sepsis may be the result of a healthcare associated infection (HAI): the most frequent adverse events during care delivery especially in Intensive Care Units (ICUs). The main aim of the present study was to describe the epidemiology of ICU-acquired sepsis and related outcomes among patients enrolled in the framework of the Italian Nosocomial Infections Surveillance in ICUs - SPIN-UTI project. STUDY DESIGN: Prospective multicenter study. METHODS: The SPIN-UTI network adopted the European protocols for patient-based HAI surveillance. RESULTS: During the five editions of the SPIN-UTI project, from 2008 to 2017, 47.0% of HAIs has led to sepsis in 832 patients. Overall, 57.0% episodes were classified as sepsis, 20.5% as severe sepsis and 22.5% as septic shock. The most common isolated microorganisms from sepsis episodes were Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The case fatality rate increased with the severity of sepsis and the mean length of ICU-stay was significantly higher in patients with ICU-acquired sepsis than in patients without. CONCLUSION: Our study provides evidence that ICU-acquired sepsis occurs frequently in Italian ICU patients and is associated with a high case fatality rate and increased length of stay. However, in order to explain these findings further analyses are needed in this population of ICU patients.noneAgodi A, Barchitta M, Auxilia F, Brusaferro S3, D'Errico MM, Montagna MT, Pasquarella C, Tardivo S, Arrigoni C, Fabiani L, Laurenti P, Mattaliano AR, Orsi GB, Squeri R, Torregrossa MV, Mura I, Aiello MR, Alliani C, Amatucci MR, Antoci M, Antonelli M, Astuto M, Arnoldo L, Arru B, Baccari G, Barbadoro P, Barbara A, Barilaro C, Battaglia P, Bellocchi P, Bernasconi MO, Bianco A, Bissolo E, Bocchi A, Bruno A, Brusaferro M, Buccheri M, Campanella F, Canino R, Cannistrà A, Carini SA, Catalano S, Castellani P, Castiglione G, Coniglio S, Consolante C, Conte C, Contrisciani R, Corallini R, Crollari P, Damiani G, Denaro C, De Remigis S, Diana F, Di Bartolo R, Di Benedetto A, Di Fabio G, Di Falco C, Digeronimo V, Di Gregorio P, Distefano R, Egitto G, Falciani E, Farruggia P, Fenaroli S, Ferlazzo G, Garofalo G, Girardis M, Giovanelli L, Giubbini G, Graceffa A, Guadagna A, Gregu G, Ingala F, Innocenzi L, La Camera G, La Rosa MC, Lesa L, Longhitano AM, Luppino G, Maida CM, Manta G, Marino G, Masia MD, Maviglia R, Mazzetti M, Maugeri A, Megna MT, Mella LM, Milazzo M, Milia M, Minari C, Minerva M, Mordacci M, Murgia P, Oliveri P, Olori MP, Pagliarulo R, Palermo R, Pandiani I, Pappalardo F, Papetti C, Partenza A, Pascu D, Pasculli M, Pavia M, Pavone ML, Pellegrino MG, Pelligra F, Pillon D, Pintaudi S, Pitzoi L, Pinto A, Piotti P, Pupo S, Quattrocchi R, Righi E, Rigo A, Rigo A, Romeo A, Rosa E, Rutigliano S, Sarchi P, Scimonello G, Seminerio A, Stefanini P, Sticca G, Taddei S, Tessari L, Tetamo R, Ticca M, Tribastoni S, Vallorani S, Venturoni F, Vitagliano E, Vitali P, Zappone A, Zei E, Zeoli MP.Agodi, A; Barchitta, M; Auxilia, F; Brusaferro, S3; D'Errico, Mm; Montagna, Mt; Pasquarella, C; Tardivo, S; Arrigoni, C; Fabiani, L; Laurenti, P; Mattaliano, Ar; Orsi, Gb; Squeri, R; Torregrossa, Mv; Mura, I; Aiello, Mr; Alliani, C; Amatucci, Mr; Antoci, M; Antonelli, M; Astuto, M; Arnoldo, L; Arru, B; Baccari, G; Barbadoro, P; Barbara, A; Barilaro, C; Battaglia, P; Bellocchi, P; Bernasconi, Mo; Bianco, A; Bissolo, E; Bocchi, A; Bruno, A; Brusaferro, M; Buccheri, M; Campanella, F; Canino, R; Cannistrà, A; Carini, Sa; Catalano, S; Castellani, P; Castiglione, G; Coniglio, S; Consolante, C; Conte, C; Contrisciani, R; Corallini, R; Crollari, P; Damiani, G; Denaro, C; De Remigis, S; Diana, F; Di Bartolo, R; Di Benedetto, A; Di Fabio, G; Di Falco, C; Digeronimo, V; Di Gregorio, P; Distefano, R; Egitto, G; Falciani, E; Farruggia, P; Fenaroli, S; Ferlazzo, G; Garofalo, G; Girardis, M; Giovanelli, L; Giubbini, G; Graceffa, A; Guadagna, A; Gregu, G; Ingala, F; Innocenzi, L; La Camera, G; La Rosa, Mc; Lesa, L; Longhitano, Am; Luppino, G; Maida, Cm; Manta, G; Marino, G; Masia, Md; Maviglia, R; Mazzetti, M; Maugeri, A; Megna, Mt; Mella, Lm; Milazzo, M; Milia, M; Minari, C; Minerva, M; Mordacci, M; Murgia, P; Oliveri, P; Olori, Mp; Pagliarulo, R; Palermo, R; Pandiani, I; Pappalardo, F; Papetti, C; Partenza, A; Pascu, D; Pasculli, M; Pavia, M; Pavone, Ml; Pellegrino, Mg; Pelligra, F; Pillon, D; Pintaudi, S; Pitzoi, L; Pinto, A; Piotti, P; Pupo, S; Quattrocchi, R; Righi, E; Rigo, A; Rigo, A; Romeo, A; Rosa, E; Rutigliano, S; Sarchi, P; Scimonello, G; Seminerio, A; Stefanini, P; Sticca, G; Taddei, S; Tessari, L; Tetamo, R; Ticca, M; Tribastoni, S; Vallorani, S; Venturoni, F; Vitagliano, E; Vitali, P; Zappone, A; Zei, E; Zeoli, Mp

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484