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Background: The impact of noninvasive ventilation (NIV) managed outside the intensive care unit in patients with early acute respiratory failure remains unclear. We aimed to determine whether adding early NIV prevents the progression to severe respiratory failure., Methods: In this multinational, randomised, open-label controlled trial, adults with mild acute respiratory failure (arterial oxygen partial pressure/fraction of inspiratory oxygen [Pao 2 /FiO 2 ] ratio ≥200) were enrolled across 11 hospitals in Italy, Greece, and Kazakhstan. Patients were randomised to receive early NIV or usual care. Patients in the early NIV group received 2-h cycles of NIV applied every 8 h for up to 12 days. The primary outcome was the progression to severe acute respiratory failure, defined by severe hypoxaemia, severe respiratory distress, or hypercapnic acidaemia during hospitalisation., Results: Between May 6, 2012, and July 18, 2023, we randomised 524 patients (44.8% female; median age 73 yr, interquartile range [IQR] 63-83 yr). One patient withdrew consent. Progression to severe acute respiratory failure occurred in 49/265 (18.5%) patients randomised to early NIV, compared with 73/258 (28.3%) patients receiving usual care (relative risk 0.65, 95% confidence interval 0.48-0.90, P=0.0080). Median length of hospital stay was 10 (IQR 6-16) days in the early NIV group and 9 (IQR 5-16) days in the usual care group (P=0.30). Respiratory complications, 28-day mortality, and adverse events were not different between early NIV and usual care., Conclusions: In patients with mild acute respiratory failure treated in nonintensive care wards, early NIV reduced the progression to severe acute respiratory failure., Clinical Trial Registration: NCT01572337., Competing Interests: Declaration of interest All authors have no conflict of interest to declare., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Introduction: The pathogenesis of inflammatory bowel disease (IBD) involves the dysregulation of multiple inflammatory pathways. The understanding of these mechanisms allows their selective targeting for therapeutic purposes. The discovery of Tumor Necrosis Factor-alpha's (TNF-α) role in mucosal inflammation ushered an exciting new era of drug development which now comprises agents targeting multiple pro-inflammatory signaling pathways, integrins, and leukocyte trafficking regulators., Area Covered: This review provides an overview of the main molecular players of IBD, their translation into therapeutic targets and the successful development of the advanced agents modulating them. We combine basic science with clinical trials data to present a critical review of both the successful and failed drug development programs. A PubMed literature search was conducted to delve into the available literature and clinical trials., Expert Opinion: The treatment landscape for IBD has rapidly expanded, particularly with the development of biologics targeting TNF-α, integrins, and S1P modulators, as well as newer agents such as IL-12/IL-23 inhibitors and JAK inhibitors, offering robust efficacy and safety profiles. However, challenges persist in understanding and effectively treating difficult-to-treat IBD, highlighting the need for continued research to uncover novel therapeutic targets and optimize patient outcomes.

Sports trainers have recently shown increasing interest in innovative methods, including transcranial electric stimulation, to enhance motor performance and boost the acquisition of new skills during training. However, studies on the effectiveness of these tools on fast visuomotor learning and brain activity are still limited. In this randomized single-blind, sham-controlled, between-subjects study, we investigated whether a single training session, either coupled or not with 2 mA online high-frequency transcranial random noise stimulation (hf-tRNS) over the bilateral primary motor cortex (M1), would affect dart-throwing performance (i.e., radial error, arm range of motion, and movement variability) in 37 healthy volunteers. In addition, potential neurophysiological correlates were monitored before and after the training through a 32-electrode portable electroencephalogram (EEG). Results revealed that a single training session improved radial error and arm range of motion during the dart-throwing task, but not movement variability. Furthermore, after the training, resting state-EEG data showed a decrease in theta power. Radial error, arm movement, and EEG were not further modulated by hf-tRNS. This indicates that a single training session, regardless of hf-tRNS administration, improves dart-throwing precision and movement accuracy. However, it does not improve movement variability, which might require multiple training sessions (expertise resulting in slow learning). Theta power decrease could describe a more efficient use of cognitive resources (i.e., attention and visuomotor skills) due to the fast dart-throwing learning. Further research could explore different sports by applying longer stimulation protocols and evaluating other EEG variables to enhance our understanding of the lasting impacts of multi-session hf-tRNS on the sensorimotor cortex within the framework of slow learning and training assistance., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Why patients with symptomatic uncomplicated diverticular disease (SUDD) may develop acute diverticulitis (AD) is still unknown. We analyzed the gut microbiota (GM) in two SUDD patients, one who did experience SUDD recurrence but not AD occurrence (case 1) and one who did experience AD occurrence during follow-up (case 2). The GM of these patients showed differences in terms of phyla (Firmicutes and Bacteroidota in case 1; Actinobacteriota and Proteobacteria in case 2) and subgenera ( Prevotella and Phascolarctobacterium in case 1 and Alloprevotella , Prevotella , Holdemanella , Turicibacter , Eubacterium eligens group, and Dialister in case 2). This novel insight may advance our ecological understanding of this complex disease., Competing Interests: Antonio TURSI served as a speaker and/or consultant for AbbVie, Bayer, Fenix Pharma, Galápagos, Janssen, Nalkein, Omega Pharma, and Sila. The remaining authors declare no competing interests., (©2025 BMFH Press.)

Background and Aim: Suboptimal disease control (SDC) and its contributing factors in IBD according to STRIDE-II criteria is unclear. IBD-PODCAST was a non-interventional, international, multicenter real-world study to assess this., Methods: Data from the Italian IBD cohort (N=220) are presented here. Participants aged ≥19 with confirmed IBD diagnosis of ≥1 year were consecutively enrolled. A retrospective chart review and cross-sectional assessment by physicians and patients within the past 12 months were performed. SDC or optimal disease control was assessed using adapted STRIDE-II criteria., Results: At the index date, 53.4 % of 116 CD patients and 49.0 % of 104 UC patients had SDC, mainly attributed to a Short Inflammatory Bowel Disease Questionnaire score <50, failure to achieve endoscopic remission, and the presence of active extra-intestinal manifestations in both diseases. Disease monitoring with imaging and/or endoscopy during the previous year was conducted in ∼50 % of patients, with endoscopy performed in ∼40 %. Potential therapeutic adjustments were reported for half of the patients., Conclusions: This study highlights SDC in a significant portion of IBD Italian patients. These results emphasize the need for more proactive management strategies in both CD and UC patients., Competing Interests: Competing interests, (Copyright © 2024. Published by Elsevier Ltd.)

Background: Excessive exposure to adrenergic vasopressors may be harmful. Non-adrenergic vasopressors may spare adrenergic agents and potentially improve outcomes. We aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of non-adrenergic vasopressors in adult patients receiving vasopressor therapy for vasodilatory shock or perioperative vasoplegia., Methods: We searched PubMed, Embase, and Cochrane Library for RCTs comparing non-adrenergic vasopressors with adrenergic vasopressors alone or placebo in critically ill or perioperative patients. Each eligible study was categorized into septic shock, cardiac surgery, or non-cardiac surgery. Non-adrenergic vasopressors included vasopressin, terlipressin, selepressin, angiotensin II, methylene blue, and hydroxocobalamin. The primary outcome was mortality at longest follow-up. We conducted a random-effects meta-analysis. We registered the protocol in PROSPERO International Prospective Register of Systematic Reviews (CRD42024505039)., Results: Among 51 eligible RCTs totaling 5715 patients, the predominant population was septic shock in 30 studies, cardiac surgery in 11 studies, and non-cardiac surgery in 10 studies. Cochrane risk-of-bias tool for randomized trials version 2 identified 17 studies as low risk of bias. In septic shock, mortality was significantly lower in the non-adrenergic group (960/2232 [43%] vs. 898/1890 [48%]; risk ratio [RR], 0.92; 95% confidence interval [95% CI], 0.86-0.97; P = 0.03; I 2  = 0%), with none of the individual non-adrenergic vasopressors showing significant survival benefits. No significant mortality difference was observed in patients undergoing cardiac surgery (34/410 [8.3%] vs. 47/412 [11%]; RR, 0.82; 95% CI, 0.55-1.22; P = 0.32; I 2  = 12%) or those undergoing non-cardiac surgery (9/388 [2.3%] vs. 18/383 [4.7%]; RR, 0.66; 95% CI, 0.31-1.41; P = 0.28; I 2  = 0%)., Conclusions: Administration of non-adrenergic vasopressors was significantly associated with reduced mortality in patients with septic shock. However, no single agent achieved statistical significance in separate analyses. Although the pooled effects of non-adrenergic vasopressors on survival did not reach statistical significance in patients undergoing cardiac or non-cardiac surgery, the confidence intervals included the possibility of both no effect and a clinically important benefit from non-adrenergic agents. These findings justify the conduct of further RCTs comparing non-adrenergic vasopressors to usual care based on noradrenaline alone., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: YK has received consultancy fees from Viatris. PMW previously received consultant fees from Viatris. AKK received consulting fees from Medtronic, Edwards Life Sciences, Philips Research North America, Hillrom, GE Healthcare, Potrero Medical, Viatris Pharma, Trevena Pharma, Fifth Eye Inc., Pharmazz Inc., Retia Medical and Caretaker Medical. He is also funded with a Wake Forest Clinical and Translational Science Institute (CTSI) grant on renin dysfunction in septic shock. GL has received speaker fees from Medis, Paion, and Viatris and consultancy fees from Paion and Viatris. RB has received grants and consultancy fees from La Jolla Pharmaceuticals, Paion AG, and Viatris. The other authors have no competing interests., (© 2024. The Author(s).)

Phosphodiesterase 2 A (PDE2A) function is stimulated by cGMP to catabolize cAMP. However, neurological and neurochemical effects of PDE2A deficiency are poorly understood. To address this gap, we studied behavioral characteristics and cerebral morpho-chemical changes of adult male heterozygous C57BL/6-PDE2A+/- (HET), and wild type C57BL/6-PDE2A+/+ (WT) mice. Behavioral functions of mice were evaluated by a wide test battery. HET mice exhibited greater tendency to explore novel environments in comparison to WT mice, but spatial working memory, anxiety, and sociability were similar in adult HET and WT mice. In HET mice, PDE2A mRNA, PDE2A protein expression, and cGMP hydrolyzing enzymatic activity were consistently reduced by about 50 %. Consequently, the cyclic nucleotide levels were significantly increased in HET mice, but unexpectedly the mean percentage variation was higher for cGMP equal to 153.23 %, and lower for cAMP equal to 16.41 %. Therefore, to try to explain the preponderant increase of cGMP to cAMP we evaluated other PDE enzymes functionally related to PDE2A. Surprisingly, results were quite contradictory: in HET mice protein levels of the other dual-specificity enzyme PDE3A and PDE10A were reduced, whereas the expressions of PDE5A and PDE9A that selectively hydrolyze cGMP were increased. Therefore, we investigated the involvement of neuronal nitric oxide synthase (nNOS) expression, as determinant of a possible increased synthesis of NO/cGMP signaling. Interestingly, in HET mice the expression level of brain nNOS, measured by western blot and immune-histochemistry was significantly increased, particularly in interneurons from the striatum. In conclusion, the deficiency of PDE2A could be compensated in the striatum by upregulating nNOS/NO/cGMP pathway, which in turn likely upregulates PDE2A-dependent cAMP hydrolysis. The neuroanatomical correlation between striatal nNOS upregulation and the behavioral phenotype of increased exploratory behavior in HET mice is advanced., Competing Interests: Declaration of competing interest All the authors do not report any disclosures., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: A controversial aspect of pediatric septic shock management is corticosteroid therapy. Current guidelines do not recommend its use in forms responsive to fluids and inotropes but leave the decision to physicians in forms refractory to the first steps of therapy. Data Sources: Review of literature from January 2013 to December 2023 from online libraries Pubmed, Medline, Cochrane Library, and Scopus. Study Selection: The keywords "septic shock", "steroids" and "children" were used. Data Extraction: Of 399 articles, 63 were selected. Data Synthesis: Regarding mortality, although the 2019 Cochrane review supports reduced mortality, benefits on long-term mortality and in patients with CIRCI (critical illness-related corticosteroid insufficiency) are not clear. Yang's metanalysis and retrospective studies of Nichols and Atkinson show no difference or even an increase in mortality. Regarding severity, the Cochrane review claims that hydrocortisone seems to reduce the length of intensive care hospitalization but influences the duration of ventilatory and inotropic support, and the degree of multi-organ failure appears limited. Further controversies exist on adrenal function evaluation: according to literature, including the Surviving Sepsis Campaign guidelines, basal or stimulated hormonal dosages do not allow the identification of patients who could benefit from hydrocortisone therapy (poor reproducibility). Regarding side effects, muscle weakness, hypernatremia, and hyperglycemia are the most observed. Conclusions: The literature does not give certainties about the efficacy of corticosteroids in pediatric septic shock, as their influence on primary outcomes (mortality and severity) is controversial. A subgroup of patients suffering from secondary adrenal insufficiency could benefit from it, but it remains to be defined how to identify and what protocol to use to treat them.

A 62-year-old woman presented with multiple ileal and colonic stenoses, initially suspected to be Crohn's disease. Despite unremarkable endoscopic biopsies, surgery was performed due to clinical deterioration, and histological analysis confirmed the presence of metastatic breast cancer. This case highlights the importance of considering metastatic disease in the differential diagnosis of gastrointestinal (GI) strictures, particularly when inflammatory bowel disease markers are inconclusive or marginal. Clinicians should be aware of the potential for breast cancer to metastasize to the GI tract, which may present with symptoms mimicking primary GI diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

IgG4-related disease (IgG4-RD) is a chronic inflammatory condition characterized by tissue infiltration with IgG4-positive plasma cells, leading to fibrosis and organ dysfunction. While primarily affecting the pancreas, bile ducts, and salivary glands, IgG4-RD can also involve the gastrointestinal tract, raising questions about its relationship with inflammatory bowel disease (IBD). Recent studies suggest that patients with IBD may exhibit histological and serological features consistent with IgG4-RD, such as a dense lymphoplasmacytic infiltration, a storiform-type of fibrosis and a prominent IgG4 immune response. This overlap represents a diagnostic challenge, as differentiating between primary IBD and IgG4-RD involving the gut is crucial for appropriate treatment. Further research is essential to delineate the prevalence of tissue and serum IgG4 expression in patients with IBD. This approach could classify subtypes of IBD, enabling advancements in non-invasive diagnosis and monitoring as well as personalized therapies. The purpose of this review is to summarize the available evidence regarding intestinal involvement in IgG4-RD and the role of both serum and tissue IgG4 in inflammatory bowel diseases IBD., Competing Interests: Declaration of competing interest SB, CSM, JF and EDT declares no conflict of interest. Ferdinando D'Amico reports a relationship with Abbvie, Galapagos, Janssen, Omega Pharma, Sandoz, Takeda, and Tillotts that includes: speaking and lecture fees. Ferdinando D'Amico reports a relationship with Abvvie, Ferring, Galapagos, Janssen, and Nestlè that includes: board membership. Silvio Danese reports a relationship with Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix that includes: board membership, consulting or advisory, and speaking and lecture fees. Silvio Danese reports a relationship with Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda that includes: board membership, consulting or advisory, and speaking and lecture fees. Silvio Danese reports a relationship with MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor that includes: board membership, consulting or advisory, and speaking and lecture fees. Laurent Peyrin-Biroulet reports a relationship with Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine that includes: board membership, consulting or advisory, and speaking and lecture fees. Laurent Peyrin-Biroulet reports a relationship with Tillots, Vifor, HospiraPfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC- Pharma that includes: board membership, consulting or advisory, and speaking and lecture fees. Laurent Peyrin-Biroulet reports a relationship with Index Pharmaceuticals, Amgen, Sandoz, For- ward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, Theravance that includes: board membership, consulting or advisory, and speaking and lecture fees. 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Human telomeres (HTs) can form DNA G-quadruplex (G4), an attractive target for anticancer and antiviral drugs. HT-G4s exhibit inherent structural polymorphism, posing challenges for understanding their specific recognition by ligands. Here, we aim to explore the impact of different topologies within a small segment of the HT (Tel22) on its interaction with BRACO19, a rationally designed G4 ligand with high quadruplex affinity, already employed in in-vivo treatments. Our multi-technique approach is based on the combined use of a set of contactless spectroscopic tools. Circular dichroism and UV resonance Raman spectroscopy probe ligand-induced conformational changes in the G4 sequence, while UV-visible absorption, coupled with steady-state fluorescence spectroscopy, provides further insights into the electronic features of the complex, exploiting the photoresponsive properties of BRACO19. Overall, we find that modifying the topology of the unbound Tel22 through cations (K + or Na + ), serves as a critical determinant for ligand interactions and binding modes, thus influencing the HT-G4's assembly capabilities. Furthermore, we show how fluorescence serves as a valuable probe for recognizing cation-driven multimeric structures, which may be present in living organisms, giving rise to pathological forms., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: The Sequential Organ Failure Assessment (SOFA) score originated as a tool for assessing organ dysfunction in critical illness but has expanded to become an outcome measure in clinical trials. We aimed to assess how the SOFA score was used as the primary or secondary endpoint of major randomized controlled trials (RCTs)., Data Sources: Independent reviewers searched MEDLINE/PubMed, Scopus, and Embase databases., Study Selection: Articles were selected when they fulfilled: 1) RCT; 2) SOFA score was primary or secondary endpoint; and 3) published in the Lancet, New England Journal of Medicine, or Journal of the American Medical Association., Data Extraction: Data collection included study details, outcomes, statistical differences in SOFA score, choice of score statistics, timepoints of SOFA reporting, and how missing data and competing risks analysis were managed., Data Synthesis: Twenty-three RCTs had SOFA score as outcome measure, eight used it as primary endpoint. Daily maximum SOFA was the key statistic in 11 RCTs, delta SOFA was used in eight, and mean SOFA in four. Mean SOFA was most frequently chosen as primary endpoint (4/8, 50%). There were 18 different outcome assessment timepoints, ranging from 1 to 28 days. Three RCTs reported statistically significant difference in SOFA between groups. Handling of missing SOFA scores was not described in ten of 23 RCTs. When described, it varied from study to study with variable imputation methods and variable accounting for the competing risk of mortality and ICU discharge., Conclusions: There is major variability in the choice of summary statistic for SOFA score analysis and assessment timepoints, when using it as outcome measure in RCTs. There was either no information or great variability in the handling of missing values, use of imputation, and accounting for competing risk. The current use of SOFA scores in RCTs lacks sufficient reproducibility and statistical and methodological robustness., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Saltwater stands as the most prevalent liquid on Earth. Consequently, substantial interest has been directed toward its characterization, both as an independent system and as a solvent for complex structures such as biomacromolecules. In the last few decades, special emphasis was placed on the investigation of the hydration properties of ions for the fundamental role they play in numerous chemical processes. In this study, we employed multi-wavelength Raman spectroscopy to examine the hydration shell surrounding bromide ions in solutions of simple electrolytes, specifically lithium bromide, potassium bromide, and cesium bromide, at two different concentrations. Cation-induced differences among electrolytes were observed in connection to their tendency to form ion pairs. An increased sensitivity to reveal the structure of the first hydration shell was evidenced when employing ultraviolet excitation in the 228-266 nm range, under resonance conditions with the charge transfer transition to the solvent peaked at about 200 nm. Other than a significant increase in the Raman cross-section for the OH stretching band when shifting from pure water to the solution, a larger enhancement for the Raman signal of the H-O-H bending mode over the stretching vibration was observed. Thus, the bending band plays a crucial role in monitoring the H-bond structure of water around the anions related to the charge distribution within the first hydration shell of anions, being an effective probe of hydration phenomena., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Early gut microbiota (GM) dysbiosis can affect a child's health and has been linked to the onset of pathologies later in life. Breast milk is recognized as a major driver of the structure and dynamics of an infant's GM. In addition to nutritious and prebiotic compounds, milk contains a microbiota that is shaped by several maternal factors, including gut microorganisms and medications. However, the impact of the latter on the milk microbiota is still largely unknown. Here, we investigated the effects of amoxicillin on the milk microbiota and GM of lactating Göttingen Minipigs sows, a promising model for studying medication transfer during lactation., Methods: Three sows were given amoxicillin (7 mg/kg/day) for three weeks starting from the second week after farrowing. Fecal and milk samples were collected before and after treatment and profiled by 16S rRNA amplicon sequencing., Results: Göttingen Minipigs' milk microbiota showed similarities to that of humans and conventional sows, with minor compositional shifts after treatment. At the genus level, we observed a decrease in Staphylococcus and o&#95;Bacteroidales;Other;Other , and an increasing trend in the abundance of Streptococcus , Stenotrophomonas , f&#95;Rhodobacteraceae;Other , Proteiniclasticum , f&#95;Propionibacteriaceae;Other and Gemella . In contrast, as expected, the GM was strongly affected by amoxicillin, even at the phylum level., Conclusions: In addition to demonstrating the relevance of Göttingen Minipigs as a valid model for studying the impact of medications on maternal milk and GM, our findings suggest that the milk microbiota may be more stable during antibiotic treatment than the GM.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by growing incidence and prevalence around the world in the last few decades. The range of available existing treatment and strategies for its management is being implemented. Given the introduction of newly developed molecules and the lack of specific guidelines, drug positioning may represent a tough clinical challenge. UC management is mostly medical, and it has been shifting toward a more personalized approach with the aim to create a tailored strategy depending on the patient's profile. A treat-to target strategy seems to be the best approach to reach disease control as it allows to carry out therapeutic choices based on objective and specific parameters: histological, ultrasonographic, and molecular targets may add to the already used clinical, endoscopic, and biochemical targets. In addition, dual-targeted therapy has emerged as an attractive therapeutic strategy for patients not achieving remission. This review aims to provide an overview of the available strategies to raise the bar in UC., Competing Interests: The article processing charges for this publication have been waived under an educational grant from Takeda Pharmaceuticals Limited. F.D. has served as a speaker for Sandoz, Janssen, Galapagos, Omega Pharma, Takeda, and Tillotts; he also served as a consultant for Ferring and as an advisory board member for Galapagos, Abbvie, and Nestlè. S.D. has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma, and Vifor. L.P.-B. declares personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris, Thermo Fisher; grants from Abbvie, MSD, Takeda, Fresenius Kabi; stock options from CTMA. F.F. received consulting fees from Amgen, AbbVie, and lecture fees from Janssen and Pfizer. G.F. received consultancy fees from Ferring, MSD, AbbVie, Takeda, Janssen, Amgen, Sandoz, Samsung Bioepis, and Celltrion. M.A. has received consulting fees from Nikkiso Europe, Mundipharma, Janssen, AbbVie, Pfizer, and Ferring. The other authors have no conflict of interest to declare., (© The Author(s), 2024.)

Background and Aims: Subcutaneous (SC) formulations of infliximab (IFX) and vedolizumab (VDZ) are approved for the treatment of inflammatory bowel diseases (IBDs). Our aim was to evaluate the effectiveness of switching from intravenous (IV) to SC formulations of IFX and VDZ in IBDs., Methods: This multicentre, retrospective study collected data of adult patients with Crohn's disease (CD) or ulcerative colitis (UC) switched to SC IFX or VDZ. The primary endpoint was clinical remission at 12 months stratified based on timing of switch. A composite endpoint consisting of therapy discontinuation, reverse-switch, need for steroids, and drug optimization was evaluated. A multivariate analysis investigated the association between patients' characteristics and outcomes., Results: Two hundred and thirty-one patients (59% UC, 53% male, mean age 44 ± 15 years, 68% IFX) from 13 centres were included. The switch occurred at Week 6 in a third of cases (36%). Median time to switch was 13 months. Most patients switched to SC IFX and VDZ were in clinical remission at 3 (87% and 77%), 6 (86% and 83%) and 12 (63% and 60%) months. In the multivariate analysis, there was no difference in clinical remission rate at 12 months; however, patients switched at Week 6 had a higher rate of experiencing any therapeutic changes at 3 (false discovery rate (FDR) = .002), 6 (FDR <1 × 10 -10 ) or 12 months (FDR = .08). Clinical disease activity at baseline (only in UC) (FDR = .07) and previous exposure to biologics (FDR = .001) were risk factors for composite endpoint at 6 and 12 months., Conclusion: SC IFX and VDZ are effective in daily clinical practice in IBD patients. Switching patients in remission reduces the risk of negative outcomes., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Context: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, many probiotic products used for AAD are not supported by rigorous independent research, and often results in non-evidence-based usage. The overarching objective is to move research forward for the most well-studied Bifidobacterium strain. Objectives: The primary aim is to test the efficacy of high dose, BB-12-supplemented yogurt in preventing AAD, compared to yogurt without BB-12, in children receiving antibiotics. Other aims are to further assess the safety of yogurt supplemented with BB-12, and to carry out longitudinal community structure and gene expression analysis of fecal microbiota to evaluate the impact of high dose BB-12 in a pediatric population receiving antibiotics. The microbiota includes hundreds of species, and its disruption is hypothesized to be an important factor in the development of AAD. AIM 1: To test the efficacy of high dose, BB-12-supplemented yogurt in preventing AAD, compared to yogurt without BB-12, in children receiving antibiotics. Hypothesis: Children receiving antibiotics who receive the yogurt with BB-12 will demonstrate less diarrhea than those receiving a control yogurt without BB-12. This is a Phase II trial that requires additional safety evaluation of high dose BB-12. Hypotheses 3: Administration of antibiotics will alter the composition and gene expression profile of the gut microbiota in pediatric patients, and concomitant ingestion of BB-12 in yogurt will mitigate the antibiotic-induced disturbance in the gut microbiota, as identified using 16S rRNA and metatranscriptomic profiling. Study Design and Analysis: We will finish in the June 2023 a Phase II, randomized, doubleblinded controlled trial with allocation concealment. Setting: Capital Areal Primary Care Practice Based Research Network. Population Studied: 270 patients, ages 3-12 years, clinically diagnosed with a respiratory infection requiring 7-10 days of antibiotics. Interventions: The two arms are, BB-12-supplemented yogurt and non-supplemented control yogurt, in a 1:1 randomized allocation. Participants of all ages will be asked to consume the same dose, 100 ml, of product per day. The 100 ml serving of probiotic yogurt will deliver ≥1010 CFU of BB-12. The BB-12 probiotic was not be added., Competing Interests: Authors report none., (2023 Annals of Family Medicine, Inc.)

Introduction: Crohn's disease (CD) is a chronic inflammatory bowel disease affecting the entire gastrointestinal tract with a progressive and relapsing course. Achieving mucosal healing has emerged as a critical therapeutic goal, as it is associated with sustained clinical remission, reduced hospitalizations, and fewer surgery rates. Therefore, targeting mucosal healing is essential for long-term control in CD., Areas Covered: This review evaluates the efficacy of novel biologic therapies and small molecules in inducing mucosal healing, specifically targeting pathways like IL-12/23, IL-23, α4β7 integrins, Janus kinase 1 (JAK1), and sphingosine-1-phosphate receptor (S1PR) in adults (≥18 years) with moderate-to-severe CD. The rationale for selecting these specific pathways is their central role in modulating key inflammatory processes implicated in CD pathogenesis. We compare these therapies with placebo for both induction and maintenance of remission, based on a PubMed literature review for published articles and ClinicalTrials.gov for ongoing trials., Expert Opinion: Upadacitinib and anti-IL23p19 agents (risankizumab, guselkumab and mirikizumab) are promising advanced non-TNF-targeting therapies for inducing endoscopic remission and mucosal healing but further studies are needed to integrate mucosal healing into a broader definition of endoscopic response, with a unified and precise definition.

Background: Analysis of [18F]-Fluorodeoxyglucose (FDG) kinetics in cancer has been most often limited to the evaluation of the average uptake over relatively large volumes. Nevertheless, tumor lesions also contain inflammatory infiltrates whose cells are characterized by a significant radioactivity washout due to the hydrolysis of FDG-6P catalyzed by glucose-6P phosphatase. The present study aimed to verify whether voxel-wise compartmental analysis of dynamic imaging can identify tumor regions characterized by tracer washout. The study included 11 patients with lung cancer submitted to PET/CT imaging for staging purposes. Tumour was defined by drawing a volume of interest loosely surrounding the lesion and considering all inside voxels with a standardized uptake value (SUV) > 40% of the maximum. Eight whole-body scans were repeated after 20 min of dynamic imaging centered on the heart. Six parametric maps were generated progressively by computing a Patlak regression line for each voxel. Each analysis considered a different set of frames: starting with all eight frames, then the last seven frames, and so on, down to the last three frames., Results: Delaying the starting point of the compartmental analysis revealed a progressive increase in the prevalence of voxels with a negative slope. In the most delayed parametric map, these voxels represented 0.5-4.5% (median 2%) of the tumor volume. This effect was independent of tumor size and was predominantly located at the lesion borders., Conclusions: The voxel-wise parametric maps provided by compartmental analysis identify a measurable volume characterized by radioactivity washout. The spatial localization of this pattern is compatible with the recognized preferential site of inflammatory infiltrates populating the tumor stroma and might improve the power of FDG imaging in monitoring the effectiveness of treatments aimed at empowering the host immune response against cancer., Trial Registration: ClinicalTrials. The study was approved by the local ethical committee and it represented a single Institution ancillary trial within the expanded-access program for Nivolumab. NCT02475382. Registered 2015-06-16. URL: https://clinicaltrials.gov/study/NCT02475382?id=NCT02475382.&rank=1., (© 2024. The Author(s).)

Anthracyclines' cardiotoxicity involves an accelerated generation of reactive oxygen species. This oxidative damage has been found to accelerate the expression of hexose-6P-dehydrogenase (H6PD), that channels glucose-6-phosphate (G6P) through the pentose phosphate pathway (PPP) confined within the endoplasmic/sarcoplasmic reticulum (SR). To verify the role of SR-PPP in the defense mechanisms activated by doxorubicin (DXR) in cardiomyocytes, we tested the effect of this drug in H6PD knockout mice (H6PD -/- ). Twenty-eight wildtype (WT) and 32 H6PD -/- mice were divided into four groups to be treated with intraperitoneal administration of saline (untreated) or DXR (8 mg/Kg once a week for 3 weeks). One week thereafter, survivors underwent imaging of 18 F-deoxyglucose (FDG) uptake and were sacrificed to evaluate the levels of H6PD, glucose-6P-dehydrogenase (G6PD), G6P transporter (G6PT), and malondialdehyde. The mRNA levels of SR Ca 2+ -ATPase 2 (Serca2) and ryanodine receptors 2 (RyR2) were evaluated and complemented with Hematoxylin/Eosin staining and transmission electron microscopy. During the treatment period, 1/14 DXR-WT and 12/18 DXR-H6PD -/- died. At microPET, DXR-H6PD -/- survivors displayed an increase in left ventricular size (p < 0.001) coupled with a decreased urinary output, suggesting a severe hemodynamic impairment. At ex vivo analysis, H6PD -/- condition was associated with an oxidative damage independent of treatment type. DXR increased H6PD expression only in WT mice, while G6PT abundance increased in both groups, mismatching a generalized decrease of G6PD levels. Switching-off SR-PPP impaired reticular accumulation of Ca 2+ decelerating Serca2 expression and upregulating RyR2 mRNA level. It thus altered mitochondrial ultrastructure eventually resulting in a cardiomyocyte loss. The recognized vulnerability of SR to the anthracycline oxidative damage is counterbalanced by an acceleration of G6P flux through a PPP confined within the reticular lumen. The interplay of SR-PPP with the intracellular Ca 2+ exchanges regulators in cardiomyocytes configure the reticular PPP as a potential new target for strategies aimed to decrease anthracycline toxicity., (© 2023. The Author(s).)

Objective: Patients with symptomatic uncomplicated diverticular disease (SUDD) may have a disrupted gut microbiota. However, current data are from small sample studies, and reported associations vary widely across studies. We aimed to profile the fecal microbiota in SUDD patients enrolled in primary care., Methods: A retrospective study was conducted in SUDD ( N  = 72) and asymptomatic diverticulosis (AD) ( N  = 30), the latter serving as a control group., Results: No significant differences in alpha and beta diversity were found between SUDD and AD, but SUDD was discriminated by a higher relative abundance of the family Streptococcaceae and the genera Alistipes , Agathobacter , and Butyricimonas . Interestingly, the gut microbiota of SUDD patients stratified by the severity of abdominal pain [according to the visual analog scale (VAS)]. In particular, higher diversity and health-associated taxa (such as Bifidobacterium , Eubacterium coprostanoligenes group, and Dorea ) characterized mild (VAS score 1-3) SUDD, Proteobacteria , Veillonellaceae and Blautia moderate (VAS score 4-7) SUDD, and Prevotellaceae and Megasphaera severe (VAS score 8-10) SUDD., Conclusion: Our analysis suggests that specific taxa may be related to SUDD, but the associations vary depending on the severity of abdominal pain. In addition to advancing our ecological understanding of this complex disease, our findings may pave the way for the incorporation of gut microbiota profiling into clinical practice to aid patient management, including stratification and treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The differentiation between association and causation is a significant challenge in medical research, often further complicated by cognitive biases that erroneously interpret coincidental observational data as indicative of causality. Such misinterpretations can lead to misguided clinical guidelines and healthcare practice, potentially endangering patient safety and leading to inefficient use of resources., Methods: We conducted an extensive search of PubMed, Cochrane, and Embase databases up to March 2024, identifying circumstances where associations from observational studies were incorrectly deemed causal. These instances led to changes in clinical practice, embodying what we have termed the 'observational interpretation fallacy'., Results: Our search identified 16 notable cases where observational study-derived associations, initially thought to influence clinical practices and guidelines positively, were later contradicted by findings from randomised controlled trials or further studies, necessitating significant revisions in clinical practice., Conclusion: In many cases, misinterpretation of observational finding negatively affecting patient care and public health policies. Addressing and rectifying the observational interpretation fallacy is crucial for the progression of medical research and the maintenance of safe and effective clinical practice. It is imperative for health policymakers, clinicians, and the lay public to critically assess research outcomes and make health-related decisions based on a foundation of evidence-based medicine. This approach ensures the alignment of medical practices with the most current and robust scientific evidence, safeguarding patient welfare and optimising resource allocation., (© 2024 John Wiley & Sons Ltd.)

Several studies reported alterations of the human gut microbiota (GM) during COVID-19. To evaluate the potential role of the GM as an early predictor of COVID-19 at disease onset, we analyzed gut microbial samples of 315 COVID-19 patients that differed in disease severity. We observed significant variations in microbial diversity and composition associated with increasing disease severity, as the reduction of short-chain fatty acid producers such as Faecalibacterium and Ruminococcus , and the growth of pathobionts as Anaerococcus and Campylobacter . Notably, we developed a multi-class machine-learning classifier, specifically a convolutional neural network, which achieved an 81.5% accuracy rate in predicting COVID-19 severity based on GM composition at disease onset. This achievement highlights its potential as a valuable early biomarker during the first week of infection. These findings offer promising insights into the intricate relationship between GM and COVID-19, providing a potential tool for optimizing patient triage and streamlining healthcare during the pandemic.IMPORTANCEEfficient patient triage for COVID-19 is vital to manage healthcare resources effectively. This study underscores the potential of gut microbiota (GM) composition as an early biomarker for COVID-19 severity. By analyzing GM samples from 315 patients, significant correlations between microbial diversity and disease severity were observed. Notably, a convolutional neural network classifier was developed, achieving an 81.5% accuracy in predicting disease severity based on GM composition at disease onset. These findings suggest that GM profiling could enhance early triage processes, offering a novel approach to optimizing patient management during the pandemic., Competing Interests: The authors declare no conflict of interest.

Herein, we report a regiodivergent 1,n-dicarbofunctionalization of unactivated olefins enabled by a Ni-catalyzed radical relay that forges both C( sp 3 )-C( sp 3 ) and C( sp 2 )-C( sp 3 ) linkages, even at long-range. Initial studies support an intertwined scenario resulting from the merger of an atom-transfer radical addition (ATRA) and a chain-walking event, with site-selectivity being dictated by a judicious choice of the ligand backbone.

Background: Rib fractures are one of the most common traumatic injuries and may result in significant morbidity and mortality. Despite growing evidence, technological advances and increasing acceptance, surgical stabilization of rib fractures (SSRF) remains not uniformly considered in trauma centers. Indications, contraindications, appropriate timing, surgical approaches and utilized implants are part of an ongoing debate. The present position paper, which is endorsed by the World Society of Emergency Surgery (WSES), and supported by the Chest Wall Injury Society, aims to provide a review of the literature investigating the use of SSRF in rib fracture management to develop graded position statements, providing an updated guide and reference for SSRF., Methods: This position paper was developed according to the WSES methodology. A steering committee performed the literature review and drafted the position paper. An international panel of experts then critically revised the manuscript and discussed it in detail, to develop a consensus on the position statements., Results: A total of 287 studies (systematic reviews, randomized clinical trial, prospective and retrospective comparative studies, case series, original articles) have been selected from an initial pool of 9928 studies. Thirty-nine graded position statements were put forward to address eight crucial aspects of SSRF: surgical indications, contraindications, optimal timing of surgery, preoperative imaging evaluation, rib fracture sites for surgical fixation, management of concurrent thoracic injuries, surgical approach, stabilization methods and material selection., Conclusion: This consensus document addresses the key focus questions on surgical treatment of rib fractures. The expert recommendations clarify current evidences on SSRF indications, timing, operative planning, approaches and techniques, with the aim to guide clinicians in optimizing the management of rib fractures, to improve patient outcomes and direct future research., (© 2024. The Author(s).)

Acute Carotid Stent Thrombosis (ACST) is a rare complication of Carotid Artery Stenting (CAS) with a potentially fatal outcome. We report a case of ACST occurring five minutes after the end of a successful CAS procedure that was promptly treated by carotid stent-in-stent implantation using a new percutaneous strategy based on the creation of a modified embolic protection device. Following the procedure, we did not observe brain lesions suggestive of acute cerebral ischemic events at the CT scan performed at 48 hours, as well as no neurological deficits in the following days., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Unspecific bone uptake (UBU) related to [ 18 F]PSMA-1007 PET/CT imaging represents a clinical challenge. We aimed to assess whether a combination of clinical, biochemical, and imaging parameters could predict skeletal metastases in patients with [ 18 F]PSMA-1007 bone focal uptake, aiding in result interpretation. Methods: We retrospectively analyzed [ 18 F]PSMA-1007 PET/CT performed in hormone-sensitive prostate cancer (PCa) patients at 3 tertiary-level cancer centers. A fourth center was involved in performing an external validation. For each, a volume of interest was drawn using a threshold method to extract SUV max , SUV mean , PSMA tumor volume, and total lesion PSMA. The same volume of interest was applied to CT images to calculate the mean Hounsfield units (HU mean ) and maximum Hounsfield units. Clinical and laboratory data were collected from electronic medical records. A composite reference standard, including follow-up histopathology, biochemistry, and imaging data, was used to distinguish between PCa bone metastases and UBU. PET readers with less ( n = 2) or more ( n = 2) experience, masked to the reference standard, were asked to visually rate a subset of focal bone uptake ( n = 178) as PCa metastases or not. Results: In total, 448 bone [ 18 F]PSMA-1007 focal uptake specimens were identified in 267 PCa patients. Of the 448 uptake samples, 188 (41.9%) corresponded to PCa metastases. Ongoing androgen deprivation therapy at PET/CT ( P < 0.001) with determination of SUV max ( P < 0.001) and HU mean ( P < 0.001) independently predicted bone metastases. A composite prediction score, the bone uptake metastatic probability (BUMP) score, achieving an area under the receiver-operating-characteristic curve (AUC) of 0.87, was validated through a 10-fold internal and external validation ( n = 89 bone uptake, 51% metastatic; AUC, 0.92). The BUMP score's AUC was significantly higher than that of HU mean (AUC, 0.62) and remained high among lesions with HU mean in the first tertile (AUC, 0.80). A decision-curve analysis showed a higher net benefit with the score. Compared with the visual assessment, the BUMP score provided added value in terms of specificity in less-experienced PET readers (88% vs. 54%, P < 0.001). Conclusion: The BUMP score accurately distinguished UBU from bone metastases in PCa patients with [ 18 F]PSMA-1007 focal bone uptake at PET imaging, offering additional value compared with the simple assessment of the osteoblastic CT correlate. Its use could help clinicians interpret imaging results, particularly those with less experience, potentially reducing the risk of patient overstaging., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

To provide some glimpses on the possibility of shaping the human gut microbiome (GM) through probiotic exchange with natural ecosystems, here we explored the impact of 15 days of daily interaction with horses on the GM of 10 urban-living Italian children. Specifically, the children were in close contact with the horses in an "educational farm", where they spent almost 10 h/day interacting with the animals. The children's GM was assessed before and after the horse interaction using metabarcoding sequencing and shotgun metagenomics, along with the horses' skin, oral and fecal microbiomes. Targeted metabolomic analysis for GM-produced beneficial metabolites (i.e., short-chain fatty acids) in the children's feces was also performed. Interaction with horses facilitated the acquisition of health-related traits in the children's GM, such as increased diversity, enhanced butyrate production and an increase in several health-promoting species considered to be next-generation probiotics. Among these, the butyrate producers Facecalibacterium prausnitzii and F. duncaniae and a species belonging to the order Christensenellales. Interaction with horses was also associated with increased proportions of Eggerthella lenta , Gordonibacter pamelae and G. urolithinfaciens , GM components known to play a role in the bioconversion of dietary plant polyphenols into beneficial metabolites. Notably, no increase in potentially harmful traits, including toxin genes, was observed. Overall, our pilot study provides some insights on the existence of possible health-promoting exchanges between children and horses microbiomes. It lays the groundwork for an implemented and more systematic enrollment effort to explore the full complexity of human GM rewilding through exchange with natural ecosystems, aligning with the One Health approach., 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 The Authors. Published by Elsevier B.V.)

Background and Aim: Criteria for "difficult-to-treat" Inflammatory Bowel Disease (IBD) (DTT-IBD) have recently been proposed to standardize terminology. We aimed to evaluate the prevalence, characteristics, management, and outcomes of DTT-IBD., Methods: We conducted a retrospective study in two tertiary centers in Italy., Results: Among 1736 IBD patients treated with biologics/advanced small molecules, 430 (24.8%) met at least one DTT-IBD criterion, of which 331 (77%) failed at least 2 mechanisms of action.In ulcerative colitis (UC), left-sided and extended colitis were risk factors for DTT compared to proctitis (OR 6.55, 1.93-40.98, p=0.011; and OR 10.12, 3.01-63.14, p=0.002, respectively). In Crohn's disease (CD), multiple localizations (L3+L4) (OR 3.04, 1.09-8.34, p=0.03), stricturing (OR 2.24, 1.52-3.34, p<0.001) and penetrating (OR 2.33, 1.55-3.53, p<0.001) behaviors, and perianal disease (OR 2.49, 1.75-3.53, p<0.001) were the main risk factors for DTT.Delay in advanced treatment initiation was positively associated with DTT-CD (OR 1.74, 1.27-2.41 p=0.001) but protective in UC (OR 0.65, 0.45-0.93 p=0.019).The rates of symptomatic, biochemical, and endoscopic remission were lower in DTT-IBD compared to non-DTT-IBD. The difference was most evident for endoscopic remission (25% vs 62%).Drug persistency in each following line of treatment progressively decreased in CD and UC. All advanced drugs used in DTT-IBD had similar persistence., Conclusions: DTT-IBD was prevalent in approximately one-quarter of patients with IBD in a tertiary care setting. Certain IBD phenotypes and the delay in initiating treatment in CD were risk factors for DTT. Drug persistency decreased progressively with every subsequent line of therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Medical therapy is the cornerstone of ulcerative colitis (UC) management and aims to induce and maintain remission. In case of mild-to-moderate UC, mesalamine (5-ASA) is the first-line option. 5-ASA requires local release at the level of the inflamed mucosa to exert its therapeutic action. While rectal preparations are useful in distal colitis, in cases of UC of at least rectosigmoid extent, guidelines suggest the association of oral and rectal 5-ASA. Mesalamine with Multi Matrix System® technology (MMX mesalamine) is an oral, high-strength (1.2 g/tablet), once-daily formulation of 5-ASA, designed to provide delayed and prolonged release throughout the entire colon. Clinical trials demonstrated a strong efficacy in inducing and maintaining clinical and endoscopic remission in active mild-to-moderate UC. The efficacy is related to specific colonic drug-delivery, to its high-dosage and once-daily administration, thus improving patients' adherence and outcomes. The specific colonic-delivery is also associated with very low rates of systemic absorption and adverse events (AEs). With this comprehensive review we aimed to summarize current knowledge on MMX mesalamine in mild-to-moderate UC, in terms of clinical pharmacology, efficacy and safety, also compared to other 5-ASA products. In addition we provided an expert opinion on the topic, examining the implications on clinical practice., Competing Interests: Conflict of interest F D'Amico has served as a speaker for Sandoz, Janssen, Galapagos, and Omega Pharma; he has also served as advisory board member for Abbvie, Ferring, Galapagos, and Nestlè. L Peyrin-Biroulet has served as a speaker, consultant and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, Theravance. S Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferrin.g, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, NikkisoEurope GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor. The other authors declare no conflicts of interest., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Cognitive reserve (CR) is an expression of brain resilience in response to damage. Education, occupational experience and leisure activities are thought to increase CR and have beneficial effects on global cognition and cognitive decline in Parkinson's disease (PD). We aimed to disclose brain metabolic and dopaminergic correlates of CR in de-novo PD patients., Methods: Sixty-two drug-naïve de-novo PD patients underwent [ 18 F]FDG-PET and DAT-SPECT. CR was quantified through the Cognitive-Reserve-Index questionnaire including total-CR and 3 subscores (educational-CR, occupational-CR, leisure-CR). Specific binding ratios (SBRs) and Z-scores in basal ganglia were obtained with 'BasGan-V2'. Z-scores were used as dependent variables in general linear models to assess the interaction between dopaminergic function and CR. Voxel-based correlation between brain metabolism and CR-scores and between SBR and [ 18 F]FDG-PET was evaluated using SPM12 (P<0.05 FWE-corrected at peak and cluster level considered significant)., Results: Dopaminergic deficit in the most affected hemisphere (MAH) putamen was significantly less marked in higher CR patients (Z-score -1.7±0.1 highly-educated versus -2.1±0.1 poorly-educated, P<0.02). Total and leisure-related-CR resulted correlated directly with z-scores of the MAH putamen (P<0.018 and P<0.003) and inversely with brain metabolism in both cerebellar hemispheres (P<0.001). MAH-putamen SBR correlated directly with metabolism in occipital and parietal cortex (P<0.003) and inversely in cerebellar hemispheres (P<0.02)., Conclusions: CR proxies demonstrated to correlate directly with dopaminergic function and inversely with metabolism in cerebellar hemispheres in de-novo PD patients. The present multi-modal approach including both metabolic and dopaminergic correlates of CR allowed to identify possible compensation mechanisms, highlighting a potential role of the cerebellum that deserves further investigation.

Objectives: Aim of this study was to identify risk factors for a progression to cystic fibrosis (CF) in individuals detected as CF Screening Positive, Inconclusive Diagnosis (CFSPID)., Methods: This is a systematic review through literature databases (2015-2023). Blood immunoreactive trypsinogen (b-IRT) values, CFTR genotype, sweat chloride (SC) values, isolation of Pseudomonas aeruginosa (Pa) from respiratory samples, Lung Clearance Index (LCI) values in CFSPIDs who converted to CF (CFSPID > CF) and age at CF transition were assessed., Results: Percentage of CFSPID > CF varies from 5.3 % to 44 %. Presence of one CF-causing CFTR variant in trans with a variant with variable clinical consequences (VVCC), an initial SC ≥ 40 mmol/L, an increase of SC > 2.5 mmol/L/year and recurrent isolation of pseudomonas aeruginosa (Pa) from airway samples could allow identification of subjects at risk of progression to CF., Conclusions: CFSPIDs with CF causing variant/VVCC genotype and first SC in the higher borderline range may require more frequent and prolonged clinical follow-up., 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 Author(s). Published by Elsevier Ltd.. All rights reserved.)

Oral HPV infection is the main risk factor for the development of oropharyngeal carcinoma. Men who have sex with men (MSM), especially if living with HIV (PLWH), are at increased risk of infection and consequently of cancer development. Aim of this study is to evaluate the impact of nonavalent vaccine on oral HPV infection in a cohort of MSM and transgender women (TGW). This prospective study included all MSM and TGW who started nonavalent HPV vaccination from May 2019 to September 2021. Oral rinse was collected before each vaccine administration and after six months of follow up. Descriptive statistics were used. Kaplan Meier probability curves and Cox regression models for HPV acquisition and clearance were calculated. The analysis included 211 individuals (202 MSM and 9 TGW). PLWH were 138 (65.4%). Baseline oral rinse was positive in 30 subjects (14.2%). Positivity rate did not change over time (p = 0.742), even when restricting the analysis only to high-risk genotypes (p = 0.575) and to genotypes covered by vaccine (p = 0.894). The risk to acquire HPV infection was 12.8% at one year and 33.4% at two years after vaccination. The probability to clear the infection was 67.6% at one year and 87.9% at two years. HIV infection had no impact on vaccine efficacy. Age above 45 years was the only factor associated to HPV acquisition (aHR 4.06, 95% CI 1.03-15.98, p = 0.045). Prevalence of oral HPV infection was higher in PLWH, but HIV had no impact on viral clearance or acquisition after vaccination., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Hypotension is associated with adverse outcomes in critically ill and perioperative patients. However, these assumptions are supported by observational studies. This meta-analysis of randomized controlled trials aims to compare the impact of lower versus higher blood pressure targets on mortality., Data Sources: We searched PubMed, Cochrane, and Scholar from inception to February 10, 2024., Study Selection: Randomized trials comparing lower versus higher blood pressure targets in the management of critically ill and perioperative settings., Data Extraction: The primary outcome was all-cause mortality at the longest follow-up available. This review was registered in the Prospective International Register of Systematic Reviews, CRD42023452928., Data Synthesis: Of 2940 studies identified by the search string, 28 (12 in critically ill and 16 in perioperative settings) were included totaling 15,672 patients. Patients in the low blood pressure target group had lower mortality (23 studies included: 1019/7679 [13.3%] vs. 1103/7649 [14.4%]; relative risk 0.93; 95% CI, 0.87-0.99; p = 0.03; I2 = 0%). This corresponded to a 97.4% probability of any increase in mortality with a Bayesian approach. These findings were mainly driven by studies performed in the ICU setting and with treatment lasting more than 24 hours; however, the magnitude and direction of the results were similar in the majority of sensitivity analyses including the analysis restricted to low risk of bias studies. We also observed a lower rate of atrial fibrillation and fewer patients requiring transfusion in low-pressure target groups. No differences were found in the other secondary outcomes., Conclusions: Based on pooled randomized trial evidence, a lower compared with a higher blood pressure target results in a reduction of mortality, atrial fibrillation, and transfusion requirements. Lower blood pressure targets may be beneficial but there is ongoing uncertainty. However, the present meta-analysis does not confirm previous findings and recommendations. These results might inform future guidelines and promote the study of the concept of protective hemodynamics., Competing Interests: Dr. Lee’s institution received funding from the Canadian Institutes of Health Research; he received funding from Fonds de Recherche Quebec—Sante. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Current management of mild-to-moderate ulcerative colitis (UC) involves monitoring clinical markers of disease activity, such as stool frequency (SF) and rectal bleeding (RB), and adjusting treatment accordingly. Our aim was to assess whether targeting treatment based on faecal calprotectin (FC) levels (treat-to-target; T2T) provides greater UC disease control versus a symptom-based approach. Methods: This was a pragmatic, randomised (1:1) controlled study of patients with mild-to-moderate UC (global Mayo score 2-6) treated with ≤2.4 g/day 5-aminosalicylic acid that compared the effectiveness of two management strategies with (interventional arm) and without (reference arm) FC home monitoring over 12 months of follow-up. Treatment was optimised in the interventional arm using FC values and clinical symptoms (PRO-2), while the reference arm used only PRO-2. Results: 193 patients completed the study. No significant difference was found for the primary endpoint (Mayo Endoscopic Subscore [MES] = 0 at 12 months). A numerical advantage for the interventional arm over the reference arm for the primary endpoint (37.0% vs. 33.4%, respectively) and for MES ≤ 1, RB = 0, and SF ≤ 1 at 12 months was found following imputation for missing data. The composite endpoint of MES = 0, RB = 0, and SF ≤ 1 at 12 months was achieved at a significantly higher rate in the interventional arm than the reference arm (effect size [ES]: 0.17, 95% CI 0.02-0.32; p < 0.05). A similar result was obtained for MES ≤ 1, RB = 0 and SF ≤ 1 (ES: 0.22; 95% CI 0.07-0.37; p < 0.05). Conclusions: T2T using FC monitoring was effective in patients with mild-to-moderate UC at 12 months. Further longer-term studies are required to confirm the results.

Infectious diseases affecting the gastrointestinal tract often present diagnostic challenges due to the variability in clinical manifestations and overlapping symptoms. Ultrasound imaging has emerged as a valuable tool in the assessment of gastrointestinal pathologies, offering non-invasive and real-time visualization of anatomical structures. This review aims to explore the role of ultrasound in the diagnosis and management of infectious diseases involving the gastrointestinal tract. We discuss the imaging features of various infectious etiologies, such as bacterial, viral, and parasitic infections, highlighting characteristic findings on ultrasound scans. Additionally, we provide insights into the utility of ultrasound for the assessment of treatment response. Through a comprehensive analysis of existing literature and clinical case studies, this review underscores the significance of ultrasound imaging as a frontline modality in the diagnosis and management of infectious diseases affecting the gastrointestinal tract.

Gut microbiota dysbiosis has a critical role in the pathogenesis of inflammatory bowel diseases, prompting the exploration of novel therapeutic approaches like fecal microbiota transplantation, which involves the transfer of fecal microbiota from a healthy donor to a recipient with the aim of restoring a balanced microbial community and attenuating inflammation. Fecal microbiota transplantation may exert beneficial effects in inflammatory bowel disease through modulation of immune responses, restoration of mucosal barrier integrity, and alteration of microbial metabolites. It could alter disease course and prevent flares, although long-term durability and safety data are lacking. This review provides a summary of current evidence on fecal microbiota transplantation in inflammatory bowel disease management, focusing on its challenges, such as variability in donor selection criteria, standardization of transplant protocols, and long-term outcomes post-transplantation.

Patients with inflammatory bowel diseases (IBDs), including both ulcerative colitis (UC) and Crohn's disease (CD), are at a higher risk of developing colorectal cancer (CRC). However, advancements in endoscopic imaging techniques, integrated surveillance programs, and improved medical therapies have led to a decrease in the incidence of CRC among IBD patients. Currently, the management of patients with IBD who have a history of or ongoing active malignancy is an unmet need. This involves balancing the risk of cancer recurrence/progression with the potential exacerbation of IBD if the medications are discontinued. The objective of this review is to provide an updated summary of the epidemiology, causes, risk factors, and surveillance approaches for CRC in individuals with IBD, and to offer practical guidance on managing IBD patients with history of previous or active cancer., Competing Interests: J. Fanizza declares no conflict of interest. S. Bencardino declares no conflict of interest. F. D&rsquo;Amico has served as a speaker for AbbVie, Sandoz, Janssen, Galapagos, Takeda, Ferring, Tillotts, and Omega Pharma; he has also served as an advisory board member for Ferring, Galapagos, AbbVie, Janssen, and Nestl&egrave;. M. Allocca received consulting fees from Nikkiso Europe, Mundipharma, Janssen, Abbvie, and Pfizer. F. Furfaro received consulting fees from Amgen and Abbvie and lecture fees from Janssen and Pfizer. A. Zilli declares no conflict of interest. T.L. Parigi declares no conflict of interest. L Peyrin-Biroulet declares consulting fees from AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax; he also declares grants from Takeda, Fresenius Kabi, Celltrion; he also has served as a speaker for Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Lilly, Gilead, Viatris, Medac. S. Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millenium Takeda, MSD, Nikkiso Europe, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma, and Vifor.

The high salt-fed stroke-prone spontaneously hypertensive rat (SHRSP) is a suitable tool to study the mechanisms underlying stroke pathogenesis. Salt intake modifies the gut microbiota (GM) in rats and humans and alterations of the GM have previously been associated with increased stroke occurrence. We aimed to characterize the GM profile in SHRSPs fed a high-salt stroke-permissive diet (Japanese diet, JD), compared to the closely related stroke-resistant control (SHRSR), to identify possible changes associated with stroke occurrence. SHRSPs and SHRSRs were fed a regular diet or JD for 4 weeks (short-term, ST) or a maximum of 10 weeks (long-term, LT). Stroke occurred in SHRSPs on JD-LT, preceded by proteinuria and diarrhoea. The GM of JD-fed SHRSPs underwent early and late compositional changes compared to SHRSRs. An overrepresentation of Streptococcaceae and an underrepresentation of Lachnospiraceae were observed in SHRSPs JD-ST, while in SHRSPs JD-LT short-chain fatty acid producers, e.g. Lachnobacterium and Faecalibacterium, decreased and pathobionts such as Coriobacteriaceae and Desulfovibrio increased. Occludin gene expression behaved differently in SHRSPs and SHRSRs. Calprotectin levels were unchanged. In conclusion, the altered GM in JD-fed SHRSPs may be detrimental to gut homeostasis and contribute to stroke occurrence., (© 2024. The Author(s).)

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) that frequently affects the small bowel. Individuals diagnosed with CD are at increased risk of developing bowel cancer compared to the general population. Small bowel cancer is a rare but significant CD complication. Adenocarcinoma represents the most prevalent of these neoplasms, followed by neuroendocrine tumors and sarcomas. The primary risk factors identified are being of the male sex, disease duration, previous surgical intervention, perianal disease, and chronic inflammation. The precise etiology remains unclear. Another crucial issue concerns the role of immunomodulators and advanced therapies. By inhibiting inflammation, these therapies can reduce the risk of cancer, which is often initiated by the inflammation-dysplasia-adenocarcinoma sequence. In accordance with the most recent guidelines, it is not necessary to conduct surveillance in patients with small bowel cancer among CD patients, as it is considered a rare disease. Nevertheless, it is of significant importance for gastroenterologists to be aware of this potential CD complication, as well as the patients who are most at risk of developing it. The purpose of this review is to provide a comprehensive overview of CD-SBC, focusing on epidemiology, etiopathogenesis, risk factors, diagnosis, and the role of advanced therapies in CD-SBC.

Takotsubo syndrome (TTS), also known as the broken-heart syndrome, is a reversible condition typically observed in female patients presenting for acute coronary syndromes (ACS). Despite its increasing incidence, TTS often remains undiagnosed due to its overlap with ACS. The pathophysiology of TTS is complex and involves factors such as coronary vasospasm, microcirculatory dysfunction, increased catecholamine levels, and overactivity of the sympathetic nervous system. Diagnosing TTS requires a comprehensive approach, starting with clinical suspicion and progressing to both non-invasive and invasive multimodal tests guided by a specific diagnostic algorithm. Management of TTS should be personalized, considering potential complications, the presence or absence of coronary artery disease (CAD), diagnostic test results, and the patient's clinical course. The current data primarily derive from case series, retrospective analyses, prospective registries, and expert opinions. In recent years, there has been growing recognition of gender differences in the pathophysiology, presentation, and outcomes of TTS. This review provides an updated overview of gender disparities, highlighting the importance of tailored diagnostic and management strategies.

The inflammatory bowel diseases (IBDs) are systemic conditions that affect not only the gastrointestinal tract but also other parts of the body. The presence of extraintestinal manifestations can significantly impact the quality of life in IBD patients. Peripheral arthritis, episcleritis, and erythema nodosum are frequently associated with active intestinal inflammation and often improve with standard treatment targeting intestinal inflammation. In contrast, anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis typically occur independently of disease flares. The incidence of these conditions in individuals with IBD can reach up to 50% of patients over the course of their lifetime. In addition, some advanced therapies utilized for the treatment of IBD potentially result in side effects that may resemble extraintestinal manifestations. This review provides a thorough analysis of the pathophysiology and treatment of extraintestinal manifestations associated with Crohn's disease and ulcerative colitis.

Objective: The aim of this study was to describe the surgeon's ability to accurately predict the margin following resection of colorectal liver metastases (CRLMs)., Background: The decision to resect CRLM is based on the surgeon's ability to predict tumor-free resection margins. However, to date, no study has evaluated the accuracy of surgeon margin prediction., Methods: In this single-institution prospective study, the operating attending and fellow independently completed a preoperative and postoperative questionnaire describing their expected resection margin in 100 consecutive cases (200 assessments) of CRLM resections. In cases with multiple metastases, the closest margin was assessed as the margin of interest for the primary outcome. Surgeon assessments were compared with the gold-standard histopathologic assessment., Results: After excluding aborted cases, 190 preoperative and 190 postoperative assessments from 95 cases were included in the analysis. The pathologic margin was noted to be wide (≥1 cm), 1 mm to 1 cm, narrow (<1 mm), and positive in 28 (29.5%), 55 (57.9%), 5 (5.3%), and 7 (7.4%) cases, respectively. The 88 cases with negative margins were all predicted to be negative. None of the cases with positive margins were predicted to be positive. Ninety-one (48%) preoperative and 104 (55%) postoperative predictions were accurate. The sensitivity of predicting a margin <1 mm was 8.3% preoperatively and 16.7% postoperatively. The positive predictive value for preoperative and postoperative predictions of margin <1 mm was 18.2% and 26.7%, respectively., Conclusions: Surgeons are inaccurate at predicting positive and close surgical margins following resection of CRLM. A predicted close margin should not necessarily preclude resection., Competing Interests: A.C.W. consults for Biosapien and Histosonics and received honorarium for teaching by Medtronic and AstraZeneca. J.A.D.’s spouse is employed by American Regent Pharmaceuticals. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Although there are well-defined guidelines for the management of mild-to-moderate ulcerative colitis (UC), there are still unmet needs. For this reason, we conducted an international expert consensus to standardize the management of patients with mild-to-moderate UC and provide practical guidance to clinicians., Areas Covered: Based on Delphi methodology, 15 statements were approved after two rounds of voting, addressing several aspects of disease management from sequencing to treatment duration, from monitoring to optimization techniques and safety profile., Expert Opinion: Growing knowledge of mild-to-moderate UC has led to the development of new ambitious outcomes such as histological remission and disease clearance. Furthermore, noninvasive tools for patient monitoring such as fecal calprotectin and intestinal ultrasound are now available. Their implementation in clinical practice will allow clinicians to tightly monitor disease activity and promptly adapt treatment, avoiding complications and disease progression and targeting better disease control.

Immune-mediated gastrointestinal (GI) diseases, including achalasia, celiac disease, and inflammatory bowel diseases, pose significant challenges in diagnosis and management due to their complex etiology and diverse clinical manifestations. While genetic predispositions and environmental factors have been extensively studied in the context of these conditions, the role of viral infections and virome dysbiosis remains a subject of growing interest. This review aims to elucidate the involvement of viral infections in the pathogenesis of immune-mediated GI diseases, focusing on achalasia and celiac disease, as well as the virome dysbiosis in IBD. Recent evidence suggests that viral pathogens, ranging from common respiratory viruses to enteroviruses and herpesviruses, may trigger or exacerbate achalasia and celiac disease by disrupting immune homeostasis in the GI tract. Furthermore, alterations in the microbiota and, specifically, in the virome composition and viral-host interactions have been implicated in perpetuating chronic intestinal inflammation in IBD. By synthesizing current knowledge on viral contributions to immune-mediated GI diseases, this review aims to provide insights into the complex interplay between viral infections, host genetics, and virome dysbiosis, shedding light on novel therapeutic strategies aimed at mitigating the burden of these debilitating conditions on patients' health and quality of life.

Emergency general surgeons often provide care to severely ill patients requiring surgical interventions and intensive support. One of the primary drivers of morbidity and mortality is perioperative bleeding. In general, when addressing life threatening haemorrhage, blood transfusion can become an essential part of overall resuscitation. However, under all circumstances, indications for blood transfusion must be accurately evaluated. When patients decline blood transfusions, regardless of the reason, surgeons should aim to provide optimal care and respect and accommodate each patient's values and target the best outcome possible given the patient's desires and his/her clinical condition. The aim of this position paper was to perform a review of the existing literature and to provide comprehensive recommendations on organizational, surgical, anaesthetic, and haemostatic strategies that can be used to provide optimal peri-operative blood management, reduce, or avoid blood transfusions and ultimately improve patient outcomes., (© 2024. The Author(s).)