Effect of Tofacitinib on One-Year Colectomy Risk in Anti-TNF Refractory Ulcerative Colitis: A Prospective Multicenter Italian Study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor recently approved to induce and maintain remission in ulcerative colitis (UC). AIMS: Considering the number of anti-TNF non-responders, this study aims to assess the effectiveness and safety of tofacitinib in a cohort of multi-failure patients with moderate-to-severe UC at 52 weeks. METHODS: From January 2021 to March 2023, we performed a prospective multicenter study observing adult patients with moderate-to-severe UC starting tofacitinib after an anti-TNF failure for a 52-week-long period. Effectiveness and safety were assessed in terms of colectomy rate, clinical remission and response, endoscopic remission, steroid-free clinical remission, and rate of adverse events. RESULTS: We included 58 patients with UC with an age of 42 ± 14.4 years, 59% males, 96.6% left-sided or pancolitis, who were failure to a single (65.5%) or more than one anti-TNF (34.5%). Only 6 (10.3%) patients underwent colectomy. Colectomy was clinically associated with the necessity and the number of extra cycles of tofacitinib 10 mg bid at W8 (p = 0.023) and W24 (p = 0.004), and with a higher partial Mayo score at W8 (p = 0.025). At W52, clinical remission, clinical response, and steroid-free clinical remission were 53.4%, 43.1%, and 48.3%, respectively. Of 22 performed colonoscopies at W52, 11 (50%) showed endoscopic remission. Adverse events occurred in 14 (24.1%) patients, but only 2 (3.4%) led to tofacitinib discontinuation. CONCLUSIONS: In a real-life setting of patients with anti-TNF refractory UC, tofacitinib has proved to be effective in preventing colectomy and inducing clinical and endoscopic remission at 52 weeks with a good safety profile.

Superior predictive value of transmural over endoscopic severity for colectomy risk in ulcerative colitis: a multicentre prospective cohort study.

BACKGROUND AND AIMS: Endoscopic activity is associated with an increased risk of surgery in patients with ulcerative colitis [UC]. Transmural activity, as defined by Milan Ultrasound Criteria [MUC] > 6.2, reliably detects endoscopic activity in patients with UC. The present study aimed to assess in UC patients whether transmural severity is a better predictor of colectomy as compared to endoscopy. METHODS: Consecutive adult UC patients were recruited in two IBD Referral Centres and underwent colonoscopy and intestinal ultrasound in a blinded fashion. The need for colectomy was assessed at follow-up. Univariable and multivariable logistic and Cox regression analyses were performed. Receiver operating characteristic [ROC] analysis was used to compare MUC baseline values and Mayo Endoscopic Scores [MES] in predicting colectomy risk. RESULTS: Overall, 141 patients were enrolled, and 13 underwent colectomy in the follow-up period. Both MES (hazard ratio [HR]: 3.15, 95% confidence interval [CI]: 1.18-8.37, p = 0.02) and MUC [HR: 1.48, 95% CI: 1.19-1.76, p < 0.001] were associated with colectomy risk, but only MUC was independently associated with this event on multivariable analysis [HR: 1.46, 95% CI: 1.06-2.02, p = 0.02]. MUC was the only independent variable associated with colectomy risk in patients with clinically active disease (odds ratio [OR]: 1.53 [1.03-2.27], p = 0.03). MUC demonstrated higher accuracy than MES (area under ROC curve [AUROC] 0.83, 95% CI: 0.75-0.92 vs 0.71, 95% CI: 0.62-0.80) and better performance for predicting colectomy [p = 0.02]. The optimal MUC score cut-off value for predicting colectomy, as assessed by the Youden index, was 7.7. CONCLUSIONS: A superior predictive value was found for transmural vs endoscopic severity for colectomy risk in UC patients.

Reproducibility and accuracy of a pocket-size ultrasound device in assessing liver steatosis.

BACKGROUND: This diagnostic prospective study compared the feasibility and diagnostic accuracy of Pocket-size Ultrasound Devices (PUDs) against standard ultrasound (US) in detecting liver steatosis using the controlled attenuation parameter (CAP) and liver biopsy as reference standards. MATERIALS AND METHODS: Consecutive patients with chronic liver diseases were assessed for the presence of steatosis using PUD and US. A CAP cut-off value >275 dB/m was applied to establish ≥S1. A 26-patient subgroup underwent liver biopsy. PUD reproducibility was evaluated using Cohen's k statistic. Diagnostic accuracy of PUD and US was given as Sensibility (Sn), Specificity (Sp), Positive and Negative Predictive Values (PPV, NPV), positive and negative Likelihood Ratio (LR+, LR-). RESULTS: 81 consecutive patients (69% males) with multiple etiologies were enroled. PUD inter-observer agreement was good (k 0.77, 95%CI 0.62-0.93). PUD and US identified ≥S1 according to CAP values respectively with Sn 0.87, Sp 0.61, PPV 0.49, NPV 0.91, LR+ 2.04, LR- 0.07, AUROC 0.74 and Sn 0.96, Sp 0.54, PPV 0.47, NPV 0.97, LR+ 2.10, LR- 0.07, AUROC 0.75. CONCLUSIONS: PUD shows good reproducibility and diagnostic accuracy in ruling liver steatosis out, representing a useful point-of-care tool to avail of hepatologists interested in excluding NAFLD, but with basic US skills.

Safety and clinical efficacy of the double switch from originator infliximab to biosimilars CT-P13 and SB2 in patients with inflammatory bowel diseases (SCESICS): A multicenter cohort study.

Data regarding double switching from originator infliximab (IFX) to IFX biosimilars in inflammatory bowel diseases (IBDs) are lacking. The purpose of this study was to evaluate the safety and efficacy of switching from originator IFX to CT-P13 and subsequently to SB2 (double switch) in patients with IBD. Patients undergoing IFX-double switch in eight Centers in Lombardy (Italy) from November 2018 to May 2019 were retrospectively analyzed. The IFX discontinuation rate, incidence and type of adverse events (AEs), and clinical remission rate were recorded. A comparison with a control group of patients with IBD single-switched from originator IFX to CT-P13 was performed, before and after an inverse probability of treatment weighting (IPTW)-based propensity score analysis. Fifty-two double-switched patients with IBD were enrolled. The 24- and 52-week proportions of patients continuing on IFX therapy following the second switch (CTP13 â†’ SB2) were 98% (95% confidence interval [CI] 94%-100%) and 90% (95% CI 81%-99%), respectively. Four patients experienced a total of five AEs, all graded 1-3 according to Common Terminology Criteria for Adverse Events (CTCAE). No infusion reactions were observed. The 24-week and follow-up end clinical remission rates following the second switch were 94% and 88%, respectively. No differences were observed in the safety and efficacy outcomes by comparing the double-switch group with a single-switch group of 66 patients with IBD; all these results were confirmed by IPTW-adjusted analysis. The study suggests both the safety and efficacy of the double switch from originator IFX to CT-P13 and SB2 in patients with IBD is maintained. This strategy may be associated with potential cost implications.

Ionized or Total Magnesium levels, what should we measure in critical ill patients?

Monitoring and measuring magnesium (Mg) values are essential to prevent the development of numerous complications in perioperative medicine and critically ill patients. Although previous studies suggest that measuring free ionized magnesium (iMg) is more useful for estimating Mg status, clinicians currently rely on measurement of total serum magnesium to determine if supplemental magnesium is needed. In this review, we analyzed the recent literature to decide whether it is better to measure ionized serum Mg or total serum Mg when assessing magnesium status, whether iMg predicts clinical outcome, and what are the difficulties in measuring serum iMg levels in intensive care patients and perioperative medicine.

Effect Of α2-Adrenergic Agonists And Antagonists On Cytokine Release From Human Lung Macrophages Cultured In Vitro.

The most trusted hypothesis to explain how α2-adrenergic agonists may preserve pulmonary functions in critically ill patients is that they directly act on macrophages by interfering with an autocrine/paracrine adrenergic system that controls cytokine release through locally synthetized noradrenaline and α1- and α2-adrenoreceptors. We tested this hypothesis in primary cultures of resident macrophages from human lung (HLMs). HLMs were isolated by centrifugation on percoll gradients from macroscopically healthy human lung tissue obtained from four different patients at the time of lung resection for cancer. HLMs from these patients showed a significant expression of α2A, α2B and α2C adrenoreceptors both at the mRNA and at the protein level. To evaluate whether α2 adrenoreceptors controlled cytokine release from HMLs, we measured IL-6, IL-8 and TNF-α concentrations in the culture medium in basal conditions and after preincubation with several α2-adrenergic agonists or antagonists. Neither the pretreatment with the α2-adrenergic agonists clonidine, medetomidine or dexdemetomidine or with the α2-adrenergic antagonist yohimbine caused significant changes in the response of any of these cytokines to LPS. These results show that, different from what reported in rodents, clonidine and dexdemetomidine do not directly suppress cytokine release from human pulmonary macrophages. This suggests that alternative mechanisms such as effects on immune cells activation or the modulation of autonomic neurotransmission could be responsible for the beneficial effects of these drugs on lung function in critical patients.

Navigator® and SmartPilot® View are helpful in guiding anesthesia and reducing anesthetic drug dosing.

BACKGROUND: The recently introduced Navigator® (GE Healthcare, Helsinki, Finland) and SmartPilot® View (Dräger Medical, Lübeck, Germany) show the concentrations and predicted effects of combined anesthetic drugs, and should facilitate more precisely their titration. Our aim was to evaluate if Navigator® or SmartPilot® View guided anesthesia was associated with a good quality of analgesia, depth of hypnosis and may reduce anesthetic requirements. METHODS: We performed a prospective non-randomized study. Sixty ASA I-II patients undergoing balanced general anesthesia for abdominal and plastic surgery were enrolled. Patients were divided in 4 groups. Group 1 (N. 15) and group 3 (N. 15) were cases in whom anesthesia was performed with standard monitoring plus the aid of Navigator® (Nav) or SmartPilot® View (SPV) display. Group 2 (N. 15) and group 4 (N. 15) were controls in whom anesthesia was performed with standard monitoring (heart rate, NIBP, SpO2, end-tidal CO2, end-expired sevoflurane concentration, train of four, Bispectral Index [Aspect Medical Systems, Natick, MA, USA] or Entropy [GE Healthcare]). Patients' vital parameters and end-expired sevoflurane concentration were recorded during anesthesia. RESULTS: All patients recovered uneventfully and showed hemodynamic stability. End-tidal sevoflurane concentrations values [median (min-max)], during maintenance of anesthesia, were significantly (P<0.05) lower in SPV [1.1% (0.8-1.5)] and Nav [1%(0.8-1.8)] groups compared to SPV-control group [1.5%(1-2.5)] and Nav-control group [1.5%(0.8-2)]. BIS and entropy values were respectively higher in the SPV group [53 (46-57)] compared to the control group [43 (37-51)] (P<0.05) and Nav group [53 (43-60)] compared to the control group [41 (35-51)] (P<0.05). No significant differences in Remifentanil dosing were observed in the four groups. CONCLUSION: Navigator® and SmartPilot® View may be of clinical use in monitoring adequacy of anesthesia. Both displays can optimize the administration and monitoring of anesthetic drugs during general anesthesia and may reduce the consumption of volatile anesthetic agents.

Coagulopathy induced by acidosis, hypothermia and hypocalcaemia in severe bleeding.

Acidosis, hypothermia and hypocalcaemia are determinants for morbidity and mortality during massive hemorrhages. However, precise pathological mechanisms of these environmental factors and their potential additive or synergistic anticoagulant and/or antiplatelet effects are not fully elucidated and are at least in part controversial. Best available evidences from experimental trials indicate that acidosis and hypothermia progressively impair platelet aggregability and clot formation. Considering the cell-based model of coagulation physiology, hypothermia predominantly prolongs the initiation phase, while acidosis prolongs the propagation phase of thrombin generation. Acidosis increases fibrinogen breakdown while hypothermia impairs its synthesis. Acidosis and hypothermia have additive effects. The effect of hypocalcaemia on coagulopathy is less investigated but it appears that below the cut-off of 0.9 mmol/L, several enzymatic steps in the plasmatic coagulation system are blocked while above that cut-off effects remain without clinical sequalae. The impact of environmental factor on hemostasis is underestimated in clinical practice due to our current practice of using routine coagulation laboratory tests such as partial thromboplastin time or prothrombin time, which are performed at standardized test temperature, after pH correction, and upon recalcification. Temperature-adjustments are feasible in viscoelastic point-of-care tests such as thrombelastography and thromboelastometry which may permit quantification of hypothermia-induced coagulopathy. Rewarming hypothermic bleeding patients is highly recommended because it improves patient outcome. Despite the absence of high-quality evidence, calcium supplementation is clinical routine in bleeding management. Buffer administration may not reverse acidosis-induced coagulopathy but may be essential for the efficacy of coagulation factor concentrates such as recombinant activated factor VII.

Biofilm-dependent airway infections: a role for ambroxol?

Biofilms are a key factor in the development of both acute and chronic airway infections. Their relevance is well established in ventilator associated pneumonia, one of the most severe complications in critically ill patients, and in cystic fibrosis, the most common lethal genetic disease in Caucasians. Accumulating evidence suggests that biofilms could have also a role in chronic obstructive pulmonary disease and their involvement in bronchiectasis has been proposed as well. When they grow in biofilms, microorganisms become multidrug-resistant. Therefore the treatment of biofilm-dependent airway infections is problematic. Indeed, it still largely based on measures aiming to prevent the formation of biofilms or remove them once that they are formed. Here we review recent evidence suggesting that the mucokinetic drug ambroxol has specific anti-biofilm properties. We also discuss how additional pharmacological properties of this drug could be beneficial in biofilm-dependent airway infections. Specifically, we review the evidence showing that: 1-ambroxol exerts anti-inflammatory effects by inhibiting at multiple levels the activity of neutrophils, and 2-it improves mucociliary clearance by interfering with the activity of airway epithelium ion channels and transporters including sodium/bicarbonate and sodium/potassium/chloride cotransporters, cystic fibrosis transmembrane conductance regulator and aquaporins. As a whole, the data that we review here suggest that ambroxol could be helpful in biofilm-dependent airway infections. However, considering the limited clinical evidence available up to date, further clinical studies are required to support the use of ambroxol in these diseases.

Perioperative anaphylactic risk score for risk-oriented premedication.

Basing on the current knowledge, this paper is aimed to review the core characteristics of the most relevant therapeutic agents (steroids and antihistamines), administered to prevent perioperative anaphylaxis. Moreover, the Authors propose the validation of a Global Anaphylactic Risk Score, built up by recording the individual scores related to the most relevant anaphylaxis parameters (i.e. medical history, symptoms and medication for asthma, rhinitis and urticaria etc) and by adding them on all together; the score could be used in the preoperative phase to evaluate the global anaphylactic risk and to prescribe risk-oriented premedication protocols.

Vasopressin vs Terlipressin in Treatment of Refractory Shock.

Arginine vasopressin (AVP) and its synthetic, long-acting analog terlipressin (TP) are potent alternative vasoconstrictors in the treatment of septic patients with catecholamine-refractive vasodilatatory shock. Recent clinical data suggest that early administration of AVP analogues may be advantageous compared to a last resort therapy. However, it is still unknown whether vasopressin and terlipressin are equally effective for hemodynamic support in shock. Despite important pharmacological differences between the two drugs the use of either substance is determined mainly by local availability and institutional inventory. The current literature suggests that neither AVP nor TP should be administered in high doses in shock. Furthermore, increasing evidence indicates that early administration of terlipressin may improve outcome as compared to a last-resort treatment. Low-dose infusion of AVP has been demonstrated to be a safe adjunct in the management of refractory shock. Evidence from experimental studies and initial clinical reports suggests that continuous low-dose infusion of TP may stabilize hemodynamics in shock. In this review we briefly described differences in pharmacokinetics and pharmacodynamics between AVP and Terlipressin (TP) in treatment of refractory shock.

S100B induces the release of pro-inflammatory cytokines in alveolar type I-like cells.

S100B, a 21kDa cytosolic calcium-binding protein of the EF-hand type, present in high abundance in the brain, stimulates inflammatory responses in different cellular types inside and outside the central nervous system. Most of extracellular S100B effects are mediated by Receptor for Advanced Glycation End-products (RAGE). RAGE is highly expressed in lung by Alveolar Type-I (AT-I) cells and its activation contributes to ALI/ARDS pathogenesis. In this in-vitro study, we tested the hypothesis that S100B stimulates an ATI-derived cell line (R3/1) to secrete inflammatory mediators involved in lung inflammation. Our main result is that S100B stimulates R3/1 cells to secrete TNF-alpha and IL-6 (well-known pro-inflammatory cytokines in lung inflammation and neurogenic pulmonary edema), but not sICAM-1, CINC-1 or CINC-3. Soluble RAGE (sRAGE) reduced S100B-dependent secretion of TNF-alpha but did not decrease S100B-dependent secretion of IL-6. Moreover, in absence of S100B, sRAGE enhanced IL-6 release. This study demonstrates that in vitro S100B dose-dependently stimulated R3/1 cells, to enhance the secretion of TNF-alpha and IL-6; S100B pro-inflammatory activity might be mediated at least in part by RAGE. Besides acting as decoy receptor, sRAGE could have pro-inflammatory properties.

Comparison of triple-lumen central venous catheters impregnated with silver nanoparticles (AgTive®) vs conventional catheters in intensive care unit patients.

BACKGROUND: Silver-impregnated central venous catheters (CVCs) have been proposed as a means for preventing CVC colonization and related bloodstream infections (CRBSIs). AIM: To evaluate the efficacy of CVCs impregnated with silver nanoparticles in a large group of critically ill patients. METHODS: A prospective, randomized clinical trial was conducted in five intensive care units (ICUs). Three hundred and thirty-eight adult patients requiring CVCs between April 2006 and November 2008 were randomized to receive AgTive silver-nanoparticle-impregnated (SC) or conventional (CC) CVCs. Primary endpoints were CVC colonization (growth of ≥15 colony-forming units from the catheter tip) and incident CRBSIs (meeting the definitions of the Centers for Disease Control and Prevention). Infection-free time (days from initial CVC insertion to initial blood culture positivity) and ICU mortality rates were measured as secondary endpoints. FINDINGS: The SC group (N = 135) and CC group (N = 137) were similar in terms of clinical and laboratory parameters at baseline, reasons for ICU admission, complications during CVC insertion, and total time with CVC (mean ± standard deviation; SC 13 ± 24 vs CC 15 ± 37 days). No significant intergroup differences were found in CVC colonization rates (SC 32.6% vs CC 30%; P = 0.7), CRBSI incidence rates (3.36 infections per 1000 catheter-days in both groups), infection-free times (SC 13 ± 34 vs CC 12 ± 12 days; P = 0.85) or ICU mortality (SC 46% vs CC 43%; P = 0.7). CONCLUSION: In critically ill patients, use of AgTive(®) silver-nanoparticle-impregnated CVCs had no significant effect on CVC colonization, CRBSI incidence or ICU mortality. These CVCs cannot be recommended as an adjunctive tool for control of CRBSIs.

Toll-like receptor kinetics in septic shock patients: a preliminary study.

The aim of this study is to evaluate some inflammatory parameter changes in septic shock patients and their possible correlation with clinical outcome, in particular when continuous veno-venous hemofiltration (CVVH) treatment is required. Considering the objective difficulty in enrolling this kind of patient, a preliminary study was initiated on seventeen septic shock patients admitted to a medical and surgical ICU. The mRNA expression of Toll-like receptor (TLR)-1, TLR-2, TLR-4, TLR-5, TLR-9, TNFα, IL-8 and IL-1ß was assessed, the plasmatic concentrations of IL-18, IL-2, IL-10 and TNFα were measured on the day of sepsis diagnosis and after 72 h. In those patients who developed acute renal failure unresponsive to medical treatment and who underwent CVVH treatment the same parameters were measured every 24 h during CVVH and after completion of the treatment. On sepsis diagnosis, gene expression of TLRs was up-regulated compared to the housekeeping gene in all the patients. After 72 h, in 35% of the patients a down-regulation of these genes was found compared to day 1, but it was not associated with a reduction of cytokine serum levels or improved clinical signs, better outcome or reduced mortality. After high volume hemofiltration treatment, cytokine serum levels and TLR expression were not significantly modified. In conclusion, considering the not numerous number of cases, from our preliminary study, we cannot certainly correlate TLR over-expression in septic shock patients with severity or outcome scores.