Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study

Journal of Neurology - To identify baseline factors associated with disease activity in patients with relapsing–remitting multiple sclerosis (RRMS) under teriflunomide treatment. This was an...     

Flow cytometry data mining by cytoChain identifies determinants of exhaustion and stemness in TCR-engineered T cells

The phenotype of infused cells is a major determinant of Adoptive T-cell therapy (ACT) efficacy. Yet, the difficulty in deciphering multiparametric cytometry data limited the fine characterization of cellular products. To allow the analysis of dynamic and complex flow cytometry samples, we developed cytoChain, a novel dataset mining tool and a new analytical workflow. CytoChain was challenged to compare state-of-the-art and innovative culture conditions to generate stem-like memory cells (T_SCM) suitable for ACT. Noticeably, the combination of IL-7/15 and superoxides scavenging sustained the emergence of a previously unidentified nonexhausted Fit-T_SCM signature, overlooked by manual gating and endowed with superior expansion potential. CytoChain proficiently traced back this population in independent datasets, and in T-cell receptor engineered lymphocytes. CytoChain flexibility and function were then further validated on a published dataset from circulating T cells in COVID-19 patients. Collectively, our results support the use of cytoChain to identify novel, functionally critical immunophenotypes for ACT and patients immunomonitoring.     

Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels

Ghrelin, the recently identified endogenous ligand of the GH secretagogue receptor, is a gut-brain peptide with endocrine, orexigenic, and gastrointestinal effects. In rodents it increases circulating gastrin and insulin levels, whereas in man it appears to decrease insulin secretion despite a rise in blood glucose levels. The aim of the present study was to evaluate the effects of ghrelin administration on total circulating somatostatin (SS), pancreatic polypeptide (PP), and gastrin levels compared with those elicited on insulin, glucose, and GH. Eight healthy volunteers of normal weight (four women and four men) were injected with 3.3 microg/kg ghrelin or saline after an overnight fast on 2 different days. Blood was taken every 15 min for 1 h and then every 30 min for 2 h. As expected, ghrelin injection elicited a prompt GH and glucose increase with a peak at 30 min and an insulin decrease with a nadir at 60 min. Gastrin concentrations were not modified, whereas significant rises were observed in both SS (in a biphasic pattern with peaks at 15 and 120 min) and PP (which increased promptly with a peak at 15 min). A significant negative correlation was found between SS (first peak) and insulin changes (r = -0.86; P < 0.01). In conclusion, this study clearly demonstrates that ghrelin stimulates SS and PP release in man. Although the underlying mechanisms and biological significance of these pharmacological effects remain to be elucidated, a causal relationship between the SS increase and the insulin changes may be hypothesized. Finally, these findings strongly support ghrelin's postulated role in linking the endocrine control of energy balance and growth with the regulation of gastrointestinal functions.     

Fine-needle liver biopsy in patients with severely impaired coagulation

ABSTRACT— Severe coagulation defects, as reflected by platelet count and prothrombin time, have always been considered a contraindication to needle biopsy of the liver, but there are very limited data on the actual rate of bleeding in patients with such severe alterations and none whatsoever on the bleeding risk associated with newer, fine-gauge needles that produce less trauma to the liver tissue. In addition, there has never been any evidence that platelet count and/or prothrombin time are the most sensitive indices of bleeding risk. This retrospective study of 85 patients, with platelet counts less than 50 000/mm³ and/or prothrombin times less than 50% of controls, subjected to ultrasound-guided fine-needle liver punctures for diagnostic or therapeutic (percutaneous ethanol injection) purposes showed no bleeding episodes after any of the 229 punctures performed. No type of replacement therapy was administered to correct clotting defects prior to the procedure. Correct pathologic diagnoses were obtained in 81.2% of all patients. Ultrasound-guided fine needle puncture appears to be safer than currently believed in patients with severe clotting defects and deserves further evaluation as an alternative to surgical procedures to diagnose and treat liver lesions, even when severe coagulation impairment is present.     

Accurate estimate of pancreatic T2* values: how to deal with fat infiltration

Purpose

We examined different approaches aimed to deal with the signal fluctuation of pancreatic T2* values due to fat infiltration in order to obtain accurate estimates of iron overload.

Methods

Pancreatic T2* values were assessed in 20 patients (13 females, 37.24 ± 9.12 years) enrolled in the Myocardial Iron Overload in Thalassemia network without and with the application of fat suppression-FS (T2*-NoFS and T2*-FS). T2* values were assessed in three different ways: (1) from the immediate fit (original T2*); (2) discarding the echoes until the achievement of a good visual concordance between the signal and the model (final_vis T2*); (3) eliminating the echoes until the achievement of a fitting error (known) <5% (final_thres T2*).

Results

For the T2*-NoFS sequence the original T2* values were significantly higher than the final_vis T2* values (difference:4.8 ± 6.1 ms; P < 0.0001) and the final_thres T2* values (difference:4.3 ± 6.1 ms; P = 0.006). For the T2*-FS sequence the original T2* values were comparable to final_vis and final_thres T2* values. The original T2*-FS values were significantly different from the original T2*-NoFS values. The final_vis T2*-FS values were comparable to the final_vis T2*-NoFS values and the final_thresh T2*-FS values were comparable to the final_thresh T2*-NoFS values. For both T2*-FS and T2*-NoFS sequences, the final_thres T2* values were not significantly different from the final_vis T2* values and no bias was present.

Conclusions

In the clinical practice, an accurate pancreatic iron overload assessment should be done by applying FS and, when needed, by discarding the TEs until the fitting error goes below 5%.

     

Ceftolozane/tazobactam for the treatment of serious Pseudomonas aeruginosa infections: a multicentre nationwide clinical experience

This study describes the largest clinical experience using ceftolozane/tazobactam (C/T) for different Pseudomonas aeruginosa infections. A retrospective study was performed at 22 hospitals in Italy (June 2016–March 2018). All adult patients treated with ≥4 days of C/T were enrolled. Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to P. aeruginosa infection and lack of microbiological evidence of infection. C/T treatment was documented in 101 patients with diverse infections, including nosocomial pneumonia (31.7%), acute bacterial skin and skin-structure infection (20.8%), complicated UTI (13.9%), complicated IAI (12.9%), bone infection (8.9%) and primary bacteraemia (5.9%). Over one-half of P. aeruginosa strains were XDR (50.5%), with 78.2% of isolates resistant to at least one carbapenem. C/T was used as first-line therapy in 39 patients (38.6%). When used as second-line or later, the most common reasons for discontinuation of previous antibiotics were in vitro resistance of P. aeruginosa and clinical failure of previous therapy. Concomitant antibiotics were reported in 35.6% of patients. C/T doses were 1.5 g q8h in 70 patients (69.3%) and 3 g q8h in 31 patients (30.7%); median duration of C/T therapy was 14 days. Overall clinical success was 83.2%. Significant lower success rates were observed in patients with sepsis or receiving continuous renal replacement therapy (CRRT). Mild adverse events were reported in only three patients. C/T demonstrated a favourable safety and tolerability profile regardless of the infection type. Clinicians should be aware of the risk of clinical failure with C/T therapy in septic patients receiving CRRT.