Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis

As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 μg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure–activity relationship analysis

Comparative Safety of Originator and Biosimilar Epoetin Alfa Drugs: An Observational Prospective Multicenter Study

Background: Erythropoiesis-stimulating agents (ESAs) are biological molecules approved for the treatment of anemia associated with chronic renal failure. Biosimilars were licensed for use in Europe in 2007. Aim: This study aimed to compare the safety profile of biosimilars with respect to the reference product in a nephrology setting. Methods: A prospective study was conducted in four Italian regions between 1 October 2013 and 30 June 2015. The study population included patients aged 65 18 years undergoing hemodialysis and treated with epoetins as per the clinical practice of the participating centers. The two comparison cohorts included patients treated with either an originator or a biosimilar epoetin alfa. Each patient was followed up until occurrence of any safety outcome of interest (grouped into three major categories), switch to a different ESA product, transplant or peritoneal dialysis, death, or end of the study period, whichever came first. Results: Overall, 867 subjects were included in the study (originator: N = 423; biosimilar: N = 444). Biosimilar users were older than originator users (median age of 76 vs 64 years, respectively), more frequently affected by arrhythmia (29.3 vs 22.5%), and less frequently candidates for transplantation (3.8 vs 18.2%). Cox-regression analysis showed no increase in risk of safety outcomes in biosimilar users, even after adjusting for confounding factors: 1.0 (95% confidence interval [CI] 0.7\u20131.3) for any outcomes; 1.1 (95% CI 0.7\u20131.8) for problems related to dialysis device; 0.9 (95% CI 0.6\u20131.5) for cardio- and cerebro-vascular conditions; 0.9 (95% CI 0.6\u20131.5) for infections. Conclusion: This study confirms the comparable safety profiles of originator and biosimilar epoetin alfa drugs when used in patients receiving dialysis

Brace technology thematic series - The Sforzesco and Sibilla braces, and the SPoRT (Symmetric, Patient oriented, Rigid, Three-dimensional, active) concept

<p>Abstract</p> <p>Background</p> <p>Bracing is an effective strategy for scoliosis treatment, but there is no consensus on the best type of brace, nor on the way in which it should act on the spine to achieve good correction. The aim of this paper is to present the family of SPoRT (Symmetric, Patient-oriented, Rigid, Three-dimensional, active) braces: Sforzesco (the first introduced), Sibilla and Lapadula.</p> <p>Methods</p> <p>The Sforzesco brace was developed following specific principles of correction. Due to its overall symmetry, the brace provides space over pathological depressions and pushes over elevations. Correction is reached through construction of the envelope, pushes, escapes, stops, and drivers. The real novelty is the drivers, introduced for the first time with the Sforzesco brace; they allow to achieve the main action of the brace: a three-dimensional elongation pushing the spine in a down-up direction.</p> <p>Brace prescription is made plane by plane: frontal (on the "slopes", another novelty of this concept, i.e. the laterally flexed sections of the spine), horizontal, and sagittal. The brace is built modelling the trunk shape obtained either by a plaster cast mould or by CAD-CAM construction. Brace checking is essential, since SPoRT braces are adjustable and customisable according to each individual curve pattern.</p> <p>Treatment time and duration is individually tailored (18-23 hours per day until Risser 3, then gradual reduction). SEAS (Scientific Exercises Approach to Scoliosis) exercises are a key factor to achieve success.</p> <p>Results</p> <p>The Sforzesco brace has shown to be more effective than the Lyon brace (matched case/control), equally effective as the Risser plaster cast (prospective cohort with retrospective controls), more effective than the Risser cast + Lyon brace in treating curves over 45 degrees Cobb (prospective cohort), and is able to improve aesthetic appearance (prospective cohort).</p> <p>Conclusions</p> <p>The SPoRT concept of bracing (three-dimensional elongation pushing in a down-up direction) is different from the other corrective systems: 3-point, traction, postural, and movement-based. The Sforzesco brace, being comparable to casting, may be the best brace for the worst cases.</p

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p &lt; 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p &lt; 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p &lt; 0.0001) or urgent (20.4% vs. 38.5%; p &lt; 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p &lt; 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

Biocatalytic carbon nitrogen double bond reduction

Within this research project the bioreduction of imines and oximes has been investigated as possible promiscuous activity of two different reductases families, the enoate reductase family (EC 1.3.1.31) and the carbonyl reductase family (EC: 1.1.1.1). The decision of targeting these enzyme classes has been based on the existing literature and on substrate analogy for the enoate reductases and based on in silico docking for the carbonyl reductase. As a carbonyl reductase was already available in our research group, an activity based screening for the isolation of enoate reductases was performed within this research project. As genetic material the DNA of Acetobacterium woodii and metagenomic DNA have been used. The DNA of Acetobacterium woodii has been cloned into E.coli and the obtained library was screened in High Throughput screening format. The same procedure, although with a different vector, has been followed for the metagenomic DNA. As no positive hits were identified within both the screened libraries, the conclusion that the adopted strategy was not successful for the isolation of enoate reductase was drawn. In order to overcome the problems that arise with an activity based screening (low protein expression and uncorrect folding), a sequence based screening was performed, designing degenerate primers based on the alignment of the already published enoate reductases. This strategy showed to be successful and led us to the isolation of a new enoate reductase from the metagenome. The obtained enoate reductase retrieved from the metagenome, together with the cloned enoate reductase from Clostridium acetobutylicum and the carbonyl reductase from Candida parapsilosis, have been tried in the bioreduction of imines and oximes, under a very diverse reaction conditions. The formation of the desired product, however, has never been detected

Biocatalytic carbon nitrogen double bond reduction

Within this research project the bioreduction of imines and oximes has been investigated as possible promiscuous activity of two different reductases families, the enoate reductase family (EC 1.3.1.31) and the carbonyl reductase family (EC: 1.1.1.1). The decision of targeting these enzyme classes has been based on the existing literature and on substrate analogy for the enoate reductases and based on in silico docking for the carbonyl reductase. As a carbonyl reductase was already available in our research group, an activity based screening for the isolation of enoate reductases was performed within this research project. As genetic material the DNA of Acetobacterium woodii and metagenomic DNA have been used. The DNA of Acetobacterium woodii has been cloned into E.coli and the obtained library was screened in High Throughput screening format. The same procedure, although with a different vector, has been followed for the metagenomic DNA. As no positive hits were identified within both the screened libraries, the conclusion that the adopted strategy was not successful for the isolation of enoate reductase was drawn. In order to overcome the problems that arise with an activity based screening (low protein expression and uncorrect folding), a sequence based screening was performed, designing degenerate primers based on the alignment of the already published enoate reductases. This strategy showed to be successful and led us to the isolation of a new enoate reductase from the metagenome. The obtained enoate reductase retrieved from the metagenome, together with the cloned enoate reductase from Clostridium acetobutylicum and the carbonyl reductase from Candida parapsilosis, have been tried in the bioreduction of imines and oximes, under a very diverse reaction conditions. The formation of the desired product, however, has never been detected

Using Cyanoacrylate Microbial Sealant for Skin Preparation Prior to the Placement of Intravenous Catheters in Horses

Venous catheters are extensively used in equine practice. Catheter-related infections are among the most serious complications of equine surgery. Our goal was to compare catheter contamination with and without cyanoacrylate microbial sealant and to evaluate tolerance in horses. Each horse (n = 20) had both jugular grooves clipped (T0). The areas were prepared (T1) either with povidone-iodine (B) or plus cyanoacrylate (InteguSEAL). At T0 and T1, skin swabs were taken. Both jugular veins were catheterized. After 36 hours (T2), catheters were aseptically removed and shipped for microbial culture. At T2 and after 4 weeks (T3), sites were clinically and ultrasonographically evaluated, measuring veins' wall thickness and recording any alteration. No significant differences between groups were detected in microbiological evaluation. The T3 measurements were lower than T2 in both groups. The use of InteguSEAL was not associated with a reduction catheter contamination rates. InteguSEAL use was overall well tolerated