Current trends in the development and use of personalized implants: Engineering concepts and regulation perspectives for the contemporary oral and maxillofacial surgeon

The recently adopted Medical Device Regulation (MDR) has finally entered into force on 26 May 2021. As innovation and especially the advent of customized prostheses has deeply modified many surgical procedures in our discipline, it is imperative for the contemporary surgeon to become aware of the impact that the MDR will have on many aspects, including the choice of the manufacturer, the evaluation of the devices, point-of-care 3D printing labs, and medical software. In this paper, the authors tried to identify the cultural gaps in clinical practice that the MDR is supposed to fill. To achieve this purpose, a task force of experts was reunited, including CMF surgeons with direct expertise in medical software and 3D printing, mechanical and material engineers, facing the topic of the MDR from a multidimensional perspective. In this article, surgeons and engineers review many crucial aspects concerning the points of the regulation that mostly affect the field of implantable devices for the cranio-maxillo-facial skeleton. The result of interdisciplinary research is a paper aiming to provide surgeons with the knowledge on the fundamental processes of additive manufacturing, increasing the clinician’s awareness on the evaluation of a customized implant before surgery and on the underlying regulatory framework

Ion Conduction Mechanism as a Fingerprint of Potassium Channels

K+-channels are membrane proteins that regulate the selective conduction of potassium ions across cell membranes. Although the atomic mechanisms of K+ permeation have been extensively investigated, previous work focused on characterizing the selectivity and occupancy of the binding sites, the role of water molecules in the conduction process, or the identification of the minimum energy pathways enabling permeation. Here, we exploit molecular dynamics simulations and the analytical power of Markov state models to perform a comparative study of ion conduction in three distinct channel models. Significant differences emerged in terms of permeation mechanisms and binding site occupancy by potassium ions and/or water molecules from 100 μs cumulative trajectories. We found that, at odds with the current paradigm, each system displays a characteristic permeation mechanism, and thus, there is not a unique way by which potassium ions move through K+-channels. The high functional diversity of K+-channels can be attributed in part to the differences in conduction features that have emerged from this work. This study provides crucial information and further inspiration for wet-lab chemists designing new synthetic strategies to produce versatile artificial ion channels that emulate membrane transport for their applications in diagnosis, sensors, the next generation of water treatment technologies, etc., as the ability of synthetic channels to transport molecular ions across a bilayer in a controlled way is usually governed through the choice of metal ions, their oxidation states, or their coordination geometries

Dispositivo Elettronico per servizi di telefonia in reti di comunicazione a commutazione di pacchetto e procedimento relativo

La presente invenzione si riferisce ad un dispositivo elettronico per servizi di telefonia in reti di comunicazione a commutazione di pacchetto. In un suo ulteriore aspetto, la presente invenzione si riferisce ad un procedimento per la gestione di traffico telefonico in una rete di comunicazione a commutazione di pacchetto

Conduction and Gating Properties of the TRAAK Channel from Molecular Dynamics Simulations with Different Force Fields

In recent years, the K2P family of potassium channels has been the subject of intense research activity. Owing to the complex function and regulation of this family of ion channels, it is common practice to complement experimental findings with the atomistic description provided by computational approaches such as molecular dynamics (MD) simulations, especially, in light of the unprecedented timescales accessible at present. However, despite recent substantial improvements, the accuracy of MD simulations is still undermined by the intrinsic limitations of force fields. Here, we systematically assessed the performance of the most popular force fields employed to study ion channels at timescales that are orders of magnitude greater than the ones accessible when these energy functions were first developed. Using 32 μs of trajectories, we investigated the dynamics of a member of the K2P ion channel family, the TRAAK channel, using two established force fields in simulations of biological systems: AMBER and CHARMM. We found that while results are comparable on the nanosecond timescales, significant inconsistencies arise at microsecond timescales

Conduction and Gating Properties of the TRAAK Channel from Molecular Dynamics Simulations with Different Force Fields

In recent years, the K2P family of potassium channels has been the subject of intense research activity. Owing to the complex function and regulation of this family of ion channels, it is common practice to complement experimental findings with the atomistic description provided by computational approaches such as molecular dynamics (MD) simulations, especially, in light of the unprecedented timescales accessible at present. However, despite recent substantial improvements, the accuracy of MD simulations is still undermined by the intrinsic limitations of force fields. Here, we systematically assessed the performance of the most popular force fields employed to study ion channels at timescales that are orders of magnitude greater than the ones accessible when these energy functions were first developed. Using 32 \u3bcs of trajectories, we investigated the dynamics of a member of the K2P ion channel family, the TRAAK channel, using two established force fields in simulations of biological systems: AMBER and CHARMM. We found that while results are comparable on the nanosecond timescales, significant inconsistencies arise at microsecond timescales

Exploring Conformational Dynamics of the Extracellular Venus flytrap Domain of the GABAB Receptor: A Path-Metadynamics Study

\u3b3-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS). Dysfunctional GABAergic neurotransmission is associated with numerous neurological and neuropsychiatric disorders. The GABAB receptor (GABAB-R) is a heterodimeric class C G protein-coupled receptor (GPCR) comprised of GABAB1a/b and GABAB2 subunits. The orthosteric binding site for GABA is located in the extracellular Venus flytrap (VFT) domain of the GABAB1a/b. Knowledge about molecular mechanisms and druggable receptor conformations associated with activation is highly important to understand the receptor function and for rational drug design. Currently, the conformational changes of the receptor upon activation are not well described. On the basis of other class C members, the VFT is proposed to fluctuate between an open/inactive and closed/active state and one of these conformations is stabilized upon ligand binding. In the present study, we investigated the dynamics of the GABAB1b-R VFT in the apo form by combining unbiased molecular dynamics with path-metadynamics. Our simulations confirmed the open/inactive and closed/active state as the main conformations adopted by the receptor. Sizeable energy barriers were found between stable minima, suggesting a relatively slow interconversion. Previously undisclosed metastable states were also identified, which might hold potential for future drug discovery efforts

An observational study of CoSeal for the prevention of adhesions in pediatric cardiac surgery.

We sought to evaluate the utility and safety of CoSeal Surgical Sealant (Baxter) for the prevention of cardiac adhesions in children. Seven cardiac surgery centers in Europe recruited consecutive pediatric patients requiring primary sternotomy for staged repair of congenital heart defects. Exclusion criteria included immune system disorder, unplanned reoperation, or reoperation within three months of primary repair. CoSeal was sprayed onto the surface of the heart at the end of surgery. Evaluation of adhesions took place at first reoperation. Data on safety, duration of surgery, and ease of CoSeal use were also collected. Seventy-nine pediatric patients were recruited between February 2005 and September 2007. Of these, 76 underwent major surgery to repair a wide range of congenital heart defects. Thirty-six patients underwent reoperation >3 months after primary repair, and were included in the efficacy analysis. Mean adhesions score was 8.3 (standard deviation [S.D.] 2.4; range 7-16). Six adverse events (5 serious) were possibly/definitely attributed to CoSeal. CoSeal's ease of use at primary operation was graded by surgeons as 12.1 mm (S.D. 9.8) on a visual analog scale of 0 ('very easy') to 100 mm ('very difficult'). Results of this prospective uncontrolled trial justify further investigation in a randomized, controlled trial

EFFECTS OF ALLOPURINOL ON RENAL FUNCTION DECLINE IN HYPERTENSIVE PATIENTS WITH CHRONIC KIDNEY DISEASES

Aim: To evaluate retrospectively the effects of allopurinol treatment on renal function decline in non-gouty hypertensive patients with moderate-to-severe CKD. Methods: We selected 22 patients treated with allopurinol (A) (100–300 mg/die) that were compared with 44 subjects not treated with this drug (B), matched with A for estimated glomerular filtration rate (eGFR), age, gender and blood pressure values. Results: After a mean follow-up period of 16 months no significant difference was observed between the two groups regarding eGFR decline (A: -6.8 ± 11.6 ml/min/1.73 m2; B: -4.2 ± 9.3 ml/min/1.73 m2). Furthermore, the percentage of subjects with a value of eGFR reduction above the median was not significantly different in the two groups (A: 59 %; B: 41 %; p = 0.16). The absence of a significant effect of allopurinol on the eGFR decline was confirmed by the multiple logistic regression analysis, where the variables associated with a greater eGFR reduction were the proteinuria and the baseline value of GFR. Conclusions: Our findings are in disagreement with previous studies showing a nephroprotective effect of allopurinol. Further studies, with a randomized controlled design, are needed to understand whether or not pharmacological treatment of asymptomatic hyperuricemia may preserve renal function

EFFETTI DELL'ALLOPURINOLO SUL DECLINO DEL FILTRATO GLOMERULARE IN PAZIENTI IPERTESI CON INSUFFICIENZA RENALE CRONICA

Il ruolo dell\u2019iperuricemia asintomatica quale fattore in grado di favorire in modo indipendente la progressione della malattia renale cronica rimane controverso. Inoltre, gli studi finalizzati a valutare l\u2019influenza della terapia ipouricemizzante sulla evoluzione delle nefropatie croniche sono poco numerosi e hanno dato risultati contrastanti. Scopo del nostro studio osservazionale \ue8 stato quello di analizzare retrospettivamente l'effetto del trattamento con allopurinolo, sul declino del filtrato glomerulare, in pazienti ipertesi con insufficienza renale cronica di grado moderato-severo. Sono stati pertanto selezionati 22 pazienti trattati con allopurinolo (A) (100-300 mg/die) che sono stati confrontati con 44 soggetti non sottoposti a trattamento con ipouricemizzanti (B) ed appaiati con il gruppo in terapia con allopurinolo per quanto attiene a filtrato glomerulare stimato (eGFR) , et\ue0, sesso e valori pressori. Dopo un follow-up medio di 16 mesi, nessuna differenza \ue8 stata osservata tra i due gruppi per quanto riguarda sia la rapidit\ue0 del declino del eGFR (A: -6.8 \ub1 11.6 ml/min/1.73 m2; B: -4.2 \ub1 9.3 ml/min/1.73 m2), sia per quanto attiene alla percentuale di soggetti che hanno manifestato una riduzione del eGFR maggiore della mediana di distribuzione di tale parametro (A: 59%; B: 41%; p =0.16). L'analisi di regressione logistica multipla ha confermato, anche dopo correzione per potenziali fattori confondenti, l'assenza di un significativo impatto dell'allopurinolo sul declino del filtrato glomerulare durante il periodo di osservazione ed ha mostrato che le variabili associate in maniera indipendente al decremento del GFR erano la presenza di proteinuria ed il GFR alla valutazione basale. I nostri dati non supportano i risultati di precedenti studi che avevano evidenziato un effetto nefroprotettivo dell\u2019allopurinolo. Ulteriori e pi\uf9 ampi studi di tipo randomizzato e controllato sono necessari per comprendere se trattare farmacologicamente i soggetti con iperuricemia asintomatica al fine di preservare la funzione renale