In Silico Predicted Antifungal Peptides: In Vitro and In Vivo Anti-Candida Activity

It has been previously demonstrated that synthetic antibody-derived peptides could exert a significant activity in vitro, ex vivo, and/or in vivo against microorganisms and viruses, as well as immunomodulatory effects through the activation of immune cells. Based on the sequence of previously described antibody-derived peptides with recognized antifungal activity, an in silico analysis was conducted to identify novel antifungal candidates. The present study analyzed the candidacidal and structural properties of in silico designed peptides (ISDPs) derived by amino acid substitutions of the parent peptide KKVTMTCSAS. ISDPs proved to be more active in vitro than the parent peptide and all proved to be therapeutic in Galleria mellonella candidal infection, without showing toxic effects on mammalian cells. ISDPs were studied by circular dichroism spectroscopy, demonstrating different structural organization. These results allowed to validate a consensus sequence for the parent peptide KKVTMTCSAS that may be useful in the development of novel antimicrobial molecules

332 Clinical and prognostic significance of junctional late gadolinium enhancement in patients with non-ischaemic cardiomyopathy

Abstract Aims Pulmonary hypertension (PH) carries a poor prognosis in patients with non-ischaemic dilated cardiomyopathy (NIDC). Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) evaluation can identify myocardial abnormalities. In particular, junctional LGE is already an established marker of adverse right ventricular (RV) remodelling in patients with pre-capillary PH. This study sought to assess the prevalence of junctional LGE by CMR in NIDC, its relationship with hemodynamic parameters and, moreover, its prognostic significance. Methods and results Patients with NIDC who underwent right heart catheterization (RHC) and CMR within 3 months in a tertiary hospital were enrolled. Patients with acute heart failure were excluded. Among others, RV and left ventricular (LV) volumes, junctional LGE at CMR, pulmonary artery pressure (PAP) and pulmonary capillary wedge pressure (PCWP) at RHC were tabulated. Pulmonary hypertension was defined accordingly to current Guidelines (median PAP at RHC ≥ 25 mmHg). The primary endpoint consisted of heart failure (HF) hospitalization during follow-up. A total of 188 patients [median age 49 (SD 15), 71% males] were evaluated. At morpho-functional CMR evaluation, most subjects (76%) had important systolic dysfunction (LV EF ≤ 35%). Junctional LGE was observed in 83 (44%) patients. Among patients with junctional LGE, 21 had LGE confined only to the junctional region, while 61 had also mid-wall interventricular septal stria and 21 a mid-wall stria in the lateral free LV wall. Patients with junctional LGE had lower RV EF (49% vs. 56%, P < 0.001) and LV EF (27% vs. 30%, P = 0.012) when compared to those without junctional LGE although no differences in LV and RV dimensions were found. RHC showed PH in 83 patients (44%). Patients with junctional LGE showed a worse hemodynamic profile in terms of PH (55% vs. 36%; P = 0.011) and increase in PCWP (PCWP > 15 mmHg in 60% vs. 42%; P = 0.015) compared to subjects without junctional LGE. Among 79 patients with PH and PCWP > 15 mmHg, 75 (95%) had a combined post capillary and pre-capillary PH (diastolic pressure gradient ≥7 mmHg). Univariate analysis showed that junctional LGE was associated with a worse hemodynamic profile; on multivariable model, RV EF was significantly associated with the presence of junctional LGE (OR: 0.91; 95% CI: 0.87–0.96, P < 0.001). During a median follow-up of 58 months, 33 patients (18%) died or underwent heart transplantation/ventricular assist device implantation, 17% in the junctional LGE group vs. 18% among those without junctional LGE. Thirty-eight patients (20%) had at least one episode of HF, 22 among junctional LGE group and 16 in control group (27% vs. 15%, P = 0.056). When adjusted for age, junctional LGE resulted a significant determinant of HF hospitalization (OR: 2.13, 95% CI: 1.02–4.44, P = 0.044). Conclusions Junctional LGE is detectable in almost half of NIDC patients and it is related to a worse haemodynamic profile, characterized by PH and elevated PCWP. Moreover, after adjustment for age, it was a significant determinant of HF hospitalization during follow-up in our population. Junctional LGE can therefore represent a useful prognostic tool, as marker of adverse ventricular remodelling likely related to ventricular interdependence

Autoimmunity and parasites.

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Nonischemic left ventricular scar as a substrate of life-threatening ventricular arrhythmias and sudden cardiac death in competitive athletes

Background\u2014The clinical profile and arrhythmic outcome of competitive athletes with isolated nonischemic left ventricular (LV) scar as evidenced by contrast-enhanced cardiac magnetic resonance remain to be elucidated. Methods and Results\u2014We compared 35 athletes (80% men, age: 14\u201348 years) with ventricular arrhythmias and isolated LV subepicardial/midmyocardial late gadolinium enhancement (LGE) on contrast-enhanced cardiac magnetic resonance (group A) with 38 athletes with ventricular arrhythmias and no LGE (group B) and 40 healthy control athletes (group C). A stria LGE pattern with subepicardial/midmyocardial distribution, mostly involving the lateral LV wall, was found in 27 (77%) of group A versus 0 controls (group C; P<0.001), whereas a spotty pattern of LGE localized at the junction of the right ventricle to the septum was respectively observed in 11 (31%) versus 10 (25%; P=0.52). All athletes with stria pattern showed ventricular arrhythmias with a predominant right bundle branch block morphology, 13 of 27 (48%) showed ECG repolarization abnormalities, and 5 of 27 (19%) showed echocardiographic hypokinesis of the lateral LV wall. The majority of athletes with no or spotty LGE pattern had ventricular arrhythmias with a predominant left bundle branch block morphology and no ECG or echocardiographic abnormalities. During a follow-up of 38\ub125 months, 6 of 27 (22%) athletes with stria pattern experienced malignant arrhythmic events such as appropriate implantable cardiac defibrillator shock (n=4), sustained ventricular tachycardia (n=1), or sudden death (n=1), compared with none of athletes with no or LGE spotty pattern and controls. Conclusions\u2014Isolated nonischemic LV LGE with a stria pattern may be associated with life-threatening arrhythmias and sudden death in the athlete. Because of its subepicardial/midmyocardial location, LV scar is often not detected by echocardiography

Variability in genes regulating vitamin D metabolism is associated with vitamin D levels in type 2 diabetes

Mortality rate is increased in type 2 diabetes (T2D). Low vitamin D levels are associated with increased mortality risk in T2D. In the general population, genetic variants affecting vitamin D metabolism (DHCR7 rs12785878, CYP2R1 rs10741657, GC rs4588) have been associated with serum vitamin D. We studied the association of these variants with serum vitamin D in 2163 patients with T2D from the "Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes". Measurements of serum vitamin D were centralised. Genotypes were obtained by Eco™ Real-Time PCR. Data were adjusted for gender, age, BMI, HbA1c, T2D therapy and sampling season. DHCR7 rs12785878 (p = 1 x 10-4) and GC rs4588 (p = 1 x 10-6) but not CYP2R1 rs10741657 (p = 0.31) were significantly associated with vitamin D levels. One unit of a weighted genotype risk score (GRS) was strongly associated with vitamin D levels (p = 1.1 x 10-11) and insufficiency (&lt;30 ng/ml) (OR, 95%CI = 1.28, 1.16-1.41, p = 1.1 x 10-7). In conclusion, DHCR7 rs12785878 and GC rs4588, but not CYP2R1 rs10741657, are significantly associated with vitamin D levels. When the 3 variants were considered together as GRS, a strong association with vitamin D levels and vitamin D insufficiency was observed, thus providing robust evidence that genes involved in vitamin D metabolism modulate serum vitamin D in T2D

Coronary artery calcium score: we know where we are but not where we may be

Cardiac computed tomography angiography (CCTA) has emerged as a cost-effective and time-saving technique for excluding coronary artery disease. One valuable tool obtained by CCTA is the coronary artery calcium (CAC) score. The use of CAC scoring has shown promise in risk assessment and stratification of cardiovascular disease. CAC scores can be complemented by plaque analysis to assess vulnerable plaque characteristics and further refine risk assessment. This paper aims to provide a comprehensive understanding of the value of the CAC as a prognostic tool and its implications for patient risk assessment, treatment strategies and outcomes. CAC scoring has demonstrated superior ability in stratifying patients, especially asymptomatic individuals, compared to traditional risk factors and scoring systems. The main evidence suggests that individuals with a CAC score of 0 had a good long-term prognosis, while elevated CAC score is associated with increased cardiovascular risk. Finally, the clinical power of CAC scoring and the develop of new models for risk stratification could be enhanced by machine learning algorithms

Surgical Antimicrobial Prophylaxis in Neonates and Children Undergoing Neurosurgery: A RAND/UCLA Appropriateness Method Consensus Study

Pediatric neurosurgery is a highly specialized branch of surgery in which surgical site infections (SSIs) are potentially serious complications that can also adversely affect a good surgical outcome, compromising functional recovery and, in some cases, even putting the patient's life at risk. The main aim of this consensus document is to provide clinicians with a series of recommendations on antimicrobial prophylaxis for neonates and children undergoing neurosurgery. The following scenarios were considered: (1) craniotomy or cranial/cranio-facial approach to craniosynostosis; (2) neurosurgery with a trans-nasal-trans-sphenoidal approach; (3) non-penetrating head injuries; (4) penetrating head fracture; (5) spinal surgery (extradural and intradural); (6) shunt surgery or neuroendoscopy; (7) neuroendovascular procedures. Patients undergoing neurosurgery often undergo peri-operative antibiotic prophylaxis, with different schedules, not always supported by scientific evidence. This consensus provides clear and shared indications, based on the most updated literature. This work has been made possible by the multidisciplinary contribution of experts belonging to the most important Italian scientific societies, and represents, in our opinion, the most complete and up-to-date collection of recommendations on the behavior to be held in the peri-operative setting in this type of intervention, in order to guide physicians in the management of the patient, standardize approaches and avoid abuse and misuse of antibiotics