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Left ventricular hypertrophy (LVH) is a frequent imaging finding in the general population. In order to identify the precise etiology, a comprehensive diagnostic approach should be adopted, including the prevalence of each entity that may cause LVH, family history, clinical, electrocardiographic and imaging findings. By providing a detailed evaluation of the myocardium, cardiovascular magnetic resonance (CMR) has assumed a central role in the differential diagnosis of left ventricular hypertrophy, with the technique of parametric imaging allowing more refined tissue characterization. This article aims to establish a parallel between pathophysiological features and imaging findings through the broad spectrum of LVH entities, emphasizing the role of CMR in the differential diagnosis.

Paget’s disease (PDB) is a late-onset bone remodeling disorder with a broad spectrum of symptoms and complications. One of the most aggressive forms is caused by the P937R mutation in the ZNF687 gene. Although the genetic involvement of ZNF687 in PDB has been extensively studied, the molecular mechanisms underlying this association remain unclear. Here, we describe the first Zfp687 knock-in mouse model and demonstrate that the mutation recapitulates the PDB phenotype, resulting in severely altered bone remodeling. Through microcomputed tomography analysis, we observed that 8-month-old mutant mice showed a mainly osteolytic phase, with a significant decrease in the trabecular bone volume affecting the femurs and the vertebrae. Conversely, osteoblast activity was deregulated, producing disorganized bone. Notably, this phenotype became pervasive in 16-month-old mice, where osteoblast function overtook bone resorption, as highlighted by the presence of woven bone in histological analyses, consistent with the PDB phenotype. Furthermore, we detected osteophytes and intervertebral disc degeneration, outlining for the first time the link between osteoarthritis and PDB in a PDB mouse model. RNA sequencing of wild-type and Zfp687 knockout RAW264.7 cells identified a set of genes involved in osteoclastogenesis potentially regulated by Zfp687, e.g., Tspan7, Cpe, Vegfc, and Ggt1, confirming its role in this process. Strikingly, in this mouse model, the mutation was also associated with a high penetrance of hepatocellular carcinomas. Thus, this study established an essential role of Zfp687 in the regulation of bone remodeling, offering the potential to therapeutically treat PDB, and underlines the oncogenic potential of ZNF687.

Manipulating the architecture of materials to achieve optimal combinations of properties (inverse design) has always been the dream of materials scientists and engineers. Lattices represent an efficient way to obtain lightweight yet strong materials, providing a high degree of tailorability. Despite massive research has been done on lattice architectures, the inverse design problem of complex phenomena (such as structural instability) has remained elusive. Via deep neural network and genetic algorithm, we provide a machine-learning-based approach to inverse-design non-uniformly assembled lattices. Combining basic building blocks, our approach allows us to independently control the geometry and topology of periodic and aperiodic structures. As an example, we inverse-design lattice architectures with superior buckling performance, outperforming traditional reinforced grid-like and bio-inspired lattices by ~30–90% and 10–30%, respectively. Our results provide insights into the buckling behavior of beam-based lattices, opening an avenue for possible applications in modern structures and infrastructures.

To analyze different types of management and one-year outcomes of anastomotic leakage (AL) after elective colorectal resection. All patients with anastomotic leakage after elective colorectal surgery with anastomosis (76/1,546; 4.9%), with the exclusion of cases with proximal diverting stoma, were followed-up for at least one year. Primary endpoints were as follows: composite outcome of one-year mortality and/or unplanned intensive care unit (ICU) admission and additional morbidity rates. Secondary endpoints were as follows: length of stay (LOS), one-year persistent stoma rate, and rate of return to intended oncologic therapy (RIOT). One-year mortality rate was 10.5% and unplanned ICU admission rate was 30.3%. Risk factors of the composite outcome included age (aOR = 1.08 per 1-year increase, p = 0.002) and anastomotic breakdown with end stoma at reoperation (aOR = 2.77, p = 0.007). Additional morbidity rate was 52.6%: risk factors included open versus laparoscopic reoperation (aOR = 4.38, p = 0.03) and ICU admission (aOR = 3.63, p = 0.05). Median (IQR) overall LOS was 20 days (14–26), higher in the subgroup of patients reoperated without stoma. At 1 year, a stoma persisted in 32.0% of patients, higher in the open (41.2%) versus laparoscopic (12.5%) reoperation group (p = 0.04). Only 4 out of 18 patients (22.2%) were able to RIOT. Mortality and/or unplanned ICU admission rates after AL are influenced by increasing age and by anastomotic breakdown at reoperation; additional morbidity rates are influenced by unplanned ICU admission and by laparoscopic approach to reoperation, the latter also reducing permanent stoma and failure to RIOT rates. ClinicalTrials.gov # NCT03560180

Although there is clear evidence that an Enhanced Recovery After Surgery (ERAS) program in colorectal surgery leads to significantly reduced morbidity rates and length of hospital stay (LOS), it is still unclear what modalities and levels of implementation of the program are necessary to achieve these results. The purpose of this study is to analyze the methods and results of the first year of structured implementation of a colorectal ERAS program in two surgical units of the Azienda Sanitaria Unica Regionale (ASUR) Marche in Italy. A two-center observational study on a prospectively maintained database was performed on 196 consecutive colorectal resections (excluding emergencies and American Society of Anesthesiologists class > III cases) over a 1-year period. More than 50 variables including adherence to the individual items of the ERAS program were considered. Primary outcomes were overall morbidity, major morbidity, mortality and anastomotic leakage rates; secondary outcomes were LOS, re-admission and re-operation. The results were evaluated by univariate and multivariate analyses through logistic regression. After a median follow-up of 39.5 days, we recorded complications in 72 patients (overall morbidity 36.7%), major complications in 14 patients (major morbidity 7.1%), 6 deaths (mortality 3.1%), anastomotic dehiscence in 9 cases (4.9%), mean overall LOS of 6.6 days, 10 readmissions (5.1%) and 13 reoperations (6.7%). The mean adherence rate to the items of the ERAS program was 85.4%, showing a significant dose–effect curve for overall and major morbidity rates, anastomotic leakage rates and LOS. The implementation methods of a colorectal ERAS program in this study led to a high adherence (> 80%) to the program items. High adherence had significant effects also on major morbidity and anastomotic leakage rates.

To investigate the present attitude of the Italian Radiation Oncologists in the management of breast cancer (BC) concerning hypofractionated radiotherapy (hRT), partial-breast irradiation (PBI), re-irradiation (rRT) and radiotherapy after neoadjuvant chemotherapy (post-NAC RT). A nationwide, 21-point questionnaire was distributed online via SurveyMonkey. Seventy-four Italian Radiotherapy Centers answered to the survey. In most cases, the responding centers treated more than 100 BC patients/year between January 2016 and December 2017. Almost half of responding centers (49%) treated patients with hRT, out of these, 95% as routine practice for early-stage BC. Dose prescriptions ranged between 39 and 45 Gy indicating a high use of moderate hRT. The chest wall and regional lymph nodes were irradiated with hRT by 13% and 15% of the responding centers, respectively. PBI was used by 60% of responders, with different techniques. Only 0.6% of participants perform rRT after BC recurrence. Finally, only 11% of the interviewed centers responded to their attitude toward post-NAC RT, which, however, was indicated in 97% of patients after breast-conserving surgery. This survey shows a fairly good use of hRT and a moderate practice of PBI in Italy. Some practices like hRT to the chest wall and regional lymph nodes as well as rRT need further verification. Likewise, the management of post-NAC RT is very heterogeneous. Future national clinical collaborative studies are advocated in order to investigate these controversial topics about breast cancer radiotherapy.

In this work, a complex graphitic high-speed steel (Gr-HSS) obtained from a spin-casting process that allows high cooling rates during solidification is considered. Differential thermal analysis is carried out at a moderate and constant heating scan speed until complete remelting. This allows linking each of the peaks observed in the DTA curve to a related phase transformation that had occurred during the initial solidification in the spin-casting process. The phases that were formed during the spin-casting process, especially solidification carbides, are characterized through light microscopy (distribution) and scanning electron microscopy (morphology) either associated with EDS (chemical composition) or associated with EBSD (crystal lattice identification). A discussion is opened about the influence of solidification rates on both supersaturation and lattice distortions in the solidification carbides. The combination of reverse DTA and SEM/EDS–EBSD applied here to the complex Gr-HSS alloy constitutes a relevant approach to understand the phase transformations during complex casting processes where relatively high solidification rates are achieved.

Aims: The Pros-IT CNR project aims to monitor a sample of Italian males ≥18years of age who have been diagnosed in the participating centers with incident prostate cancer, by analyzing their clinical features, treatment protocols and outcome results in relation to quality of life. Methods: Pros-IT CNR is an observational, prospective, multicenter study. The National Research Council (CNR), Neuroscience Institute, Aging Branch (Padua) is the promoting center. Ninety-seven Italian centers located throughout Italy were involved. The field study began in September 1, 2014. Subjects eligible were diagnosed with biopsy-verified prostate cancer, naïve. A sample size of 1500 patients was contemplated. A baseline assessment including anamnestic data, clinical history, risk factors, the initial diagnosis, cancer staging information and quality of life (Italian UCLA Prostate Cancer Index; SF-12 Scale) was completed. Six months after the initial diagnosis, a second assessment evaluating the patient’s health status, the treatment carried out, and the quality of life will be made. A third assessment, evaluating the treatment follow-up and the quality of life, will be made 12months after the initial diagnosis. The 4th, 5th, 6th and 7th assessments, similar to the third, will be completed 24, 36, 48 and 60months after the initial diagnosis, respectively, and will include also a Food Frequency Questionnaire and the Physical Activity Scale for the Elderly. Discussion: The study will provide information on patients’ quality of life and its variations over time in relation to the treatments received for the prostate cancer.

Ancora oggi il trattamento insulinico rappresenta il cardine nella gestione dei pazienti affetti da diabete mellito tipo 1 (DMT1). Al fine di garantire una maggior flessibilita nella gestione della terapia, sono state recentemente immesse in commercio nuove insuline basali, ad azione piu prolungata e stabile, e nuove insuline prandiali a minor latenza d’azione, che mostrano una farmacocinetica in grado di ricalcare piu da vicino la fisiologica produzione pancreatica di insulina. Analogamente, l’aggiunta di trattamenti ipoglicemizzanti tipicamente utilizzati nel diabete mellito tipo 2 (DMT2) ha mostrato risultati incoraggianti sia in termini di miglioramento del compenso glicemico che di sicurezza terapeutica nei pazienti con DMT1. Per tale motivo, sulla base delle evidenze scientifiche emerse dai diversi trial clinici e sempre piu diffuso l’utilizzo nella pratica clinica di farmaci come la metformina, gli inibitori del co-trasportatore di sodio glucosio 2 (SGLT2), gli agonisti del recettore del peptide 1 glucagone-simile (GLP-1) e gli inibitori della dipeptidil peptidasi-4 (DPP-4). Cio nonostante, sono necessari ulteriori studi multicentrici e randomizzati al fine di confermarne l’efficacia e la sicurezza a lungo termine.

Genetic cardiomyopathies are complex diseases with heterogeneous clinical presentation and phenotypes. Early descriptions of cardiomyopathies originated from case studies involving individuals with severe, paradigmatic presentation, which provided insight into the worst-case scenarios of these conditions. With time, improved diagnostic sensitivity and awareness of cardiomyopathies has uncovered a more heterogeneous disease spectrum, including mild phenotypes overlapping with physiological variation. This diagnostic 'grey area' poses important dilemmas, particularly in athletes. Current screening policies have the potential to identify affected individuals at very early stages, leading to effective prevention of cardiomyopathy-related complications such as sudden cardiac death. Conversely, however, some physicians actively impose diagnoses on individuals who perceive themselves to be disease-free. In addition, the high sensitivity of contemporary diagnostic techniques carries a serious risk of misinterpreting physiological variation as disease. In this Review, three of the most common and controversial areas are discussed, including left ventricular hypertrophy; left ventricular dilatation, noncompaction, and fibrosis; and arrhythmias originating from the right ventricle. A systematic and cautious approach is necessary in patients with mild phenotypes suggestive of, but not definitely diagnostic for, cardiomyopathies. Preventing the mislabelling of healthy individuals and overdiagnosis should be a priority, with the aim to combine adequate counselling and optimal protection.

The study of behavioural ecology of rare and elusive species can be challenging, but it is an important issue for monitoring populations in planning conservation actions. This is especially true for arboreal insects inhabiting old-growth forests, whose habits are scarcely known and rely on many anecdotal data, such as the stag beetle Lucanus cervus (Linnaeus, 1758). In order to gather information on daily activity and behaviour of this species, a radio-telemetry study was conducted in a relict broadleaf forest surrounded by intensively cultivated land in northern Italy. During 2014 and 2015, from May to July, 55 stag beetles (34 males, 21 females) were radio-tagged. Most of them were caught with the aid of an entomological hand net, but nine of them were captured by emergence traps set up on deadwood. Visual contact analysis confirmed that stag beetle males were less elusive than females. Males were more frequently radio-tracked in flight, females mostly underground and in proximity of deadwood. Males were mostly observed flying at sunset, and resting or walking on standing trees during the day. The combination of air temperature and humidity determined the optimal weather conditions for male flights (temperature range: 20.7–26 °C, humidity range: 65.5–78.3%). Flying at sunset, mostly performed by males, significantly increased the detectability of the species and supported the selection of the ‘transect walk at dusk’ as the best monitoring method for the stag beetle.

Background Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) are exceptionally rare in the first decade of life (mostly if multifocal) and there is a lack of standardized recommendations for the pediatric age. Case presentation We describe the case of a 9-year-old boy with a diagnosis of PUNLMP, who underwent to cystoscopic lesion removal and later to endoscopic lesion removal and intra-bladder Mitomycin-c (MMC) instillations for relapsed disease. Follow-up investigations at five years showed disease negativity. Conclusions Intra-bladder MMC instillation may allow obtaining the complete remission with bladder-sparing for paediatric patients with a high-risk relapsed PUNLMP.

The potential ability to differentiate dedifferentiated adipocytes into a neural lineage is attracting strong interest as an emerging method of producing model cells for the treatment of a variety of neurological diseases. Here, we describe the efficient conversion of dedifferentiated adipocytes into a neural-like cell population. These cells grew in neurosphere-like structures and expressed a high level of the early neuroectodermal marker Nestin. These neurospheres could proliferate and express stemness genes, suggesting that these cells could be committed to the neural lineage. After neural induction, NeuroD1, Sox1, Double Cortin, and Eno2 were not expressed. Patch clamp data did not reveal different electrophysiological properties, indicating the inability of these cells to differentiate into mature neurons. In contrast, the differentiated cells expressed a high level of CLDN11, as demonstrated using molecular method, and stained positively for the glial cell markers CLDN11 and GFAP, as demonstrated using immunocytochemistry. These data were confirmed by quantitative results for glial cell line-derived neurotrophic factor production, which showed a higher secretion level in neurospheres and the differentiated cells compared with the untreated cells. In conclusion, our data demonstrate morphological, molecular, and immunocytochemical evidence of initial neural differentiation of mature adipocytes, committing to a glial lineage.

Due to an increasingly aging population, Alzheimer disease (AD) represents a crucial issue for the healthcare system because of its widespread prevalence and the burden of its care needs. Several hypotheses on AD pathogenesis have been proposed and current therapeutical strategies have shown limited effectiveness. In the last decade, more evidence has supported a role for neuroinflammation and immune system dysregulation in AD. It remains unclear whether astrocytes, microglia and immune cells influence disease onset, progression or both. Amyloid-β peptides that aggregate extracellularly in the typical neuritic plaques generate a constant inflammatory environment. This causes a prolonged activation of microglial and astroglial cells that potentiate neuronal damage and provoke the alteration of the blood brain barrier (BBB), damaging the permeability of blood vessels. Recent data support the role of the BBB as a link between neuroinflammation, the immune system and AD. Hence, a thorough investigation of the neuroinflammatory and immune system pathways that impact neurodegeneration and novel exciting findings such as microglia-derived microvesicles, inflammasomes and signalosomes will ultimately enhance our understanding of the pathological process. Eventually, we should proceed with caution in defining a causal or consequential role of neuroinflammation in AD, but rather focus on identifying its exact pathological contribution.

Background We report our experience and outcomes about the management of Askin’s tumors [AT], which are rare primitive neuroectodermal tumors (PNETs) that develop within the soft tissue of the thoracopulmonary region, typically in children and adolescents. Methods We retrospectively analyzed the charts of 9 patients affected by AT (aged 6–15 years), treated at the Paediatric Oncology Unit of Gemelli University Hospital in Rome between January 2001 and December 2016. Results All nine patients underwent to biopsy followed by neoadjuvant chemotherapy. At the end of the neoadjuvant chemotherapy, they underwent to surgical removal of the residual tumor. Five patients with positive tumor margins and/or necrosis

CRISPR/Cas9-based therapeutics hold the possibility for permanent treatment of genetic disease. The potency and specificity of this system has been used to target dominantly inherited conditions caused by heterozygous missense mutations through inclusion of the mutated base in the short-guide RNA (sgRNA) sequence. This research evaluates a novel approach for targeting heterozygous single-nucleotide polymorphisms (SNPs) using CRISPR/Cas9. We determined that a mutation within KRT12, which causes Meesmann's epithelial corneal dystrophy (MECD), leads to the occurrence of a novel protospacer adjacent motif (PAM). We designed an sgRNA complementary to the sequence adjacent to this SNP-derived PAM and evaluated its potency and allele specificity both in vitro and in vivo. This sgRNA was found to be highly effective at reducing the expression of mutant KRT12 mRNA and protein in vitro. To assess its activity in vivo we injected a combined Cas9/sgRNA expression construct into the corneal stroma of a humanized MECD mouse model. Sequence analysis of corneal genomic DNA revealed non-homologous end-joining repair resulting in frame-shifting deletions within the mutant KRT12 allele. This study is the first to demonstrate in vivo gene editing of a heterozygous disease-causing SNP that results in a novel PAM, further highlighting the potential for CRISPR/Cas9-based therapeutics.

To evaluate the efficacy of hypofractionated stereotactic radiotherapy performed as reirradiation in combination with fotemustine or bevacizumab as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2013, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT, 25 Gy in 5-Gy fractions) plus either fotemustine or bevacizumab at University of Rome Sapienza, Sant’Andrea Hospital. All patients had Karnofsky performance score (KPS) ≥ 60 and were previously treated with standard chemoradiotherapy. Forty-two patients had a GBM and 12 patients had an anaplastic astrocytoma (AA). The median overall survival (OS) time and 12-month OS rates after HSRT was 11 months and 30 % for patients treated with HSRT plus bevacizumab and 8.3 months and 5 % for those treated with HSRT plus fotemustine (p = 0.01). Median PFS times were 4 and 6 months for patients treated with HSRT plus fotemustine or bevacizumab, respectively (p = 0.01). KPS > 70 (p = 0.04), AA histology, and the treatment with bevacizumab were independent favourable prognostic factors for OS. In general, both treatments were well tolerated with relatively low treatment-related toxicity. HSRT combined with bevacizumab or fotemustine may represent a feasible treatment option for patients with progressive malignant gliomas, although most of the tumors recur in a few months. Efficacy of bevacizumab or alkylating agents in combination with different radiation schedules needs to be evaluated in prospective studies.

Model simulations of tropospheric NO2 vertical column density are performed using the online-coupled BOLCHEM model. Model output is compared to ozone monitoring instrument (OMI) data from the Tropospheric Emission Monitoring Internet Service (TEMIS) over Europe for the year 2007. European hot-spots (Po Valley and BeNeLux) are simulated at finer resolution and analysed separately, along with the area of Gibraltar. Standard statistical analysis reveals good model performances, even in highly polluted regions, with spatial correlation 0.90 for the whole of Europe, 0.74 for the Po Valley, 0.85 for BeNeLux and 0.79 for Gibraltar. Seasonal analysis shows some dependency on time, with lowest scores in winter, when the satellite product also suffers weaker statistical significance due to the presence of clouds. The increase in resolution is found to affect the spatial correlation more the Po Valley (+23 %) than in BeNeLux (+5 %). This difference is likely to depend on the very different meteorology of the two hot-spots.

Over the years reducing the number of ports during Video-assisted thoracic surgery (VATS) has allowed to accomplish pulmonary lobectomy with a single incision. Endoscopic view and instruments maneuvers issues could be improved by using flexible endoscope. We report our experience of fifteen uniportal VATS (UVATS) using a flexible thoracoscope. A single incision of about 4–5 cm long was performed at the 5th intercostal space along the anterior axillary line. No additional skin incisions were made. A flexible videoscope and multiple VATS instruments were simultaneously inserted into the uniport. Pulmonary lobectomy with systematic mediastinal lymph node dissection was performed. Verbal pain scores were registered using the visual analog scale from 0 to 10 at the first post-operative day. No post-operative complications or hospital mortality were recorded. Mean operative time was 112.6 min (range 70–200) and mean postoperative hospital stay 3.2 days (range 2–6). Mean pain score was 0.5 (range 0–2). Single-incision VATS lobectomy using a flexible thoracoscope is a feasible and safe approach.

Several molecular markers have been proposed as predictors of outcome in patients with high grade gliomas. We report a retrospective multicenter study of 97 consecutive adult patients with anaplastic astrocytoma (AA) treated with radiation therapy (RT) plus concomitant and adjuvant temozolomide (TMZ) between October 2004 and March 2012. Correlations between the isocitrate dehydrogenase 1 (IDH1) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. At a median follow-up time of 46 months (range 12–89 months), median and 5-year overall survival rates were 50.5 months (95 % CI, 37.8–63.2) and 38 % (95 % CI, 25.7–50.7 %), and median and 5-year progression-free survival rates were 36 months (95 % CI, 28.5–44.0) and 22 % (95 % CI, 10–34 %), respectively. IDH1 mutation and MGMT promoter methylation were present in 54 and 60 % of evaluable patients, respectively. Multivariate Cox proportional hazards regression analysis showed that IDH1 mutation (P = 0.001), MGMT methylation (P = 0.01), age

Amyloids escape elimination by the proteasome, and their accumulation and subsequent aggregation contribute to various neurodegenerative conditions. A signature feature of amyloidogenic proteins is extended sequences rich in single amino acids. In this issue, Matouschek and colleagues now show that, to initiate degradation, the proteasome prefers substrates that have disordered regions with complex amino acid composition, thus indicating why it fails to rid the cell of most amyloids.