Combining germline, tissue and liquid biopsy analysis by comprehensive genomic profiling to improve the yield of actionable variants in a real-world cancer cohort.

BACKGROUND: Comprehensive next-generation sequencing is widely used for precision oncology and precision prevention approaches. We aimed to determine the yield of actionable gene variants, the capacity to uncover hereditary predisposition and liquid biopsy appropriateness instead of, or in addition to, tumor tissue analysis, in a real-world cohort of cancer patients, who may benefit the most from comprehensive genomic profiling. METHODS: Seventy-eight matched germline/tumor tissue/liquid biopsy DNA and RNA samples were profiled using the Hereditary Cancer Panel (germline) and the TruSight Oncology 500 panel (tumor tissue/cfDNA) from 23 patients consecutively enrolled at our center according to at least one of the following criteria: no available therapeutic options; long responding patients potentially fit for other therapies; rare tumor; suspected hereditary cancer; primary cancer with high metastatic potential; tumor of unknown primary origin. Variants were annotated for OncoKB and AMP/ASCO/CAP classification. RESULTS: The overall yield of actionable somatic and germline variants was 57% (13/23 patients), and 43.5%, excluding variants previously identified by somatic or germline routine testing. The accuracy of tumor/cfDNA germline-focused analysis was demonstrated by overlapping results of germline testing. Five germline variants in BRCA1, VHL, CHEK1, ATM genes would have been missed without extended genomic profiling. A previously undetected BRAF p.V600E mutation was emblematic of the clinical utility of this approach in a patient with a liver undifferentiated embryonal sarcoma responsive to BRAF/MEK inhibition. CONCLUSIONS: Our study confirms the clinical relevance of performing extended parallel tumor DNA and cfDNA testing to broaden therapeutic options, to longitudinally monitor cfDNA during patient treatment, and to uncover possible hereditary predisposition following tumor sequencing in patient care.

Preoperative infection risk assessment in hip arthroplasty a matched-pair study of the reliability of 3 validated risk scales.

Peri-prosthetic infection (PJI) represents one of the most devastating complications of total hip arthroplasty (THA). The aim of this study is to assess the reliability of different PJI risk assessment scales between two matched pairs of THA groups. This study included 37 patients with PJI following THA performed between 2012 and 2020 (Group A). Each patient in this group was matched, based on sex, age, and follow-up duration, with a control patient who underwent the same surgical procedure without any septic complications (Group B) during the same period. Each patient's assessment included the American Society of Anesthesiologists (ASA) score and a retrospective evaluation using three different preoperative, specific PJI risk assessment scales: the International Consensus Meeting (ICM) Preoperative Risk Calculator for PJI, the Mayo PJI Risk Score, and the KLIC-score. The two groups were statistically compared using descriptive analyses, both for binomial data and numerical variables. Statistically significant higher values were observed in the preoperative ASA score and surgical time in Group A. Statistically different higher scores were determined only with the ICM risk calculator score in Group A. No significant differences were found using the KLIC score and Mayo score between the two groups. We emphasize the reliability of the ASA score as a nonspecific preoperative assessment scale for PJI. The ICM risk calculator was confirmed as a reliable, specific preoperative assessment scale for PJI, suggesting its routine adoption in THA clinical practice.

Chemical data of contaminants in water and sediments from the Doce River four years after the mining dam collapse disaster.

Chemical datasets describing the occurrence of both inorganic and organic contaminants along the Doce River Basin (DRB) could provide a better understanding of the potential impacts of a major mining dam collapse disaster combined to additional chronic sources of contamination. This data article presents datasets of main contaminants detected in the water and sediments sampled four years after the mining dam collapse in the DRB. A summary table of data obtained in the literature is also provided to allow a comparison of the variation of chemicals before, right after in 2015/2016 and after the event (current data). In addition, there are also provided physical-chemical parameters of water and sediments of different sampling sites, which could support the investigation of chemicals distribution. For this purpose, triplicate samples of water and sediment were obtained in 8 sampling sites along the DRB during wet and dry seasons of 2019, totalizing 48 samples of each environmental matrix. The sampling sites were strategically selected according to their different main sources of pollution along the river. Concentrations of trace elements and organic contaminants (polycyclic aromatic hydrocarbons, and pyrethroids) were determined in samples of water and sediments by inductively coupled plasma mass spectrometry (ICP-MS) and gas chromatography - mass spectrometry GC-MS, respectively. Main data obtained in the literature consisted in published reports from environmental agencies (IGAM) and private companies (RENOVA) as well as journal articles. The datasets provided may be useful to the stakeholders, which include scientific community, authorities and public agencies, and private companies interested to understand the impacts of the contaminants introduced along the River Basin four years after the environmental disaster.

Dissolution of irregularly-shaped drug particles: mathematical modelling.

The prediction of drug dissolution profiles is crucial for elucidating the pharmacokinetic behaviour of drugs and the bioavailability of dosage forms. In this work, we develop a mathematical model to describe the dissolution process of irregularly shaped particles. We use a complete dissolution model that accounts for both surface kinetics and convective diffusion. The mechanistic relationship between the mass transfer coefficient and the local curvature is derived from the fundamental physical laws governing these processes. Our model theoretically shows that the dissolution rate depends nonlinearly on the surface curvature. The subsequent recrystallization process in the bulk fluid is also considered. The main result of this work is its simplicity, since only two coupled nonlinear ordinary differential equations are needed to describe the dissolution process. Another remarkable advantage is the possibility to determine the model parameters using common independent techniques, so that the importance of the wettability of solids on the dissolution process can be evaluated. Finally, the proposed model demonstrated the importance of particle shape in describing the experimental dissolution data of theophylline monohydrate.

Joint Determination of Reactor Antineutrino Spectra from

A joint determination of the reactor antineutrino spectra resulting from the fission of ^{235}U and ^{239}Pu has been carried out by the Daya Bay and PROSPECT Collaborations. This Letter reports the level of consistency of ^{235}U spectrum measurements from the two experiments and presents new results from a joint analysis of both data sets. The measurements are found to be consistent. The combined analysis reduces the degeneracy between the dominant ^{235}U and ^{239}Pu isotopes and improves the uncertainty of the ^{235}U spectral shape to about 3%. The ^{235}U and ^{239}Pu antineutrino energy spectra are unfolded from the jointly deconvolved reactor spectra using the Wiener-SVD unfolding method, providing a data-based reference for other reactor antineutrino experiments and other applications. This is the first measurement of the ^{235}U and ^{239}Pu spectra based on the combination of experiments at low- and highly enriched uranium reactors.

Efficacy of bio- and neurofeedback for depression: a meta-analysis.

BACKGROUND: For many years, biofeedback and neurofeedback have been implemented in the treatment of depression. However, the effectiveness of these techniques on depressive symptomatology is still controversial. Hence, we conducted a meta-analysis of studies extracted from PubMed, Scopus, Web of Science and Embase. METHODS: Two different strings were considered for each of the two objectives of the study: A first group comprising studies patients with major depressive disorder (MDD) and a second group including studies targeting depressive symptomatology reduction in other mental or medical conditions. RESULTS: In the first group of studies including patients with MDD, the within-group analyses yielded an effect size of Hedges' g = 0.717, while the between-group analysis an effect size of Hedges' g = 1.050. Moderator analyses indicate that treatment efficacy is only significant when accounting for experimental design, in favor of randomized controlled trials (RCTs) in comparison to non RCTs, whereas the type of neurofeedback, trial design, year of publication, number of sessions, age, sex and quality of study did not influence treatment efficacy. In the second group of studies, a small but significant effect between groups was found (Hedges' g = 0.303) in favor of bio- and neurofeedback against control groups. Moderator analyses revealed that treatment efficacy was not moderated by any of the sociodemographic and clinical variables. CONCLUSIONS: Heart rate variability (HRV) biofeedback and neurofeedback are associated with a reduction in self-reported depression. Despite the fact that the field has still a large room for improvement in terms of research quality, the results presented in this study suggests that both modalities may become relevant complementary strategies for the treatment of MDD and depressive symptomatology in the coming years.

Femoral Neck Fractures in HIV-Positive Patients: Analysis of 10 Years Short-Term Post-operative Complications.

INTRODUCTION: Aging and effect of antiretroviral therapy on bone mass could increase the risk of femoral neck fractures (FNF) in HIV patient. The aim of this study was specifically to determine whether intracapsular FNF in HIV-positive patients are more prone to short-term post-operative complications than similar fractures occurring in HIV-negative patients. MATERIALS AND METHODS: A group of 25 HIV-positive patients with intracapsular FNF were enrolled and matched to HIV-negative patient with similar fractures according to gender, age, a modified Charlson Comorbidity Index (CCI), fracture classification, surgical treatment and time interval between fracture event and surgery. For each group, length of stay, surgical time, early clinical outcomes and short-term surgical and medical complications were compared to determine the impact on the early outcome. RESULTS: At the time of the fracture occurrence, 56% of HIV-positive patients were on antiretroviral therapy and 12% started with therapy in the perioperative period. At three months follow-up, there were no statistically significant differences between the two study groups in length of stay, Harris hip score and total number of early complications. However, a statistically significant increase in urinary tract infections and longer surgical time using hip sliding screw fixation were seen in the HIV-positive group. The poorest post-operative result was seen in a patient who failed to adequately adhere to the HIV therapy protocol. CONCLUSIONS: This study failed to show any statistically significant increase in short-term complications or worse clinical outcomes for intracapsular FNF in HIV-positive patients compared to HIV-negative patients to recommend their treatment in dedicated centres.

E-learning course improves knowledge in tobacco dependence, electronic nicotine delivery systems and heat-not-burn products in Medical School students.

BACKGROUND: Adequate training in tobacco, nicotine dependence and treatment is lacking in Medical School education. With the rise in popularity of electronic alternatives to cigarettes, future physicians should also be provided with the more recent scientific evidence on these products during their undergraduate studies. We introduced an e-learning course for Medical School students and assessed its effec-tiveness of increasing knowledge on these topics. METHODS: We developed 16 didactic modules divided in 3 courses: tobacco dependence (TDI), treating tobacco dependence (TDII) and electronic products and tobacco control (TDIII). The course was offered to 4th, 5th, and 6th year Medical School students in Italy. To assess learning outcomes, we examined the pre- to post- changes in knowledge scores associated with each course. Paired and independent samples t-tests were performed overall, and among smokers and non-smokers separately. RESULTS: A total of 1318 students completed at least one of the courses; 21% were self-reported smokers. A significant increase in knowledge was observed at the end of TDI (pre-course: 52.1±15.9, post-course: 79.9±13.5, p<0.001), TDII (pre-course: 52.5±13.0, post-course: 66.5±12.0, p<0.001) and TDIII (pre-course: 52.2±15.3, post-course: 76.1±17.7, p<0.001). Smokers showed significantly lower improvements compared to non-smokers. CONCLUSIONS: The e-learning course was effective in increasing knowledge about tobacco dependence, treatments, and electronic ni-cotine products in advanced medical students. Given the fundamental role for healthcare practitioners in encouraging and assisting people in quitting smoking, e-learning may be a useful tool in providing up-to-date and standardized training in the area during Medical School.

Cardiac sources of cerebral embolism in people with migraine.

BACKGROUND AND PURPOSE: Whether the reported association between migraine with aura (MA) and cardioembolic stroke may be explained by a higher rate of atrial fibrillation (AF) or by other potential cardiac sources of cerebral embolism remains to be determined. METHODS: In the setting of a single centre cohort study of consecutive patients with acute brain ischaemia stratified by migraine status, the association between AF as well as patent foramen ovale (PFO) and migraine was explored. RESULTS: In all, 1738 patients (1017 [58.5%] men, mean age 67.9 ± 14.9 years) qualified for the analysis. Aging was inversely associated with migraine, whilst women had a >3-fold increased disease risk (odds ratio [OR] 3.82, 95% confidence interval [CI] 2.58-5.66). No association between AF and history of migraine or its pathogenic subtypes was detected. Conversely, migraine was associated with PFO, both in the entire cohort (OR 1.84, 95% CI 1.07-3.16) and in patients aged ≤55 years (OR 2.21, 95% CI 1.16-4.22). This association was significant for MA (OR 2.92, 95% CI 1.32-6.45 in the entire cohort; OR 2.92, 95% CI 1.15-7.41 in patients aged ≤55 years) and in women (OR 8.23, 95% CI 2.06-32.77), but not for migraine without aura. CONCLUSIONS: In patients with brain ischaemia migraine is not associated with AF. Conversely, there is a probable relation between migraine, especially MA, and PFO in patients who are younger and have a more favourable vascular risk factor profile, and in women.

Skeletal muscle repair in a rat muscle injury model: the role of growth hormone (GH) injection.

OBJECTIVE: Muscle injury tends to heal with incomplete functional recovery. Among the growth factors released in the physio-pathological response of muscle lesion, the Insulin-like Growth-Factor-1 (IGF-1) results in an engine factor of the reparation program. The therapeutic use of growth factors has been exploited to improve healing. As IGF-1 is a primary mediator of the effects of growth hormone (GH), we exploited its systemic administration to muscle recovery in a rat model of muscle injury. MATERIALS AND METHODS: Monolateral lesion of the longissimus dorsi muscle of rats was performed. Animals were divided into 5 groups: four groups for histological studies and serum hormone dosage, whilst the fifth group represented the uninjured control. Rat GH was intraperitoneally administered after 24h from the surgical lesion at three different concentrations (0.1, 0.2, 0.4 mg/kg). At 3 days from surgery, immunohistochemical and histological analyses evaluated the expression of MyoD and Myogenin, and the presence of neovascularization and inflammation, respectively. After 2 months, we analyzed the presence of muscle regeneration and fibrosis. RESULTS: The treatment with GH resulted in a significant increase in neovascularization and Myogenin expression at 24h from injury in comparison with the control. This suggested speed up biological recovery times. After two-months, a dose-dependent increase of the connective component was observed. CONCLUSIONS: The potential effect of GH on muscle repair and regeneration, through the activation of satellite cells already demonstrated in vitro, was confirmed in this in vivo experimental approach. This study sheds light on the role of growth factors in damage repair mechanisms to find an appropriate biological treatment for muscle injury.

Global Health Professions Student Survey among Healthcare students: a cross sectional study.

BACKGROUND: Healthcare professionals have the potential to influence patients' smoking status; however, their smoking habits and their opinions about tobacco use can hamper an effective counselling about smoking to patients. METHODS: A cross-sectional survey was carried out among healthcare students from the Sapienza University of Rome using a previously validated Italian version of Global Health Professions Student Survey (GHPSS) online questionnaire. RESULTS: Overall, 349 students filled out the online survey: 158 (45%) were current smokers and 191 (55%) were nonsmokers. Nurses students had the highest percentage of smokers (55%). Healthcare students declared they had learned about the health consequences about tobacco use during their academic course (90%), however, only 24% received specific training on smoking cessation. CONCLUSIONS: It is necessary to implement a smoking cessation course in the undergraduate curriculum in order to train healthcare professionals to provide patients an effective counselling against smoking.

Unilateral multifocal choroiditis following EBV-positive mononucleosis responsive to immunosuppression: a case report.

BACKGROUND: Multifocal choroiditis (MFC) is a relatively uncommon bilateral inflammatory chorioretinopathy affecting Caucasian young women with myopia. We present images from a case of completely unilateral multifocal choroiditis following EBV-positive mononucleosis that demonstrated a dramatic clinical response to immunosuppression. CASE PRESENTATION: A 20-year-old woman with bilateral high myopia (-6D) and a documented normal prior retinal examination presented with visual loss in the right eye 2 months following confirmed Epstein-Barr virus (EBV) positive mononucleosis. Ophthalmoscopic examination showed completely unilateral placoid lesions of variable age. The left eye was unaffected. Fluorescein angiography revealed active leakage, especially in the parafovea. Spectral domain optical coherence tomography (SD-OCT) demonstrated sub-retinal pigment epithelial nodular deposits, some of which were confluent with overlying intra-retinal fluid and indistinct margins. Upon treatment with the immunosuppressant azathioprine there was significant resolution of the lesions in her right eye along with improvement in vision. CONCLUSION: This is a rare case of completely unilateral MFC following an episode of EBV positive mononucleosis that showed a dramatic response to immunosuppression.

Gastrointestinal stromal tumors and second primary malignancies: a retrospective monocentric analysis.

In the post-Imatinib era, the median survival of patients diagnosed with GIST has reached almost 5 years. Prolonging GIST-specific survival, GIST patients have an increased incidence of secondary neoplasia. Data on the prognostic impact of second tumors in GIST patients are very poor with few and small retrospective analyses available in the literature. We conducted a retrospective monocentric analysis on 145 patients diagnosed with GIST between April 2001 and October 2018. Kaplan-Meier and Cox hazard methods were used for survival analysis. A total of 154 GIST patients were included and 31 patients of them (21%) were diagnosed with at least one additional malignancy. The most common second tumors associated with GIST were gastrointestinal tumors. GIST patients with additional malignancies showed to have lower size (>5 cm: 35% vs 45%; p=0.75), higher mitotic rate (>5/50 HPFs: 42% vs 29%; p=0.24), higher presence of c-KIT mutation (85% vs 69%), a lower presence of PDGFRα mutation (8% vs 17%; p=0.05) and shorter survival (mOS: 9.6 vs 15.5 years; p=0.30). In conclusion, our study did not find any significant correlation between clinicopathological characteristics and the development of a second tumor in GIST patients. Further analyses and strict follow up protocols are needed in order to early diagnose and promptly treat a second primary tumor in the GIST population.

Effectiveness of a training course on smoking cessation knowledge and behaviour for health profession students: the SISMA project.

INTRODUCTION: University students are at risk of starting smoking or continuing and increasing the consumption of tobacco products. The aim of the study was to assess the impact of the training course, Sisma Project, about smoking in healthcare degree courses, in terms of knowledge, behaviour and to evaluate the course. METHODS: SISMA project was a pre- post study about an intervention delivered to healthcare profession students about smoking and smoking cessation. It had a before-after design and was an online optional course available on the eLearning platform Moodle 2. The course was structured in four lessons of sixty minutes, a debate among experts and a final test of evaluation. The McNemar test was used to measure the effectiveness of Sisma on smoking behaviour of students after the intervention. Students rated the course assigning a score from one to ten, and expressed free comments about point of strength and weakness of Sisma project. RESULTS: The participants were 365 students, 28.5% males and 71.5% females, most were nursing 194 (53.2%) and dental hygienists students 105 (28.8%). Current smokers were 161 (44.1%) before and 142 (38.9%) after the course, there was statistical significant difference in smoking status after attending the course (p < 0.001). Students evaluated the course giving a high score with a mean of 8.13 (SD: 1.1); the main points of strength were the content (33.2%), the structure (15.6%) and knowledge given by the course (12.6%). The main point of weakness were the online structure 62 (37%), problem related to length and time 17 (10%) and the final test 15 (9%). DISCUSSION: Given the central role health professionals play in patient care, students need to be aware and trained in tobacco cessation techniques. Our results indicate that smoking behaviour significantly changed after attending a university course for smoking cessation and students appreciated its contents and structure.

Smoking E-CigaRette and HEat-noT-burn products: validation of the SECRHET questionnaire.

BACKGROUND: The nicotine market has rapidly evolved with the emergence of newer forms of smoking device that have been expanded worldwide, such as electronic cigarettes (eCig) which heat a solution (e-liquid) to create vapour and heat-not-burn (HNB) tobacco products, which heats tobacco at a temperature below the point of combustion. Their use is increasing at an alarming rate; it is believed it will surpass the use of traditional cigarettes in next 5 years, mostly among never-smokers and young people. OBJECTIVE: There are not many studies investigating knowledge and behaviour about heat tobacco products (HTP) among teenagers, so the aim of this study is to validate the SECRHET questionnaire (Smoking E-CigaRette and HEat-noT-burn products) on knowledge and behaviour on cigarette and HTP among youth. METHODS: The study was conducted in February and March 2019 inside Sapienza University of Rome and high school Giulio Cesare of Rome. A self-administered anonymous questionnaire was performed to investigate smoking habits and measures knowledge about HTP among Italian teenagers. OUTCOMES: A sample of 60 students took part in the validation of the questionnaire. The overall Cronbach's alpha was 0,635, corresponding to a sufficient reliability. CONCLUSIONS: There is little or no data on consumption or perceptions of HTP products among youth and evidence suggests the usefulness of a standardized and validated questionnaire available to monitoring of awareness, interest in trying and prevalence of use of these novel products among young people.

Knowledge of nicotine dependence and treatment in clinical practice improved after an e-learning course among medical students.

OBJECTIVE: Tobacco smoking is the leading cause of preventable death in developed countries and smokers should be encouraged to quit. Physicians are instrumental in this, but recent reports suggest inadequate training in medical school. We aimed to assess the knowledge of nicotine dependence and its treatment among Italian medical students. STUDY DESIGN: Prospective observational study. METHODS: We developed an online course consisting of 11 Didactic Modules (6 for Tobacco Dependence I, TDI, and 5 for TDII) on nicotine dependence and treatment. The course was administered to 4th and 5th year medical students in Italy in Academic Years 2016-17 (Course A) and 2017-18 (Course B). A validated questionnaire was used before and after each part in order to measure knowledge of smoking epidemiology, health effects and benefits of giving up smoking ("Score 1", TDI), and effectiveness of cessation treatments ("Score 2", TDII). RESULTS: 324 students took both TDI and TDII and completed all questionnaires (Course A, n = 245; Course B, n = 79). 55 students were current smokers (17%). A significant increase in score 1 and 2 was observed at the end of both TDI (pre-course 47.2±13.1, post-course 66.0±12.3, p <0.0001) and TDII (pre-course 55.6±11.5, post-course 68.1±10.9, p <0.0001). The prevalence of students wishing for a smoke-free medical school significantly increased between the beginning of TDI (74.4%, 241/324) and the end of TDII (88%, 285/324; p <0.0001). CONCLUSIONS: This e-learning course has proven to be an effective tool in teaching students on nicotine dependence and treatment.

Investigation on the thermal gelation of Chitosan/ß-Glycerophosphate solutions.

This work deals with the effect of temperature on the thermal-gelation process of water solutions containing chitosan ß-glycerolphosphate disodium salt hydrate. In particular, the attention is focused on the role played by temperature on the gel final properties, a very important aspect in the frame of drug delivery systems. The study was performed by combining rheology and low field nuclear magnetic resonance, two approaches that revealed to be highly synergic as they can detect different aspects of the developing polymeric network. This study indicates that 30 °C represent a sort of threshold for both the gelation kinetics and the gel final properties. Indeed, above this temperature, gelation kinetics was rapid and yielded to a strong gel. On the contrary, a slow kinetics and a final weak gel occurred below 30 °C. Finally, rheology and low field NMR allowed, independently, evaluating the time evolution of the network mesh size upon gelation.

Epidemiological, clinical and pathological characteristics of gastric neoplasms in the province of Cremona: the experience of the first population-based specialized gastric cancer registry in Italy.

BACKGROUND: The gastric cancer incidence rate differs widely across geographical areas. In Italy, in the province of Cremona the incidence is high, compared to the national situation. For this reason a specialized population-based registry was set up. METHODS: The collection encompasses all gastric cancers diagnosed in the three districts of the province since January 1, 2010. The main data sources were the pathological and Hospital Discharge Records and patient clinical charts. Only diagnoses of primary gastric cancer were considered. For each case the following variables were registered: personal data, medical history and symptoms at diagnosis; imaging assessments performed, details on surgery and other treatments received; genetic background and biomolecular characteristics; social and environmental factors. RESULTS: As of November 2017, 1087 cases were collected; of which 876, diagnosed up to December 2015, were analyzed. Male/female ratio was 1.4. The European Age-standardized Incidence Rate was 41.4 for males and 28.3 for females as compared to a national average of 33.3 and 17.0 respectively. Median age at diagnosis was 73 for male and 78 for female. Helicobacter Pylori infection was present in fewer than 20% of cases. HER-2 gene was amplified in about 25% of cases. Primary tumour location was the gastro-esophageal junction or cardia in 17.5% in males and 8.3% in females. The majority of cases (58.3%) were diagnosed at an advanced stage and overall only 41.2% underwent surgery. Median overall survival was 14.8 months for men and 18.5 for women. Age standardized 5-year relative survival was 31.4% for men and 40.5% for females. Neoadjuvant treatment was performed in fewer than 10% of patients who underwent surgery, and the rate of postoperative therapy adherence was low. DISCUSSION: This study shows a high gastric cancer incidence in the province of Cremona, with a geographical spread across different districts. Moreover, a high percentage of gastric cancers were detected at an advanced stage of disease and a low rate of 5-year relative survival was registered. Based on these findings, effective preventive interventional health strategies and screening procedures need to be implemented to reduce the impact of this pathology in this geographical area.