Multianalyte Serum Biomarker Panel for Early Detection of Pancreatic Adenocarcinoma.

PURPOSE: We determined whether a large, multianalyte panel of circulating biomarkers can improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We defined a biologically relevant subspace of blood analytes on the basis of previous identification in premalignant lesions or early-stage PDAC and evaluated each in pilot studies. The 31 analytes that met minimum diagnostic accuracy were measured in serum of 837 subjects (461 healthy, 194 benign pancreatic disease, and 182 early-stage PDAC). We used machine learning to develop classification algorithms using the relationship between subjects on the basis of their changes across the predictors. Model performance was subsequently evaluated in an independent validation data set from 186 additional subjects. RESULTS: A classification model was trained on 669 subjects (358 healthy, 159 benign, and 152 early-stage PDAC). Model evaluation on a hold-out test set of 168 subjects (103 healthy, 35 benign, and 30 early-stage PDAC) yielded an area under the receiver operating characteristic curve (AUC) of 0.920 for classification of PDAC from non-PDAC (benign and healthy controls) and an AUC of 0.944 for PDAC versus healthy controls. The algorithm was then validated in 146 subsequent cases presenting with pancreatic disease (73 benign pancreatic disease and 73 early- and late-stage PDAC cases) and 40 healthy control subjects. The validation set yielded an AUC of 0.919 for classification of PDAC from non-PDAC and an AUC of 0.925 for PDAC versus healthy controls. CONCLUSION: Individually weak serum biomarkers can be combined into a strong classification algorithm to develop a blood test to identify patients who may benefit from further testing.

Comparing the COVID-19-related PTSD symptoms between psychiatric patients and healthy subjects: an observational retrospective study from Northern Italy.

COVID-19 pandemic had a great impact on mental health, both in the general population and psychiatric patients. Little is known about the difference between these two populations in perceiving the pandemic as a traumatic event. The aim of the study was to compare psychiatric patients and healthy controls (HC) in terms of change over time of post-traumatic (PTSD) symptoms. Demographic and clinical variables were collected. Impact of Event Scale Revised (IES-R) scores were registered at T1 as lockdown period (March-April 2020) and T2 as restarting (May-June 2020). Descriptive analyses and linear regression models were performed. A total of 166 outpatients and 57 HC were recruited. Time (F = 15.76; p < 0.001) and diagnosis (F = 4.94; p < 0.001) had a significant effect on the change of IES-R scores, which resulted T1 > T2 (p < 0.001), except for subjects affected by Obsessive-Compulsive Disorder (OCD). Overall, IES-R scores were < in patients than in HC (p = 0.02), particularly in the schizophrenia (SKZ) subgroup (p < 0.001). IES-R scores of subjects with personality disorders (PDs) resulted to be > HC, although not statistically significant. The lockdown period was perceived as more traumatic than the reopening phase by both groups, with the exception of OCD patients, probably because of the clinical worsening associated with the urge of control against risks of contamination. Overall, HC reported more PTSD symptoms than psychiatric patients did, particularly SKZ ones. PD patients, in contrast, may be more vulnerable to PTSD symptoms probably as a result of poor coping skills. Together with OCD patients, subjects with PDs may need closer monitoring during the different phases of the pandemic. Trial Registration: ClinicalTrials.gov Identifier: NCT04694482.

Critical investigation of the pre-surgical anatomic factors that influence the aesthetic result in post-extractive implantology and immediate prosthetic.

The aesthetic goals of implant dentistry should be similar to those of conventional prostheses. In implant-prosthetic rehabilitations of the anterior sectors, the quantity and quality of hard and soft tissue play a fundamental role in achieving the desired aesthetics and in integrating the restoration in a complete and harmonious way into the existing anterior dentition. Post-extraction implantology is a treatment option for implant therapy after the extraction of a single tooth in the anterior jaw. This article presents some key factors to analyze and follow in order to achieve a predictable and acceptable aesthetic result. The creation of a predictable peri-implant aesthetics requires adequate preservation of the bone and soft tissues around the teeth that will be extracted and a correct positioning of the 3D implant. Furthermore, aesthetic success requires the creation of a correct transmucosal path, during the provisional prosthetic phases, which must be replicated and maintained with the definitive crowns.

Aesthetic results following breast cancer surgery: A prospective study on 6515 cases from ten Italian Senonetwork breast centers.

Breast cancer treatment has deeply changed in the last decades, since clinical and oncological cure cannot be achieved without patient's satisfaction in term of aesthetic outcomes. Several methods have been proposed to objectively assess these results. However, Italian breast centers have not yet agreed on measurable, reproducible and validated aesthetic outcome indicators to monitor their performance. METHODS: The study was designed and conducted by Senonetwork, a not-for-profit association of Italian breast centers. Ten breast centers were selected based on specific eligibility criteria. This multicentre observational prospective study recruited 6515 patients with diagnosis of in situ or invasive breast cancer who underwent breast surgery in the years 2013-2016. Thirteen indicators of aesthetic results and of related quality of care were analyzed. Data collection and analysis were conducted using a common study database. RESULTS: On average, seven out of ten centers were able to collect data on the proposed indicators with a proportion of missing values < 25%. By expert consensus based on study results, some seven indicators have been defined as "mandatory" while the remaining six have been defined as "recommended" because they require further refinement before they can be proposed for monitoring aesthetic outcomes or because there are doubts on the feasibility of data collection. The minimum standard is reached for 5 of 13 indicators. This finding and the wide range between centers reveal that there is ample room for improvement. CONCLUSIONS: From the present study useful measurable aesthetic parameters have emerged, leading to the definition of target objectives that breast centers can use for benchmarking and improvement of quality of care.

Impact of evolving greenhouse gas forcing on the warming signal in regional climate model experiments.

Variations in the atmospheric concentrations of greenhouse gases (GHG) may not be included as external forcing when running regional climate models (RCMs); at least, this is a non-regulated, non-documented practice. Here we investigate the so far unexplored impact of considering the rising evolution of the CO2, CH4, and N2O atmospheric concentrations on near-surface air temperature (TAS) trends, for both the recent past and the near future, as simulated by a state-of-the-art RCM over Europe. The results show that the TAS trends are significantly affected by 1-2 K century-1, which under 1.5 °C global warming translates into a non-negligible impact of up to 1 K in the regional projections of TAS, similarly affecting projections for maximum and minimum temperatures. In some cases, these differences involve a doubling signal, laying further claim to careful reconsideration of the RCM setups with regard to the inclusion of GHG concentrations as an evolving external forcing which, for the sake of research reproducibility and reliability, should be clearly documented in the literature.

Time trends (2006-2015) of quality indicators in EUSOMA-certified breast centres.

AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast centres to establish minimum standards and ensure specialist multidisciplinary care. Prospectively collected anonymous information on primary breast cancer cases diagnosed and treated in the units is transferred annually to a central EUSOMA data warehouse for continuous monitoring of quality indicators (QIs) to improve quality of care. Units have to comply with the EUSOMA Breast Centre guidelines and are audited by peers. The database was started in 2006 and includes over 110,000 cancers from breast centres located in Germany, Switzerland, Belgium, Austria, The Netherlands, Spain, Portugal and Italy. The aim of the present study is assessing time trends of QIs in EUSOMA-certified breast centres over the decade 2006-2015. MATERIALS AND METHODS: Previously defined QIs were calculated for 22 EUSOMA-certified breast centres (46122 patients) during 2006-2015. RESULTS: On the average of all units, the minimum standard of care was achieved in 8 of 13 main EUSOMA QIs in 2006 and in all in 2015. All QIs, except removal of at least 10 lymph nodes at axillary clearance and oestrogen receptor-negative tumours (T > 1 cm or N+) receiving adjuvant chemotherapy, improved significantly in this period. The desirable target was reached for two QIs in 2006 and for 7 of 13 QIs in 2015. CONCLUSION: The EUSOMA model of audit and monitoring QIs functions well in different European health systems and results in better performance of QIs over the last decade. QIs should be evaluated and adapted on a regular basis, as guidelines change over time.

Diurnal preference, mood and the response to morning light in relation to polymorphisms in the human clock gene PER3.

PER3 gene polymorphisms have been associated with differences in human sleep-wake phenotypes, and sensitivity to light. The aims of this study were to assess: i) the frequency of allelic variants at two PER3 polymorphic sites (rs57875989 length polymorphism: PER3 4, PER3 5; rs228697 SNP: PER3 C, PER3 G) in relation to sleep-wake timing; ii) the effect of morning light on behavioural/circadian variables in PER3 4 /PER3 4 and PER3 5 /PER3 5 homozygotes. 786 Caucasian subjects living in Northern Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/mood questionnaires. 19 PER3 4 /PER3 4 and 11 PER3 5 /PER3 5 homozygotes underwent morning light administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin (aMT6s) rhythm. No significant relationship was observed between the length polymorphism and diurnal preference. By contrast, a significant association was observed between the PER3 G variant and morningness (OR = 2.10), and between the PER3 G-PER3 4 haplotype and morningness (OR = 2.19), for which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/aMT6s rhythms between PER3 5 /PER3 5 and PER3 4 /PER3 4 subjects at baseline. After light administration, PER3 4 /PER3 4 subjects advanced their aMT6s acrophase (p < 0.05), and showed a trend of advanced sleep-wake timing. In conclusion, significant associations were observed between PER3 polymorphic variants/their combinations and both diurnal preference and the response to light.

Volume of Larvae Is the Most Important Single Predictor of Mass Temperatures in the Forensically Important Calliphorid, Chrysomya megacephala (Diptera: Calliphoridae).

Calliphorid species form larval aggregations that are capable of generating heat above ambient temperature. We wanted to determine the relationship between volume, number of larvae, and different combinations of instars on larval mass heat generation. We compared different numbers of Chrysomya megacephala (F.) larvae (40, 100, 250, 600, and 2,000), and different combinations of instars (∼50/50 first and second instars, 100% second instars, ∼50/50 second and third instars, and 100% third instars) at two different ambient temperatures (20 and 30 °C). We compared 13 candidate multiple regression models that were fitted to the data; the models were then scored and ranked with Akaike information criterion and Bayesian information criterion. The results indicate that although instar, age, treatment temperature, elapsed time, and number of larvae in a mass were significant, larval volume was the best predictor of larval mass temperatures. The volume of a larval mass may need to be taken into consideration for determination of a postmortem interval.

Development of the Oriental Latrine Fly, Chrysomya megacephala (Diptera: Calliphoridae), at Five Constant Temperatures.

Chrysomya megacephala (Fabricius) is a forensically important fly that is found throughout the tropics and subtropics. We calculated the accumulated development time and transition points for each life stage from eclosion to adult emergence at five constant temperatures: 15, 20, 25, 30, and 35 °C. For each transition, the 10th, 50th, and 90th percentiles were calculated with a logistic linear model. The mean transition times and % survivorship were determined directly from the raw laboratory data. Development times of C. megacephala were compared with that of two other closely related species, Chrysomya rufifacies (Macquart) and Phormia regina (Meigen). Ambient and larval mass temperatures were collected from field studies conducted from 2001-2004. Field study data indicated that adult fly activity was reduced at lower ambient temperatures, but once a larval mass was established, heat generation occurred. These development times and durations can be used for estimation of a postmortem interval (PMI).

The self-morningness/eveningness (Self-ME): An extremely concise and totally subjective assessment of diurnal preference.

The assessment of diurnal preference, or the preferred timing of sleep and activity, is generally based on comprehensive questionnaires such as the Horne-Östberg (HÖ). The aim of the present study was to assess the reliability of a subject's self-classification as extremely morning (Self-MM), more morning than evening (Self-M), more evening than morning (Self-E) or extremely evening (Self-EE) type, based on the last question of the HÖ (Self-ME). A convenience sample of 461 subjects [23.8 ± 4.7 years; 322 females] completed a full sleep-wake assessment, including diurnal preference (HÖ), night sleep quality (Pittsburgh Sleep Quality Index, PSQI), daytime sleepiness (Karolinska Sleepiness Scale, KSS), and habitual sleep-wake timing (12 d sleep diaries; n = 296). Significant differences in HÖ total score were observed between Self-ME classes, with each class being significantly different from neighboring classes (p < 0.0001). Significant differences in sleep-wake timing (bed time, try to sleep and sleep onset, wake up, and get up time) were observed between Self-ME classes. Such differences were maintained when sleep-wake habits were analysed separately on work and free days, and also in a smaller group of 67 subjects who completed the Self-ME as a stand-alone rather than as part of the original questionnaire. Significant differences were observed in the time-course of subjective sleepiness by Self-ME class in both the large and the small group, with Self-MM and Self-M subjects being significantly more alert in the morning and sleepier in the evening hours compared with their Self-E and Self-EE counterparts. Finally, significant differences were observed in night sleep quality between Self-ME classes, with Self-EE/Self-E subjects sleeping worse than their Self-MM/Self-M counterparts, and averaging just over the abnormality PSQI threshold of 5. In conclusion, young, healthy adults can define their diurnal preference based on a single question (Self-ME) in a way that reflects their sleep-wake timing, their sleepiness levels over the daytime hours, and their night sleep quality. Validation of the Self-ME across the decades and in diseased populations seems worthy.

A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy.

Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3'-untranslated region (3'-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3'-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis.

The effect of EUSOMA certification on quality of breast cancer care.

AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast units to establish minimum standards and ensure specialist multidisciplinary care. In the present study we assess the impact of EUSOMA certification for all breast units for which sufficient information was available before and after certification. MATERIALS AND METHODS: For 22 EUSOMA certified breast units data of 30,444 patients could be extracted from the EUSOMA database on the evolution of QI's before and after certification. RESULTS: On the average of all units, the minimum standard of care was achieved for 12/13 QI's before and after EUSOMA certification (not met for DCIS receiving just one operation). There was a significant improvement of 5 QI's after certification. The proportion of patients with invasive cancer undergoing an axillary clearance containing >9 lymph nodes (91.5% vs 89.4%, p 0.003) and patients with invasive cancer having just 1 operation (83.1% vs 80.4%, p < 0.001) dropped, but remained above the minimum standard. The targeted standard of breast care was reached for the same 4/13 QI's before and after EUSOMA certification. CONCLUSION: Although the absolute effect of EUSOMA certification was modest it further increases standards of care and should be regarded as part of a process aiming for excellence. Dedicated units already provide a high level of care before certification, but continuous monitoring and audit remains of paramount importance as complete adherence to guidelines is difficult to achieve.

BAG3 regulates formation of the SNARE complex and insulin secretion.

Insulin release in response to glucose stimulation requires exocytosis of insulin-containing granules. Glucose stimulation of beta cells leads to focal adhesion kinase (FAK) phosphorylation, which acts on the Rho family proteins (Rho, Rac and Cdc42) that direct F-actin remodeling. This process requires docking and fusion of secretory vesicles to the release sites at the plasma membrane and is a complex mechanism that is mediated by SNAREs. This transiently disrupts the F-actin barrier and allows the redistribution of the insulin-containing granules to more peripheral regions of the ß cell, hence facilitating insulin secretion. In this manuscript, we show for the first time that BAG3 plays an important role in this process. We show that BAG3 downregulation results in increased insulin secretion in response to glucose stimulation and in disruption of the F-actin network. Moreover, we show that BAG3 binds to SNAP-25 and syntaxin-1, two components of the t-SNARE complex preventing the interaction between SNAP-25 and syntaxin-1. Upon glucose stimulation BAG3 is phosphorylated by FAK and dissociates from SNAP-25 allowing the formation of the SNARE complex, destabilization of the F-actin network and insulin release.

Analysis of BAG3 plasma concentrations in patients with acutely decompensated heart failure.

BACKGROUND: BCL-2-associated athanogene 3 (BAG3) is a protein implicated in the cardiomyocyte stress response and genesis of cardiomyopathy. Extracellular BAG3 is measurable in patients with heart failure (HF), but the relationship of BAG3 with HF prognosis is unclear. METHODS: BAG3 plasma concentrations were measured in 39 acutely decompensated HF patients; the primary endpoint was death at 1 year. Baseline characteristics were compared by vital status and median BAG3 concentration. Correlation of BAG3 with left ventricular ejection fraction (LVEF) and other biomarkers was performed. Prognostic value was assessed using Cox proportional hazards regression and Kaplan-Meier analysis. RESULTS: At baseline, median BAG3 was significantly higher in decedents (N=11) than survivors (N=28; 1489 ng/mL versus 50 ng/mL; P=0.04); decedents also had worse renal function and higher median natriuretic peptide (NP) and sST2. BAG3 was not significantly correlated with NPs, mid-regional pro-adrenomedullin, sST2, or eGFR, however. Mortality was increased in patients with supra-median BAG3 (>336 ng/mL; 42.1% versus 15.0%, P=0.06). In age and LVEF-adjusted Cox proportional hazards, BAG3 remained a significant mortality predictor (HR=3.20; 95% CI=1.34-7.65; P=0.02); those with supra-median BAG3 had significantly shorter time-to-death (P=0.04). CONCLUSION: The stress response protein BAG3 is measurable in patients with ADHF and may be prognostic for death.

WW domain of BAG3 is required for the induction of autophagy in glioma cells.

Autophagy is an evolutionarily conserved, selective degradation pathway of cellular components that is important for cell homeostasis under healthy and pathologic conditions. Here we demonstrate that an increase in the level of BAG3 results in stimulation of autophagy in glioblastoma cells. BAG3 is a member of a co-chaperone family of proteins that associates with Hsp70 through a conserved BAG domain positioned near the C-terminus of the protein. Expression of BAG3 is induced by a variety of environmental changes that cause stress to cells. Our results show that BAG3 overexpression induces autophagy in glioma cells. Interestingly, inhibition of the proteasome caused an increase in BAG3 levels and induced autophagy. Further analysis using specific siRNA against BAG3 suggests that autophagic activation due to proteosomal inhibition is mediated by BAG3. Analyses of BAG3 domain mutants suggest that the WW domain of BAG3 is crucial for the induction of autophagy. BAG3 overexpression also increased the interaction between Bcl2 and Beclin-1, instead of disrupting them, suggesting that BAG3 induced autophagy is Beclin-1 independent. These observations reveal a novel role for the WW domain of BAG3 in the regulation of autophagy.

Evaluating the impact of pluridisciplinary training on proper glove use in hospital.

OBJECTIVE: The authors of this randomized study had for aim to evaluate the impact of training on proper glove use by comparing compliance to glove use recommendations between trained and untrained healthcare personnel according to healthcare professional groups. PATIENTS AND METHODS: A random selection of trained and untrained nurses, nurse aids, and hospital housekeepers was performed in a French University hospital, using a listing of healthcare personnel. The audits were conducted by two infection control nurses, in series of 10 observations, with a maximum time limit of two hours. The evaluation criteria were compliance or non-compliance of glove-wearing practices with internal hospital recommendations, disclosed to professionals during training. RESULTS: Overall, 111 professionals were audited and 794 acts were observed. Hand hygiene was significantly better in trained vs. untrained healthcare professionals (P < 0.01). Proper glove use practices were similar between trained and untrained nurses (85% of compliance), whereas the difference was statistically significant in favor of trained healthcare personnel for the other categories (P < 0.001 for nurse aids and P = 0.02 for housekeepers). CONCLUSION: We demonstrated the impact of pluridisciplinary training on proper glove use practices in hospital settings, but with different benefits found according to professional groups. The lower the initial training level, the greater the overall benefit appeared to be.

The requirements of a specialist Breast Centre.

INTRODUCTION: In recognition of the advances and evidence based changes in clinical practice that have occurred in recent years and taking into account the knowledge and experience accumulated through the voluntary breast unit certification programme, Eusoma has produced this up-dated and revised guidelines on the requirements of a Specialist Breast Centre (BC). METHODS: The content of these guidelines is based on evidence from the recent relevant peer reviewed literature and the consensus of a multidisciplinary team of European experts. The guidelines define the requirements for each breast service and for the specialists who work in specialist Breast Centres. RESULTS: The guidelines identify the minimum requirements needed to set up a BC, these being an integrated Breast Centre, dealing with a sufficient number of cases to allow effective working and continuing expertise, dedicated specialists working with a multidisciplinary approach, providing all services throughout the patients pathway and data collection and audit. It is essential that the BC also guarantees the continuity of care for patients with advanced (metastatic) disease offering treatments according to multidisciplinary competencies and a high quality palliative care service. The BC must ensure that comprehensive support and expertise may be needed, not only through the core BC team, but also ensure that all other medical and paramedical expertise that may be necessary depending on the individual case are freely available, referring the patient to the specific care provider depending on the problem. CONCLUSIONS: Applying minimum requirements and quality indicators is essential to improve organisation, performance and outcome in breast care. Efficacy and compliance have to be constantly monitored to evaluate the quality of patient care and to allow appropriate corrective actions leading to improvements in patient care.