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The translocation t(5;12)(q31;p13)/ETV6::ACSL6 is a rare cytogenetic abnormality, although it is reported in various myeloid malignancies. To date, only 16 cases of t(5;12) and ETV6::ACSL6 rearrangement, confirmed by either molecular or Fluorescence In Situ Hyridization (FISH) analysis, have been reported. Eosinophilia is a distinctive and common feature associated with this rearrangement. Although few cases have been described, the prognosis of patients with ETV6::ACSL6 is considered poor. We report two additional cases of t(5;12)(q31;p13)/ETV6::ACLS6 rearrangement and eosinophilia. Unusually, in our cases, the ETV6::ACSL6 rearrangement occurred at the relapse of Acute Myeloid Leukemia (AML) patients who had t(6;9)(p23;q34)/DEK::NUP214 rearrangement at disease onset. The concurrence of these two rare abnormalities has never been reported and may suggest a cooperative role of t(5;12) and t(6;9), leading to disease relapse. Moreover, at relapse, both cases presented with eosinophilia, further strengthening the association of t(5;12) with eosinophilia in myeloid malignancies. Given the poor prognosis and the non-responsiveness to tyrosine kinase inhibitors of cases of ETV6::ACSL6 rearrangement, in contrast to cases of ETV6::PDGFRB rearrangement, we recommend the introduction of testing for this abnormality in myeloid malignancies with eosinophilia.

To evaluate the feasibility and early outcomes of below the ankle orbital atherectomy in chronic limb-threatening ischemia in patients with calcified foot arteries.12 patients (mean age 69.4 ± 14.7; range 57 to 85 years) who were affected by diabetes underwent orbital atherectomy below the knee and ankle arterial segments. Technical success was defined as orbital atherectomy passage and debulked the calcified lesion, delivery of adjunctive therapy, and30% residual stenosis at final angiogram. The procedural outcome included complications, amputation-free survival, and freedom from clinically-driven target lesion revascularization at 30-days and 6-months of follow-up.Orbital atherectomy was performed in 3 cases in Anterior tibial (AT) and dorsalis pedis (Ped) arteries + Posterior tibial (PT) and Lateral Plantar (Lat Plan), 5 cases in PT and Lat Plan arteries, 1 case of PT and Medial Plantar, 1 case of Peroneal and Plan Lat, and 2 cases of AT and Ped. After atherectomy, we used a drug-coated balloon (DCB) angioplasty. Technical success was achieved in 11 (91.6%) cases. No deaths were registered during the follow-up. The limb salvage rate was 100%, and no major amputations were registered. Amputation-free survival was 50%. Freedom from CD-TLR was 100% at 30 days and 91.7% at 6-months. One patient underwent a TLR at three months. No major cardiovascular events, limb events, or significant procedure-related complications were registered.CSI orbital atherectomy and DCB angioplasty appear a feasible and promissor treatment options in diabetic CLTI patients.

International and national oncology societies had released recommendations in favor of COVID-19 vaccination in cancer patients. In the context of the national vaccination campaign targeting the so called extremely vulnerable, we aimed to assess the safety and efficacy of the mRNA vaccines in a cohort of 623 patients.Between March 26 and April 04, 2021, the Pfizer and BioNTech BNT162b2 mRNA and the Moderna mRNA-1273 vaccines were given as a two-dose prime-boost regimen. Starting on September 25th 2021 a third dose was offered to patients in whom a suboptimal immunogenicity with COVID-19 vaccination could be expected. Safety assessments were performed by phone call 7 days after each dose. Electronic health records were accessed to review demographic information, disease history, treatment detail, and outcome events of participants patients'.No toxicities were reported in 63.7%, 54%, and in 48.7% patients with cancer after each dose. Mild-to-moderate pain at the injection site was the most commonly adverse event. After the second dose, 46% of the 610 patients reported toxicity, with more systemic side-effects observed. Fever was reported in 45% of patients, with a temperature ≥ 38 °C in 21.4% of them. Of the 335 patients receiving a third vaccine dose, 51% reported toxicity, with 13% of patients reporting more than one effect. Logistic regression analysis reported mixed results, with limited variables or categories reporting a significant odd ratio. The type of vaccine reported a significant value at first dose (OR = 0.12; CI 0.52, 0.26; p = 0.00). Thirty-four cases of COVID-19 infection were reported with only one patient requiring a short-term hospitalization for monitoring.The safety profile of the mRNA vaccines does not raise any specific concerns and support prioritization of vaccination for cancer patients.

Nowadays, catheter-based ablation in patients with post-ischemic ventricular tachycardia (VT) is performed in arrhythmogenic sites identified by electrophysiologists by visual inspection during electroanatomic mapping. This work aims to present the development of machine learning tools aiming at supporting clinicians in the identification of arrhythmogenic sites by exploiting innovative features that belong to different domains. This study included 1584 bipolar electrograms from nine patients affected by post-ischemic VT. Different features were extracted in the time, time scale, frequency, and spatial domains and used to train different supervised classifiers. Classification results showed high performance, revealing robustness across the different classifiers in terms of accuracy, true positive, and false positive rates. The combination of multi-domain features with the ensemble tree is the most effective solution, exhibiting accuracies above 93% in the 10-time 10-fold cross-validation and 84% in the leave-one-subject-out validation. Results confirmed the effectiveness of the proposed features and their potential use in a computer-aided system for the detection of arrhythmogenic sites. This work demonstrates for the first time the usefulness of supervised machine learning for the detection of arrhythmogenic sites in post-ischemic VT patients, thus enabling the development of computer-aided systems to reduce operator dependence and errors, thereby possibly improving clinical outcomes.

Venetoclax (VEN) and hypomethylating agent (HMAs) regimens are emerging as the standard of care for unfit for chemotherapy acute myeloid leukemia (AML) patients, but the safety and feasibility of a total outpatient management have not been fully investigated. Fifty-nine AML patients with active disease received VEN and HMAs. Nineteen out of 59 (32.2%) patients received the first cycle as inpatients, whereas 40/59 (67.8%) patients were treated in the outpatient setting. No significant differences were observed with regard to incidence of adverse events (AEs), including tumor lysis syndrome (TLS), and the 30-day and 60-day mortality was comparable. Notably, an infectious prophylaxis inspired to that adopted during intensive chemotherapy resulted in a low infection rate with a reduced bacterial infections incidence in out- versus hospitalized patients (p .0001). The overall time of hospitalization was significantly shorter in patients who received a total outpatient treatment as compared to those who received the first cycle as inpatients (5.9 vs. 39.7 days, p .0001). Despite the adopted differences in treatment management, the efficacy was similar. These data indicate that a total outpatient management of VEN and HMAs is feasible in AML patients without negatively impacting on treatment efficacy and may yield pharmacoeconomic and quality-of-life benefits.

In the same silicon photonic integrated circuit, we compare two types of integrated degenerate photon-pair sources (microring resonators or waveguides) by means of Hong-Ou-Mandel (HOM) interference experiments. Two nominally identical microring resonators are coupled to two nominally identical waveguides which form the arms of a Mach-Zehnder interferometer. This is pumped by two lasers at two different wavelengths to generate by spontaneous four-wave mixing degenerate photon pairs. In particular, the microring resonators can be thermally tuned in or out of resonance with the pump wavelengths, thus choosing either the microring resonators or the waveguides as photon-pair sources, respectively. In this way, an on-chip HOM visibility of 94% with microring resonators and 99% with straight waveguides is measured. We compare our experimental results with theoretical simulations of the joint spectral intensity and the purity of the degenerate photon pairs. We verify that the visibility is connected to the sources' indistinguishability, which can be quantified by the overlap between the joint spectral amplitudes (JSA) of the photon pairs generated by the two sources. We estimate a JSA overlap of 98% with waveguides and 89% with microring resonators.

Background: A limited number of studies investigating perioperative risk factors associated with emergency appendectomy in elderly patients have been published to date. Whether older age may be associated with poorer outcomes following appendectomy is still a matter of debate. The primary aim of this study was to determine the predictors of postoperative morbidity following appendectomy in patients aged ≥ 65years. Methods: Data regarding all elderly patients who underwent emergency appendectomy from January 2017 to June 2018 admitted 36 Italian surgical departments were prospectively collected and analyzed. Baseline demographics and perioperative variables were evaluated. Uni- and multivariate analyses adjusted for differences between groups were carried out to determine possible predictors of adverse outcomes after appendectomy. Results: Between January 2017 and June 2018, 135 patients aged ≥ 65years with a diagnosis of AA met the study inclusion criteria. Twenty-six patients (19.3%) were diagnosed with some type of postoperative complication. Decreasing the preoperative hemoglobin level showed a statistically significant association with postoperative complications (OR 0.77, CI 0.61–0.97, P = 0.03). Preoperative creatinine level (P = 0.02, OR 2.04, CI 1.12–3.72), and open appendectomy (P = 0.03, OR 2.67, CI 1.11–6.38) were significantly associated with postoperative morbidity. After adjustment, the only independent predictor of postoperative morbidity was preoperative creatinine level (P = 0.04, OR 2.01, CI 1.05–3.89). Conclusions: In elderly patients with AA, perioperative risk assessment in the emergency setting must be as accurate as possible to identify modifiable risk factors that can be addressed before surgery, such as preoperative hemoglobin and creatinine levels.

BackgroundVagal nerve stimulation (VNS) improves seizure frequency and quality of life in patients with drug-resistant epilepsy (DRE), although the exact mechanism is not fully understood. Previous studies have evaluated the effect of VNS on functional connectivity using the phase lag index (PLI), but none has analyzed its effect on EEG aperiodic parameters (offset and exponent), which are highly conserved and related to physiological functions.ObjectiveThis study aimed to evaluate the effect of VNS on PLI and aperiodic parameters and infer whether these changes correlate with clinical responses in subjects with DRE.Materials and methodsPLI, exponent, and offset were derived for each epoch (and each frequency band for PLI), on scalp-derived 64-channel EEG traces of 10 subjects with DRE, recorded before and 1 year after VNS. PLI, exponent, and offset were compared before and after VNS for each patient on a global basis, individual scalp regions, and channels and separately in responders and non-responders. A correlation analysis was performed between global changes in PLI and aperiodic parameters and clinical response.ResultsPLI (global and regional) decreased after VNS for gamma and delta bands and increased for an alpha band in responders, but it was not modified in non-responders. Aperiodic parameters after VNS showed an opposite trend in responders vs. non-responders: both were reduced in responders after VNS, but they were increased in non-responders. Changes in aperiodic parameters correlated with the clinical response.ConclusionThis study explored the action of VNS therapy from a new perspective and identified EEG aperiodic parameters as a new and promising method to analyze the efficacy of neuromodulation.

According to databases such as OMIM, Humsavar, Clinvar and Monarch, 1494 human enzymes are presently associated to 2539 genetic diseases, 75% of which are rare (with an Orphanet code). The Mondo ontology initiative allows a standardization of the disease name into specific codes, making it possible a computational association between genes, variants, diseases, and their effects on biological processes. Here, we tackle the problem of which biological processes enzymes can affect when the protein variant is disease-associated. We adopt Reactome to describe human biological processes, and by mapping disease-associated enzymes in the Reactome pathways, we establish a Reactome-disease association. This allows a novel categorization of human monogenic and polygenic diseases based on Reactome pathways and reactions. Our analysis aims at dissecting the complexity of the human genetic disease universe, highlighting all the possible links within diseases and Reactome pathways. The novel mapping helps understanding the biochemical/molecular biology of the disease and allows a direct glimpse on the present knowledge of other molecules involved. This is useful for a complete overview of the disease molecular mechanism/s and for planning future investigations. Data are collected in DAR, a database that is free for search and available at https://dar.biocomp.unibo.it.

Hartmann's procedure (HP) is used in surgical emergencies such as colonic perforation and colonic obstruction. "Temporary" colostomy performed during HP is not always reversed in part due to potential morbidity and mortality associated with reversal. There are several contributing factors for patients requiring a permanent colostomy following HP. Therefore, there is still some discussion about which technique to use. The aim of this study was to evaluate perioperative variables of patients undergoing Hartmann's reversal using a laparoscopic and open approach.The multicenter retrospective cohort study was done between January 2009 and December 2019 at 14 institutions globally. Patients who underwent Hartmann's reversal laparoscopic (LS) and open (OS) approaches were evaluated and compared. Sociodemographic, preoperative, intraoperative variables, and surgical outcomes were analyzed. The main outcomes evaluated were 30-day mortality, length of stay, complications, and postoperative outcomes.Five hundred and two patients (264 in the LS and 238 in the OS group) were included. The most prevalent sex was male in 53.7%, the most common indication was complicated diverticular disease in 69.9%, and 85% were American Society of Anesthesiologist (ASA) II-III. Intraoperative complications were noted in 5.3% and 3.4% in the LS and OS groups, respectively. Small bowel injuries were the most common intraoperative injury in 8.3%, with a higher incidence in the OS group compared with the LS group (12.2% vs. 4.9%,Laparoscopic Hartmann's reversal is safe and feasible, associated with superior clinical outcomes compared with open surgery.

Aims Out of hospital cardiac arrest (OHCA) is still a leading cause of mortality worldwide. In recent years, resuscitative endovascular balloon occlusion of the aorta (REBOA) has been progressively studied as an adjunct to standard advanced life support (ALS) in both traumatic and non-traumatic refractory OHCA. Since January 2019, the REBOA procedure has been applied to all the patients experiencing both traumatic and non-traumatic refractory OHCA (≥15 min of cardiopulmonary resuscitation) not eligible for ECPR for clinical or logistic reasons. We aimed at describing the feasibility and effects of REBOA performed both in the Emergency Department and in the pre-hospital environment served by the local HEMS for refractory OHCA. Methods Twenty consecutive patients experiencing refractory OHCA and in whom REBOA was attempted in 2019 and 2020 were included in the study, Utstein data and REBOA specific variables were recorded. Results Successful catheter placement was achieved in 18 out of 20 patients, 11 of these were non-traumatic OHCAs while 7 were traumatic OHCAs, the 2 failures were related to repeated arterial puncture failure. Median time between the EMS dispatch and REBOA catheter placing attempt was 46 min. An increase in etCO2 over 10 mmHg was observed after balloon inflation in 12 out of 18 patients (8/11 non-traumatic and 4/7 traumatic OHCAs), a sustained ROSC was observed in 5 patients (1 traumatic and 4 non-traumatic OHCA) that were subsequently admitted to the ICU. Four out of the 5 patients reached the criteria for brain death in the subsequent 24 h while one patient experienced another episode of refractory cardiac arrest in ICU and subsequently died. Conclusion Our data confirm the feasibility of REBOA technique as an adjunct to ALS in both the ED and prehospital phase and most of the treated patients experienced a transient ROSC after balloon inflation while 5 out of 18 experienced a sustained ROSC. However, while in the trauma setting increasing evidence suggests an improved survival when REBOA is applied to refractory OHCA, in non-traumatic OHCA this has yet to be demonstrated and large studies are needed.

Recently, a new approach for measuring well-being was developed by eighteen European countries in the wake of the “Beyond GDP movement” started in the 1990 and continued by the Stiglitz Commission. Among these European economies, eleven of them use measures of well-being for monitoring public policy. The Italian Statistical Institute (Istat) jointly with the National Council for Economics and Labor (CNEL) developed a multi-dimensional framework for measuring “equitable and sustainable well-being” (Bes) and since 2013 Istat publishes an annual report on well-being. The Bes framework is continuously updated to take into account new challenges: the exploitation of new data sources, to produce better indicators; new ways for making the communication more effective and foster public awareness; the inclusion of well-being indicators in the budget documents, as established by law. Especially for the latter, the Italian Bes can be considered a forerunner and, more generally, the Italian experience is one of the most relevant at the European level, showing potential of become a benchmark for other countries. This article illustrates the development of the Italian Bes, focusing on its recent progresses and challenges.

Background The widespread nature of coronavirus disease 2019 (COVID-19) has been unprecedented. We sought to analyze its global impact with a survey on colorectal cancer (CRC) care during the pandemic. Methods The impact of COVID-19 on preoperative assessment, elective surgery, and postoperative management of CRC patients was explored by a 35-item survey, which was distributed worldwide to members of surgical societies with an interest in CRC care. Respondents were divided into two comparator groups: 1) ‘delay’ group: CRC care affected by the pandemic; 2) ‘no delay’ group: unaltered CRC practice. Results A total of 1,051 respondents from 84 countries completed the survey. No substantial differences in demographics were found between the ‘delay’ (745, 70.9%) and ‘no delay’ (306, 29.1%) groups. Suspension of multidisciplinary team meetings, staff members quarantined or relocated to COVID-19 units, units fully dedicated to COVID-19 care, personal protective equipment not readily available were factors significantly associated to delays in endoscopy, radiology, surgery, histopathology and prolonged chemoradiation therapy-to-surgery intervals. In the ‘delay’ group, 48.9% of respondents reported a change in the initial surgical plan and 26.3% reported a shift from elective to urgent operations. Recovery of CRC care was associated with the status of the outbreak. Practicing in COVID-free units, no change in operative slots and staff members not relocated to COVID-19 units were statistically associated with unaltered CRC care in the ‘no delay’ group, while the geographical distribution was not. Conclusions Global changes in diagnostic and therapeutic CRC practices were evident. Changes were associated with differences in health-care delivery systems, hospital’s preparedness, resources availability, and local COVID-19 prevalence rather than geographical factors. Strategic planning is required to optimize CRC care., Global changes in both diagnostic and therapeutic practices in colorectal cancer care were evident in this survey conducted to analyze the impact of COVID-19 outbreak. The importance of this finding is that changes were associated with differences in health care delivery systems, hospital’s preparedness, resources availability, and local COVID-19 prevalence rather than geographical variations.

Julius Caesar has been remembered in popular memory as a tyrant whose death serves as a warning to future despots. However, this image of Julius Caesar is skewed by several factors that do not acknowledge the unique context of Caesar’s rise to power. The image of Caesar created after his death by his political opponents, alongside modern concepts of government and leadership, portray him as a despot. This paper will examine how this concept is misguided by demonstrating how Caesar’s rise to power was consensual and disproving the claims of his opponents.

Sudden death guidelines make emphasis on the need to identify the etihiology of the arrest in survived patients or in their family members. If cardio–pulmonary resuscitation techniques are almost standardized throughout the world, the intra– and post–hospital treatment of the patient changes in the different centers and countries. The local discrepancies related to the survival rate of the patients can instead be considered as an indirect index of the good network in the management of the victims. Given the impossibility of carrying out randomized, controlled and prospective studies, registries represent the only alternative system for collecting and analyzing data in this area. The SCARe (Sudden Cardiac Arrest Registry) project – unique for being multidisciplinary – represents the most effective system for carrying out an epidemiological investigation, optimizing the treatment of patients affected by cardiac arrest, creating collaborations and integrations between hospitals and the territory, identifying diagnostic pathways for study of family members, monitoring the efficiency of the work performed. 646 interventions for "code blue" (out–of–hospital cardiac arrest) carried out in the Province of Rimini from 2019 to 2021 were analysed. There were 318 patients less than 75 yrs old, with a median age of 63 years: only 24% of the victims presented with a shockable rhythm, in 98% of them with ventricular fibrillation; autopulse was used in 20%; 217 patiente died out from hospital, 5 in the emergency room. Of the remaining 72% was hospitalized in Intensive Care, 28% in CCU or Emergency Medicine. A multi–specialist database can evaluate the adherence to the guidelines and the methods of approach of the different professional figures to the patient. Data analysis will allow to increase the survival rate of patients.

Background: The thymus gland is a lymphoid organ normally located in the anterior mediastinum. Location abnormalities of the thymus, such as ectopic thymus or the superior herniation of a mediastinal thymus, could be responsible for the occurrence of cervical masses in pediatric patients, raising concerns among clinicians. The knowledge of these conditions is essential for a thorough differential diagnosis and for preventing unnecessary invasive procedures. Methods: Descriptive retrospective series of three patients with a cervical mass, that was later diagnosed as ectopic thymic tissue. Results: The thymus has a unique and distinctive ultrasound appearance that is the keystone to detecting thymic parenchyma in locations other than anterior mediastinum. In selected patients, an accurate ultrasound could be conclusive for the diagnosis, with no need for further and potentially risky procedures. Conclusions: This case series supports the use of ultrasound in both diagnosis and follow-up of thymus location abnormalities, advocating a minimal invasive and conservative approach.

The Bologna ENZyme Web Server (BENZ WS) annotates four-level Enzyme Commission numbers (EC numbers) as defined by the International Union of Biochemistry and Molecular Biology (IUBMB). BENZ WS filters a target sequence with a combined system of Hidden Markov Models, modelling protein sequences annotated with the same molecular function, and Pfams, carrying along conserved protein domains. BENZ returns, when successful, for any enzyme target sequence an associated four-level EC number. Our system can annotate both monofunctional and polyfunctional enzymes, and it can be a valuable resource for sequence functional annotation., Graphical Abstract Graphical AbstractBENZ WS annotates with a four-digit EC number a query protein. Its association with EC code/s depends on the interplay of the two different sets of Hidden Markov Models (HMMs), considering protein domains, and clusters of similar sequences.

Background Fluorescence-guided visualization is a recently proposed technology in colorectal surgery. Possible uses include evaluating perfusion, navigating lymph nodes and searching for hepatic metastases and peritoneal spread. Despite the absence of high-level evidence, this technique has gained considerable popularity among colorectal surgeons due to its significant reliability, safety, ease of use and relatively low cost. However, the actual use of this technique in daily clinical practice has not been reported to date. Methods This survey was conducted on April 2020 among 44 centers dealing with colorectal diseases and participating in the Italian ColoRectal Anastomotic Leakage (iCral) study group. Surgeons were approximately equally divided based on geographical criteria from multiple Italian regions, with a large proportion based in public (89.1%) and nonacademic (75.7%) centers. They were invited to answer an online survey to snapshot their current behaviors regarding the use of fluorescence-guided visualization in colorectal surgery. Questions regarding technological availability, indications and techniques, personal approaches and feelings were collected in a 23-item questionnaire. Results Questionnaire replies were received from 37 institutions and partially answered by 8, as this latter group of centers do not implement fluorescence technology (21.6%). Out of the remaining 29 centers (78,4%), fluorescence is utilized in all laparoscopic colorectal resections by 72.4% of surgeons and only for selected cases by the remaining 27.6%, while 62.1% of respondents do not use fluorescence in open surgery (unless the perfusion is macroscopically uncertain with the naked eye, in which case 41.4% of them do). The survey also suggests that there is no agreement on dilution, dosing and timing, as many different practices are adopted based on personal judgment. Only approximately half of the surgeons reported a reduced leak rate with fluorescence perfusion assessment, but 65.5% of them strongly believe that this technique will become a minimum requirement for colorectal surgery in the future. Conclusion The survey confirms that fluorescence is becoming a widely used technique in colorectal surgery. However, both the indications and methods still vary considerably; furthermore, the surgeons' perceptions of the results are insufficient to consider this technology essential. This survey emphasizes the need for further research to reach recommendations based on solid scientific evidence.

Patients with MetS or SIRS experience higher rates of mortality and morbidity, across both cardiac and noncardiac surgery. Frailty assessment has acquired increasing importance in recent years as it predisposes elderly patients to a worse outcome. The aim of our study was to investigate the influence of MetS, SIRS, and with or without frailty on elderly patients undergoing emergency surgical procedures.We analyzed data of all patients with nonmalignant diseases requiring an emergency surgical procedure from January 2017 to December 2020. The occurrence of MetS was identified using modified definition criteria used by the NCEP-ATP III Expert Panel: obesity, hypertension, diabetes, or if medication for high triglycerides or for low HDL cholesterol was taken. Systemic inflammatory response syndrome (SIRS) was evaluated according to the original consensus study (Sepsis-1). The frailty profile was investigated by the 5-modified Frailty Index (5-mFI) and the Emergency Surgery Frailty Index (EmSFI). Postoperative complications have been reported and categorized according to the Clavien-Dindo (C-D) classification system. Morbidity and mortality have been mainly considered as the 30-day standard period definition.Of the 2,318 patients included in this study, 1,010 (43.6%) fulfilled the criteria for MetS (MetsG group). Both 5-Items score and EmsFI showed greater fragility in patients with MetS. All patients with MetS showed more frequently a CACI index greater than 6. The occurrence of SIRS was higher in MetSG. LOS was longer in patients with MetS (MetSG 11.4 ± 12 days vs.Impact of MetS and SIRS on elderly surgical patient outcomes has yet to be fully elucidated. The present study showed a 43.6% incidence of MetS in the elderly population. In conclusion, age per se should be not considered anymore as the main variable to estimate patient outcomes, while MetS and Frailty should have always a pivotal role.

Ileocolic intussusception is a common cause of bowel obstruction. When spontaneous reduction does not occur, non-operative management through enema reduction is necessary. Despite the evidence indicating that sedatives favor success in the reduction, their use is still not a common practice. To determine if midazolam (MDZ) before enema improves the rate of procedure success, we retrospectively reviewed charts of patients admitted to two Italian pediatric emergency departments. Outcome measures were the success rate of the enema, recurrence, and need for surgery. Patients were grouped according to the use of MDZ or not, before hydrostatic reduction attempt. We included 69 and 37 patients in the MDZ and non-MDZ groups, respectively. The two groups did not differ in demographics, clinical characteristics, and ultrasound findings. Intussusception reduction after the first enema attempt occurred in 75% (MDZ group) and 32.4% (non-MDZ group) of patients (P .001); 27.9% (MDZ group) and 77.8% (non-MDZ group) of patients underwent surgery (P .001). Among them, spontaneous reduction of intussusception during the induction of general anesthesia occurred in 31.6% and 42.9% of patients, respectively (P .43). Multivariate logistic regression analysis showed that only MDZ had a positive effect on the result of the enema (OR 7.602, 95%CI 2.669-21.652, P .001).Procedural sedation with MDZ for enema reduction of intussusception can increase the success rate and lead to a better management of patients.• Despite the evidence of the usefulness of sedatives in the reduction of intussusception, their use is still not a common practice.• Midazolam during enema reduction of intussusception can increase the success rate and consequently lead to better management of patients.

Congenital adrenal hyperplasia includes autosomal recessive conditions that affect the adrenal cortex steroidogenic enzymes (cholesterol side-chain cleavage enzyme; 3β-hydroxysteroid dehydrogenase; 17α-hydroxylase/17,20 lyase; P450 oxidoreductase; 21-hydroxylase; and 11β-hydroxylase) and proteins (steroidogenic acute regulatory protein). These are located within the three major pathways of the steroidogenic apparatus involved in the production of mineralocorticoids, glucocorticoids, and androgens. Many countries have introduced newborn screening program (NSP) based on 17-OH-progesterone (17-OHP) immunoassays on dried blood spots, which enable faster diagnosis and treatment of the most severe forms of 21-hydroxylase deficiency (21-OHD). However, in several others, the use of this diagnostic tool has not yet been implemented and clinical diagnosis remains challenging, especially for males. Furthermore, less severe classic forms of 21-OHD and other rarer types of CAHs are not identified by NSP. The aim of this mini review is to highlight both the main clinical characteristics and therapeutic options of these conditions, which may be useful for a differential diagnosis in the neonatal period, while contributing to the biochemical evolution taking place in the steroidogenic field. Currently, chromatographic techniques coupled with tandem mass spectrometry are gaining attention due to an increase in the reliability of the test results of NPS for detecting 21-OHD. Furthermore, the possibility of identifying CAH patients that are not affected by 21-OHD but presenting elevated levels of 17-OHP by NSP and the opportunity to include the recently investigated 11-oxygenated androgens in the steroid profiles are promising tools for a more precise diagnosis and monitoring of some of these conditions.

Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis, and new therapies are a major clinical need. When mutated, FLT3 drives neoplastic cell proliferation. New drugs (i.e., tyrosine kinase inhibitors, TKIs) showed effectiveness in FLT3-AML and promise to change disease history and outcome. We evaluated the benefit conferred by TKIs in terms of survival, burden of complications and surrogate endpoint of quality of life in a retrospective cohort of 49 FLT3 positive, R/R AML patients. Patients who received TKIs were compared to those treated with conventional chemotherapy. Treatment with TKIs conferred a better OS and wea associated with a lower burden and severity of adverse events. Importantly, patients who received TKIs showed reduced time of hospitalization. In conclusion, treatment with TKI in R/R FLT3-AML was related to a better survival, less and milder AEs, and shorter hospitalization.

The first measurement of the temperature dependence of the muon transfer rate from muonic hydrogen to oxygen was performed by the FAMU collaboration in 2016. The results provide evidence that the transfer rate rises with the temperature in the range 104-300 K. This paper presents the results of the experiment done in 2018 to extend the measurements towards lower (70 K) and higher (336 K) temperatures. The 2018 results confirm the temperature dependence of Λ p O observed in 2016 and sets firm ground for comparison with the theoretical predictions.

The aim of this study is to compare the short and long-term outcomes of intracorporeal anastomosis (IA) versus extracorporeal anastomosis (EA) during laparoscopic resection of splenic flexure for cancer, in 3 high-volume Italian centers.A retrospective analysis was conducted on a multicenter database of a consecutive series of patients who underwent an elective laparoscopic resection of the splenic flexure for colon cancer in 3 high-volume centers between January 2008 and August 2017. Propensity score matching analysis was performed to overcome patients' selection bias between the 2 surgical techniques. Data on patients' demographics, operative details, short-term and long-term outcomes were prospectively recorded.In total, 102 patients were selected. After propensity score match, 72 patients were compared: 36 for the IA group, 36 for the EA group. The IA group showed a significantly shorter median time to first flatus, time to first stool, time to oral feeding, and time to discharge, as well as significantly lower incidence of postoperative severe surgical complications, especially in terms of wound infections, and of incisional hernia (IH).Risk factors for IH on logistic regression were longer operative time, EA, longer incision, postoperative blood transfusions, and longer specimen.The IA in laparoscopic resection of the splenic flexure is feasible and safe in terms of short-term and long-term outcomes. Major advantages are shorter time to first flatus and first stool, complete oral feeding and time to discharge, with minor incidence of severe surgical complications, such as wound infection, and lower incidence of IH.

Objective Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH. Methods All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed. Results The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40–82%). An additive effect on the reduction of enzymatic activity (1–17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro. Conclusions Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH.

Objective Traumatic brain injury (TBI) is a leading cause of death and disability among trauma patients. The final outcome of TBI results from a complex interaction between primary and secondary mechanisms of injury that begin immediately after the traumatic event. The aim of this review was to evaluate the latest evidence regarding the impact of prehospital airway management and the outcome after traumatic brain injury. Methods PubMed, Embase, and Cochrane searches were conducted using the MeSH database. Airway management, traumatic brain injury, pneumonia, and the subheadings of these Medical Subject Headings were combined. Results The review is structured into 4 major topics: airway management devices, prehospital pharmacologic management, mortality and neurologic outcomes, and early respiratory infections. The available literature shows a shift toward a more comprehensive view of prehospital airway management, taking into account not only the location where airway management is attempted but also the drugs administered, the airway management devices used, and the skills of the main professional figures attending the scene. Conclusions Literature about this topic is still inconclusive; however, new evidence taking into consideration more complex aspects of airway management rather than orotracheal intubation per se shows improved outcomes with aggressive prehospital airway management.

The enhanced recovery after surgery (ERAS) is nowadays a widely accepted multimodal programme of care in colorectal surgery, but still there is some reluctance in its application to very elderly patients. The aim of this study is to investigate short-term outcomes of laparoscopic resection for colorectal cancer in octogenarian patients within the ERAS programme. Data on 162 consecutive patients aged ≥ 80 years receiving elective minimally invasive colorectal resections within ERAS programme were collected in a multicentre, retrospective database in the period 2008–2017 in Italy. Univariate and multivariate analyses were performed to assess possible risk factors for poor clinical outcomes. The postoperative minor morbidity rate (Clavien–Dindo 1 and 2) was 25.9%. The incidence of postoperative major morbidity rate (severe medical and surgical complications defined as Clavien–Dindo 3 and 4) accounted 6.1% and only 1.8% had an anastomotic leakage. Reoperation rate was 5.5%, perioperative 30-day mortality was 1.8%, and 30-day readmission rate was 6.8%. On average, patients were released after 6 days. A univariate analysis showed that possible risk factors for severe medical complications were: low preoperative albumin level, high Charlson Age Comorbidity Index Score and number of days in the intensive care unit (ICU); risk factors for severe surgical complications were: low preoperative albumin level; risk factors for late hospital discharge were: multivisceral resections, number of days in ICU and body mass index (BMI) > 25 kg/m2. The multivariate analysis confirmed a low level of preoperative albumin and a longer ICU stay as independent risk factors for both postoperative severe surgical complications and late hospital discharge. The minimal invasive nature of the laparoscopic approach together with a multimodal analgesia therapy, the early resumption to oral diet and mobilisation could minimize the surgical stress and play an essential role in order to reduce medical morbidity in high-risk patients. Colorectal surgery within ERAS programme in octogenarians is a safe and flexible treatment in high-volume centres.

FLARES is an innovative project in the field of rare events searches, such as the search for the neutrinoless double beta decay. It aims at demonstrating the high potential of a technique that combines ultra-pure scintillating crystals with arrays of high performance silicon drift detectors, operated at about 120 K, to reach a 1% level energy resolution. The proposed technique will combine in a single device all the demanding features needed by an ideal experiment looking for rare events. The performance of a first production of matrices of silicon drift detectors as well as first measurements of the low temperature light yield of a selection of high purity scintillating crystals will be presented and discussed. © 2016 Elsevier B.V.

The idea of the CHNET-TANDEM experiment is to develop and optimize a non-destructive technique, which allows analysis deep inside the sample with a good spatial resolution, using a negative muon beam. By selecting the primary muon energies appropriately, bulk analysis can be performed without destructing the sample. The experimental setup used for this experiment, made by 2 hodoscopes and 5 HpGe, allowed us to collect very interesting preliminary data concerning scan momentum, positioning and centering of the samples by means of two hodoscopes, analysis of standard material targets and elemental characterization of Nuragic “Bronze Age” votive ship fragments.

Objective: We aimed at defining the most effective routine immunoassay- or liquid chromatography-tandem mass spectrometry (LC–MS/MS)-determined steroid biomarkers for identifying non-classic adrenal hyperplasia due to 21-hydroxylase deficiency (21-NCAH) in a PCOS-like population before genotyping. Methods: Seventy PCOS-like patients in reproductive age with immunoassay-determined follicular 17OH-progesterone (17OHP) ≥ 2.00 ng/mL underwent CYP21A2 gene analysis and 1–24ACTH test. Serum steroids were measured by immunoassays at baseline and 60 min after ACTH stimulation; basal steroid profile was measured by LC–MS/MS. Results: Genotyping revealed 23 21-NCAH, 15 single allele heterozygous CYP21A2 mutations (21-HTZ) and 32 PCOS patients displaying similar clinical and metabolic features. Immunoassays revealed higher baseline 17OHP and testosterone, and after ACTH stimulation, higher 17OHP (17OHP60) and lower cortisol, whereas LC–MS/MS revealed higher 17OHP (17OHPLC-MS/MS), progesterone and 21-deoxycortisol and lower corticosterone in 21-NCAH compared with both 21-HTZ and PCOS patients. Steroid thresholds best discriminating 21-NCAH from 21-HTZ and PCOS were estimated, and their diagnostic accuracy in identifying 21-NCAH from PCOS was established by ROC analysis. The highest accuracy was observed for 21-deoxycortisol ≥ 0.087 ng/mL, showing 100% sensitivity, while the combination of 17OHPLC-MS/MS ≥ 1.79 ng/mL and corticosterone ≤ 8.76 ng/mL, as well as the combination of ACTH-stimulated 17OHP ≥ 6.77 ng/mL and cortisol ≤ 240 ng/mL by immunoassay, showed 100% specificity. Conclusions: LC–MS/MS measurement of basal follicular 21-deoxycortisol, 17OHP and corticosterone seems the most convenient method for diagnosing 21-NCAH in a population of PCOS with a positive first level screening, providing high accuracy and reducing the need for ACTH stimulation test.

We discuss theories of gravity with independent metric (or frame field) and connection, from the point of view of effective field theory. We count the parity-even Lagrangian terms of dimension up to four and give explicit bases for the independent terms that contribute to the two-point function. We then give the decomposition of the linearized action on a complete basis of spin projectors and consider various subclasses of Metric-Affine Gravity theories (MAGs). We show that teleparallel theories can be dynamically equivalent to any metric theory of gravity and give the particle content of those whose Lagrangian contains only dimension-two terms. We point out the existence of a class of MAGs whose EOMs do not admit propagating degrees of freedoms. Finally, we construct simple MAGs that contain only a massless graviton and a state of spin/parity $2^-$ or $3^-$. As a side result, we write the relativistic wave equation for a spin/parity $2^-$ state., Comment: 96 pages

Ex vivo gene editing of CD34+ hematopoietic stem and progenitor cells (HSPCs) offers great opportunities to develop new treatments for a number of malignant and non-malignant diseases. Efficient gene-editing in HSPCs has been achieved using electroporation and/or viral transduction to deliver the CRISPR-complex, but cellular toxicity is a drawback of currently used methods. Nanoparticle (NP)-based gene-editing strategies can further enhance the gene-editing potential of HSPCs and provide a delivery system for in vivo application. Here, we developed CRISPR/Cas9-PLGA-NPs efficiently encapsulating Cas9 protein, single gRNA and a fluorescent probe. The initial ‘burst’ of Cas9 and gRNA release was followed by a sustained release pattern. CRISPR/Cas9-PLGA-NPs were taken up and processed by human HSPCs, without inducing cellular cytotoxicity. Upon escape from the lysosomal compartment, CRISPR/Cas9-PLGA-NPs-mediated gene editing of the γ-globin gene locus resulted in elevated expression of fetal hemoglobin (HbF) in primary erythroid cells. The development of CRISPR/Cas9-PLGA-NPs provides an attractive tool for the delivery of the CRISPR components to target HSPCs, and could provide the basis for in vivo treatment of hemoglobinopathies and other genetic diseases.

We propose a novel scheme for the exact renormalisation group motivated by the desire of reducing the complexity of practical computations. The key idea is to specify renormalisation conditions for all inessential couplings, leaving us with the task of computing only the flow of the essential ones. To achieve this aim, we utilise a renormalisation group equation for the effective average action which incorporates general non-linear field reparameterisations. A prominent feature of the scheme is that, apart from the renormalisation of the mass, the propagator evaluated at any constant value of the field maintains its unrenormalised form. Conceptually, the simplifications can be understood as providing a description based only on quantities that enter expressions for physical observables since the redundant, non-physical content is automatically disregarded. To exemplify the scheme's utility, we investigate the Wilson-Fisher fixed point in three dimensions at order two in the derivative expansion. In this case, the scheme removes all order $\partial^2$ operators apart from the canonical term. Further simplifications occur at higher orders in the derivative expansion. Although we concentrate on a minimal scheme that reduces the complexity of computations, we propose more general schemes where inessential couplings can be tuned to optimise a given approximation. We further discuss the applicability of the scheme to a broad range of physical theories., Comment: Version 3: Extended version, typos corrected, 41 pages

Ventricular abnormal potentials (VAPs) identification is a challenging issue, since they constitute the ablation targets in substrate-guided mapping and ablation procedures for ventricular tachycardia (VT) treatment. In this work, two approaches for the supervised classification of VAPs in bipolar intracardiac electrograms are evaluated and compared. To this aim, 954 bipolar electrograms were retrospectively annotated by an expert cardiologist. All signals were acquired from six patients affected by post-ischemic VT by the CARTO3 system at the San Francesco Hospital (Nuoro, Italy) during routine procedures. The first classification approach was based on a support vector machine trained and tested on four different features, extracted from both the time and time-scale domain, to identify physiological and abnormal potentials. Conversely, in order to assess the significance of the first approach and its features, in the second approach all the samples constituting a time-domain segment of each bipolar electrogram were given as input to a feed-forward artificial neural network. In both cases, the accuracy in VAPs and physiological potentials identification exceeded 79%, suggesting their efficacy and the possibility of VAPs automatic recognition without identifying peculiar features.