Experimental validation of a patient-specific model of orthotic action in adolescent idiopathic scoliosis

This is the author accepted manuscript. The final version is available from Springer via the DOI in this record.PURPOSE: Personalized modeling of brace action has potential in improving brace efficacy in adolescent idiopathic scoliosis (AIS). Model validation and simulation uncertainty are rarely addressed, limiting the clinical implementation of personalized models. We hypothesized that a thorough validation of a personalized finite element model (FEM) of brace action would highlight potential means of improving the model. METHODS: Forty-two AIS patients were included retrospectively and prospectively. Personalized FEMs of pelvis, spine and ribcage were built from stereoradiographies. Brace action was simulated through soft cylindrical pads acting on the ribcage and through displacements applied to key vertebrae. Simulation root mean squared errors (RMSEs) were calculated by comparison with the actual brace action (quantified through clinical indices, vertebral positions and orientations) observed in in-brace stereoradiographies. RESULTS: Simulation RMSEs of Cobb angle and vertebral apical axial rotation was lower than measurement uncertainty in 79 % of the patients. Pooling all patients and clinical indices, 87 % of the indices had lower RMSEs than the measurement uncertainty. CONCLUSIONS: In-depth analysis suggests that personalization of spinal functional units mechanical properties could improve the simulation's accuracy, but the model gave good results, thus justifying further research on its clinical application

Anthropogenic modifications to the drainage network of Rome (Italy). The case study of the Aqua Mariana

Rome is characterized by millennia of urbanization. Long lasting geomorphological investigations have allowed the geomorphological description of the city centre and the valorisation of its geomorphological heritage. In this paper the spatial change of the hydrographic network in historical times is illustrated, with some examples showing how deep has been, and still it is, the link between the historical-cultural development and the natural geomorphological and hydrological characteristics of the Roman territory. In particular, the most relevant human interventions on the drainage network, in the southern area of the city centre, have been investigated. Before the land-use modifications of Roman-age, this area was drained by the most important left tributary of the Tiber River within the city walls, the Nodicus River, more recently known as Aqua Mariana. This stream has undergone many anthropogenic modifications and diversions during the centuries, and its original path is known only downstream of the San Giovanni Basilica. According to geomorphological, archaeological and geological evidences, it is possible to hypothesize that the dimension of the pre-urbanization drainage basin, as known and reconstructed in the available literature, should have been until now underestimated

Random sum-product networks: A simple and effective approach to probabilistic deep learning

Sum-product networks (SPNs) are expressive probabilistic models with a rich set of exact and efficient inference routines. However, in order to guarantee exact inference, they require specific structural constraints, which complicate learning SPNs from data. Thereby, most SPN structure learners proposed so far are tedious to tune, do not scale easily, and are not easily integrated with deep learning frameworks. In this paper, we follow a simple “deep learning” approach, by generating unspecialized random structures, scalable to millions of parameters, and subsequently applying GPU-based optimization. Somewhat surprisingly, our models often perform on par with state-of-the-art SPN structure learners and deep neural networks on a diverse range of generative and discriminative scenarios. At the same time, our models yield well-calibrated uncertainties, and stand out among most deep generative and discriminative models in being robust to missing features and being able to detect anomalies

An Outlook on Uterine Neoplasms: From Hormonal and DNA Damaging to Cervical and Endometrial Cancer Development and Minimally Invasive Management.

Uterine neoplasms are common tumors, formed by endometrial and cervical cancers; endometrial cancer is the fourth most frequently diagnosed cancer in developed countries and the eighth leading cause of cancer death in women, and cervical cancer is the second most common cancer in women worldwide and is a leading cause of cancer-related death in women in underdeveloped countries. Cervical cancer arises by HPV DNA damaging; in fact cervical cancer starts in the cells on the surface of the cervix, exposed to viral infective agents, as HPV, founded in 80% of patients affected by cervical cancer. Thus, more than 99% of cervical uterine cancer cases show HPV presence. Nevertheless, Endometrial cancer involves cancerous growth of the endometrium, and increasing evidence indicates that different biological and genetic factors play relevant roles its onset so as carcinogenesis generally develops by hormonal modifications. Both tumors can be safely and feasibly managed from minimally invasive surgical techniques till to endoscopic radical operations, such as hysterectomy, bilateral salpingo- oophorectomy, pelvic and para-aortic lymphadenectomy for surgical treatment. The authors reviewed several excellent reviews and studies in the area of hormonal, viral and genetical risk factors associated with endometrial and cervical cancer risk and development, analyzing the area of biologic markers, all papers dealing with serum and plasma markers involved in uterine cancer detection, development, progression and minimally invasive treatment

Transcutaneous spinal direct current stimulation

In the past 10\u2009years renewed interest has centered on non-invasive transcutaneous weak direct currents applied over the scalp to modulate cortical excitability ("brain polarization" or transcranial direct current stimulation, tDCS). Extensive literature shows that tDCS induces marked changes in cortical excitability that outlast stimulation. Aiming at developing a new, non-invasive, approach to spinal cord neuromodulation we assessed the after-effects of thoracic transcutaneous spinal DC stimulation (tsDCS) on somatosensory potentials (SEPs) evoked in healthy subjects by posterior tibial nerve (PTN) stimulation. Our findings showed that thoracic anodal tsDCS depresses the cervico-medullary PTN-SEP component (P30) without eliciting adverse effects. tsDCS also modulates post-activation H-reflex dynamics. Later works further confirmed that transcutaneous electric fields modulate spinal cord function. Subsequent studies in our laboratory showed that tsDCS modulates the flexion reflex in the human lower limb. Besides influencing the laser evoked potentials (LEPs), tsDCS increases pain tolerance in healthy subjects. Hence, though the underlying mechanisms remain speculative, tsDCS modulates activity in lemniscal, spinothalamic, and segmental motor systems. Here we review currently available experimental evidence that non-invasive spinal cord stimulation (SCS) influences spinal function in humans and argue that, by focally modulating spinal excitability, tsDCS could provide a novel therapeutic tool complementary to drugs and invasive SCS in managing various pathologic conditions, including pain

Transcranial direct current stimulation (tDCS) for fatigue in multiple sclerosis

BACKGROUND: The debilitating fatigue that patients with multiple sclerosis (MS) commonly experience during day-to-day living activities responds poorly to current therapeutic options. Direct currents (DC) delivered through the scalp (transcranial DC stimulation or tDCS) at weak intensities induce changes in motor cortical excitability that persist for almost an hour after current offset and depend on current polarity. tDCS successfully modulates cortical excitability in various clinical disorders but no information is available for MS related fatigue. OBJECTIVE: In this study we aimed to assess fatigue symptom after five consecutive sessions of anodal tDCS applied over the motor cortex in patients with MS. METHODS: We enrolled 25 patients with MS all of whom experienced fatigue. We delivered anodal and sham tDCS in random order in two separate experimental sessions at least 1 month apart. The stimulating current was delivered for 15 minutes once a day for 5 consecutive days. In each session the Fatigue Impact Scale (FIS) and the Back Depression Inventory (BDI) were administered before the treatment (baseline), immediately after treatment on day five (T1), one week (T2) and three weeks (T3) after the last tDCS session. RESULTS: All patients tolerated tDCS well without adverse events. The fatigue score significantly decreased after anodal tDCS in 65% of the patients (responders). After patients received tDCS for 5 days their FIS scores improved by about 30% and the tDCS-induced benefits persisted at T2 and T3. CONCLUSION: Our preliminary findings suggest that anodal tDCS applied over the motor cortex, could improve fatigue in most patients with MS. \ua9 2014-IOS Press and the authors. All rights reserved

GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.We thank David Wiggins for excellent technical assistance. This work was supported by the Medical Research Council, Diabetes UK (to R. Ramracheya ), Oxford Biomedical Research Centre (to A. Tarasov), the Wellcome Trust (Senior Investigator Awards to A. Galione and P. Rorsman), the Warwick Impact Fund (to C. Weston and G. Ladds), the Biotechnology and Biological Sciences Research Council (to G. Ladds), the Knut and Alice Wallenberg Foundation (to P. Rorsman), and the Swedish Research Council (to P. Rorsman). The initial stages of M. Shigeto’s stay in Oxford were supported by a fellowship from Kawasaki Medical School.This is the final version of the article. It was first available from the American Society for Clinical Investigation via http://dx.doi.org/10.1172/JCI8197

Visualization of Murine Intranasal Dosing Efficiency Using Luminescent Francisella tularensis: Effect of Instillation Volume and Form of Anesthesia

Intranasal instillation is a widely used procedure for pneumonic delivery of drugs, vaccine candidates, or infectious agents into the respiratory tract of research mice. However, there is a paucity of published literature describing the efficiency of this delivery technique. In this report we have used the murine model of tularemia, with Francisella tularensis live vaccine strain (FTLVS) infection, to evaluate the efficiency of pneumonic delivery via intranasal dosing performed either with differing instillation volumes or different types of anesthesia. FTLVS was rendered luminescent via transformation with a reporter plasmid that constitutively expressed the Photorhabdus luminescens lux operon from a Francisella promoter. We then used an IVIS Spectrum whole animal imaging system to visualize FT dissemination at various time points following intranasal instillation. We found that instillation of FT in a dose volume of 10 µl routinely resulted in infection of the upper airways but failed to initiate infection of the pulmonary compartment. Efficient delivery of FT into the lungs via intranasal instillation required a dose volume of 50 µl or more. These studies also demonstrated that intranasal instillation was significantly more efficient for pneumonic delivery of FTLVS in mice that had been anesthetized with inhaled (isoflurane) vs. parenteral (ketamine/xylazine) anesthesia. The collective results underscore the need for researchers to consider both the dose volume and the anesthesia type when either performing pneumonic delivery via intranasal instillation, or when comparing studies that employed this technique

Consensus protocol for EEG and amplitude-integrated EEG assessment and monitoring in neonates

The aim of this work is to establish inclusive guidelines on electroencephalography (EEG) applicable to all neonatal intensive care units (NICUs). Guidelines on ideal EEG monitoring for neonates are available, but there are significant barriers to their implementation in many centres around the world. These include barriers due to limited resources regarding the availability of equipment and technical and interpretive round-the-clock personnel. On the other hand, despite its limitations, amplitude-integrated EEG (aEEG) (previously called Cerebral Function Monitor [CFM]) is a common alternative used in NICUs. The Italian Neonatal Seizure Collaborative Network (INNESCO), working with all national scientific societies interested in the field of neonatal clinical neurophysiology, performed a systematic literature review and promoted interdisciplinary discussions among experts (neonatologists, paediatric neurologists, neurophysiologists, technicians) between 2017 and 2020 with the aim of elaborating shared recommendations. A consensus statement on videoEEG (vEEG) and aEEG for the principal neonatal indications was established. The authors propose a flexible frame of recommendations based on the complementary use of vEEG and aEEG applicable to the various neonatal units with different levels of complexity according to local resources and specific patient features. Suggestions for promoting cooperation between neonatologists, paediatric neurologists, and neurophysiologists, organisational restructuring, and teleneurophysiology implementation are provided

Mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov-2 infection: An international cohort study

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (740%) had emergency surgery and 280 (248%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (261%) patients. 30-day mortality was 238% (268 of 1128). Pulmonary complications occurred in 577 (512%) of 1128 patients; 30-day mortality in these patients was 380% (219 of 577), accounting for 817% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 175 [95% CI 128-240], p<00001), age 70 years or older versus younger than 70 years (230 [165-322], p<00001), American Society of Anesthesiologists grades 3-5 versus grades 1-2 (235 [157-353], p<00001), malignant versus benign or obstetric diagnosis (155 [101-239], p=0046), emergency versus elective surgery (167 [106-263], p=0026), and major versus minor surgery (152 [101-231], p=0047). Interpretation Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research