Blocking the NGF-TrkA Interaction Rescues the Developmental Loss of LTP in the Rat Visual Cortex Role of the Cholinergic System

AbstractAlthough nerve growth factor (NGF) is a crucial factor in the activity-dependent development and plasticity of visual cortex, its role in synaptic efficacy changes is largely undefined. We demonstrate that the maintenance phase of long-term potentiation (LTP) is blocked by local application of exogenous NGF in rat visual cortex at an early stage of postnatal development. Long-term depression (LTD) and bidirectional plasticity are unaffected. At later postnatal ages, blockade of either endogenous NGF by immunoadhesin (TrkA-IgG) or TrkA receptors by monoclonal antibody rescues LTP. Muscarinic receptor activation/inhibition suggests that LTP dependence on NGF is mediated by the cholinergic system. These results indicate that NGF regulates synaptic strength in well-characterized cortical circuitries

Mechanical ventilation parameters in critically ill COVID-19 patients: a scoping review

Background: The mortality of critically ill patients with COVID-19 is high, particularly among those receiving mechanical ventilation (MV). Despite the high number of patients treated worldwide, data on respiratory mechanics are currently scarce and the optimal setting of MV remains to be defined. This scoping review aims to provide an overview of available data about respiratory mechanics, gas exchange and MV settings in patients admitted to intensive care units (ICUs) for COVID-19-associated acute respiratory failure, and to identify knowledge gaps. Main text: PubMed, EMBASE, and MEDLINE databases were searched from inception to October 30, 2020 for studies providing at least one ventilatory parameter collected within 24 h from the ICU admission. The quality of the studies was independently assessed using the Newcastle-Ottawa Quality Assessment Form for Cohort Studies. A total of 26 studies were included for a total of 14,075 patients. At ICU admission, positive end expiratory pressure (PEEP) values ranged from 9 to 16.5 cm of water (cmH2O), suggesting that high levels of PEEP were commonly used for setting MV for these patients. Patients with COVID-19 are severely hypoxemic at ICU admission and show a median ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ranging from 102 to 198 mmHg. Static respiratory system compliance (Crs) values at ICU admission were highly heterogenous, ranging between 24 and 49 ml/cmH2O. Prone positioning and neuromuscular blocking agents were widely used, ranging from 17 to 81 and 22 to 88%, respectively; both rates were higher than previously reported in patients with "classical" acute respiratory distress syndrome (ARDS). Conclusions: Available data show that, in mechanically ventilated patients with COVID-19, respiratory mechanics and MV settings within 24 h from ICU admission are heterogeneous but similar to those reported for "classical" ARDS. However, to date, complete data regarding mechanical properties of respiratory system, optimal setting of MV and the role of rescue treatments for refractory hypoxemia are still lacking in the medical literature

Monitor and sensors 2.0 for exposure assessment to airborne pollutants

In recent years, the issue of exposure assessment to airborne pollutants has become increasingly popular, both in the occupational and environmental fields. The increasingly stringent national and international air quality standards and exposure limit values both for indoor environments and occupational exposure limit values have been developed with the aim of protecting the health of the general population and workers. On the other hand, this requires a considerable and continuous development of the technologies used to monitor the concentrations of the pollutants to ensure the reliability of the exposure assessment studies. In this regard, one of the most interesting aspects is certainly the development of “new generation” instrumentation for monitoring airborne pollutants (“Next Generation Monitors and Sensors” – NGMS). The main purpose of this work is to analyze the state of the art regarding the afore-mentioned instrumentation, to be able to investigate any practical applications within exposure assessment studies. In this regard, a systematic review of the scientific literature was carried out using three different databases (Scopus, PubMed and Web of Knowledge) and the results were analyzed in terms of the objectives set out above. What emerged is the fact that the use of NGMSs is increasingly growing within the scientific community for exposure assessment studies applied to the occupational and environmental context. The investigated studies have emphasized that NGMSs cannot be considered, in terms of the reliability of the results, to be equal to the reference measurement tools and techniques (i.e., those defined in recognized methods used for regulatory purposes), but they can certainly be integrated into the internal exposure assessment studies to improve their spatial-temporal resolution. These tools have the potential to be easily adapted to different types of studies, are characterized by a small size, which allows them to be worn comfortably without affecting the normal activities of workers or citizens, and by a relatively low cost. Despite this, there is certainly a gap with respect to the reference instrumentation, regarding the measurement performance and quality of the data provided; the objective to be set, however, is not to replace the traditional instrumentation with NGMSs but to integrate and combine the two typologies of instruments to benefit from the strengths of both, therefore, the desirable future developments in this sense has been discussed in this work

First in-Lab Testing of a Cost-Effective Prototype for PM2.5 Monitoring: The P.ALP Assessment

The goal of the present research was to assess, under controlled laboratory conditions, the accuracy and precision of a prototype device (named ‘P.ALP’: Ph.D. Air-quality Low-cost Project) developed for PM2.5 concentration level monitoring. Indeed, this study follows a complementary manuscript (previously published) focusing on the in-field evaluation of the device’s performance. Four P.ALP prototypes were co-located with the reference instrument in a calm-air aerosol chamber at the NIOSH laboratories in Pittsburgh, PA (USA), used by the Center for Direct Reading and Sensor Technologies. The devices were tested for 10 monitoring days under several exposure conditions. To evaluate the performance of the prototypes, different approaches were employed. After the data from the devices were stored and prepared for analysis, to assess the accuracy (comparing the reference instrument with the prototypes) and the precision (comparing all the possible pairs of devices) of the P.ALPs, linear regression analysis was performed. Moreover, to find out the applicability field of this device, the US EPA’s suggested criteria were adopted, and to assess error trends of the prototype in the process of data acquisition, Bland–Altman plots were built. The findings show that, by introducing ad hoc calibration factors, the P.ALP’s performance needs to be further implemented, but the device can monitor the concentration trend variations with satisfying accuracy. Overall, the P.ALP can be involved in and adapted to a wide range of applications because of the inexpensive nature of the components, the small dimensions, and the high data storage capacity

An In-Field Assessment of the P.ALP Device in Four Different Real Working Conditions: A Performance Evaluation in Particulate Matter Monitoring

This study aimed to assess the performance, in terms of precision and accuracy, of a prototype (called “P.ALP”—Ph.D. Air Quality Low-cost Project) developed for monitoring PM2.5 concentration levels. Four prototypes were co-located with reference instrumentation in four different microenvironments simulating real-world and working conditions, namely (i) office, (ii) home, (iii) outdoor, and (iv) occupational environments. The devices were evaluated for a total of 20 monitoring days (approximately 168 h) under a wide range of PM2.5 concentrations. The performances of the prototypes (based on the light-scattering working principle) were tested through different statistical methods. After the data acquisition and data cleaning processes, a linear regression analysis was performed to assess the precision (by comparing all possible pairs of devices) and the accuracy (by comparing the prototypes against the reference instrumentation) of the P.ALP. Moreover, the United States Environmental Protection Agency (US EPA) criteria were applied to assess the possible usage of this instrumentation, and to evaluate the eventual error trends of the P.ALP in the data storage process, Bland–Altman plots were also adopted. The outcomes of this study underlined that the P.ALP performed differently depending on the microenvironment in which it was tested and, consequently, on the PM2.5 concentrations. The device can monitor PM2.5 variations with acceptable results, but the performance cannot be considered satisfactory at extremely low and remarkably high PM2.5 concentrations. Thanks to modular components and open-source software, the tested device has the potential to be customized and adapted to better fit specific study design needs, but it must be implemented with ad hoc calibration factors depending on the application before being used in field

Time to change the single-centre approach to management of patients with tuberculosis: a novel network platform with automatic data import and data sharing

Time to change the single-centre approach to TB http://ow.ly/lCeM30hBcbB

The redshift evolution of the distribution of star formation among dark matter halos as seen in the infrared

Recent studies revealed a strong correlation between the star formation rate (SFR) and stellar mass of star-forming galaxies, the so-called star-forming main sequence. An empirical modeling approach (2-SFM) which distinguishes between the main sequence and rarer starburst galaxies is capable of reproducing most statistical properties of infrared galaxies. In this paper, we extend this approach by establishing a connection between stellar mass and halo mass with the technique of abundance matching. Based on a few, simple assumptions and a physically motivated formalism, our model successfully predicts the (cross-)power spectra of the cosmic infrared background (CIB), the cross-correlation between CIB and cosmic microwave background (CMB) lensing, and the correlation functions of bright, resolved infrared galaxies measured by Herschel, Planck, ACT and SPT. We use this model to infer the redshift distribution these observables, as well as the level of correlation between CIB-anisotropies at different wavelengths. We also predict that more than 90% of cosmic star formation activity occurs in halos with masses between 10^11.5 and 10^13.5 Msun. Taking into account subsequent mass growth of halos, this implies that the majority of stars were initially (at z>3) formed in the progenitors of clusters, then in groups at 0.5<z<3 and finally in Milky-Way-like halos at z<0.5. At all redshifts, the dominant contribution to the star formation rate density stems from halos of mass ~10^12 Msun, in which the instantaneous star formation efficiency is maximal (~70%). The strong redshift-evolution of SFR in the galaxies that dominate the CIB is thus plausibly driven by increased accretion from the cosmic web onto halos of this characteristic mass scale

Stem Cells for Huntington's Disease (SC4HD): An International Consortium to Facilitate Stem Cell-Based Therapy for Huntington's Disease

Huntington's disease (HD) research is entering an exciting phase, with new approaches such as huntingtin lowering strategies and cell therapies on the horizon. Technological advances to direct the differentiation of stem cells to desired neural types have opened new strategies for restoring damaged neuronal circuits in HD. However, challenges remain in the implementation of cell therapy approaches for patients suffering from HD. Cell therapies, together with other invasive approaches including allele specific oligonucleotides (ASOs) and viral delivery of huntingtin-lowering agents, require direct delivery of the therapeutic agents locally into the brain or cerebrospinal fluid. Delivering substances directly into the brain is complex and presents multiple challenges, including those related to regulatory requirements, safety and efficacy, surgical instrumentation, trial design, patient profiles, and selection of suitable and sensitive primary and secondary outcomes. In addition, production of clinical grade cell-based medicinal products also requires adherence to regulatory standards with extensive quality control of the protocols and cell products across different laboratories and production centers. Currently, there is no consensus on how best to address these challenges. Here we describe the formation of Stem Cells For Huntington's Disease (SC4HD: https://www.sc4hd.org/), a network of researchers and clinicians working to develop guidance and greater standardization for the HD field for stem cell based transplantation therapy for HD with a mission to work to develop criteria and guidance for development of a neural intra-cerebral stem cell-based therapy for HD

MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial.

BACKGROUND Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. METHODS This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. FINDINGS Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93). INTERPRETATION MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. FUNDING Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League