Summary Background Immobilisation predicts adverse outcomes in patients in the surgical intensive care unit (SICU). Attempts to mobilise critically ill patients early after surgery are frequently ...restricted, but we tested whether early mobilisation leads to improved mobility, decreased SICU length of stay, and increased functional independence of patients at hospital discharge. Methods We did a multicentre, international, parallel-group, assessor-blinded, randomised controlled trial in SICUs of five university hospitals in Austria (n=1), Germany (n=1), and the USA (n=3). Eligible patients (aged 18 years or older, who had been mechanically ventilated for <48 h, and were expected to require mechanical ventilation for ≥24 h) were randomly assigned (1:1) by use of a stratified block randomisation via restricted web platform to standard of care (control) or early, goal-directed mobilisation using an inter-professional approach of closed-loop communication and the SICU optimal mobilisation score (SOMS) algorithm (intervention), which describes patients’ mobilisation capacity on a numerical rating scale ranging from 0 (no mobilisation) to 4 (ambulation). We had three main outcomes hierarchically tested in a prespecified order: the mean SOMS level patients achieved during their SICU stay (primary outcome), and patient's length of stay on SICU and the mini-modified functional independence measure score (mmFIM) at hospital discharge (both secondary outcomes). This trial is registered with ClinicalTrials.gov ( NCT01363102 ). Findings Between July 1, 2011, and Nov 4, 2015, we randomly assigned 200 patients to receive standard treatment (control; n=96) or intervention (n=104). Intention-to-treat analysis showed that the intervention improved the mobilisation level (mean achieved SOMS 2·2 SD 1·0 in intervention group vs 1·5 0·8 in control group, p<0·0001), decreased SICU length of stay (mean 7 days SD 5–12 in intervention group vs 10 days 6–15 in control group, p=0·0054), and improved functional mobility at hospital discharge (mmFIM score 8 4–8 in intervention group vs 5 2–8 in control group, p=0·0002). More adverse events were reported in the intervention group (25 cases 2·8%) than in the control group (ten cases 0·8%); no serious adverse events were observed. Before hospital discharge 25 patients died (17 16% in the intervention group, eight 8% in the control group). 3 months after hospital discharge 36 patients died (21 22% in the intervention group, 15 17% in the control group). Interpretation Early, goal-directed mobilisation improved patient mobilisation throughout SICU admission, shortened patient length of stay in the SICU, and improved patients’ functional mobility at hospital discharge. Funding Jeffrey and Judy Buzen.
Over 40 000 patients with COVID-19 have been hospitalised in New York City (NY, USA) as of April 28, 2020. Data on the epidemiology, clinical course, and outcomes of critically ill patients with ...COVID-19 in this setting are needed.
This prospective observational cohort study took place at two NewYork-Presbyterian hospitals affiliated with Columbia University Irving Medical Center in northern Manhattan. We prospectively identified adult patients (aged ≥18 years) admitted to both hospitals from March 2 to April 1, 2020, who were diagnosed with laboratory-confirmed COVID-19 and were critically ill with acute hypoxaemic respiratory failure, and collected clinical, biomarker, and treatment data. The primary outcome was the rate of in-hospital death. Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal replacement therapy, and time to in-hospital clinical deterioration following admission. The relation between clinical risk factors, biomarkers, and in-hospital mortality was modelled using Cox proportional hazards regression. Follow-up time was right-censored on April 28, 2020 so that each patient had at least 28 days of observation.
Between March 2 and April 1, 2020, 1150 adults were admitted to both hospitals with laboratory-confirmed COVID-19, of which 257 (22%) were critically ill. The median age of patients was 62 years (IQR 51–72), 171 (67%) were men. 212 (82%) patients had at least one chronic illness, the most common of which were hypertension (162 63%) and diabetes (92 36%). 119 (46%) patients had obesity. As of April 28, 2020, 101 (39%) patients had died and 94 (37%) remained hospitalised. 203 (79%) patients received invasive mechanical ventilation for a median of 18 days (IQR 9–28), 170 (66%) of 257 patients received vasopressors and 79 (31%) received renal replacement therapy. The median time to in-hospital deterioration was 3 days (IQR 1–6). In the multivariable Cox model, older age (adjusted hazard ratio aHR 1·31 1·09–1·57 per 10-year increase), chronic cardiac disease (aHR 1·76 1·08–2·86), chronic pulmonary disease (aHR 2·94 1·48–5·84), higher concentrations of interleukin-6 (aHR 1·11 95%CI 1·02–1·20 per decile increase), and higher concentrations of D-dimer (aHR 1·10 1·01–1·19 per decile increase) were independently associated with in-hospital mortality.
Critical illness among patients hospitalised with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extrapulmonary organ dysfunction, and substantial in-hospital mortality.
National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health, and the Columbia University Irving Institute for Clinical and Translational Research.
SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response ...to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development.
The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRAS
i, CDK4/6i, and anti-programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models
and
, and their effects on downstream signaling were examined.
In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAF
colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRAS
cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRAS
i and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient-derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti-PD-1 antibody.
Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported ...oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an ...important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein–ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
Advances in the field of quantum sensing mean that magnetic field sensors, operating at room temperature, are now able to achieve sensitivity similar to that of cryogenically cooled devices (SQUIDs). ...This means that room temperature magnetoencephalography (MEG), with a greatly increased flexibility of sensor placement can now be considered. Further, these new sensors can be placed directly on the scalp surface giving, theoretically, a large increase in the magnitude of the measured signal. Here, we present recordings made using a single optically-pumped magnetometer (OPM) in combination with a 3D-printed head-cast designed to accurately locate and orient the sensor relative to brain anatomy. Since our OPM is configured as a magnetometer it is highly sensitive to environmental interference. However, we show that this problem can be ameliorated via the use of simultaneous reference sensor recordings. Using median nerve stimulation, we show that the OPM can detect both evoked (phase-locked) and induced (non-phase-locked oscillatory) changes when placed over sensory cortex, with signals ~4 times larger than equivalent SQUID measurements. Using source modelling, we show that our system allows localisation of the evoked response to somatosensory cortex. Further, source-space modelling shows that, with 13 sequential OPM measurements, source-space signal-to-noise ratio (SNR) is comparable to that from a 271-channel SQUID system. Our results highlight the opportunity presented by OPMs to generate uncooled, potentially low-cost, high SNR MEG systems.
Imaging human brain function with techniques such as magnetoencephalography typically requires a subject to perform tasks while their head remains still within a restrictive scanner. This artificial ...environment makes the technique inaccessible to many people, and limits the experimental questions that can be addressed. For example, it has been difficult to apply neuroimaging to investigation of the neural substrates of cognitive development in babies and children, or to study processes in adults that require unconstrained head movement (such as spatial navigation). Here we describe a magnetoencephalography system that can be worn like a helmet, allowing free and natural movement during scanning. This is possible owing to the integration of quantum sensors, which do not rely on superconducting technology, with a system for nulling background magnetic fields. We demonstrate human electrophysiological measurement at millisecond resolution while subjects make natural movements, including head nodding, stretching, drinking and playing a ball game. Our results compare well to those of the current state-of-the-art, even when subjects make large head movements. The system opens up new possibilities for scanning any subject or patient group, with myriad applications such as characterization of the neurodevelopmental connectome, imaging subjects moving naturally in a virtual environment and investigating the pathophysiology of movement disorders.
Digital waxing procedures should be guided by facial references to improve the esthetic outcome of a restoration. The development of facial scanners has allowed the digitalization of the extraoral ...soft tissues of the patient’s face. However, the reliability of facial digitizers is questionable.
The purpose of this study was to evaluate the accuracy (trueness and precision) of extraoral 3D facial reconstructions performed by using a dual-structured light facial scanner and to measure the interexaminer variability.
Ten participants were included. Six soft-tissue landmarks were determined on each participant, specifically reference (Ref), glabella (Gb), subnasal (Sn), menton (Me), chelion right (ChR), and chelion left (ChL). Interlandmark distances Ref-Sn, Sn-Gb, Ref-Gb, Sn-Me, and ChR-ChL (intercommissural) were measured by 2 different operators by using 2 different methods: directly on the participant’ face (manual group) and digitally (digital group) on the 3D facial reconstruction of the participant (n=20). For the manual group, interlandmark measurements were made by using digital calipers. For the digital group, 10 three-dimensional facial reconstructions were acquired for each participant by using a dual-structured light facial scanner (Face Camera Pro Bellus; Bellus3D). Interlandmark measurements were made by using an open-source software program (Meshlab; Meshlab). Both operators were used to note 10 measurements for each manual and digital interlandmark distance per participant. The intraclass correlation coefficient between the 2 operators was calculated. The Shapiro-Wilk test revealed that the data were not normally distributed. The data were analyzed by using the Mann-Whitney U test.
Significant differences were found between manual and digital interlandmark measurements in all participants. The mean value of the manual and digital group discrepancy was 0.91 ±0.32 mm. The dual-structured light facial scanner tested obtained a trueness mean value of 0.91 mm and a precision mean value of 0.32 mm. Trueness values were always higher than precision mean values, indicating that precision was relatively high. The intraclass correlation coefficient between the 2 operators was 0.99.
The facial digitizing procedure evaluated produced clinically acceptable outcomes for virtual treatment planning. The interexaminer reliability between the 2 operators was rated as excellent, suggesting that the type of facial landmark used in this study provides reproducible results among different examiners.
Magnetoencephalography (MEG) is a sophisticated tool which yields rich information on the spatial, spectral and temporal signatures of human brain function. Despite unique potential, MEG is limited ...by a low signal-to-noise ratio (SNR) which is caused by both the inherently small magnetic fields generated by the brain, and the scalp-to-sensor distance. The latter is limited in current systems due to a requirement for pickup coils to be cryogenically cooled. Recent work suggests that optically-pumped magnetometers (OPMs) might be a viable alternative to superconducting detectors for MEG measurement. They have the advantage that sensors can be brought to within ~4 mm of the scalp, thus offering increased sensitivity. Here, using simulations, we quantify the advantages of hypothetical OPM systems in terms of sensitivity, reconstruction accuracy and spatial resolution. Our results show that a multi-channel whole-head OPM system offers (on average) a fivefold improvement in sensitivity for an adult brain, as well as clear improvements in reconstruction accuracy and spatial resolution. However, we also show that such improvements depend critically on accurate forward models; indeed, the reconstruction accuracy of our simulated OPM system only outperformed that of a simulated superconducting system in cases where forward field error was less than 5%. Overall, our results imply that the realisation of a viable whole-head multi-channel OPM system could generate a step change in the utility of MEG as a means to assess brain electrophysiological activity in health and disease. However in practice, this will require both improved hardware and modelling algorithms.
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