This study aims to assess how clinical outcomes of immunotherapy in real-world (effectiveness) correspond to outcomes in clinical trials (efficacy) and to look into factors that might explain an ...efficacy-effectiveness (EE) gap. All patients diagnosed with stage IV non-small cell lung cancer (NSCLC) in 2015-2018 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. Progression-free survival (PFS) and overall survival (OS) from first-line (1L) pembrolizumab and second-line (2L) nivolumab were compared with clinical trial data by calculating hazard ratios (HRs). From 1950 diagnosed patients, 1005 (52%) started with any 1L treatment, of which 83 received pembrolizumab. Nivolumab was started as 2L treatment in 141 patients. For both settings, PFS times were comparable between real-world and trials (HR 1.08 (95% CI 0.75-1.55), and HR 0.91 (95% CI 0.74-1.14), respectively). OS was significantly shorter in real-world for 1L pembrolizumab (HR 1.55; 95% CI 1.07-2.25). Receiving subsequent lines of treatment was less frequent in real-world compared to trials. There is no EE gap for PFS from immunotherapy in patients with stage IV NSCLC. However, there is a gap in OS for 1L pembrolizumab. Fewer patients proceeding to a subsequent line of treatment in real-world could partly explain this.
Our perceptual experience of sound depends on the integration of multiple sensory and cognitive domains, however the networks subserving this integration are unclear. Connections linking different ...cortical domains have been described, but we do not know the extent to which connections also exist between multiple cortical domains and subcortical structures. Retrograde tracing in adult male rats (
) revealed that the inferior colliculus, the auditory midbrain, receives dense descending projections not only, as previously established, from the auditory cortex, but also from the visual, somatosensory, motor, and prefrontal cortices. While all these descending connections are bilateral, those from sensory areas show a more pronounced ipsilateral dominance than those from motor and prefrontal cortices. Injections of anterograde tracers into the cortical areas identified by retrograde tracing confirmed those findings and revealed cortical fibers terminating in all three subdivisions of the inferior colliculus. Immunolabeling showed that cortical terminals target both GABAergic inhibitory, and putative glutamatergic excitatory neurons. These findings demonstrate that auditory perception and behavior are served by a network that includes extensive descending connections to the midbrain from sensory, behavioral, and executive cortices.
Making sense of what we hear depends not only on the analysis of sound, but also on information from other senses together with the brain's predictions about the properties and significance of the sound. Previous work suggested that this interplay between the senses and the predictions from higher cognitive centers occurs within the cerebral cortex. By tracing neural connections in rat, we show that the inferior colliculus, the subcortical, midbrain center for hearing, receives extensive connections from areas of the cerebral cortex concerned with vision, touch, movement, and cognitive function, in addition to areas representing hearing. These findings demonstrate that wide-ranging cortical feedback operates at an earlier stage of the hearing pathway than previously recognized.
Introduction This study was designed to test the feasibility and face validity of the composite time trade-off (composite TTO), a new approach to TTO allowing for a more consistent elicitation of ...negative health state values. Methods The new instrument combines a conventional TTO to elicit values for states regarded better than dead and a lead-time TTO for states worse than dead. Results A total of 121 participants completed the composite TTO for ten EQ-5D-5L health states. Mean values ranged from -0.104 for health state 53555 to 0.946 for 21111. The instructions were clear to 98 % of the respondents, and 95 % found the task easy to understand, indicating feasibility. Further, the average number of steps taken in the iteration procedure to achieve the point of indifference in the TTO and the average duration of each task were indicative of a deliberate cognitive process. Conclusion Face validity was confirmed by the high mean values for the mild health states (>0.90) and low mean values for the severe states (<0.42). In conclusion, this study demonstrates the feasibility and face validity of the composite TTO in a face-to-face standardized computer-assisted interview setting.
Crystallinity is seldomly utilized as part of the microphase segregation process in ultralow-molecular-weight block copolymers. Here, we show the preparation of two types of discrete, semicrystalline ...block co-oligomers, comprising an amorphous oligodimethylsiloxane block and a crystalline oligo-l-lactic acid or oligomethylene block. The self-assembly of these discrete materials results in lamellar structures with unforeseen uniformity in the domain spacing. A systematic introduction of dispersity reveals the extreme sensitivity of the microphase segregation process toward chain length dispersity in the crystalline block.
Exosomes are important mediators of intercellular communication. Additionally, they contain a variety of components capable of interacting with the extracellular matrix (ECM), including integrins, ...matrix metalloproteinases and members of the immunoglobin superfamily. Despite these observations, research on exosome‐ECM interactions is limited. Here, we investigate whether the exosome‐associated lysyl oxidase family member lysyl oxidase‐like 2 (LOXL2) is involved in ECM remodelling. We found that LOXL2 is present on the exterior of endothelial cell (EC)‐derived exosomes, placing it in direct vicinity of the ECM. It is up‐regulated twofold in EC‐derived exosomes cultured under hypoxic conditions. Intact exosomes from hypoxic EC and LOXL2 overexpressing EC show increased activity in a fluorometric lysyl oxidase enzymatic activity assay as well as in a collagen gel contraction assay. Concordantly, knockdown of LOXL2 in exosome‐producing EC in both normal and hypoxic conditions reduces activity of exosomes in both assays. Our findings show for the first time that ECM crosslinking by EC‐derived exosomes is mediated by LOXL2 under the regulation of hypoxia, and implicate a role for exosomes in hypoxia‐regulated focal ECM remodelling, a key process in both fibrosis and wound healing.
Background & Aims Radiofrequency ablation (RFA), with or without endoscopic resection effectively eradicates Barrett’s esophagus (BE) containing high-grade intraepithelial neoplasia and/or ...early-stage cancer. We followed patients who received RFA for BE containing high-grade intraepithelial neoplasia and/or early-stage cancer for 5 years to determine the durability of treatment response. Methods We followed 54 patients with BE (2−12 cm), previously enrolled in 4 consecutive cohort studies in which they underwent focal endoscopic resection in case of visible lesions (n = 40 72%), followed by serial RFA every 3 months. Patients underwent high-resolution endoscopy with narrow-band imaging at 6 and 12 months after treatment and then annually for 5 years (median, 61 months; interquartile range, 53−65 months); random biopsy samples were collected from neosquamous epithelium and gastric cardia. After 5 years, endoscopic ultrasound and endoscopic resection of neosquamous epithelium were performed. Outcomes included sustained complete remission of neoplasia or intestinal metaplasia (IM), IM in gastric cardia, or buried glands in neosquamous epithelium. Results After 5 years, Kaplan-Meier analysis showed sustained complete remission of neoplasia and intestinal metaplasia in 90% of patients; neoplasia recurred in 3 patients and was managed endoscopically. Focal IM in the cardia was found in 19 of 54 patients (35%), in 53 of 1143 gastric cardia biopsies (4.6%). The incidence of IM of the cardia did not increase over time; and IM was diagnosed based on only a single biopsy in 89% of patients. Buried glands were detected in 3 of 3543 neosquamous epithelium biopsies (0.08%, from 3 patients). No endoscopic resection samples had buried glands. Conclusions Among patients who have undergone RFA with or without endoscopic resection for neoplastic BE, 90% remain in remission at 5-year follow-up, with all recurrences managed endoscopically. This treatment approach is therefore an effective and durable alternative to esophagectomy; www.trialregister.nl number, NTR2938.
Objective:
This study was designed to establish the reliability of neurologic examination, neuron‐specific enolase (NSE), and median nerve somatosensory‐evoked potentials (SEPs) to predict poor ...outcome in patients treated with mild hypothermia after cardiopulmonary resuscitation (CPR).
Methods:
This multicenter prospective cohort study included adult comatose patients admitted to the intensive care unit (ICU) after CPR and treated with hypothermia (32–34°C). False‐positive rates (FPRs 1 − specificity) with their 95% confidence intervals (CIs) were calculated for pupillary light responses, corneal reflexes, and motor scores 72 hours after CPR; NSE levels at admission, 12 hours after reaching target temperature, and 36 hours and 48 hours after collapse; and SEPs during hypothermia and after rewarming. The primary outcome was poor outcome, defined as death, vegetative state, or severe disability (Glasgow Outcome Scale 1–3) after 6 months.
Results:
Of 391 patients included, 53% had a poor outcome. Absent pupillary light responses (FPR 1; 95% CI, 0–7) or absent corneal reflexes (FPR 4; 95% CI, 1–13) 72 hours after CPR, and absent SEPs during hypothermia (FPR 3; 95% CI, 1–7) and after rewarming (FPR 0; 95% CI, 0–18) were reliable predictors. Motor scores 72 hours after CPR (FPR 10; 95% CI, 6–16) and NSE levels were not.
Interpretation:
In patients with persisting coma after CPR and therapeutic hypothermia, use of motor score or NSE, as recommended in current guidelines, could possibly lead to inappropriate withdrawal of treatment. Poor outcomes can reliably be predicted by testing brainstem reflexes 72 hours after CPR and performing SEP. ANN NEUROL 2012;71:206–212
Nitric oxide (NO) is a neurotransmitter synthesized in the brain by neuronal nitric oxide synthase (nNOS). Using immunohistochemistry and confocal imaging in the inferior colliculus (IC, auditory ...midbrain) of the guinea pig (
, male and female), we show that nNOS occurs in two distinct cellular distributions. We confirm that, in the cortices of the IC, a subset of neurons show cytoplasmic labeling for nNOS, whereas in the central nucleus (ICc), such neurons are not present. However, we demonstrate that all neurons in the ICc do in fact express nNOS in the form of discrete puncta found at the cell membrane. Our multi-labeling studies reveal that nNOS puncta form multiprotein complexes with NMDA receptors, soluble guanylyl cyclase (sGC), and PSD95. These complexes are found apposed to glutamatergic terminals, which is indicative of synaptic function. Interestingly, these glutamatergic terminals express both vesicular glutamate transporters 1 and 2 denoting a specific source of brainstem inputs. With
electrophysiological recordings of multiunit activity in the ICc, we found that local application of NMDA enhances sound-driven activity in a concentration-dependent and reversible fashion. This response is abolished by blockade of nNOS or sGC, indicating that the NMDA effect is mediated solely via the NO and cGMP signaling pathway. This discovery of a ubiquitous, but highly localized, expression of nNOS throughout the ICc and demonstration of the dramatic influence of the NMDA activated NO pathway on sound-driven neuronal activity imply a key role for NO signaling in auditory processing.
We show that neuronal nitric oxide synthase (nNOS), the enzyme that synthesizes nitric oxide (NO), occurs as puncta in apparently all neurons in the central nucleus of the inferior colliculus (ICc) in the auditory midbrain. Punctate nNOS appears at glutamatergic synapses in a complex with glutamate NMDA receptors (NMDA-Rs), soluble guanylyl cyclase (sGC, the NO receptor), and PSD95 (a protein that anchors receptors and enzymes at the postsynaptic density). We show that NMDA-R modulation of sound-driven activity in the ICc is solely mediated by activation of nNOS and sGC. The presence of nNOS throughout this sensory nucleus argues for a major role of NO in hearing. Furthermore, this punctate form of nNOS expression may exist and have gone unnoticed in other brain regions.
Understanding cell/material interactions is essential to design functional cell‐responsive materials. While the scientific literature abounds with formulations of biomimetic materials, only a ...fraction of them focused on mechanisms of the molecular interactions between cells and material. To provide new knowledge on the strategies for materials/cell recognition and binding, supramolecular benzene‐1,3,5‐tricarboxamide copolymers bearing benzoxaborole moieties are anchored on the surface of human erythrocytes via benzoxaborole/sialic‐acid binding. This interaction based on both dynamic covalent and non‐covalent chemistries is visualized in real time by means of total internal reflection fluorescence microscopy. Exploiting this imaging method, we observe that the functional copolymers specifically interact with the cell surface. An optimal fiber affinity towards the cells as a function of benzoxaborole concentration demonstrates the crucial role of multivalency in these cell/material interactions.
Drawn to the blood: When benzene‐1,3,5‐tricarboxamide 1D fibers are decorated with benzoxaborole moieties, a dynamic interaction with human red blood cells is induced via the adaptive covalent reaction between boronic acids and cell sialic acids. Total internal reflection fluorescence microscopy is exploited as a powerful tool to allow real‐time imaging of cells/fiber binding, revealing the multivalency of this interaction.
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