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Introduction: Single-station N2 (ssN2) versus multi-station N2 has been used as a selection criterion for treatment recommendations between surgical versus non-surgical multimodality treatment in stage III-N2 NSCLC. We hypothesized that clinical staging would be susceptible to upstaging on pathologic staging and, therefore, challenge this practice. Methods: A retrospective study of prospectively collected routine clinical data for patients with stage III-N2 NSCLC that had completed computed tomography (CT), positron emission tomography (PET), and staging endobronchial ultrasound (EBUS) and had been confirmed clinical stage III-ssN2 at multidisciplinary team discussion and went on to complete surgical resection as the first treatment to provide pathologic staging. The study was completed in two cohorts (A) across a single cancer alliance in England (Greater Manchester) January 1, 2015 to December 31, 2018 and (B) across five United Kingdom centers to validate the findings in part A January 1, 2016 to December 31, 2020. Results: A total of 115 patients met the inclusion criteria across cohort A (56 patients) and cohort B (59 patients) across 15 United Kingdom hospitals. The proportion of cases in which clinical stage III-ssN2 was upstaged to pathologic stage III-multi-station N2 was 34% (19 of 56) in cohort A, 32% in cohort B (19 of 59), and 33% across the combined study cohort (38 of 115). Most patients had a single radiologically abnormal lymph node on CT and PET (88%, 105 of 115). In the majority, the reasons for missed N2 disease on staging EBUS were due to inaccessible (stations 5, 6, 8, 9) N2 nodes at EBUS (34%, 13 of 38) and accessible lymph nodes not sampled during staging EBUS as not meeting sampling threshold (40%, 15 of 38) rather than false-negative sampling during EBUS (26%, 10 of 38). Conclusions: During multidisciplinary team discussions, clinicians must be aware that one-third of patients with stage III-ssN2 on the basis of CT, PET, and staging EBUS do not truly have ssN2 and this questions the use of this criterion to define treatment recommendations.

This book review discusses Daniel Conway’s Nietzsche’s “Before Good and Evil”, part of the ongoing Edinburgh Critical Guides to Nietzsche edited by Keith Ansell-Pearson and Daniel Conway. Aspects of Conway’s discussion highlighted in the review include Nietzsche’s relation to Plato, the significance of psychology, and the notion of German identity.

The directed energy deposition (DED) parameters were determined for near-β alloy Ti-55511 by employing statistical design of experiments (DOEs) methods. Parameters resulting in fully dense freeform deposits were identified using two sequential DOEs. Single laser tracks were printed with several laser power, traverse rate, and powder feed rate settings in an initial DOE to identify promising build parameters. The capture efficiency and effective deposition rate were used to characterize and rank the single track deposits. The best parameters were then used to print a solid cube with various X–Y and Z overlaps (different hatch spacing, HS, and layer thickness, ZS) in a second DOE. Suitable deposition parameters were selected based on the cube density and microstructure and were used to fabricate larger tensile samples for mechanical testing. Multiple parameter sets were found to provide dense Ti-55511 deposits with acceptable mechanical properties and the parametric models showed statistical significance.

Purpose The retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study.Participants UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40–69 enrolled in 2006–2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs.Findings to date UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes.Future plans The collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022–2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia.

Botulinum neurotoxins (BoNTs) are extremely potent naturally occurring poisons that act by silencing neurotransmission. Intriguingly, in addition to preventing presynaptic vesicle fusion, BoNT serotype A (BoNT/A) can also promote axonal regeneration in preclinical models. Here we report that the non-toxic C-terminal region of the receptor-binding domain of heavy chain BoNT/A (HCC/A) activates the small GTPase Rac1 and ERK pathway to potentiate axonal outgrowth, dendritic protrusion formation and synaptic vesicle release in hippocampal neurons. These data are consistent with HCC/A exerting neurotrophic properties, at least in part, independent of any BoNT catalytic activity or toxic effect.

Changes in chromatin structure are key determinants of genomic responses. Thus, methods that enable such measurements are instrumental for investigating genome regulation and function. Here, we report further developments and validation of a streamlined method of histone-based fluorescence lifetime imaging microscopy (FLIM) that robustly detects chromatin compaction states in fixed and live cells, in 2D and 3D. We present a quality-controlled and detailed method that is simpler and faster than previous methods, and uses FLIMfit open-source software. We demonstrate the versatility of this chromatin FLIM through its combination with immunofluorescence and implementation in immortalised and primary cells. We applied this method to investigate the regulation of chromatin organisation after genotoxic stress and provide new insights into the role of ATM in controlling chromatin structure independently of DNA damage. Collectively, we present an adaptable chromatin FLIM method for examining chromatin structure and establish its utility in mammalian cells.

PURPOSE:Preliminary assessment of a new prototype ultrasound-based hypersonic vitrector (HV) by qualitatively examining the histopathological changes in the retina and vitreous body after pars plana vitrectomy (PPV) and its ability to fragment vitreous collagen. METHODS:Fourteen porcine cadaveric eyes, 20 eyes in live swine and six human cadaveric eyes underwent PPV using the HV or a pneumatic guillotine vitrector (GV). An additional 4 porcine crystalline lenses were touched with either the HV or GV for 1 minute. Following PPV, human vitreous was removed and processed for electron microscopy (EM). Eyes and lenses were fixed and sectioned for light microscopy (LM). RESULTS:There were no macroscopic retinal or optic nerve defects associated with either HV or GV PPVs. Cadaveric retinal specimens showed separation of the inner limiting membrane (ILM) and vacuolization and fragmentation at the nerve fiber layer (NFL) and the ganglion cell layer (GCL). ILM fragmentation and separation were found after PPV in live swine with both vitrectors. Small disruptions of the posterior capsule or structural lens defects were found after HV touch. The EM analysis revealed more fragmentation of human vitreous collagen fibrils after HV compared to GV PPV. CONCLUSIONS:LM and EM analysis of retina, vitreous, and crystalline lens after PPV showed similar morphological changes using the HV or the GV. Vitreous fragmentation appeared more effective with the HV. Overall this study suggests that the HV may be a promising new technology. More work is needed to quantitatively assess its safety and efficacy.

Cet article prend son point de départ dans un poème de Goethe, « Les poèmes sont des vitraux », où la visite d’une église sert comme paradigme de l’expérience esthétique, pour se demander dans quelle mesure on peut comprendre Le Livre Rouge de C. G. Jung du point de vue d’une « cathédrale » pour « les lieux silencieux de l’esprit » (comme Jung le dit dans une conversation avec Christiana Morgan du 12 juillet 1926). Par ailleurs, la conférence de Jung intitulée « À propos de la compréhension psychologique des processus pathologiques » (1914) offre une clé pour résoudre le problème herméneutique qu’est Le Livre Rouge, parce que Jung y mène une enquête sur les relations entre l’art et la nature, entre l’art et la science et entre l’art et la vie. En fin de compte les considérations de Jung sur son Livre Rouge dans Ma vie : Souvenirs, rêves et pensées (1961) posent la question suivante : qu’est-ce que « la fidélité aux obligations intellectuelles et éthiques »? Si on les considère de manière appropriée, il n’y a pas de contradiction entre l’éthique et l’esthétique, car si le monde est justifié comme un phénomène esthétique, si l’on considère sa vie dans sa dimension symbolique et si l’on comprend sa vie comme une œuvre d’art, alors l’éthique est bel et bien l’esthétique.

An elderly patient, with a history of depression with psychosis, presented with breathlessness, a right exudative pleural effusion and a peripheral eosinophilia. The pleural fluid was eosinophil-rich (10% of leucocytes). Olanzapine therapy had been commenced 12 months previously. There was a family history of TB and the patient was of African origin. A full diagnostic work-up ensued including computed tomography of the thorax and local anaesthetic thoracoscopy. The pleura was unremarkable on CT and displayed bland smooth thickening at visual inspection during thoracoscopy. Pleural biopsies demonstrated chronic inflammation with eosinophils but no evidence of granulomatous inflammation or malignancy. Pleural tissue culture did not yield mycobacteria. A diagnosis of olanzapine-induced eosinophilic pleuritis was suspected and the pleural disease resolved with withdrawal of olanzapine. Eosinophilic pleural fluid is not a marker of non-malignant aetiology and eosinophilic pleural effusions require a careful and systematic diagnostic work-up. This is the second case report to identify olanzapine as a causative agent in eosinophilic pleural effusion.

Cet article prend son point de départ dans un poème de Goethe, « Les poèmes sont des vitraux », où la visite d’une église sert comme paradigme de l’expérience esthétique, pour se demander dans quelle mesure on peut comprendre Le Livre Rouge de C. G. Jung du point de vue d’une « cathédrale » pour « les lieux silencieux de l’esprit » (comme Jung le dit dans une conversation avec Christiana Morgan du 12 juillet 1926). Par ailleurs, la conférence de Jung intitulée « À propos de la compréhension psychologique des processus pathologiques » (1914) offre une clé pour résoudre le problème herméneutique qu’est Le Livre Rouge, parce que Jung y mène une enquête sur les relations entre l’art et la nature, entre l’art et la science et entre l’art et la vie. En fin de compte les considérations de Jung sur son Livre Rouge dans Ma vie : Souvenirs, rêves et pensées (1961) posent la question suivante : qu’est-ce que « la fidélité aux obligations intellectuelles et éthiques » ? Si on les considère de manière appropriée, il n’y a pas de contradiction entre l’éthique et l’esthétique, car si le monde est justifié comme un phénomène esthétique, si l’on considère sa vie dans sa dimension symbolique et si l’on comprend sa vie comme une œuvre d’art, alors l’éthique est bel et bien l’esthétique.

Background: The hierarchical use of remotely-sensed imagery from satellites, and then proximally-sensed imagery from helicopter sand drones, can provide a range of spatial and temporal coverage that supports water quality monitoring of complex pollution scenarios. Methods: The study used hierarchical satellite-, helicopter-, and drone-acquired thermal imagery of coastal plumes ranging from 3 to 300 m, near Naples, Italy, and captured temporally- and spatially-overlapping in situ samples to correlate thermal and water quality parameters in each plume and the seawater. Results: In situ sampling determined that between-plume salinity varied by 37%, chlorophyll-a varied by 356%, dissolved oxygen varied by 81%, and turbidity varied by 232%. The radiometric temperature, Trad, for the plume area of interest had a correlation of 0.81 with salinity, 0.74 with chlorophyll-a, 0.98 with dissolved oxygen, and −0.61 with turbidity. Conclusion: This study established hierarchical use of remote and proximal thermal imagery can provide monitoring of complex coastal areas.

CD317/tetherin (aka BST2 or HM1.24 antigen) is an interferon inducible membrane protein present in regions of the lipid bilayer enriched in sphingolipids and cholesterol (often termed lipid rafts). It has been implicated in an eclectic mix of cellular processes including, most notably, the retention of fully formed viral particles at the surface of cells infected with HIV and other enveloped viruses. Expression of the HIV viral accessory protein Vpu has been shown to lead to intracellular sequestration and degradation of tetherin, thereby counteracting the inhibition of viral release. There is evidence that tetherin interacts directly with Vpu, but it remains unclear where in the cell this interaction occurs or if Vpu expression affects the lipid raft localisation of tetherin. We have addressed these points using biochemical and cell imaging approaches focused on endogenous rather than ectopically over-expressed tetherin. We find i) no evidence for an interaction between Vpu and endogenous tetherin at the cell surface, ii) the vast majority of endogenous tetherin that is at the cell surface in control cells is in lipid rafts, iii) internalised tetherin is present in non-raft fractions, iv) expression of Vpu in cells expressing endogenous tetherin leads to the loss of tetherin from lipid rafts, v) internalised tetherin enters early endosomes, and late endosomes, in both control cells and cells expressing Vpu, but the proportion of tetherin molecules destined for degradation rather than recycling is increased in cells expressing Vpu vi) lysosomes are the primary site for degradation of endogenous tetherin in cells expressing Vpu. Our studies underlie the importance of studying endogenous tetherin and let us propose a model in which Vpu intercepts newly internalised tetherin and diverts it for lysosomal destruction rather than recycling to the cell surface.

Chronic pulmonary aspergillosis is a progressive debilitating disease with multiple underlying pulmonary diseases described. Here we report the association of chronic pulmonary aspergillosis and long term marijuana smoking in 2 patients and review the literature related to invasive and allergic aspergillosis