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We consider the relationship between time in bed (TIB) and sleeping difficulties with demographic variables and nutrient intakes in the second (T2) and third (T3) trimester of pregnancy. Data were acquired from a volunteer sample of New Zealand pregnant women. In T2 and T3, questionnaires were administered, diets were obtained from one 24 h recall and three weighed food records, and physical activity was measured with the use of three 24 h diaries. In total, 370 women had complete information in T2 and 310 in T3. In both trimesters, TIB was associated with welfare or disability status, marital status and age. In T2, TIB was associated with work, childcare, education and pre-pregnancy alcohol consumption. There were fewer significant lifestyle covariates in T3. In both trimesters, TIB declined with increasing dietary intake, especially water, protein, biotin, potassium, magnesium, calcium, phosphorus and manganese. Adjusted for weight of dietary intake and welfare/disability, TIB declined with increasing nutrient density of B vitamins, saturated fats, potassium, fructose and lactose; and TIB increased with carbohydrate, sucrose and vitamin E. Subjective sleeping difficulties increased with the week of gestation, morning sickness severity, anxiety, dairy and saturated fat intake, and they decreased with fruit, vegetable and monounsaturated fat intake. The study highlights the changing influence of covariates throughout the pregnancy and corroborates several published findings on the relationship of diet and sleep.

Introduction: Low-grade neuroepithelial tumors are a heterogeneous group of central nervous system tumors that are generally indolent in nature but in rare instances can progress to include leptomeningeal dissemination. Case Presentation: We present a case of a patient with a low-grade neuroepithelial tumor of indeterminate type with symptomatic leptomeningeal dissemination despite 3 chemotherapy regimens and radiotherapy. Somatic targetable mutation testing showed an FGFR1_TACC1 fusion. Therapy with pazopanib/topotecan was initiated, and disease stabilization was achieved. He received pazopanib/topotecan for a total of 2 years and is now >2 years from completion of treatment and continues to do well with no evidence of disease. Discussion: This case highlights the utility of targetable mutation testing in therapeutic decision-making and the novel use of systemic pazopanib/topotecan therapy for refractory low-grade neuroepithelial tumor within the context of this clinical situation and specific mutation profile.

The partial spatial separation of cold dark matter (DM) and gas is a ubiquitous feature in the formation of cosmic large-scale structure. This separation, termed dissociation, is prominent in galaxy clusters that formed through collisions of massive progenitors, such as the famous `Bullet' cluster. A direct comparison of the incidence of such dissociated structures with theoretical predictions is challenged by the rarity of strongly dissociated systems and the difficulty to quantify dissociation. This paper introduces a well-defined dimensionless dissociation index $S\in[-1,1]$ that encodes the quadrupole difference between DM and gas in a custom region. Using a simulation of cosmic large-scale structure with cold DM and ideal non-radiating gas, in $Λ$CDM cosmology, we find that 90 per cent of the haloes are positively dissociated ($S>0$), meaning their DM is more elongated than their gas. The spatial density of highly dissociated massive structures appears consistent with observations. Through idealised $N$-body+SPH simulations of colliding gaseous DM haloes, we further explore the details of how ram-pressure causes dissociation in binary collisions. A suite of 300 such simulations reveals a scale-free relation between the orbital parameters of binary collisions and the resulting dissociation. Building on this relation, we conclude that the frequency of dissociated structures in non-radiative cosmological simulations is nearly fully accounted for by the major (mass ratio $>1:10$) binary collisions predicted by such simulations. In principle, our results allow us to constrain the orbital parameters that produced specific observed dissociated clusters., 20 pages, 24 figures. This is a pre-copyedited, author-produced PDF of an article accepted for publication in Monthly Notices of the Royal Astronomical Society (MNRAS) following peer review

Summary Background Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. Methods We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. Findings Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p Interpretation [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. Funding Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

Species radiations have long fascinated biologists, but the contribution of adaptation to observed diversity and speciation is still an open question. Here, we explore this question using the clove genus, Syzygium, the world’s largest genus of tree species comprising approximately 1200 species. We dissect Syzygium diversity through shotgun sequencing of 182 distinct species and 58 additional as-yet unidentified taxa, and assess their genetic diversity against a chromosome-level reference genome of the sea apple, Syzygium grande. We show that Syzygium grande shares a whole genome duplication (WGD) event with other Myrtales. Genomic analyses confirm that Syzygium originated in Sahul (Australia-New Guinea), and later diversified eastward to the Hawaiian Islands and westward in multiple independent migration events. The migrations were associated with bursts of speciation events, visible by poorly resolved branches on phylogenies and networks, some of which were likely confounded by incomplete lineage sorting. Clinal genomic variation in some sublineages follows phylogenetic progression, which coupled with sympatric occurrences of distantly related species suggests that both geographic and ecological speciation have been important in the diversification of Syzygium. Together, these results point to a mixture of both neutral and adaptive drivers having contributed to the radiation of the genus.

This paper motivates the idea that social robots should be credited as moral patients, building on an argumentative approach that combines virtue ethics and social recognition theory. Our proposal answers the call for a nuanced ethical evaluation of human-robot interaction that does justice to both the robustness of the social responses solicited in humans by robots and the fact that robots are designed to be used as instruments. On the one hand, we acknowledge that the instrumental nature of robots and their unsophisticated social capabilities prevent any attribution of rights to robots, which are devoid of intrinsic moral dignity and personal status. On the other hand, we argue that another form of moral consideration—not based on rights attribution—can and must be granted to robots. The reason is that relationships with robots offer to the human agents important opportunities to cultivate both vices and virtues, like social interaction with other human beings. Our argument appeals to social recognition to explain why social robots, unlike other technological artifacts, are capable of establishing with their human users quasi-social relationships as pseudo-persons. This recognition dynamic justifies seeing robots as worthy of moral consideration from a virtue ethical standpoint as it predicts the pre-reflective formation of persistent affective dispositions and behavioral habits that are capable of corrupting the human user’s character. We conclude by drawing attention to a potential paradox drawn forth by our analysis and by examining the main conceptual conundrums that our approach has to face.

Although cardiac myxomas have been known to cause acute ischemic stroke and other cerebrovascular complications, intracranial embolization of metastatic tumor fragments is rare. This is likely because venous emboli generally cause pulmonary embolism. Pulmonary vein metastases and patent foramen ovales have previously shown to propagate intracranial embolic carcinomas, but these events are very uncommon, and are not well characterized. We report a rare case of large-cell, high-grade neuroendocrine lung cancer embolus occluding the basilar artery, which likely detached into the bloodstream from the lung after intruding into a pulmonary vein. The embolus was treated with endovascular aspiration, and achieved modified Thrombolysis In Cerebral Infarction 2c revascularization. After initial neurological recovery, the patient suffered respiratory arrest and support was withdrawn 48 h later. We discuss the tumor characteristics and implications for treatment of acute ischemic stroke in patients with cancer diagnoses.

Since the addition of robotic technology to the minimally invasive surgery armamentarium, its utilization has greatly increased. This has been applied mostly in reconstructive surgeries and complex oncologic cases where difficult dissection and suturing are required. However, when it comes to extirpative procedures, there is still resistance to the utilization of this new approach because of the high costs involved and unclear benefits compared with the standard laparoscopic technique. The aim of this chapter is to review the contemporary literature on robotic adrenal surgery and describe the surgical technique and its most important variations.

Context.— We previously examined pituitary adenomas with immunohistochemical (IHC) stains for steroidogenic factor 1, Pit-1, anterior pituitary hormones, cytokeratin CAM 5.2, and the α-subunit of human chorionic gonadotropin and found that a screening panel comprising stains for steroidogenic factor 1, Pit-1, and adrenocorticotropic hormone successfully classified most cases and reduced the overall number of stains required. Objectives.— To examine the potential role of IHC stain for T-box transcription factor (Tpit) in the classification of our series of pituitary adenomas and to update our screening panel as necessary. Design.— We collected 157 pituitary adenomas from 2 institutions and included these in tissue microarrays. Immunostains for Tpit were scored in a blinded fashion using the Allred system. Adenomas were assigned to a gold standard class based on IHC pattern followed by application of available clinical and serologic information. Test characteristics were calculated. Correlation analyses, cluster analyses, and classification tree analyses were used to see whether IHC staining patterns reliably reflected adenoma class. Results.— Of the cases collected, 147 (93.6%) had sufficient material for Tpit analysis. IHC stain for Tpit identified 8 null cell adenomas (all nonfunctioning clinically) as silent corticotrophs; Tpit stains showed better sensitivity, specificity, positive predictive value, and negative predictive value than IHC for adrenocorticotropic hormone and cytokeratin CAM 5.2. Correlation analyses continued to show the expected relationships among IHC stains. Cluster analyses showed grouping of adenomas into clinically consistent groups. Classification tree analysis underscored the central role of transcription factor IHC stains, including Tpit, in adenoma classification. Conclusions.— Substitution of Tpit stain for the adrenocorticotropic hormone stain improves our prior algorithm by reducing the number of false-negatives and false-positives. As a result, fewer adenomas are classified as null cell adenoma, and more adenomas are classified as silent corticotroph adenoma.

Renal masses are diagnosed with an increasing incidence recently, especially as an incidental finding, due to the high frequency of imaging investigations being performed. Options of management for those situations are multiple, ranging from active surveillance (AS), ablation techniques, to partial or radical nephrectomies. Currently, most renal masses are managed based on imaging evaluation only. There are many shortcomings to this approach, due to limitations of radiologic techniques. This is especially true on specific masses where it can be difficult to differentiate benign from malignant features. Percutaneous renal mass biopsies (RMBs) may be of extreme value and can produce a tremendous impact on management of renal masses, providing a more accurate diagnosis and guiding management discussion with patients, as well as potentially avoiding unnecessary procedures and their associated morbidity. Contrary to initial studies and misconceptions, RMB has shown to have low morbidity, minimal risks, and excellent accuracy. The indications for RMB are increasing, and this approach may become the standard of care in the near future.

We report a novel case of a radiation-induced cavernous malformation developing in a vestibular schwannoma previously treated with stereotactic radiosurgery. Eleven years after treatment, the patient presented with a large predominantly cystic lesion in the cerebellopontine angle. We performed surgery, and a solid vascular lesion was identified within the schwannoma, which was determined to be a cavernous malformation after histopathological analysis. We review the literature of radiation-induced cavernous lesions, illustrating that while rare, these lesions do pose concern as a long-term complication of brain radiation therapy. We also discuss the possibility that radiation-induced cavernous malformation-like lesions are pathologically distinct from cavernous malformations.

Background Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a very rare tumor with fewer than 70 cases reported in the literature. In general, this tumor occurs intracranially either within the brain parenchyma or in an extra-axial location, but it has also been described within the spine as an extra-axial lesion. Case Description We describe an unusual case of intracranial-extradural CAPNON involving the mastoid region. This may be only the second such case reported in the literature, as one patient with CAPNON has been reported involving the sinonasal region. Our patient was managed with surgical resection through a translabyrinthine approach with good early result. Conclusions We describe an unusual case of extradural CAPNON involving the mastoid bone. It appears that when located extradurally, this tumor may have a predilection for the bony sinuses. This little-known, generally benign entity can mimic more common lesions such as meningiomas, and should be considered in the differential diagnosis of skull base tumors, particularly when associated with heavy calcification.

Knowledge of the role of conserved residues in the ligand channel of heme-copper oxidases is critical for understanding how the protein scaffold modulates the function of these enzymes. In this study, we investigated the role of the conserved valine 236 in the ligand channel of ba3 cytochrome c oxidase from Thermus thermophilus by mutating the residue to a more polar (V236T), smaller (V236A), or larger (V236I, V236N, V236L, V236M, and V236F) residue. The crystal structures of the mutants were determined, and the effects of the mutations on the rates of CO, O2, and NO binding were investigated. O2 reduction and NO binding were unaffected in V236T, while the oxidation of heme b during O–O bond cleavage was not detected in V236A. The V236A results are attributed to a decrease in the rate of electron transfer between heme b and heme a3 during O–O bond cleavage in V236A, followed by faster re-reduction of heme b by CuA. This interpretation is supported by classical molecular dynamics simulations of diffusion o...

Much of the recent psychological literature on boredom aims to define, categorize, and measure boredom in order to assess it, to identify correlated mental pathologies, to find the psychophysiological bases of boredom, or to apply the findings to specific settings or social groups. This literature uses both quantitative and qualitative methods to seek an objective, scientific understanding of boredom. It presupposes that boredom is an aversive, individual experience, which psychology can help ameliorate, prevent, or divert. By contrast, Kierkegaard uses his methods of ‘experimenting psychology’ and ‘indirect communication’ to deploy boredom in awakening his reader to the task of becoming a self. He uses literary devices and exemplary characters to this end. Heidegger pursues a similar aim: to awaken the reader/listener to the possibility of attuning herself to profound boredom in a way that will enable her to become an authentic self (Dasein). Heidegger uses a method of historical, hermeneutic phenomenology to enable his reader to hear the call of being through an attunement to profound boredom. He starts with the familiar experience of boredom, then defamiliarizes his listener to enable an original grasp of the meaning of being.

Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are benign glioneuronal tumors that typically occur in infants, involve the superficial cerebral cortex, and have an excellent prognosis. DIA/DIG are a distinct molecular entity based on DNA methylation profiling. BRAF600 mutations are frequently reported in DIG/DIA. A recent comprehensive genetic analysis of infantile hemispheric gliomas identified 2 unique groups: group 1 harbored alterations in the receptor tyrosine kinase (RTK) genes ALK, ROS1, NTRK, and MET and group 2 harbored alterations in the RAS/MAPK pathway. We report a case of a 6.5-year-old girl who presented with seizures and right homonymous hemianopia. MRI of her brain demonstrated a large cystic/solid left hemispheric mass with remodelling of the overlying skull, consistent with a long-standing process. She underwent a gross total resection (GTR) and pathology demonstrated a DIG with a PPP1CB-ALK gene fusion (exon 5 to exon 20) identified by RNA sequencing. She remains disease free 12 months following GTR. A literature review identified 4 reported cases of pediatric brain tumors with PPP1CB-ALK gene fusions including: a 3-month-old with a hemispheric high-grade glioma which recurred 4 years later and pathology showed mature ganglioglioma, with both tumors showing the identical PPP1CB-ALK gene fusion; a 10-month-old infant with a hemispheric low-grade glioma; an infant with a “congenital” hemispheric high-grade glioma; and a child with an astrocytoma with no further clinical data. PPP1CB-ALK gene fusion appears to be a rare oncogenic driver in gliomas of infancy, including DIG.

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant CNS neoplasms that typically occur in children

Introduction: Unnecessary use of lights and sirens during transport of noncritical patients is a major cause of vehicle crashes contributing to injury and death among emergency medical technicians (EMTs), patients and bystanders. This study examines whether EMT stress levels and ambulance transport times differ as a function of using lights and sirens, and whether EMTs support policies for their use. Methods: Data for this quasi-experimental quantitative study was collected from 80 New Jersey EMTs using the Depression Anxiety Stress Scale. Results were assessed for ambulance transport times for noncritical patients and EMT stress levels, both with and without the use of lights and sirens. Data were analyzed using the t test and regression procedures. Results: Analysis shows no statistically significant difference in transport times with lights and sirens in use compared to when they were not used. Findings are statistically significant in the undue and increased stress level of the EMTs when lights and sirens are used. Participants demonstrated support for a policy for their use. Conclusion: Findings suggest that the use of lights and sirens in transporting noncritical patients is unnecessary. Practical applications: Recommendations include the development of a state Emergency Medical Services policy to provide guidelines on the use of lights and sirens, or a system that allows for the objective evaluation of whether the situation warrants the use of lights and sirens. The implications for positive social change include savings of money, property and, most importantly, human lives.

This article explores the challenges and practices of citizenship engagement in sustainability policymaking in the local governments worldwide. The analysis focuses on 52 case studies from the ICLEI-local governments [1] for sustainability database. Cases document successful sustainability experiences from 48 urban communities in 20 different countries. The article offers a broader-than-national overview of existing public administration practices to advance our understanding of how they evolve in response to the global environmental challenges. The analysis concludes that successful sustainability policies may take place disregarding the size or geographical location of the urban community, which is consistent with previous literature on the topic. Moreover, the study explores in detail cases with the strongest citizen engagement and suggests that bottom-up public participation is particularly strong when citizens have to deal with a specific problem. The strongest government-led frameworks of support for citizen engagement have been found in the medium-size European cities.

Cytochrome bo3 ubiquinol oxidase from Escherichia coli catalyzes the reduction of O2 to water by ubiquinol. The reaction mechanism and the role of ubiquinol continue to be a subject of discussion. In this study, we report a detailed kinetic scheme of the reaction of cytochrome bo3 with O2 with steps specific to ubiquinol. The reaction was investigated using the CO flow-flash method, and time-resolved optical absorption difference spectra were collected from 1 μs to 20 ms after photolysis. Singular value decomposition-based global exponential fitting resolved five apparent lifetimes, 22 μs, 30 μs, 42 μs, 470 μs, and 2.0 ms. The reaction mechanism was derived by an algebraic kinetic analysis method using frequency-shifted spectra of known bovine states to identify the bo3 intermediates. It shows 42 μs O2 binding (3.8 × 107 M–1 s–1), producing compound A, followed by faster (22 μs) heme b oxidation, yielding a mixture of PR and F, and rapid heme b rereduction by ubiquinol (30 μs), producing the F intermediat...

Oligodendrogliomas are an important adult form of diffuse gliomas with a distinctive clinical and genetic profile. Histologically similar tumors occurring rarely in children are incompletely characterized. We studied 50 patients with oligodendrogliomas (median age at diagnosis 8 y, range 7 mo to 20 y). Tumors resembling dysembryoplastic neuroepithelial tumors or pilocytic astrocytomas or those having a "mixed" histology were excluded. Tumors at first diagnosis were low grade (n=38) or anaplastic (n=12). Histologic features included uniform round cells with perinuclear halos (100%), secondary structures (predominantly perineuronal satellitosis) (90%), calcifications (46%), and microcysts (44%). Sequential surgical specimens were obtained in 8 low-grade oligodendroglioma patients, with only 1 progressing to anaplasia. Studies for 1p19q performed in 40 cases demonstrated intact 1p19q loci in 29 (73%), 1p19q codeletion in 10 (25%), and 1p deletion with intact 19q in 1 (2%). Except for 2 young patients (3 and 11 y of age), patients with 1p19q codeletion were older than 16 years at diagnosis. Mutant IDH1 (R132H) protein immunohistochemistry was positive in 4 (of 22) (18%) cases, 3 of which also had 1p19q codeletion, whereas 1p19q status was not available on the fourth case. There was a nonsignificant trend for worse overall survival in grade III tumors, but no significant association with age, extent of resection, or 1p19q status. In summary, oligodendrogliomas with classic histology occur in the pediatric population but lack 1p19q codeletion and IDH1 (R132H) mutations in most instances. They are predominantly low grade, recur/clinically progress in a subset, but demonstrate a relatively low frequency of histologic progression.

Protein Tyrosine kinase 6 (PTK6/BRK) is overexpressed in the majority of human breast tumors and breast tumor cell lines. It is also expressed in normal epithelial linings of the gastrointestinal tract, skin, and prostate. To date, expression of PTK6 has not been extensively examined in the normal human mammary gland. We detected PTK6 mRNA and protein expression in the immortalized normal MCF-10A human mammary gland epithelial cell line, and examined PTK6 expression and activation in a normal human breast tissue microarray, as well as in human breast tumors. Phosphorylation of tyrosine residue 342 in the PTK6 activation loop corresponds with its activation. Similar to findings in the prostate, we detect nuclear and cytoplasmic PTK6 in normal mammary gland epithelial cells, but no phosphorylation of tyrosine residue 342. However, in human breast tumors, striking PTK6 expression and phosphorylation of tyrosine 342 is observed at the plasma membrane. PTK6 is expressed in the normal human mammary gland, but does not appear to be active and may have kinase-independent functions that are distinct from its cancer promoting activities at the membrane. Understanding consequences of PTK6 activation at the plasma membrane may have implications for developing novel targeted therapies against this kinase.

Knowledge of the role of conserved residues in the ligand channel of heme-copper oxidases is critical for understanding how the protein scaffold modulates the function of these enzymes. In this study, we investigated the role of the conserved valine 236 in the ligand channel of ba