This review describes the oculo-visual problems likely to be encountered in Parkinson's disease (PD) with special reference to three questions: (1) are there visual symptoms characteristic of the ...prodromal phase of PD, (2) is PD dementia associated with specific visual changes, and (3) can visual symptoms help in the differential diagnosis of the parkinsonian syndromes, viz. PD, progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD)? Oculo-visual dysfunction in PD can involve visual acuity, dynamic contrast sensitivity, colour discrimination, pupil reactivity, eye movement, motion perception, and visual processing speeds. In addition, disturbance of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations may be present. Prodromal features of PD may include autonomic system dysfunction potentially affecting pupil reactivity, abnormal colour vision, abnormal stereopsis associated with postural instability, defects in smooth pursuit eye movements, and deficits in visuo-motor adaptation, especially when accompanied by idiopathic rapid eye movement (REM) sleep behaviour disorder. PD dementia is associated with the exacerbation of many oculo-visual problems but those involving eye movements, visuo-spatial function, and visual hallucinations are most characteristic. Useful diagnostic features in differentiating the parkinsonian symptoms are the presence of visual hallucinations, visuo-spatial problems, and variation in saccadic eye movement dysfunction.
During imbibition, initially connected oil is displaced until it is trapped as immobile clusters. While initial and final states have been well described before, here we image the dynamic transient ...process in a sandstone rock using fast synchrotron‐based X‐ray computed microtomography. Wetting film swelling and subsequent snap off, at unusually high saturation, decreases nonwetting phase connectivity, which leads to nonwetting phase fragmentation into mobile ganglia, i.e., ganglion dynamics regime. We find that in addition to pressure‐driven connected pathway flow, mass transfer in the oil phase also occurs by a sequence of correlated breakup and coalescence processes. For example, meniscus oscillations caused by snap‐off events trigger coalescence of adjacent clusters. The ganglion dynamics occurs at the length scale of oil clusters and thus represents an intermediate flow regime between pore and Darcy scale that is so far dismissed in most upscaling attempts.
Key Points
Ganglion dynamics contributes to nonwetting phase transport
Coalescence of nonwetting phase clusters is triggered by snap off
Ganglion dynamics occurs from 75% nonwetting phase saturation on
Abstract
The Protein Data Bank in Europe (PDBe), a founding member of the Worldwide Protein Data Bank (wwPDB), actively participates in the deposition, curation, validation, archiving and ...dissemination of macromolecular structure data. PDBe supports diverse research communities in their use of macromolecular structures by enriching the PDB data and by providing advanced tools and services for effective data access, visualization and analysis. This paper details the enrichment of data at PDBe, including mapping of RNA structures to Rfam, and identification of molecules that act as cofactors. PDBe has developed an advanced search facility with ∼100 data categories and sequence searches. New features have been included in the LiteMol viewer at PDBe, with updated visualization of carbohydrates and nucleic acids. Small molecules are now mapped more extensively to external databases and their visual representation has been enhanced. These advances help users to more easily find and interpret macromolecular structure data in order to solve scientific problems.
Families in high mortality settings need regular contact with high quality services, but existing population-based measurements of contacts do not reflect quality. To address this, in 2012, we ...designed linked household and frontline worker surveys for Gombe State, Nigeria, Ethiopia, and Uttar Pradesh, India. Using reported frequency and content of contacts, we present a method for estimating the population level coverage of high quality contacts.
Linked cluster-based household and frontline health worker surveys were performed. Interviews were conducted in 40, 80 and 80 clusters in Gombe, Ethiopia, and Uttar Pradesh, respectively, including 348, 533, and 604 eligible women and 20, 76, and 55 skilled birth attendants. High quality contacts were defined as contacts during which recommended set of processes for routine health care were met. In Gombe, 61% (95% confidence interval 50-72) of women had at least one antenatal contact, 22% (14-29) delivered with a skilled birth attendant, 7% (4-9) had a post-partum check and 4% (2-8) of newborns had a post-natal check. Coverage of high quality contacts was reduced to 11% (6-16), 8% (5-11), 0%, and 0% respectively. In Ethiopia, 56% (49-63) had at least one antenatal contact, 15% (11-22) delivered with a skilled birth attendant, 3% (2-6) had a post-partum check and 4% (2-6) of newborns had a post-natal check. Coverage of high quality contacts was 4% (2-6), 4% (2-6), 0%, and 0%, respectively. In Uttar Pradesh 74% (69-79) had at least one antenatal contact, 76% (71-80) delivered with a skilled birth attendant, 54% (48-59) had a post-partum check and 19% (15-23) of newborns had a post-natal check. Coverage of high quality contacts was 6% (4-8), 4% (2-6), 0%, and 0% respectively.
Measuring content of care to reflect the quality of contacts can reveal missed opportunities to deliver best possible health care.
The potato late blight pathogen Phytophthora infestans secretes an array of effector proteins thought to act in its hosts by disarming defences and promoting pathogen colonisation. However, little is ...known about the host targets of these effectors and how they are manipulated by the pathogen. This work describes the identification of two putative membrane-associated NAC transcription factors (TF) as the host targets of the RxLR effector PITG_03192 (Pi03192). The effector interacts with NAC Targeted by Phytophthora (NTP) 1 and NTP2 at the endoplasmic reticulum (ER) membrane, where these proteins are localised. Transcripts of NTP1 and NTP2 rapidly accumulate following treatment with culture filtrate (CF) from in vitro grown P. infestans, which acts as a mixture of Phytophthora PAMPs and elicitors, but significantly decrease during P. infestans infection, indicating that pathogen activity may prevent their up-regulation. Silencing of NTP1 or NTP2 in the model host plant Nicotiana benthamiana increases susceptibility to P. infestans, whereas silencing of Pi03192 in P. infestans reduces pathogenicity. Transient expression of Pi03192 in planta restores pathogenicity of the Pi03192-silenced line. Moreover, colonisation by the Pi03192-silenced line is significantly enhanced on N. benthamiana plants in which either NTP1 or NTP2 have been silenced. StNTP1 and StNTP2 proteins are released from the ER membrane following treatment with P. infestans CF and accumulate in the nucleus, after which they are rapidly turned over by the 26S proteasome. In contrast, treatment with the defined PAMP flg22 fails to up-regulate NTP1 and NTP2, or promote re-localisation of their protein products to the nucleus, indicating that these events follow perception of a component of CF that appears to be independent of the FLS2/flg22 pathway. Importantly, Pi03192 prevents CF-triggered re-localisation of StNTP1 and StNTP2 from the ER into the nucleus, revealing a novel effector mode-of-action to promote disease progression.
Summary
Randomised controlled trials are the gold standard in clinical research, but remain rare due to their expense and a perceived lack of ‘real‐world’ applicability. At the same time, there has ...been an exponential increase in routinely collected data which presents opportunities for audit, quality improvement, adverse event reporting and more efficient clinical research. Registry‐based research benefits from reduced cost, large sample size and real‐world applicability, with methodological developments, particularly registry‐based randomised controlled trials and causal inference techniques, showing promise. Limitations include data quality and validity, the need for data linkage, the restrictions of fixed data fields, regulatory barriers, and privacy and security concerns. However, the principal factor hampering current efforts is a lack of anaesthesia‐specific datasets in the UK and the fact that most surgical registries do not collect any anaesthetic data. This presents an opportunity for anaesthetists, through enhanced engagement and collaboration, to influence and improve the design of these datasets and increase the value and volume of data collected. Better datasets, coupled with a growing appreciation of new analysis methodologies, would allow significant progress towards realising the potential of routinely collected data for patient benefit. At the same time, work should begin on the development of a minimum dataset for anaesthesia to underpin new data sharing networks and, ideally, a national registry of anaesthesia.
We argue that the production of mantle-derived or juvenile continental crust during the accretionary history of the Central Asian Orogenic Belt (CAOB) has been grossly overestimated. This is because ...previous assessments only considered the Palaeozoic evolution of the belt, whereas its accretionary history already began in the latest Mesoproterozoic. Furthermore, much of the juvenile growth in Central Asia occurred in late Permian and Mesozoic times, after completion of CAOB evolution, and perhaps related to major plume activity. We demonstrate from zircon ages and Nd–Hf isotopic systematics from selected terranes within the CAOB that many Neoproterozoic to Palaeozoic granitoids in the accreted terranes of the belt are derived from melting of heterogeneous Precambrian crust or through mixing of old continental crust with juvenile or short-lived material, most likely in continental arc settings. At the same time, juvenile growth in the CAOB occurred during the latest Neoproterozoic to Palaeozoic in oceanic island arc settings and during accretion of oceanic, island arc, and Precambrian terranes. However, taking together, our data do not support unusually high crust-production rates during evolution of the CAOB. Significant variations in zircon εHf values at a given magmatic age suggest that granitoid magmas were assembled from small batches of melt that seem to mirror the isotopic characteristics of compositionally and chronologically heterogeneous crustal sources. We reiterate that the chemical characteristics of crustally-derived granitoids are inherited from their source(s) and cannot be used to reconstruct tectonic settings, and thus many tectonic models solely based on chemical data may need re-evaluation. Crustal evolution in the CAOB involved both juvenile material and abundant reworking of older crust with varying proportions throughout its accretionary history, and we see many similarities with the evolution of the SW Pacific and the Tasmanides of eastern Australia.
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► Crustal growth in the Central Asian Orogenic Belt is not as high as previously estimated. ► Distinct areas in the CAOB show voluminous juvenile crust and others mostly reworked crust. ► A combination of Nd and Hf isotopes helps to understand crustal growth and reworking in Central Asia.
We aimed to systematically determine the impact of tumor burden on 68Ga-prostate-specific membrane antigen-11 (68Ga-PSMA) PET biodistribution by the use of quantitative measurements. Methods: This ...international multicenter, retrospective analysis included 406 men with prostate cancer who underwent 68Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into a very low (quintile 1, ≤25 cm3), low (quintile 2, 25–189 cm3), moderate (quintile 3, 189–532 cm3), high (quintile 4, 532–1,355 cm3), or very high (quintile 5, ≥1,355 cm3) total PSMA-positive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semiautomatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as a control group. Normal organs, which included salivary glands, liver, spleen, and kidneys, were semiautomatically segmented using 68Ga-PSMA PET images, and SUVmean was obtained. Correlations between the SUVmean of normal organs and PSMA-VOL as continuous and categoric variables by quintiles were evaluated. Results: The median PSMA-VOL was 302 cm3 (interquartile range IQR, 47–1,076 cm3). The median SUVmean of salivary glands, kidneys, liver, and spleen was 10.0 (IQR, 7.7–11.8), 26.0 (IQR, 20.0–33.4), 3.7 (IQR, 3.0–4.7), and 5.3 (IQR, 4.0–7.2), respectively. PSMA-VOL showed a moderate negative correlation with the SUVmean of the salivary glands (r = −0.44, P < 0.001), kidneys (r = −0.34, P < 0.001), and liver (r = −0.30, P < 0.001) and a weak negative correlation with the spleen SUVmean (r = −0.16, P = 0.002). Patients with a very high PSMA-VOL (quintile 5, ≥1,355 cm3) had a significantly lower PSMA uptake in the salivary glands, kidneys, liver, and spleen than did the control group, with an average difference of −38.1%, −40.0%, −43.2%, and −34.9%, respectively (P < 0.001). Conclusion: Tumor sequestration affects 68Ga-PSMA biodistribution in normal organs. Patients with a very high tumor load showed a significantly lower uptake of 68Ga-PSMA in normal organs, confirming a tumor sink effect. As similar effects might occur with PSMA-targeted radioligand therapy, these patients might benefit from increased therapeutic activity without exceeding the radiation dose limit for organs at risk.
In this work, the spatial (in)homogeneity of aqueous processed silicon electrodes using standard poly(acrylic acid)-based binders and slurry preparation conditions is demonstrated. X-ray ...nanotomography shows segregation of materials into submicron-thick layers depending on the mixing method and starting binder molecular weights. Using a dispersant, or in situ production of dispersant from the cleavage of the binder into smaller molecular weight species, increases the resulting lateral homogeneity while drastically decreasing the vertical homogeneity as a result of sedimentation and separation due to gravitational forces. This data explains some of the variability in the literature with respect to silicon electrode performance and demonstrates two potential ways to improve slurry-based electrode fabrications.
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