Childhood trauma and the enduring consequences of forcibly separating children from parents at the United States border.
Forcible separation and detention of children from parents seeking asylum in the United States has been decried as immoral and halted by court order. Babies and children have been separated and transported to facilities sometimes many miles away. Limited data on forced detention of unaccompanied minors reveal high incidence of posttraumatic stress, anxiety disorders, depression, aggression, and suicidal ideation. These consequences will be magnified in youths forcibly separated from their parents, particularly younger children who depend on attachment bonds for self-regulation and resilience. Studies exploring the neuropsychiatric consequences of traumatic stress have revealed consistent effects of early life stress on brain structure, function and connectivity, and the identification of sensitive periods, which occur throughout childhood when specific regions and pathways are strongly influenced by adversity. Studies of epigenetics, inflammation and allostatic load are similarly enhancing our awareness of the molecular mechanisms underpinning the long-term consequences of traumatic stress. We must consider effects on the developing brain, mind and body to appreciate the long-term consequences of policies that force separation and detention of children.


Epigenetic-based therapies in the preclinical and clinical treatment of Huntington's disease.
The study of epigenetics is providing novel insights about the functional and developmental complexity of the nervous system. In neuropathology, therapies aimed at correcting epigenetic dysregulation have been extensively documented in a large variety of models for neurodegenerative, neurodevelopmental and psychiatric disorders. Taking the treatment of Huntington's disease as a paradigm for the study of these ameliorative strategies, this review updates the main conclusions derived from the use of epigenetic drugs at the preclinical and clinical stages, including actions beyond epigenetics. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.


The development of a national approach to monitoring estuarine health based on multivariate analysis.
New Zealand has a complex coastal environment spanning a large latitudinal gradient and three water masses. Here we assess whether multivariate analyses of benthic macrofaunal community composition can be a sensitive approach to assessing relative estuarine health across the country, negating the need for regional indices and reducing reliance on reference sites. Community data were used in separate canonical analyses of principal coordinates to create multivariate models of community responses to gradients in mud content and heavy metal contamination. Both models performed well (R2 = 0.81, 0.71), and were unaffected by regional and estuarine typology differences. The models demonstrate a sensitive and standardized approach to assessing estuarine health that allowed separation of the two stressors. This approach could be applied to other stressors, countries or regions.


Morphological and molecular differentiation of two new species of Pseudoacanthocephalus Petrochenko, 1958 (Acanthocephala: Echinorhynchidae) from amphibians and reptiles in the Philippines, with identification key for the genus.
The genus Pseudoacanthocephalus Petrochenko, 1958 currently includes 14 species of acanthocephalans parasitic in amphibians and reptiles worldwide. This work describes two new species of Pseudoacanthocephalus from amphibians and reptiles collected in several localities on Luzon Island, Philippines. Pseudoacanthocephalus nickoli n. sp. was found in two species of frogs, Rana luzonensis Boulenger and Rana similis (Günther), and Pseudoacanthocephalus smalesi n. sp. was found in a scincid lizard, Sphenomorphus abdictus Brown & Alcala. Differential diagnoses of the two new species of Pseudoacanthocephalus from their congeners are provided. Comparative analysis of nuclear ribosomal rRNA sequences encompassing the 3' end of 18S nuclear rDNA gene, internal transcribed spacer region (ITS1+5.8S+ITS2), and 5' end of the 28S gene strongly corroborated the morphological evidence and demonstrated significant differences between the two new species as well as between these species and closely related species from continental China and Vietnam. No intraspecific sequence variability was detected among different individuals representing each of the examined species. This is the first report of Pseudoacanthocephalus in the Philippines. A key to known species of Pseudoacanthocephalus is provided.


CrkIII: a novel and biologically distinct member of the Crk family of adaptor proteins.
As the role for adaptor proteins constantly proliferates, appreciation of their importance has never been higher. The Crk family of adaptor proteins is no exception. Currently comprising four members, v-Crk, CrkI, CrkII and Crk-like protein, we have introduced a fifth member, CrkIII. Cloned by the CORT technique, CrkIII is identical in sequence to CrkII until the second of its two SH3 domains, which is disrupted partway through and results in a nonfunctional domain and a unique C-terminal sequence. We have demonstrated the existence of native CrkIII at the message level using RT-PCR and RNAse protection assays, and at the protein level in mouse fibroblasts. We show that CrkII overexpression is capable of enhancing insulin-stimulated ERK activity, whereas CrkIII is not, thus partially characterizing a novel member of the Crk family and elucidating important effects mediated by the c-terminal SH3 domain.


Sputum procalcitonin: a potential biomarker in stable bronchiectasis.
Sputum procalcitonin is elevated in exacerbations of bronchiectasis. The primary aim of this study was to investigate whether sputum procalcitonin levels are higher in patients with stable bronchiectasis than in healthy controls. We also assessed differences in procalcitonin levels in spontaneously expectorated and induced sputum samples and their repeatability 1 week later. Participants included were aged over 18 years and either had radiologically confirmed bronchiectasis or were healthy controls. Patients with bronchiectasis were clinically stable for at least 6 weeks and had spontaneous and induced sputum collected at visit 1 and again 7 days later. Only induced sputum samples were collected from healthy controls during visit 1. Sputum procalcitonin concentrations in sputum were measured. In total, 30 patients with bronchiectasis and 15 healthy controls were enrolled in this observational study. In the pooled data from visit 1 and 2, the geometric mean procalcitonin level in induced sputum was significantly higher in the bronchiectasis group than in the healthy control group (1.5 ng·mL-1, 95% CI 1.0-2.1 ng·mL-1 versus 0.4 ng·mL-1, 95% CI 0.2-0.9 ng·mL-1; mean ratio 3.6, 95% CI 1.5-8.6; p=0.006). Mean procalcitonin level was higher in spontaneous sputum than in induced sputum at visit 1 (1.8 ng·mL-1, 95% CI 1.2-2.7 ng·mL-1 versus 1.1 ng·mL-1, 95% CI 0.7-1.8 ng·mL-1) and visit 2 (1.5 ng·mL-1, 95% CI 1.0-2.5 ng·mL-1 versus 1.2 ng·mL-1, 95% CI 0.8-1.6 ng·mL-1; p=0.001). Repeating spontaneous and induced sputum procalcitonin levels 1 week later produced similar concentrations (p=0.29, intraclass correlation coefficient (ICC)=0.76 and p=0.72, ICC=0.70, respectively). Sputum procalcitonin is increased in patients with stable bronchiectasis and has potential as a biomarker of airway inflammation and infection in bronchiectasis.


A new site-specific endonuclease showing phenotypical crypticity in a tumorigenic strain of Agrobacterium tumefaciens.
AtuBVI, an endonuclease showing new site-specificity, has been isolated from the tumorigenic strain IIBV7 of Agrobacterium tumefaciens, and is undetectable in the non-tumorigenic sister strain IIBNV6. AtuBVI degrades IIBV7 DNA in vitro and should, therefore, be regarded as being phenotypically cryptic in the bacterial cell; it also shows anomalous behavior under cerain incubation conditions. These properties point to a possible role for this enzyme in the insertion of exogenous Ti-plasmid DNA into plant tissues during tumorigenesis.


Density of plasma-perfused capillaries in the rat heart during carbocromene-induced vasodilation.
Urethane-anesthetized thoracotomized rats were used to ascertain whether the density of plasma-perfused capillaries increases in the heart during pharmacologically induced vasodilation. Carbocromene, in a dose of 3.0 mg/(kg x min) i.v., infused for 5 min, raised coronary blood flow from 6.2 +/- 0.6 to 15.6 +/- 0.1 ml/(min x g); heart rate and blood pressure were only slightly changed. Capillary density was determined by timed infusions of a plasma label (FITC or RB 200 coupled with gamma-globulin), infused for different periods of time in the same animal. No significant difference could be observed in the number of capillaries marked for 10 min in the carbocromene-treated rats as compared to the controls (carbocromene-treated rats: 3,630 +/- 90 cap/mm2 subepicardium, 3,360 +/- 70 cap/mm2 subendocardium; controls: 3,750 +/- 140 cap/mm2 subepicardium, 3,210 +/- 90 cap/mm2 subendocardium). In those rats treated with the vasodilator the filling of the microcirculatory system was nearly complete within a labelling period of 1 sec (3,500 +/- 170 cap/mm2 subepicardium, 3,070 +/- 110 cap/mm2 subendocardium), whereas significantly lower values were found when the dye was infused for 1 sec in the controls (2,560 +/- 460 cap/mm2 subepicardium, 1,960 +/- 400 cap/mm2 subendocardium). The results indicate that the filling of the cardiac microcirculatory system is accelerated by a pharmacologically induced vasodilation, the maximal density of plasma-perfused capillaries is not raised, however.


Photochemical stabilities of some dihydropyridine calcium-channel blockers in powdered pharmaceutical tablets.
Photostabilities of some dihydropyridine calcium-channel blockers in pulverized pharmaceutical tablets were studied. Powdered tablets including amlodipine, nifedipine, or nilvadipine were exposed to D65 daylight lamp radiation according to an ICH guideline (ICH Q1B). The photodegradation of pharmaceutical components and their degradation products were monitored by HPLC using a reversed phase column with UV detection; their peak components were identified using MS analysis. Photochemical reactions involved in the photodegradation of these pharmaceuticals include aromatization of the dihydropyridine moiety and conversion to nitroso group from the nitro group in benzene rings. Chemical stability studies of these drugs indicate that nifedipine is the most photosensitive. The rate constant of nifedipine is indicated as seven times higher than those of the other two drugs.


Endovascular suitability and outcome after open surgery for ruptured abdominal aortic aneurysm.
Endovascular repair of ruptured abdominal aortic aneurysm (rAAA) has rapidly gained popularity, but superior results may be biased by patient selection. The aim was to investigate whether suitability for endovascular repair predicted survival, irrespective of technique of repair. Two blinded investigators independently evaluated preoperative computed tomography angiograms of a consecutive cohort of patients with rAAA. Patients were categorized either 'suitable' or 'unsuitable' for endovascular repair, if assessments agreed. If assessments disagreed, they were classified 'borderline suitable'. Correlations between endovascular suitability and clinical outcome were adjusted for suspected confounding factors and tested for robustness using sensitivity analyses. A total of 248 patients with rAAA from January 2001 to December 2010 were included, of whom 237 (95·6 per cent) underwent open repair. Seventy patients (28·2 per cent) were classified as 'suitable' and 100 (40·3 per cent) as 'unsuitable' for endovascular repair; 63 (25·4 per cent) were considered 'borderline suitable'. Fifteen (6·0 per cent) could not be assessed and were included in the sensitivity analyses. The postoperative 30-day mortality rate was 15·3 per cent (38 deaths). Multiple logistic regression demonstrated that the odds of perioperative death increased 9·21 (95 per cent confidence interval 2·16 to 39·23) fold for 'unsuitable' rAAA (P = 0·003) and 6·80 (1·47 to 31·49) fold for 'borderline' rAAA (P = 0·014), compared with 'suitable' rAAA. This selection effect was robust across sensitivity analyses and sustained for at least 5 years of follow-up. Endovascular suitability was an independent and strongly positive predictor of survival after open repair of rAAA.


Epidemiological analysis of maxillofacial fractures in Brazil: a 5-year prospective study.
The aim of this study was to assess the characteristics of maxillofacial fractures in the Piracicaba region of Brazil during a 5-year period and to delineate comparisons with worldwide facial fracture patterns. A descriptive statistical analysis was developed based on data collected using a specifically designed clinical survey of all patients who attended the Division of Oral and Maxillofacial Surgery at the Piracicaba Dental School from 1999 to 2004. Information regarding age, gender, etiology, and type of maxillofacial injury and its associated lesions were evaluated. In addition, treatment modalities and complication rates during patient follow-up were assessed. A total of 1024 patients presenting 1399 maxillofacial fractures were analyzed. Patients' ages ranged from 0 to 88 years (mean age, 28 +/- 16.4 years). The ratio of men to women was 4:1. Most fractures were caused by traffic accidents (45%), followed by assaults (22.6%), falls (17.9%), sports accidents (7.8%), and work accidents (4.5%). The prevalent anatomic regions of facial fractures (in percentages) were the mandible (44.2%), the zygomatic complex (32.5%), and the nasal bones (16.2%). Associated systemic lesions were found in 41.9% of patients, with prevalence for injuries to the upper (24.1%) and lower limbs (15.4%). Patient management was considered to be conservative in 490 patients (47.9%), and surgical therapy was performed in 493 patients (48.1%), of whom 399 (80.9%) were treated with open reduction and rigid internal fixation. Complications occurred in 76 patients (7.4%), mainly due to infection and malocclusion. The findings of this study indicated that epidemiological research of maxillofacial fractures allows the presentation patterns of the most affected individuals and the nature of their lesions to be outlined according to the region evaluated. Furthermore, treatment evaluation and complication rate analysis permits a more realistic interpretation of how patients should be managed.


Improved respiratory efficiency of 3D late gadolinium enhancement imaging using the continuously adaptive windowing strategy (CLAWS).
Acquisition durations of navigator-gated high-resolution three-dimensional late gadolinium enhancement studies may typically be up to 10 min, depending on the respiratory efficiency and heart rate. Implementation of the continuously adaptive windowing strategy (CLAWS) could increase respiratory efficiency, but the resulting non-smooth k-space acquisition order during gadolinium wash-out could result in increased artifact. Navigator-gated three-dimensional late gadolinium enhancement acquisitions were performed in 18 patients using tracking end-expiratory accept/reject (EE-ARA) and CLAWS algorithms in random order. Retrospective analysis of the stored navigator data shows that CLAWS scan times are very close to (within 1%) or equal to the fastest achievable scan times while EE-ARA significantly extends the acquisition duration (P < 0.0001). EE-ARA acquisitions are 26% longer than CLAWS acquisitions (378 ± 104 s compared to 301 ± 85 s, P = 0.002). Image quality scores for CLAWS and EE-ARA acquisitions are not significantly different (4.1 ± 0.6 compared to 4.3 ± 0.6, P = ns). Numerical phantom simulations show that the non-uniform k-space ordering introduced by CLAWS results in slight, but not statistically significant, reductions in both blood signal-to-noise ratio (10%) and blood-myocardium contrast-to-noise ratio (12%). CLAWS results in markedly reduced acquisition durations compared to EE-ARA without significant detriment to the image quality.


Long-acting injectable donepezil microspheres: Formulation development and evaluation.
Novel formulations of donepezil (DNP)-loaded microspheres based on a bio-degradable polymer of poly(lactic-co-glycolic acid) (PLGA) with a one-month duration of effect were developed, aimed at reducing dosing frequency and adverse effects and improving patient adherence. The spherical and monodispersed DNP-loaded microspheres were precisely fabricated by the Inventage Lab Precision Particle Fabrication method (IVL-PPFM®) based on micro-electromechanical systems (MEMS) and microfluidic technology. The types of polymers and end-groups, the drug/polymer ratio (DPR), and the routes of administration for DNP were studied to ensure an effective concentration and desired duration. Laser-light particle size analysis and scanning electron microscopy were used to characterization. Also, non-clinical animal models of beagle dogs are used to optimize DNP formulations and evaluate their pharmacokinetic properties. The PK results showed that the DPR was a critical factor in determining the exposure level and duration of DNR release. Furthermore, the lactide ratio, which varied depending upon the type of polymer, determined the hydrophobic interaction and was also an important factor affecting the desired DNP release. Since DNP shows a large inter-species variation between dogs and humans, PK modeling and simulation of the reference drug (i.e., Aricept®) and DNP-loaded microspheres were used for formulation development to overcome and interpret these variations. In addition, the developed PK model was extrapolated to humans using the estimated PK parameter and published clinical pharmacology data for DNP. The predicted PK profile of the DNP-loaded microsphere in humans showed that the formulation with PLGA 7525A and the DPR of 1/9 could maintain drug concentration for a month and could control initial burst release. The data obtained from the study could be used as scientific evidence for decision-making in future formulation development.


Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams.
Recent reports have suggested residual gadolinium deposition in the brain in subjects undergoing multiple contrast-enhanced MRI exams. These findings have raised some concerns regarding gadolinium-based contrast agent (GBCA) usage and retention in brain tissues. To summarize findings of hyperintense brain structures on precontrast T1-weighted images in 21 children undergoing multiple GBCA MRI exams. This retrospective study involved 21 patients, each of whom received multiple MRI examinations (range: 5-37 exams) with GBCA over the course of their medical treatment (duration from first to most recent exam: 1.2-12.9 years). The patients were between 0.9 and 14.4 years of age at the time of their first GBCA exam. Regions of interest were drawn in the dentate nucleus and the globus pallidus on 2-D fast spin echo images acquired at 1.5 T. The signal intensities of these two structures were normalized by that of the corpus callosum genu. Signal intensity ratios from these patients were compared to control patients of similar ages who have never received GBCA. Signal intensity ratios increased between the first and the most recent MRI exam in all 21 patients receiving GBCA, with an increase of 18.6%±12.7% (range: 0.5% to 47.5%) for the dentate nucleus and 12.4%±7.4% (range: -1.2% to 33.7%) for the globus pallidus (P<0.0001). Signal intensity ratios were also higher in GBCA patients than in controls (P<0.01). The degree of signal intensity enhancement did not correlate with statistical significance to the cumulative number or volume of GBCA administrations each patient received, the patient's age or the elapsed time between the first and most recent GBCA MRI exams. These results in children are consistent with recent findings in adults, suggesting possible gadolinium deposition in the brain.


High-performance silicon nanowire array photoelectrochemical solar cells through surface passivation and modification.
Nanowire solar cells: Pt nanoparticle (PtNP) decorated C/Si core/shell nanowire photoelectrochemical solar cells show high conversion efficiency of 10.86 % and excellent stability in aggressive electrolytes under 1-sun AM 1.5 G illumination. Superior device performance is achieved by improved surface passivation of the nanowires by carbon coating and enhanced interfacial charge transfer by PtNPs.


Design and Synthesis of Organic Molecules as Antineoplastic Agents.
The fight against cancer is one of the most challenging tasks currently for lots of researchers in many fields, such as pharmaceuticals, medicine, and chemicals [...].


Does land use change, waterlogging, and salinity impact on sustainability of agriculture and food security? Evidence from southwestern coastal region of Bangladesh.
The United Nation's sustainable development goal is to achieve zero hunger by 2030 and achieve food security throughout the world. In this context, we analyze the anthropogenic factors such as land use and land cover change, waterlogging, and soil salinity which combinedly affecting the agricultural sustainability and threatening the food security in the southwestern region of Bangladesh. Landsat satellite images from 1991 to 2021 were used to detect the changes and identify how anthropogenic activities have altered the land cover and land use and impede the sustainability of agriculture. Terra MODIS vegetation indices from 2000 to 2020 were used to detect waterlogging. Soil salinity was measured from the soil samples and vegetation soil salinity index (VSSI) from Landsat images. Findings of the study revealed that agricultural lands have decreased because of an increase in shrimp farming. Waterlogging and soil salinity are increasing due to increased shrimp farms also for poor drainage infrastructure and human modification. The area of agricultural land in 2011 was 19,657.12 acres,12,750.14 acres, and 38,774.70 acres in Keshabpur, Abhaynagar, and Manirampur, which changed to 12,668.70 acres (-36%), 7151.27 acres (-44%), and 32,809.30 acres (-16%) in 2021. Our hotspot analysis reveals that very high vulnerability to waterlogging due to floods was highest in Manirampur (15,464.09 acres). Finally, we proposed a new framework called IDCEM designed for monitoring land-use change, salinity, and waterlogging in the interior coast, which will indirectly help to promote food security and help in achieving sustainable development goal.


Naja mossambica mossambica venom. Purification, some properties and the amino acid sequences of three phospholipases A (CM-I, CM-II and CM-III).
Three phospholipases A, CM-I, CM-II and CM-III, were purified from Naja mossambica mossambica venom by gel filtration on Sephadex G-50 followed by ion-exchange chromatography on CM-cellulose. They comprise each 118 amino acid residues and are close-linked by seven intrachain disulphide bridges. The complete primary structure of the three phospholipases A have been elucidated. The sequences and the invariant amino acid residues of CM-I, CM-II and CM-III resemble those of phospholipases A from other snake venoms and also from porcine pancreas. However, the letality (LD50 values) of the three phospholipases A from Naja mossambica mossambica venom, differ among themselves, and are also much higher than the LD100 value encountered for notexin from Notechis scutatus scutatus venom.


Ascorbic acid-selenite interactions in humans studied with an oral dose of 74SeO3(2-).
The interaction between dietary ascorbic acid at extremes of ascorbic acid intake and selenium in young adult male humans was investigated with a stable-isotope approach using 74Se-selenite. Measurements were made of 74Se in plasma, urine, and feces with neutron-activation analysis after oral administration of 74SeO3(2-). Urine excretion and total body retention of isotope and the selenite-exchangeable metabolic pool (Se-EMP) were calculated. Limiting dietary ascorbic acid to about 20 mg/d appeared to reduce the time-related retention of absorbed selenite and the size of Se-EMP. Compared with a diet providing 1 g ascorbic acid/d the low ascorbic acid intake was associated with a lower fractional absorption of the isotope, a reduced retention of the label, and a smaller Se-EMP. These data and those previously obtained in subjects with more usual ascorbic acid intakes point to a possible important role for ascorbic acid in the maintenance of Se homeostasis.


Acute liver failure due to herpes simplex viral hepatitis diagnosed by skin lesions and blood tests: a case report.
The incidence of acute liver failure from herpes simplex virus is rare. A 71-year-old Japanese man was diagnosed with acute liver failure and was transferred to our hospital. Steroid therapy, plasma exchange, and hemodiafiltration were started for liver failure, and antimicrobial therapy was initiated for pneumonia. Staphylococcus epidermidis was detected in blood culture. Skin rash appeared; a positive anti-herpes simplex virus result led to the diagnosis of acute liver failure from herpes simplex virus. Hence, acyclovir was started. After blood tests improved, treatments for acute liver failure were discontinued. Antimicrobial therapy was continued; however, he died. In this case, persistent bacteremia and drug-induced liver damage due to acyclovir may have contributed to his death. Acute liver failure can lead to complications and death. Thus, careful observation is crucial, even if the patient has shown some improvements.


CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy.
Synonymous recoding of RNA virus genomes is a promising approach for generating attenuated viruses to use as vaccines. Problematically, recoding typically hinders virus growth, but this may be rectified using CpG dinucleotide enrichment. CpGs are recognised by cellular zinc-finger antiviral protein (ZAP), and so in principle, removing ZAP sensing from a virus propagation system will reverse attenuation of a CpG-enriched virus, enabling high titre yield of a vaccine virus. We tested this using a vaccine strain of influenza A virus (IAV) engineered for increased CpG content in genome segment 1. Virus attenuation was mediated by the short isoform of ZAP, correlated with the number of CpGs added, and was enacted via turnover of viral transcripts. The CpG-enriched virus was strongly attenuated in mice, yet conveyed protection from a potentially lethal challenge dose of wildtype virus. Importantly for vaccine development, CpG-enriched viruses were genetically stable during serial passage. Unexpectedly, in both MDCK cells and embryonated hens' eggs that are used to propagate live attenuated influenza vaccines, the ZAP-sensitive virus was fully replication competent. Thus, ZAP-sensitive CpG enriched viruses that are defective in human systems can yield high titre in vaccine propagation systems, providing a realistic, economically viable platform to augment existing live attenuated vaccines.


Nematocyst sequestration within the family Fionidae (Gastropoda: Nudibranchia) considering ecological properties and evolution.
Aeolid nudibranchs are well-known for their ability to incorporate cnidarian nematocysts and use them for defense; this process is tightly linked with the feeding preferences of molluscs. As many nudibranch groups show signs of ecology-based adaptive radiation, studies of prey-based defensive mechanisms can provide valuable insight into details of nudibranch evolutionary history. The main goal of this study is to test the correlation of ecological traits, feeding mechanisms, and prey preferences with cnidosac fine morphology and to pinpoint the phylogenetic value of these traits. We study the cnidosac morphology in thirteen species-representatives of the main lineages within the family Fionidae s.l. The morphological analysis includes histological sections, transmission electron microscopy, confocal laser scanning microscopy, and scanning electron microscopy. For phylogenetic study, available molecular data from public repositories were used, and phylogenetic trees were produced based on Bayesian Inference and Maximum likelihood analysis for a concatenated dataset of three molecular markers (COI, 16S, H3). In general, fionid cnidosacs fit the common aeolid pattern, but among different species we detected a high variation in type of obtained nematocysts, their arrangement within cnidophages, and in number of cell types within cnidosacs. We report on presence of cellules speciale in the haemocoel of all studied species, and for the first time, we report on cells with chitinous spindles in the haemocoel of all fionids except Eubranchus. The function of both these cell types remains unknown. The loss of functional cnidosacs occurred at least three times within Fionidae, and in case of the genera Phestilla, Calma, and Fiona, this loss is linked to their non-cnidarian diet. The diversity of cnidosac fine structure within Fionidae s.l. correlates with that of the radular morphology and feeding preferences of each species. Prey shifts between cnidarian and non-cnidarian prey (both through evolutionary shifts and individual variation) rarely occur within Fionidae s.l.; however, microevolutionary shifts between different hydrozoan species within a single genus are more common. Cnidosac morphology demonstrates considerable resulting changes even when switching between similar hydrozoan species, or changing the feeding site on same prey species. These data indicate that cnidosac morphology likely follows microevolutionary prey shifts-in other words, it is affected by switches in prey species and changes in feeding sites with a single prey species. Thus, the cnidosac morphology may be a useful indicator when studying ecological features of particular species.


Corneal confocal microscopy detects small fibre neurodegeneration in Parkinson's disease using automated analysis.
We studied the utility of corneal confocal microscopy (CCM) in detecting a reduction in corneal nerve parameters in a large cohort of patients with Parkinson's disease (PD) compared to controls using a fully automated potentially scalable method of analysis. We also assessed if CCM parameters are related to the severity and sub-type of PD. 98 participants with PD and 26 healthy controls underwent CCM with automated corneal nerve quantification, MDS-UPDRS III, Hoehn and Yahr scale, Montreal Cognitive Assessment, Parkinson's Disease Questionnaire-39 and PD subtype assessment. Corneal nerve fibre density (mean difference: - 5.00 no/mm2, 95% confidence interval (CI) [- 7.89, - 2.12], p = 0.001), corneal nerve branch density (mean difference: - 10.71 no/mm2, 95% CI [- 16.93, - 4.48], p = 0.003), corneal total branch density (mean difference: - 14.75 no/mm2, 95% CI [- 23.58, - 5.92], p = 0.002), and corneal nerve fibre length (mean difference: - 2.57 mm/mm2, 95% CI [- 4.02, - 1.12], p = 0.001) were significantly lower in PD participants compared to controls. There was no correlation between corneal nerve parameters and duration, severity or subtype of PD, cognitive function or quality of life. CCM with automated corneal nerve analysis identifies nerve fibre damage and may act as a biomarker for neurodegeneration in PD.


A randomized trial comparing health-related quality-of-life and utility measures between routine fine-needle aspiration cytology (FNAC) and surveillance alone in patients with thyroid incidentaloma measuring 1-2 cm.
To present the impact of treatment on health-related quality-of-life (HRQOL) and health utility measures from the randomized controlled trial (ClinicalTrials.gov Identifier: NCT02398721) that investigated the FNAC versus watchful surveillance in patients with incidental benign thyroid nodules. Health utility and HRQOL were evaluated using the EQ-5D 5-level (EQ-5D-5L), 6-item Short-Form Health Survey (SF-6D), and generic 12-item Short-Form Health Survey (SF-12v2) at baseline, 3-month, 6-month, and 12-month assessments. A repeated measure analysis of variance evaluated differences in HRQOL scores between treatment groups over time. Multiple imputations were used to impute missing data at each time point. HRQOL data completion rates were 99.7% at baseline, 92.7% at 3-month, 93.9% at 6-month, 92.7% at 12-month, and 88.6% at 18-month follow-up after baseline. There were significant mean differences in SF-6D, EQ-5D-5L, and SF-12v2 over time except the domain of vitality and mental health of SF-12v2. Mean change of SF-12v2 scores and utility scores from baseline between groups did not exceed minimal important difference. No significant treatment group by time interactions were found in all HRQOL and utility scores except in the vitality domain and PCS of SF-12v2 (p value = 0.033; 0.024). When compared with watchful surveillance, FNAC intervention was associated with better vitality and physical-related HRQOL scores but did not provide better preservation of utility score improvement over the 18-month period. These findings support the routine FNAC approach for nodules that have a low-suspicion sonographic pattern and measure between 1.0 and 2.0 cm.


p300 modulates HIV-1 gp120-induced apoptosis in human proximal tubular cells: associated with alteration of TGF-beta and Smad signaling.
p300 is a key protein, which determines acceleration or deceleration of signal transduction. Recently, renal proximal tubular cells have not only been found to be a harboring site for HIV-1 but have also been shown to undergo apoptosis in response to HIV-1 exposure. Both HIV-1 and its envelop glycoprotein, i.e. gp120, triggered tubular cell apoptosis in the same magnitude. In the present study, we evaluated the role of p300 in gp120-induced tubular cell apoptosis and associated downstream signaling. We have demonstrated that by transient transfection assays, p300 significantly increases susceptibility of human proximal renal tubular HK-2 cells to apoptosis triggered by HIV-1 gp120. A mutant p300, missing the E1A/TFIIB binding site, fails to produce such sensitization potential. Smad7 and an anti-TGF-beta antibody rescue the p300 sensitization. Furthermore, p300 and HIV-1 gp120 synergistically increase TGF-beta, ATF-2 and activating protein-1 (AP-1) expression. In addition, HIV-1 gp120 results in phosphorylation of Smad2 and decreases c-Jun. These findings suggest that p300 acts as a potent transcriptional cofactor in HIV-1 gp120-induced apoptosis via TGF-beta and Smad signaling.


Elastic plastic fracture mechanics investigation of toughness of wet colloidal particulate materials: Influence of saturation.
Previous use of linear elastic fracture mechanics to estimate toughness of wet particulate materials underestimates the toughness because it does not account for plastic deformation as a dissipation mechanism. Plastic deformation is responsible for the majority of energy dissipated during the fracture of wet colloidal particulate materials. Plastic deformation around the crack tip increases with saturation of the particulate body. The toughness of the body increases with increasing saturation. Elastic plastic fracture mechanics using the J-integral approach was used for the first time to measure the fracture toughness (JIC) of wet micron sized alumina powder bodies as a function of saturation. The samples were prepared by slip casting. The saturation was controlled by treatment in a humidity chamber. The elastic modulus (E) and the energy dissipated by plastic flow (Apl) were measured in uniaxial compression. The critical stress intensity factor (KIC) was measured using a diametral compression sample with a flaw of known size. The fracture toughness (JIC) was calculated from these measured quantities and the geometry of the specimen. Elastic plastic fracture mechanics was used for the first time to quantitively account for plastic deformation of wet particulate materials. The linear elastic fracture mechanics approach previously used accounted for less than 1% of the total energy dissipated in fracture. Toughness (JIC) was found to increase with increasing saturation due to plastic deformation that increased with saturation level. The improved understanding of toughness as a function of saturation will aid in providing quantitative analysis of cracking in drying colloidal films and bodies.


Additional confirmation of action constant for bremsstrahlung from electron-and-nucleus collisions.
A new action constant for bremsstrahlung has been derived and published by the author (Journal of X-Ray Science and Technology 6, 1996, 261). Experimental confirmation of that action constant by measurements of the intensity of bremsstrahlung produced by electron beams on pure metal targets, has also been published by the author (Journal of X-Ray Science and Technology 7, 1997, 327-330). From the data in the second paper, additional experimental evidence is obtained for this paper by overcoming the limitations associated with normalization of the number of atoms per unit volume. The dependence of the intensity on the exponent of the atomic number, Z, of the target elements is measured to be 1.32, with a standard deviation of plus or minus 0.05, in close agreement with the predicted value of 4/3.


[Immuno-oncologic monitoring of patients with bronchial carcinoma. IV. Aspects of the immunocompetence system].
Some aspects of the immunocompetent system are tested in 84 lung cancer patients at time of diagnosis and during the natural course of the disease. Results show no significant variations for many immunological tests during the course of the neoplasia. Significant alterations are observed in T-lymphocyte and macrophage evaluation. Moreover, some immunological data are related to lung cancer post-surgical survival.


Lenvatinib is independently associated with the reduced risk of progressive disease when compared with sorafenib in patients with advanced hepatocellular carcinoma.
Recently, lenvatinib demonstrated non-inferiority to sorafenib in terms of overall survival (OS) in a randomized phase III study that was conducted at 154 sites in 20 countries. Here, we investigated treatment outcomes and safety of lenvatinib compared with sorafenib and identified independent predictors of poor outcomes, including shorter progression-free survival (PFS) and OS in Korean patients with unresectable hepatocellular carcinoma (HCC). Patients with advanced HCC treated with lenvatinib or sorafenib at Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine between October 2018 to October 2019 were considered eligible. Response evaluation was performed according to the modified Response Evaluation Criteria in Solid Tumors. The lenvatinib arm had a significantly lower proportion of patients who received prior anti-HCC treatments (47.7% vs 78.7%; P < 0.001) than those in the sorafenib arm. Univariate analysis showed that ECOG 1 (vs 0), serum albumin, alpha-fetoprotein (AFP), previous anti-HCC treatments, and lenvatinib (vs sorafenib) were significant predictors of progressive disease (all P < 0.05). In the subsequent multivariate analysis, ECOG 1 (vs 0) (hazard ratio [HR] = 4.721, 95% confidence interval [CI] 1.371-16.259; P = 0.014), higher AFP level (HR = 1.000, 95% CI 1.000-1.000; P = 0.015), and lenvatinib treatment (vs sorafenib) (HR = 0.461, 95% CI 0.264-0.804; P = 0.006) independently predicted a higher probability of progressive disease. Patients treated with lenvatinib demonstrated significantly longer PFS than those treated with sorafenib. Furthermore, no significant differences were observed in mortality rates between the two groups, which indicated that lenvatinib is non-inferior to sorafenib in terms of OS.


Influence of foot orthoses on plantar pressures, foot pain and walking ability of rheumatoid arthritis patients--a randomised controlled study.
To compare the effectiveness of functional foot orthoses and unshaped (flat) orthotic material on plantar pressure redistribution, forefoot pain reduction and walking ability in rheumatoid arthritis (RA) patients. Forty patients with RA were randomised to receive unshaped material (UM) (n = 20) or functional foot orthoses (n = 20). Plantar pressure measurement was performed with an F-scan system. Foot pain was assessed by the pain subscale of the Foot Function Index. Walking ability was assessed by the 6-min walking test. Investigations were performed at baseline, 1 week after the patient received shoes with orthoses and 6 months later. Plantar pressures were significantly higher at painful than at non-painful foot areas. No differences in plantar pressure redistribution were found between the groups. Notable reduction of pain and improvement of activity (walking ability) was observed in both groups. Foot pain has moderate impact on the walking ability of RA patients. The study showed no clear advantage of functional foot orthoses over UM.


Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography.
Improvement in subjective symptoms has been reported in functional dyspepsia (FD) patients administered with acotiamide. Improvement was confirmed in meal-related symptoms, such as postprandial fullness, upper abdominal bloating, and early satiety. We examined the mechanism underlying the effects of acotiamide on gastric accommodation reflex (GAR) and gastroduodenal motility in FD patients. Thirty-four FD patients (mean age, 40.4 years) were examined ultrasonographically before and after 14-18 days of acotiamide (100 mg t.i.d.) or placebo administration. To assess GAR, expansion rate in cross-sectional area of the proximal stomach was measured after every 100-mL ingestion, using a straw, of up to 400 mL of a liquid meal (consommé soup, 13.1 kcal; 400 mL) in a supine position. Next, we measured gastric emptying rate (GER), motility index (MI, antral contractions), and reflux index (RI, duodenogastric reflux) to assess gastroduodenal motility. Patients also completed a survey based on the seven-point Likert scale both before and after drug administration. Of the 37 cases, 19 and 18 were administered with acotiamide and placebo A respectively, significant difference was observed in GAR between the acotiamide and placebo groups (21.7%vs 4.4%) after 400 mL ingestion. GER significantly accelerated after treatment in the acotiamide group (P = 0.012), no significant differences were observed in MI and RI between the two groups. Improvement rates were 35.3 and 11.8% for the acotiamide and placebo groups. Acotiamide significantly enhances GAR and GER in FD patients. Acotiamide may have therapeutic potential for FD patients.


Comparison of inactivation and unfolding of methanol dehydrogenase during denaturation in guanidine hydrochloride and urea.
The activity and the conformational changes of methanol dehydrogenase (MDH), a quinoprotein containing pyrrolo-quinoline quinone as its prosthetic group, have been studied during denaturation in guanidine hydrochloride (GdnHCl) and urea. The unfolding of MDH was followed using the steady-state and time resolved fluorescence methods. Increasing the denaturant concentration in the denatured system significantly enhanced the inactivation and unfolding of MDH. The enzyme was completely inactivated at 1 M GdnHCl or 6 M urea. The fluorescence emission maximum of the native enzyme was at 332 nm. With increasing denaturant concentrations, the fluorescence emission maximum red-shifted in magnitude to a maximum value (355 nm) at 5 M GdnHCl or 8 M urea. Comparison of inactivation and conformational changes during denaturation showed that in general accord with the suggestion made previously by Tsou, the active sites of MDH are situated in a region more flexible than the molecule as a whole.


Liver Transplantation for Acetaminophen-Induced Acute Liver Failure: Role of Psychiatric Comorbidity in Listing Decisions and Outcomes.
Psychiatric co-morbidities are thought to deter listing of patients with acetaminophen-induced acute liver failure (APAP-ALF) for liver transplantation (LT). We examined the listing process and short-term outcomes via a cohort study of APAP-ALF patients with and without psychiatric comorbidity. We analyzed listing determinants, listing rates, and short-term (21-day) outcomes in APAP-ALF patients with and without psychiatric comorbidity (mental illness and/or substance abuse) enrolled in the ALFSG registry between 2000 and 2016. Of the 910 APAP-ALF patients, 801 (88%) had evidence of psychiatric comorbidity. There was no difference in listing between patients with (169/801, 21%) and without (26/109, 24%) psychiatric comorbidity (p = 0.59). Listed patients in both groups were younger with more severe admission clinical parameters than those not listed. Patients with and without psychiatric comorbidity had similar short-term outcomes: transplant rates among listed patients [57/169 (34%) vs 10/26 (39%), p = 0.80], spontaneous (transplant-free) survival (SS) [544/801 (68%) vs 73/109 (67%), p = 0.93], and overall death [207/801 (26%) vs 26/109 (24%), p = 0.74]. In our study, which is limited by informal psychiatric assessments, psychiatric comorbidity in APAP-ALF patients does not appear to impact listing, or short-term outcomes-SS, LT, or death. Transplant listing decisions primarily appear to be based on clinical severity of disease, rather than concern that APAP-ALF patients' psychiatric comorbidity will compromise outcomes.


[Anti thyroglobulin antibodies in the follow up of patients with differentiated thyroid cancer: residual or relapsing disease markers?].
Anti thyroglobulin antibodies are present in 25% of patients treated for a differentiated thyroid cancer, invalidating thyroglobulin determination. Those patients subjected to total thyroidectomy and free of disease, should reduce the production of these antibodies, due to the lack of antigenic stimulus. Therefore, anti thyroglobulin antibodies could be useful to detect early relapses. To assess the relationship between anti thyroglobulin antibodies and the evolution of the disease in patients treated for thyroid cancer. Retrospective analysis of 26 patients treated for thyroid cancer with positive anti thyroglobulin antibodies, followed for three years. These were divided in those with or without lymphocytic thyroiditis (19 and 7 respectively). At the first year of follow up, anti thyroglobulin antibody concentration was 401 +/- 94.9 UI/ml (x +/- sem) in patients with thyroiditis and 38.9 +/- 8.9 UI/ml in those without thyroiditis (p < 0.005). During the three years of follow up, no differences in anti thyroglobulin antibodies were observed between patients with or without tumor relapse. Concentration of anti thyroglobulin antibodies was higher in patients with thyroiditis and did not differentiate patients with tumor relapse.


Quantifying the effectiveness of desk dividers in reducing droplet and airborne virus transmission.
The utilization of physical dividers has been recommended as a practical approach to reducing the droplet and aerosol transmissions of the COVID-19 virus (SARS-CoV-2). This study conducted a series of experiments using video recording with a high-speed camera, particle image velocimetry (PIV) technique, and concentration measurements. The effectiveness of Perspex desk dividers impeding the transient transmission during coughing in five representative layouts was investigated. The results showed that the divider effectively protected the exposed person from an infector's cough seated in a face-to-face arrangement at a distance of 1.5 m. The aerosol concentration at the breathing zone was reduced by 99% compared to the layout without dividers. However, the reflection of aerosols from the dividers increased the exposure risk to the person seated beside the infector. Such risk was substantially reduced if the dividers were placed parallel between the infector and exposed person seated side-by-side. When the exposed person was staggered (face-to-face but displaced sideways laterally) to the infector with a 0.55-m lateral distance, the dividers reduced the potential exposure at the breathing zone by 60%. Considering the effectiveness in exposure reduction, the staggered configuration of desk dividers between the infector and exposed persons offers the best reduction to exposure.


Exilic effects of illness and pain in Solzhenitsyn's Cancer Ward: how sharpening the moral imagination can facilitate repatriation.
This essay uses Solzhenitsyn's Cancer Ward to explore the exilic effects of illness and pain. The novel is uniquely suited for such an analysis given the theme of exile that predominates both in the narrative and in the composition of multiple characters within that narrative. I argue that illness, and in particular pain, is a liminal state, an existential hinterlands. The ethical approach to literature and medicine may suggest, as a response to these exilic effects, the need to cultivate connection and empathy by sharpening the moral imagination. If pain and illness exile the sufferer, the imperative to reach out takes on ethical content.


Rapid recombination screening to test gene essentiality demonstrates that pyrH is essential in Mycobacterium tuberculosis.
The availability of the complete genome of Mycobacterium tuberculosis affords the possibility of screening genes for essentiality under defined conditions. We tested a rapid recombination method for screening and confirmation of gene essentiality which would be more amenable to higher throughput applications. Non-replicating vectors carrying the internal portion of a gene were used as recombination substrates. Such vectors would lead to inactivation of the target gene in a single recombination step. For non-essential genes, recombinants can be obtained; for essential genes, no recombinants can be obtained, thus providing a rapid screening method to determine essentiality in a targeted manner. The incorporation of a promoter in the vector allowed us to establish the essentiality of a single gene in an operon. We confirmed this method worked with several essential (proC, glnE, mtrB, trpD) and one non-essential (tlyA) gene. In addition, we used the method to demonstrate that the pyrH gene is essential.


Longitudinal associations between depressive symptoms and body mass index in a 20-year follow-up.
Longitudinal studies have rarely investigated changes in depressive symptoms and indicators of obesity simultaneously, although it is often proposed that the positive relationship between depression and obesity is bidirectional. The present study examined the reciprocal nature of the relationship between depressive symptoms and body mass index (BMI) in a 20-year follow-up survey. Participants of a Finnish cohort study in 1989 at 22 years (N=1656) were followed up at ages 32 (N=1262) and 42 (N=1155) with postal questionnaires. BMI was calculated on the basis of self-reported weight and height, and depressive symptoms were assessed using the short form of the Beck Depression Inventory. Latent growth models (LGM) and cross-lagged autoregressive models were used to determine prospective associations between depressive symptoms and BMI. LGM analyses indicated that men with higher initial levels of depressive symptoms experienced a faster rate of increase in BMI (β=0.20, P<0.01). Among women, change in BMI or depressive symptoms was not predicted by the other construct, but initial levels of BMI and depressive symptoms as well as their rate of change correlated positively with each other (r=0.15 and 0.37, respectively). In cross-lagged models, depressive symptoms at age 32 predicted greater BMI at 42 (β=0.10, P<0.001) among men, whereas women with higher BMI at age 32 were more likely to have more depressive symptoms at 42 (β=0.08, P<0.05). Elevated depressive symptoms predicted weight gain in men, while changes in depressive symptoms and body weight occurred concurrently in women. Tentative evidence showed that women with excess body weight were more likely to have increased symptoms of depression 10 years later. More emphasis should be placed on depressive symptoms in weight control programs as well as on reducing weight-based stigmatization and discrimination in society.


Provider advice about pregnancy weight gain and adequacy of weight gain.
To explore the association between health care provider advice about weight gain and gestational weight gain. Using data from a prospective cohort study, we explored the association between provider advice about weight gain in pregnancy with weight gain adequacy among 1,454 pregnant women. Provider advice was measured by maternal self-report at 27-30 weeks' gestation. Linear and Poisson regression were used to explore associations. Seventy-eight percent of the women gained outside current recommendations. Fifty-one percent reported receiving weight gain advice from a health care provider. Adjusted Generalized Linear Model (GLM) estimates showed weak effect of provider advice on inadequate or excessive gain (Relative Risk (RR) 0.96, 95% CI 0.74, 1.26 for inadequate gain and RR 1.01, 95% CI 0.97, 1.06 for excessive gain). There is a need for more women to hear about their targeted weight gains during pregnancy and the present advice that exists does little to influence actual gains. Further studies are warranted to find better strategies for providers to motivate their patients to gain weight within the appropriate ranges.


Solid-state electronic spin coherence time approaching one second.
Solid-state spin systems such as nitrogen-vacancy colour centres in diamond are promising for applications of quantum information, sensing and metrology. However, a key challenge for such solid-state systems is to realize a spin coherence time that is much longer than the time for quantum spin manipulation protocols. Here we demonstrate an improvement of more than two orders of magnitude in the spin coherence time (T₂) of nitrogen-vacancy centres compared with previous measurements: T₂≈0.6 s at 77 K. We employed dynamical decoupling pulse sequences to suppress nitrogen-vacancy spin decoherence, and found that T₂ is limited to approximately half of the longitudinal spin relaxation time over a wide range of temperatures, which we attribute to phonon-induced decoherence. Our results apply to ensembles of nitrogen-vacancy spins, and thus could advance quantum sensing, enable squeezing and many-body entanglement, and open a path to simulating driven, interaction-dominated quantum many-body Hamiltonians.


High Dietary Inflammatory Index Is Associated With Increased Plaque Vulnerability of Carotid in Patients With Ischemic Stroke.
Long-term dietary patterns can influence the intensity of systemic inflammation and, therefore, the development of atherosclerosis. This study aimed to evaluate the association between dietary inflammatory index (DII) and vulnerability characteristics of carotid atherosclerotic plaques in patients with ischemic stroke. Patients with ischemic stroke within 7 days of onset were enrolled. DII was calculated from 32 food components with the help of a food frequency questionnaire. Vulnerable plaque was defined as presence of artery positive remodeling (remodeling index >1.1) and low CT attenuation plaques (<35 HU) on carotid arteries by computed tomography angiography. Of the 398 enrolled patients, 144 (36.2%) were detected with vulnerable plaque. Their DII ranged from -4.58 to 4.18. Patients with vulnerable plaques consumed less nutrients with anti-inflammatory properties, less fruits and vegetables (85.6±64.3 versus 94.6±74.4 g/d, P=0.027), and less nuts (5.66±7.14 versus 8.84±15.9 g/d, P=0.024) than patients without vulnerable plaques. Patients with vulnerable plaque had higher DII than patients without vulnerable plaque (-0.26±1.54 versus -0.64±1.53, P=0.018). Logistic regression analysis revealed that DII was associated with vulnerable plaques after adjusted for major confounding factors (odds ratio=1.307; 95% CI, 1.113-1.533). DII is associated with the vulnerability of carotid plaques in patients with ischemic stroke. Considering a possible causal relationship, the mechanisms underlying the association between diet and atherosclerosis warrant further study.


[COVID-19-related respiratory distress in emergency departments: reality and perspectives.]
COVID-19 was initially considered exclusively as a respiratory disease. It now appears that it is also a systemic disease with vascular inflammation and thromboses. In the most severe forms, these plurifactorial pulmonary lesions are responsible for acute respiratory distress syndrome. The treatment of this syndrome, which causes hypoxemia, requires urgent oxygen therapy. While initial recommendations favoured the rapid use of intubation and mechanical ventilation, experience seems to confirm that it must be delayed as long as possible, in favour of non-invasive ventilation, less aggressive for the patient.


A cell-based backup to speed up pandemic influenza vaccine production.
Influenza vaccines are currently produced through egg-based methods, with one drawback being that this system is slow to respond to the surging global demand during an influenza pandemic. Alternative influenza vaccine production strategies, such as using a cell-based strategy, should be considered in pandemic situations.


Photocatalytic degradation of bisphenol A using titanium dioxide@nanodiamond composites under UV light illumination.
Different types of organic impurities such as dyes, acids, and alcohols are discharged into potable water sources. The removal of these hazardous organic pollutants from wastewater is an important task globally. However, the conventional methods used to remove organic impurities suffer from low efficiency and recycling problems. Photocatalysis is a promising advanced oxidation process for the degradation of organic compounds in aqueous solution. Titanium dioxide (TiO2) is commonly used as a photocatalyst. However, the wide bandgap of TiO2 means that it is activated by ultraviolet light, which restrains its ability to harvest solar energy. In this study, a simple water-based precipitation method was used to synthesize TiO2@nanodiamond composites. The ability of the composites to degrade bisphenol A as a model organic pollutant was investigated. It was found that 10 ppm of bisphenol A was completely degraded in 100 min by the TiO2@nanodiamond photocatalyst under ultraviolet illumination.


CO2 back-diffusion in the rete aids O2 secretion in the swimbladder of the eel.
In order to estimate the relative importance of back-diffusion of O2 and CO2 for their partial pressure enhancement in the swimbladder, we have determined O2 and CO2 partial pressure and content and pH in microsamples collected non-obstructively from the afferent and efferent rete vessels in the European eel. 1. The PO2 increased significantly along the arterial vessels of the rete (from 33 to 303 Torr), with no change in O2 content, suggesting O2 not to be exchanged in the rete counter-current system. 2. A corresponding increase of PCO2 (from 4 to 35 Torr) was accompanied by a significant rise in CO2 content (from 8 to 15 mmol.L-1), suggesting significant CO2 back-diffusion in the rete. 3. Changes in PO2 during passage of blood through the swimbladder epithelium were variable and small, and the PO2 in rete venous blood was similar to that in rete arterial blood, explaining the lack of O2 back-diffusion. 4. Using blood CO2 dissociation data, about 70% of the rise in arterial CO2 content was estimated to derive from diffusion of CO2, the remaining 30% from diffusion of HCO3-, from venous to arterial rete capillaries, or from H+ transport in the opposite direction. The data indicate that CO2 back-diffusion in the rete does not only raise the rete arterial PCO2; it also reduces the O2 capacity (Root effect) and thus enhances the arterial PO2.


The solution conformations of the subclasses of human IgG deduced from sedimentation and small angle X-ray scattering studies.
The solution conformations of human immunoglobulin G subclass molecules have been investigated by sedimentation and small-angle X-ray scattering techniques. Both methods qualitatively indicate IgG3 to be an extended molecule relative to IgG1. Sedimentation data have been collected for a number of paraproteins of all four subclasses and the hinge-deleted IgG1Dob protein. The known crystal structure of Dob allows the use of this protein as a basis for the proposal of models of the average conformations of IgG subclasses which are consistent with experimental s(0)20,w values. IgG1 is suggested to have a hinge length of 0-15 A and non-coplanar Fab arms; IgG2 to be effectively hingeless with folded-back Fab arms; IgG3 to have an extended hinge of the order of 100 A and IgG4 to be effectively hingeless and T-shaped. The possible correlation of these conformations with subclass function is discussed.


The effect of epidural anaesthesia on peripheral resistance and graft flow following femorodistal reconstruction.
To determine the extent to which epidural anaesthesia influences peripheral resistance and graft blood flow following femorocrural reconstruction. Prospective, controlled study measuring blood flow, arterial pressure and peripheral resistance in femorocrural bypass grafts for 20 min following onset of epidural anaesthesia with 15ml of 0.25% bupivacaine. Twenty patients undergoing femorocrural reconstruction for critical lower-limb ischaemia with in situ long saphenous vein, under general anaesthesia. Ten patients had epidural cannulae inserted preoperatively and injected with bupivacaine after completion of the graft. Peripheral resistance fell in all 10 patients receiving epidural anaesthesia from a mean (range) of 1.07 PRU (0.32-2.2) to 0.49 PRU (0.19-0.72), compared to control values of 0.95 PRU (0.39-2.0) to 0.91 PRU (0.41-1.51; P < 0.01, Wilcoxon). There was a tendency for blood pressure to fall in the study patients (not significant) but graft blood flow still increased from 98 ml min-1 (41-221) to 160 ml min-1 (101-250), compared to flow in the control patients of 101 ml min-1 (45-176) at baseline to 104 ml min-1 (56-168; p < 0.01) at 20 min. Epidural anaesthesia significantly decreases peripheral resistance and increases graft blood flow in femorocrural grafts and would appear, therefore, to be of benefit for patients undergoing femorodistal reconstruction.


Haematological classification of the chronic myeloid leukaemias.
Chronic myeloid leukaemia (CML) includes five subtypes, and the term should be used in the same way as the term chronic lymphoid leukaemia to refer to a group of related conditions. The subtypes of CML are: 1. Chronic granulocytic leukaemia (CGL) (95% of all CML; 90% are Ph+, BCR+, 5% are Ph-, BCR+); 2. Juvenile CML (extremely rare; Ph-, BCR- in the few so far examined); 3. Chronic neutrophilic leukaemia (CNL) (extremely rare; Ph-, BCR- in the few so far examined); 4. Chronic myelomonocytic leukaemia (CMML). CMML with low or normal leukocyte counts is classified as a myelodysplastic syndrome; CMML with high leukocyte count is both myelodysplastic and myeloproliferative. Ph-, BCR-; 5. Atypical CML (aCML). Intermediate between CGL and CMML but has distinctive features. Ph-, mostly BCR-. Significance of few reported BCR+ uncertain. Markedly worse survival than CGL and probably worse than CMML. Definition needs refining. Types 2, 3, 4 and 5 account for 5% of all CML. CGL, CMML, aCML and CNL can be diagnosed in the great majority of cases from the morphological profile of presentation peripheral blood films, but high-quality Romanowsky staining is essential.


Issues in the design of a pilot concept-based query interface for the neuroinformatics information framework.
This paper describes a pilot query interface that has been constructed to help us explore a "concept-based" approach for searching the Neuroscience Information Framework (NIF). The query interface is concept-based in the sense that the search terms submitted through the interface are selected from a standardized vocabulary of terms (concepts) that are structured in the form of an ontology. The NIF contains three primary resources: the NIF Resource Registry, the NIF Document Archive, and the NIF Database Mediator. These NIF resources are very different in their nature and therefore pose challenges when designing a single interface from which searches can be automatically launched against all three resources simultaneously. The paper first discusses briefly several background issues involving the use of standardized biomedical vocabularies in biomedical information retrieval, and then presents a detailed example that illustrates how the pilot concept-based query interface operates. The paper concludes by discussing certain lessons learned in the development of the current version of the interface.


Fast vesicle reloading and a large pool sustain high bandwidth transmission at a central synapse.
What limits the rate at which sensory information can be transmitted across synaptic connections in the brain? High-frequency signalling is restricted to brief bursts at many central excitatory synapses, whereas graded ribbon-type synapses can sustain release and transmit information at high rates. Here we investigate transmission at the cerebellar mossy fibre terminal, which can fire at over 200 Hz for sustained periods in vivo, yet makes few synaptic contacts onto individual granule cells. We show that connections between mossy fibres and granule cells can sustain high-frequency signalling at physiological temperature. We use fluctuation analysis and pharmacological block of desensitization to identify the quantal determinants of short-term plasticity and combine these with a short-term plasticity model and cumulative excitatory postsynaptic current analysis to quantify the determinants of sustained high-frequency transmission. We show that release is maintained at each release site by rapid reloading of release-ready vesicles from an unusually large releasable pool of vesicles (approximately 300 per site). Our results establish that sustained vesicular release at high rates is not restricted to graded ribbon-type synapses and that mossy fibres are well suited for transmitting broad-bandwidth rate-coded information to the input layer of the cerebellar cortex.


Nuclear and nucleolar changes in preimplantation mouse embryos expressing numerous virus-like particles.
Preimplantation mouse embryos spontaneously arrested in development at the two-cell and three-cell stages were obtained from a pregnant Slc: ICR mouse. Numerous intracisternal A-type virus-like particles were expressed in the cytoplasm of these abnormal mouse embryos. Several nuclear and nucleolar changes observed in these embryos, probably related to the hyperactive synthesis of virus-like particles, were reported.


Retrovirus mediated transfer and expression of GM-CSF in haematopoietic cells.
Two retrovirus vectors were compared for their ability to express granulocyte-macrophage colony stimulating factor (GM-CSF) in a haematopoietic cell line, FDCP1, which is dependent on GM-CSF for survival. Both a MoMLV-based vector pVneoGM, and a MPSV-based vector, M3neoGM, were found to be capable of transmitting and expressing both GM-CSF and neomycin sequences in the myeloid FDCP1 cell line. Our results also demonstrate that pVneoGM is more efficient at generating GM-CSF independent colonies than M3neoGM. Analysis of cell lines derived after infection confirmed pVneoGM expressed higher levels of GM-CSF. Cell lines generated by infection with pVneoGM responded to levels of exogenous recombinant GM-CSF which did not stimulate growth of the parental cell line, suggesting autocrine stimulation may convey a proliferative advantage under sub-optimal growth conditions. Finally the parental vectors pVneo and M3neo were shown to be capable of expressing the neomycin gene in both murine haematopoietic progenitor and stem cells.


LF-UNet - A novel anatomical-aware dual-branch cascaded deep neural network for segmentation of retinal layers and fluid from optical coherence tomography images.
Computer-assistant diagnosis of retinal disease relies heavily on the accurate detection of retinal boundaries and other pathological features such as fluid accumulation. Optical coherence tomography (OCT) is a non-invasive ophthalmological imaging technique that has become a standard modality in the field due to its ability to detect cross-sectional retinal pathologies at the micrometer level. In this work, we presented a novel framework to achieve simultaneous retinal layers and fluid segmentation. A dual-branch deep neural network, termed LF-UNet, was proposed which combines the expansion path of the U-Net and original fully convolutional network, with a dilated network. In addition, we introduced a cascaded network framework to include the anatomical awareness embedded in the volumetric image. Cross validation experiments showed that the proposed LF-UNet has superior performance compared to the state-of-the-art methods, and that incorporating the relative positional map structural prior information could further improve the performance regardless of the network. The generalizability of the proposed network was demonstrated on an independent dataset acquired from the same types of device with different field of view, or images acquired from different device.


How to improve WEEE management? Novel approach in mobile collection with application of artificial intelligence.
In global demand of improvement of electrical and electronic waste management systems, stakeholders look for effective collection systems that generate minimal costs. In this study we propose a novel model for application in mobile collection schemes - on demand that waste be taken back from household residents. This type of the waste equipment collection is comfortable for residents as they can indicate day and time windows for the take-back. Collecting companies are interested in lowering operational costs required for service. This lowering includes selection of a sufficient number of vehicles and employees, and then minimising the routes' length in order to achieve savings in fuel consumption, and lowering of emissions. In the proposed model we use a genetic algorithm for optimisation of the route length and number of vehicles and fuzzy logic for representation of the household residents' satisfaction on the take-back service provided by collection companies. Also, modern communication channels like websites or mobile phone applications can be used to send the waste equipment take-back request from the household, so it has the potential to be developed in future applications. The operation of the model has been presented in the case study of a city in southern Poland. The results can be useful for collecting companies and software producers for preparation of new applications to be used in waste collection.


Are Patients With an International Classification of Diseases, 10th Edition Discharge Diagnosis Code for Sepsis Different in Regard to Demographics and Outcome Variables When Comparing Those With Sepsis Only to Those Also Diagnosed With COVID-19 or Those With a COVID-19 Diagnosis Alone?
We analyzed whether patients with the International Classification of Diseases, 10th Edition (ICD-10) discharge diagnosis code for sepsis are different in regard to demographics and outcome variables when comparing those with sepsis only to those also diagnosed with COVID-19 or those with a COVID-19 diagnosis alone. Retrospective cohort study. Nine hospitals in an academic health system. Patients with a final ICD-10 discharge diagnostic code for sepsis only, a diagnosis of COVID-19-only, or a final sepsis ICD-10 discharge code + a diagnosis of COVID-19 admitted to the hospital were analyzed for demographic and outcome differences between the cohorts. None. A total of 11,395 patients met inclusion criteria: 6,945 patients (60.9%) were ICD-10 sepsis code only, 3,294 patients (28.9%) were COVID-19 diagnosis-only, and 1,153 patients (10.1%) were sepsis ICD-10 code + COVID-19 diagnosis. Comparing sepsis ICD-10 code + COVID-19 diagnosis patients to sepsis ICD-10 code only and COVID-19 diagnosis-only patients, the sepsis ICD-10 code + COVID-19 diagnosis patients were: older (69 [58-78] vs 67 [56-77] vs 64 [51-76] yr), less likely to be female (40.3% vs 46.7% vs 49.5%), more frequently admitted to the ICU (59.3% [684/1,153] vs 54.9% [1,810/3,297] vs 15% [1,042/6,945]), more frequently required ventilatory support (39.3% [453/1,153] vs 31.8% [1,049/3,297] vs 6.0% [417/6,945]), had longer median hospital length of stay (9 [5,16] vs 5 [3,8] vs 7. [4,13] d), and were more likely to die in the hospital (39.2% [452/1,153] vs 22.3% [735/3,297] vs 6.4% [444/6,945]). During the COVID-19 pandemic the sickest cohort of patients was those receiving an explicit ICD-10 code of sepsis + a COVID-19 diagnosis. A significant percentage of COVID-19 diagnosis-only patients appear to have been under-coded as they received a level of critical care (ICU admission; intubation) suggestive of the presence of acute organ dysfunction during their admission.


The high-resolution X-ray structure of vinca-domain inhibitors of microtubules provides a rational approach for drug design.
Tubulin vinca-domain ligands can inhibit microtubule polymerization, causing cell death in mitosis, and their potential against multiple cancer types has been demonstrated. However, due to drug resistance and toxicities, development of novel vinca-domain ligands is still needed. In this study, we determined the high-resolution crystal structures of vinorelbine, YXD, and Phomopsin A in complex with tubulin at 2.5 Å. Additionally, we recapitulated all previously published high-resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca-domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt-bridge and H-bond interactions with Asp179β1 and Asn329α2 . Our studies provided the structural basis for designing novel tubulin vinca-domain ligands.


Stabilization of Endothelial Receptor Arrays by a Polarized Spectrin Cytoskeleton Facilitates Rolling and Adhesion of Leukocytes.
Multivalent complexes of endothelial adhesion receptors (e.g., selectins) engage leukocytes to orchestrate their migration to inflamed tissues. Proper anchorage and sufficient density (clustering) of endothelial receptors are required for efficient leukocyte capture and rolling. We demonstrate that a polarized spectrin network dictates the stability of the endothelial cytoskeleton, which is attached to the apical membrane, at least in part, by the abundant transmembrane protein CD44. Single-particle tracking revealed that CD44 undergoes prolonged periods of immobilization as it tethers to the cytoskeleton. The CD44-spectrin "picket fence" alters the behavior of bystander molecules-notably, selectins-curtailing their mobility, inducing their apical accumulation, and favoring their clustering within caveolae. Accordingly, depletion of either spectrin or CD44 virtually eliminated leukocyte rolling and adhesion to the endothelium. Our results indicate that a unique spectrin-based apical cytoskeleton tethered to transmembrane pickets-notably, CD44-is essential for proper extravasation of leukocytes in response to inflammation.


The misuse of the faecal occult blood test under the lower gastrointestinal two week wait rule.
To find the proportion of patients with a faecal occult blood (FOB) performed as part of the referral for the lower gastrointestinal two week wait (2WW) referral system, and whether this correlates with the cancer status. All patients referred to the colorectal cancer service using the 2WW referral criteria, between August 2005 and August 2007, were identified using the hospital's cancer audit database. Faecal occult bloods and cancer status were recorded for each patient. Two thousand one hundred and fifty-nine patients (1177 female: 903 male; median age 58; age range 18-98) were referred by general practitioners. The FOBT was only performed on three samples in all cases. In total, 172 of 2159 patients (7.9%) had an FOB performed prior to their referral, with 55 of 172 patients (31.9%) as part of the referral for 2WW. Sixteen of 172 patients (9.3%) had an FOB performed in the presence of overt rectal bleeding. In only 2 of 172 patients (1.1%) the FOB correlated with a colorectal cancer. Unnecessary testing for FOB costs has cost pound4072.96 in total. A significant number of faecal occult bloods are being performed and the detection rate, even in this symptomatic group of patients, is very low. It is evident that the test is being performed in the community on three samples and not six. This, combined with the high false positive rate, leads to patients not only undergoing unnecessary psycho-social consequences but could potentially lead to significant risks from unnecessary invasive investigation as well as the added financial burden of test itself.


Tacrolimus may induce the production of nucleolar anti-nuclear antibody in liver transplant patients.
Immunosuppressive drugs have been used to prevent graft rejection in most allo-liver recipients and the immune state of these patients differs greatly before and after transplant operation. This study aims at evaluating the immune state of liver transplant patients treated with tacrolimus by investigating the production of anti-nuclear antibodies (ANA). A hundred and eighty-eight serum samples from 94 allo-liver recipients treated with tacrolimus and from 94 patients with matched liver diseases were tested for ANA by indirect immunofluorescence assay with HEp-2 cells as substrate. ANA were detected as positive in 20.2% of the liver transplant patients treated with tacrolimus, and in 12.8% of disease-matched control patients, but this difference was not statistically significant (P=0.17). However, the frequency of nucleolar ANA pattern in ANA-positive cases was significantly higher in the liver transplant patients (63.2%) than in the control group (16.7%) (P=0.01). Tacrolimus may contribute to producing nucleolar ANA in liver transplant patients. The autoimmune disease susceptibility of allo-liver recipients treated with tacrolimus requires further studying.


The Impact of MicroRNA-133a on Prognosis and Clinicopathological Parameters for Digestive System Cancers: a Comprehensive Study Based on Meta-Analysis and TCGA Database.
We conducted a meta-analysis on the impact of microRNA-133a (miR-133a) on digestive system cancers, and verified the results through The Cancer Genome Atlas (TCGA). Relevant studies were searched in English and Chinese database and meta-analysis was performed using Stata 12.0. The corresponding information of miR-133a and digestive system cancers were obtained from TCGA database and analysis was performed using SPSS. Increased miR-133a expression was linked with favorable overall survival (OS) in digestive system cancers (HR = 0.539, 95% CI: 0.416-0.698, P < 0.001), digestive tract cancers (HR =0.558, 95% CI: 0.406-0.767, P < 0.001), esophageal squamous cell carcinoma (ESCC) (HR = 0.427, 95% CI: 0.265-0.690, P = 0.001) and gastric cancer (HR = 0.541, 95% CI: 0.385-0.761, P < 0.001). The expression of miR-133a was significantly lower in cancer tissue compared with adjacent tissue for ESCC (P < 0.001), gastric cancer (P < 0.001), colorectal cancer (P < 0.001) and hepatocellular carcinoma (P = 0.002). Meanwhile, the area under the ROC curve (AUC) value for miR-133a was 0.836, 0.888, and 0.99 in ESCC, gastric cancer and colorectal cancer. MiR-133a is a tumor suppressor with prognostic and diagnostic values for digestive system cancers. High miR-133a expression was associated with better prognosis and less adverse clinicopathological parameters. More research should be performed to test these findings.


Prolonged presence of VEGF promotes vascularization in 3D bioprinted scaffolds with defined architecture.
Timely vascularization is essential for optimal performance of bone regenerative constructs. Vascularization is efficiently stimulated by vascular endothelial growth factor (VEGF), a substance with a short half-life time. This study investigates the controlled release of VEGF from gelatin microparticles (GMPs) as a means to prolong VEGF activity at the preferred location within 3D bioprinted scaffolds, and the effects on subsequent vascularization. The release of VEGF from GMPs was continuous for 3 weeks during in vitro studies, and bioactivity was confirmed using human endothelial progenitor cells (EPCs) in migration assays. Traditional and real-time migration assays showed immediate and efficient EPC migration in the presence of GMP-released VEGF, indistinguishable from VEGF-solution that was added to the medium. Matrigel scaffolds containing EPCs and VEGF, which was released either in a fast or sustained fashion by application of GMPs, were investigated for their in vivo vasculogenic capacity. Implantation in subcutaneous pockets in nude mice for one week demonstrated that vessel formation was significantly higher in the VEGF sustained-release group compared to the fast release group. In addition, regional differences with respect to VEGF release were introduced in 3D bioprinted EPC-laden scaffolds and their influence on vasculogenesis was investigated in vivo. The different regions were retained and vessel formation occurred analogous with the results seen in the Matrigel plugs. We conclude that GMPs are suitable to generate sustained release profiles of bioactive VEGF, and that they can be used to create defined differentiation regions in 3D bioprinted heterogeneous constructs, allowing a new generation of smart scaffold design. The prolonged presence of VEGF led to a significant increase in scaffold vascularization when applied in vivo.


Fat deposition surrounding intracerebral hemorrhage in a patient suffering from Zieve syndrome.
In a 42-year-old man, admitted a few hours after an acute cerebrovascular event, CT demonstrated a hyperdense hemorrhage surrounded by a hypodense rim similar to perifocal edema or liquefying blood, thus raising doubts about the acuteness of the event. Laboratory findings revealed Zieve-syndrome (alcoholic hyperlipemia, hemolytic anemia, and alcoholic fatty liver) and negative Hounsfield Unit measurement of the hypodense rim finally identified it as a layer of fat around the clot.


Dynamics of single cell property distributions in Chinese hamster ovary cell cultures monitored and controlled with automated flow cytometry.
Two important variables that are often not measured online in Chinese hamster ovary (CHO) cell cultures are cell number concentration and culture viability. We have developed an automated flow cytometry system that measured the cell number concentration, single cell viability based on propidium iodide (PI) exclusion, and single cell light scattering from bioreactor samples every 30 min. The bioreactor was monitored during batch growth, and then the cell number concentration was controlled at a set point during cytostat operation. NH(4)Cl was added during steady state operation in cytostat mode to monitor the transient cell population response to adverse growth conditions. The automated measurements correlated well to cell concentration and viability determined manually using a hemacytometer. The described system provides a method to study mammalian cell culture physiology and dynamics in great detail. It presents a new method for the monitoring and control of animal cell culture.


New insights on the potential effect of vinpocetine in Parkinson's disease: one of the neglected warden and baffling topics.
Vinpocetine (VPN) is an ethyl apovincaminate that has anti-inflammatory and antioxidant effects by inhibiting the expression of nuclear factor kappa B (NF-κB) and phosphodiesterase enzyme 1 (PDE-1). VPN is used in the management of stroke, dementia, and other neurodegenerative brain diseases. VPN may be effective in treating Parkinson's disease (PD). Therefore, this review aimed to clarify the mechanistic role of VPN in the management of PD. VPN has protective and restorative effects against neuronal injury by reducing neuroinflammation, and improvement of synaptic plasticity and cerebral blood flow. VPN protects dopaminergic neurons by reducing oxidative stress, lipid peroxidation, glutamate neurotoxicity, and regulation of Ca+ 2 overloads. VPN can alleviate PD neuropathology through its anti-inflammatory, antioxidant, antiapoptotic and neurogenic effects. VPN through inhibition of PDE1 improves cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) signaling in the dopaminergic neurons of the substantia nigra (SN). VPN improves PD neuropathology through PDE1 inhibition with a subsequent increase of the cAMP/cGMP signaling pathway. Therefore, increasing cAMP leads to antioxidant effects, while augmentation of cGMP by VPN leads to anti-inflammatory effects which reduced neurotoxicity and development of motor severity in PD. In conclusion, this review indicated that VPN could be effective in the management of PD.


eHealth 2015 Special Issue: Effects of an Assistance Service on the Quality of Life of Elderly Users.
The 'Confidence' smartphone application aims to support elderly people's independence as long as possible. This paper presents first findings on the impact of the system on elderlies' lives. 41 end-users tested 'Confidence' for six weeks in their daily routine. Before and after the test period the participants assessed their quality of life (QoL). These assessments were analyzed together with additional QoL statements and the usage of 'Confidence' which were collected with questionnaires. Six participants assessed their QoL after the trial better than before and six participants assessed it as worse. Five individuals felt that 'Confidence' positively influenced their life and these five testers had a positive attitude towards 'Confidence' from the start of the trial. After the trial 38 % of the participants said that they felt safer, 37 % communicated more with others, 27 % forgot less, 13 % felt better oriented outside, and 7 % were more on the move due to 'Confidence'. Three percent said that they were less on the move, two percent felt more unsafe and two percent were less outside. 'Confidence' has the potential to affect elderly users' lives. However, within this analysis positive or negative effects of its usage were not correlated with the QoL assessment. A connection between positive attitude towards technology prior use and a positive impact afterwards was found.


Automated reanalysis application to assist in detecting novel gene-disease associations after genome sequencing.
This study aimed to investigate whether a bioinformatics application can streamline genome reanalysis and yield new diagnoses for patients with rare diseases. We developed TierUp to identify variants in new disease genes for unresolved rare disease cases recruited to the 100,000 Genomes Project, all of whom underwent genome sequencing. TierUp uses the NHS Genomic Medicine Service bioinformatics infrastructure by securely accessing case details from the Clinical Interpretation Portal application programming interface and by querying the curated PanelApp database for novel gene-disease associations. We applied TierUp to 948 cases, and a subset of variants were reclassified according to the American College of Medical Genetics and Genomics/Association of Molecular Pathology guidelines. A rare form of spondylometaphyseal dysplasia was diagnosed through TierUp reanalysis, and an additional 4 variants have been reported to date. From a total of 564,441 variants across patients, TierUp highlighted 410 variants present in novel disease genes in under 77 minutes, successfully expediting an important reanalysis strategy. TierUp supports claims that automation can reduce the time taken to reanalyze variants and increase the diagnostic yield from molecular testing. Clinical services should leverage bioinformatics expertise to develop tools that enable routine reanalysis. In addition, services must also explore the ethical, legal, and health economic considerations raised by automation.


Benefit of Rare-Earth "Smart Doping" and Material Nanostructuring for the Next Generation of Er-Doped Fibers.
Erbium-doped fiber amplifiers (EDFAs) for harsh environments require to develop specific fabrication methods of Er 3+-doped fibers (EDFs) so as to limit the impact of radiation-induced absorption. In this context, a compromise has to be found between the concentration of Erbium and the glass composition. On the one hand, high concentration of Er 3+ ions helps to reduce the length of the EDF and hence the cumulated attenuation but generally leads to luminescence quenching mechanisms that limit the performances. On the other hand, so as to avoid such quenching effect, glass modifiers like Al 3+ or P 5+ ions are used in the fabrication of commercial EDFs but are not suitable for applications in harsh environment because these glass modifiers are precursors of radiation-induced structural defects and consequently of optical losses. In this work, we investigate the concept of smart doping via material nanostructuring as a way to fabricate more efficient optical devices. This approach aims at optimizing the glass composition of the fiber core in order to use the minimal content of glass modifiers needed to reach the suited level of performances for EDFA. Er 3+-doped alumina nanoparticles (NPs), as precursor of Er 3+ ions in the preform fabrication process, were used to control the environment of rare-earth ions and their optical properties. Structural and optical characterizations of NP-doped preforms and optical fibers drawn from such preforms demonstrate the interest of this approach for small concentrations of aluminum in comparison to similar glass compositions obtained by a conventional technique.


Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression.
Programmed death-ligand 1 (PD-L1) ensures that tumor cells escape T-cell-mediated tumor immune surveillance. However, gliomas are characteristic of the low immune response and high-resistance therapy, it is necessary to understand molecular regulatory mechanisms in glioblastoma, especially the limited regulation of PD-L1 expression. Herein, we show that low expression of AP-2α is correlated with high expression of PD-L1 in high-grade glioma tissues. AP-2α binds directly to the promoter of the CD274 gene, not only inhibits the transcriptional activity of PD-L1 but enhances endocytosis and degradation of PD-L1 proteins. Overexpression of AP-2α in gliomas enhances CD8+ T cell-mediated proliferation, effector cytokine secretion, and cytotoxicity in vitro. Tfap2a could increase the cytotoxic effect of Cd8+ T cells in CT26, B16F10, and GL261 tumor-immune models, improve anti-tumor immunity, and promote the efficacy of anti-PD-1 therapy. Finally, the EZH2/H3K27Me3/DNMT1 complex mediates the methylation modification of AP-2α gene and maintains low expression of AP-2α in gliomas. 5-Aza-dC (Decitabine) treatment combines with anti-PD-1 immunotherapy to efficiently suppress the progression of GL261 gliomas. Overall, these data support a mechanism of epigenetic modification of AP-2α that contributes to tumor immune evasion, and reactivation of AP-2α synergizes with anti-PD-1 antibodies to increase antitumor efficacy, which may be a broadly applicable strategy in solid tumors.


Age-stratified anti-tuberculosis drug resistance profiles in South Korea: a multicenter retrospective study.
The emergence of drug-resistant tuberculosis (DR-TB) is a major healthcare concern worldwide. Here, we analyzed age-related trends in DR-TB rates in South Korea. Drug susceptibility test results were collected from patients with culture-confirmed TB between 2015 and 2018 from eight university-affiliated hospitals. Patients were divided into three subgroups: younger (15-34 years), middle (35-59 years), and older (≥60 years) to compare drug-resistance patterns. To evaluate trends in age-stratified drug-resistance, chi-square test for linear trends was performed. Among enrolled native patients aged ≥15 years, 4.1% (179/4417), 1.2% (53/4417) and 7.2% (316/4417) were multidrug-resistant TB (MDR-TB), rifampicin-mono-resistant TB (RR-TB), and isoniazid-mono-resistant TB (Hr-TB), respectively. Proportions of Hr-TB cases were 5.4% (40/734), 7.2% (114/1593), and 7.8% (162/2090) in the younger, middle and older age groups, respectively. MDR/RR-TB case rates decreased significantly with age from 8.6% (63/734) in younger age group to 3.3% (68/2090) in older age group. Fluoroquinolone resistance was highest among second-line drugs, and there were no differences in resistance to fluoroquinolones and second-line injectable drugs among the three age groups. The number of MDR/RR-TB cases was highest in young patients. Effective public health interventions should include increased focus on rifampicin resistance in young patients.


Treatment of capillary hemangiomas causing refractive and occlusional amblyopia.
Capillary hemangiomas of the eyelid and orbit are treated when amblyopia secondary to anisometropic astigmatism or pupillary occlusion is present or when rapid growth of the hemangioma threatens to occlude the pupil. The goal of this study was to determine whether treatment of hemangiomas resolves or prevents occlusion or results in decrease in astigmatism. The records of 54 patients who underwent treatment for reduction in the size of a capillary hemangioma causing amblyopia or threatened amblyopia in two pediatric ophthalmology practices were reviewed. Twenty-eight patients were treated for amblyopia due to anisometropic astigmatism. The average amount of pretreatment astigmatism was 2.71 D, while the average amount of post-treatment astigmatism was 0.46 D. Fifteen of these patients could be tested for optotype visual acuity and all had vision acuity of 20/40 or better. Only 1 of the 15 patients treated for threatened occlusion of the pupil developed occlusion. Six of these patients cooperated with optotype visual acuity and all had vision acuity of 20/30 or better. Eleven patients were treated for pupillary occlusion. Occlusion resolved in all cases. Of the five patients treated for occlusion who cooperated with optotype visual acuity, two had a vision acuity of 20/100 or worse. Treatment to reduce the size of capillary hemangiomas results in resolution of occlusion, reduction in astigmatism, and prevention of pupillary occlusion. Those with occlusion are at higher risk for severe residual amblyopia and require prompt and definitive treatment.


Proliferative kinetics of human lymphocytes in culture measured by autoradiography and sister chromatid differential staining.
A simple combination of autoradiography, to determine when a cell synthesized DNA, and sister chromatid differential staining, to determine how many times a cell has divided, was used to follow up the proliferating fate of human lymphocytes in culture. Cells were incubated continuously with 5-bromodeoxyuridine (BrdU) and pulse-labelled with 0.1 muCi/ml [3H]thymidine at various times after stimulation with phytohemagglutinin (PHA). The cells were then harvested at 4 h intervals up to 72 h, and the percentage of labelled mitoses was determined separately in first, second, or third division cells. The data showed that the cycling cells, whether they began cycling at earlier or later times after stimulation, had about the same generation times of 12--14 h. This confirms that the heterogeneity of cell generations seen in short-term lymphocyte cultures is in large part due to the difference in the times when cells began cell cycling in response to PHA.


How Accurate Are We in Detecting Biceps Tendinopathy?
Biceps tendon pain is frequently called biceps "tendinitis," or inflammation of the biceps tendon. Histologic analysis of biceps tendon biopsies demonstrates changes in tenocyte size, ground substance, collagen organization, and vascularity observed with many different tendinopathies. There are distinct symptoms of biceps tendinopathy and a few provocative maneuvers can help make the diagnosis. Imaging studies (eg, MRI) can show changes in signal sequence or tears. However, MRI has a low sensitivity and frequently results in missed or misdiagnosed biceps pathology. Clinical decision making is best guided by a strong clinical suspicion based on patient history, physical examination, and MRI.


High physical activity is associated with post-traumatic stress disorder among individuals aged 15 years and older in South Africa.
Some research seems to suggest that physical activity (PA) was beneficial for post-traumatic stress disorder (PTSD). This study examined the association between levels of PA and PTSD among individuals 15 years and above in South Africa. Community-based survey sample representative of the national population in South Africa. In all, 15 201 individuals (mean age 36.9 years) responded to the cross-sectional South African National Health and Nutrition Examination Survey (SANHANES-1) in 2012. One in five (20.1%) of participants reported exposure to at least one traumatic event in a lifetime, and 2.1% were classified as having a PTSD, 7.9% fulfilled PTSD re-experiencing criteria, 3.0% PTSD avoidance criteria and 4.3% PTSD hyperarousal criteria. Almost half (48.1%) of respondents had low PA, 17.4% moderate PA and 34.5% high PA. In logistic regression analysis, adjusted for age, sex, population group, employment status, residence status, number of trauma types, problem drinking, current tobacco use, sleep problems and depressive symptoms, high PA was associated with PTSD (odds ratio [OR] = 1.75, confidence interval [CI] = 1.11-2.75), PTSD re-experiencing symptom criteria (OR = 1.43, CI = 1.09-1.86) and PTSD avoidance symptom criteria (OR = 1.74, CI = 1.18-2.59), but high PA was not associated with PTSD hyperarousal symptom criteria. In generalised structural equation modelling, total trauma events had a positive direct and indirect effect on PTSD mediated by high PA, and high PA had a positive indirect effect on PTSD, mediated by psychological distress and problem drinking. After controlling for relevant covariates, high PA was associated with increased PTSD symptomatology.