Andreev Bound States in the Kondo Quantum Dots Coupled to Superconducting Leads

We have studied the Kondo quantum dot coupled to two superconducting leads and investigated the subgap Andreev states using the NRG method. Contrary to the recent NCA results [Clerk and Ambegaokar, Phys. Rev. B 61, 9109 (2000); Sellier et al., Phys. Rev. B 72, 174502 (2005)], we observe Andreev states both below and above the Fermi level.Comment: 5 pages, 5 figure

Clinical Validation of an Ultra High-Throughput Spiral Microfluidics for the Detection and Enrichment of Viable Circulating Tumor Cells

Background: Circulating tumor cells (CTCs) are cancer cells that can be isolated via liquid biopsy from blood and can be phenotypically and genetically characterized to provide critical information for guiding cancer treatment. Current analysis of CTCs is hindered by the throughput, selectivity and specificity of devices or assays used in CTC detection and isolation. Methodology/Principal Findings: Here, we enriched and characterized putative CTCs from blood samples of patients with both advanced stage metastatic breast and lung cancers using a novel multiplexed spiral microfluidic chip. This system detected putative CTCs under high sensitivity (100%, n = 56) (Breast cancer samples: 12–1275 CTCs/ml; Lung cancer samples: 10–1535 CTCs/ml) rapidly from clinically relevant blood volumes (7.5 ml under 5 min). Blood samples were completely separated into plasma, CTCs and PBMCs components and each fraction were characterized with immunophenotyping (Pan-cytokeratin/CD45, CD44/CD24, EpCAM), fluorescence in-situ hybridization (FISH) (EML4-ALK) or targeted somatic mutation analysis. We used an ultra-sensitive mass spectrometry based system to highlight the presence of an EGFR-activating mutation in both isolated CTCs and plasma cell-free DNA (cf-DNA), and demonstrate concordance with the original tumor-biopsy samples. Conclusions/Significance: We have clinically validated our multiplexed microfluidic chip for the ultra high-throughput, low-cost and label-free enrichment of CTCs. Retrieved cells were unlabeled and viable, enabling potential propagation and real-time downstream analysis using next generation sequencing (NGS) or proteomic analysis.Singapore-MIT Alliance for Research and Technolog

Optimization of ex vivo hematopoietic stem cell expansion in intermittent dynamic cultures

For the ex vivo expansion of CD34+ cells, culture conditions were optimized using cytokine cocktails and media change methods. In addition, static, orbital-shake, and stirred cultures were compared. After cultivation, total cell expansion, immunophenotypes, clonogenic ability, and metabolite concentration in media were analyzed. Optimized media change methods enhanced the number of total nucleated cells (TNCs) by 600-fold (from 104 to 6 × 106 cells) in static cultures. Furthermore, intermittent orbital-shake cultures gave the highest fold increase of TNCs and CD34+/CD38− cells. These results imply that proliferation of CD34+ cells in intermittent shake cultures was more efficient than that in static cultures under optimized culture conditions

Theropod courtship: large scale physical evidence of display arenas and avian-like scrape ceremony behaviour by Cretaceous dinosaurs

Relationships between non-avian theropod dinosaurs and extant and fossil birds are a major focus of current paleobiological research. Despite extensive phylogenetic and morphological support, behavioural evidence is mostly ambiguous and does not usually fossilize. Thus, inferences that dinosaurs, especially theropods displayed behaviour analogous to modern birds are intriguing but speculative. Here we present extensive and geographically widespread physical evidence of substrate scraping behavior by large theropods considered as compelling evidence of "display arenas" or leks, and consistent with "nest scrape display" behaviour among many extant ground-nesting birds. Large scrapes, up to 2 m in diameter, occur abundantly at several Cretaceous sites in Colorado. They constitute a previously unknown category of large dinosaurian trace fossil, inferred to fill gaps in our understanding of early phases in the breeding cycle of theropods. The trace makers were probably lekking species that were seasonally active at large display arena sites. Such scrapes indicate stereotypical avian behaviour hitherto unknown among Cretaceous theropods, and most likely associated with terrirorial activity in the breeding season. The scrapes most probably occur near nesting colonies, as yet unknown or no longer preserved in the immediate study areas. Thus, they provide clues to paleoenvironments where such nesting sites occurred

Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison

We compared concurrent combination chemotherapy and radiotherapy with surgery and adjuvant radiotherapy in patients with stage III/IV nonmetastatic squamous cell head and neck cancer. Patients with non-nasopharyngeal and nonsalivary resectable squamous cell head and neck cancer were randomised to receive either surgery followed by adjuvant radiotherapy (60 Gy over 30 fractions) or concurrent combination chemotherapy and radiotherapy (66 Gy in 33 fractions). Combination chemotherapy comprised two cycles of i.v. cisplatin 20 mg m− 2 day− 1 and i.v. 5-fluorouracil 1000 mg m− 2 day− 1, both to run over 96 h given on days 1 and 28 of the radiotherapy. A total of 119 patients were randomised. At a median follow-up of 6 years, there was no significant difference in the 3-year disease-free survival rate between the surgery and concurrent chemoradiotherapy (50 vs 40% respectively). The overall organ preservation rate or avoidance of surgery to primary site was 45%. Those with laryngeal/hypopharyngeal disease subsite had a higher organ-preservation rate than the rest (68 vs 30%). Combination chemotherapy and concurrent irradiation with salvage surgery was not superior to conventional surgery and postoperative radiotherapy for resectable advanced squamous cell head and neck cancer. However, this form of treatment schedule with a view to organ-preservation can be attempted especially for those with laryngeal/hypopharyngeal and possibly oropharyngeal disease subsites

EGb761, a Ginkgo Biloba Extract, Is Effective Against Atherosclerosis In Vitro, and in a Rat Model of Type 2 Diabetes

BACKGROUND: EGb761, a standardized Ginkgo biloba extract, has antioxidant and antiplatelet aggregation and thus might protect against atherosclerosis. However, molecular and functional properties of EGb761 and its major subcomponents have not been well characterized. We investigated the effect of EGb761 and its major subcomponents (bilobalide, kaemferol, and quercetin) on preventing atherosclerosis in vitro, and in a rat model of type 2 diabetes. METHODS AND RESULTS: EGb761 (100 and 200 mg/kg) or normal saline (control) were administered to Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, for 6 weeks (from 3 weeks before to 3 weeks after carotid artery injury). Immunohistochemical staining was performed to investigate cell proliferation and apoptosis in the injured arteries. Cell migration, caspase-3 activity and DNA fragmentation, monocyte adhesion, and ICAM-1/VCAM-1 levels were explored in vitro. Treatment with EGb761 dose-dependently reduced intima-media ratio, proliferation of vascular smooth muscle cells (VSMCs) and induced greater apoptosis than the controls. Proliferation and migration of VSMCs in vitro were also decreased by the treatment of EGb761. Glucose homeostasis and circulating adiponectin levels were improved, and plasma hsCRP concentrations were decreased in the treatment groups. Caspase-3 activity and DNA fragmentation increased while monocyte adhesion and ICAM-1/VCAM-1 levels decreased significantly. Among subcomponents of EGb761, kaemferol and quercetin reduced VSMC migration and increased caspase activity. CONCLUSIONS: EGb761 has a protective role in the development of atherosclerosis and is a potential therapeutic agent for preventing atherosclerosis

Why do women not use antenatal services in low and middle income countries? A metasynthesis of qualitative studies

Background: Almost 50% of women in low & middle income countries (LMIC’s) don’t receive adequate antenatal care. Women’s views can offer important insights into this problem. Qualitative studies exploring inadequate use of antenatal services have been undertaken in a range of countries, but the findings are not easily transferable. We aimed to inform the development of future antenatal care programmes through a synthesis of findings in all relevant qualitative studies. Methods and Findings: Using a pre-determined search strategy, we identified robust qualitative studies reporting on the views and experiences of women in LMIC’s who received inadequate antenatal care. We used meta-ethnographic techniques to generate themes and a line of argument synthesis. We derived policy relevant hypotheses from the findings. We included 21 papers representing the views of more than 1230 women from 15 countries. Three key themes were identified: ‘Pregnancy as socially risky and physiologically healthy’; ‘Resource use and survival in conditions of extreme poverty’and ‘Not getting it right first time’. The line of argument synthesis describes a dissonance between programme design and cultural contexts that may restrict access and discourage return visits. We hypothesize that centralized, risk-focused antenatal care programmes may be at odds with the resources, beliefs and experiences of pregnant women who underuse antenatal services. Conclusions: Our findings suggest that there may be a mis-alignment between current antenatal provision and the social and cultural context of some women in LMIC’s. Antenatal care provision that is theoretically and contextually at odds with local contextual beliefs and experiences are likely to be underused, especially when attendance generates increased personal risks of lost family resource or physical danger during travel; when the promised care is not delivered due to resource constraints; and when women experience covert or overt abuse in care settings

Auto-aggressive metallic mercury injection around the knee joint: a case report

<p>Abstract</p> <p>Background</p> <p>Accidental or intentional subcutaneous and/or intramuscular injection of metallic mercury is an uncommon form of poisoning. Although it does not carry the same risk as mercury vapour inhalation, it may cause destructive early and late reactions.</p> <p>Case Presentation</p> <p>Herein we present the case of a 29-year-old male patient who developed an obsessive-compulsive disorder causing auto-aggressive behaviour with injection of elemental mercury and several other foreign bodies into the soft tissues around the left knee about 15 years before initial presentation. For clinical examination X-rays and a CT-scan of the affected area were performed. Furthermore, blood was taken to determine the mercury concentration in the blood, which showed a concentration 17-fold higher than recommended. As a consequence, the mercury depots and several foreign bodies were resected marginally.</p> <p>Conclusion</p> <p>Blood levels of mercury will decrease rapidly following surgery, especially in combination with chelating therapy. In case of subcutaneous and intramuscular injection of metallic mercury we recommend marginal or wide excision of all contaminated tissue to prevent migration of mercury and chronic inflammation. Nevertheless, prolonged clinical and biochemical monitoring should be performed for several years to screen for chronic intoxication.</p

Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non -diabetic patients with chronic kidney disease (DIAMOND):a randomised, double-blind, crossover trial

Background: SGLT2 inhibition decreases albuminuria and reduces the risk of kidney disease progression in patients with type 2 diabetes. These benefits are unlikely to be mediated by improvements in glycaemic control alone. Therefore, we aimed to examine the kidney effects of the SGLT2 inhibitor dapagliflozin in patients with proteinuric kidney disease without diabetes. Methods: DIAMOND was a randomised, double-blind, placebo-controlled crossover trial done at six hospitals in Canada, Malaysia, and the Netherlands. Eligible participants were adult patients (aged 18–75 years) with chronic kidney disease, without a diagnosis of diabetes, with a 24-h urinary protein excretion greater than 500 mg and less than or equal to 3500 mg and an estimated glomerular filtration rate (eGFR) of at least 25 mL/min per 1·73 m2, and who were on stable renin–angiotensin system blockade. Participants were randomly assigned (1:1) to receive placebo and then dapagliflozin 10 mg per day or vice versa. Each treatment period lasted 6 weeks with a 6-week washout period in between. Participants, investigators, and study personnel were masked to assignment throughout the trial and analysis. The primary outcome was percentage change from baseline in 24-h proteinuria during dapagliflozin treatment relative to placebo. Secondary outcomes were changes in measured GFR (mGFR; via iohexol clearance), bodyweight, blood pressure, and concentrations of neurohormonal biomarkers. Analyses were done in accordance with the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03190694. Findings: Between Nov 22, 2017, and April 5, 2019, 58 patients were screened, of whom 53 (mean age 51 years [SD 13]; 32% women) were randomly assigned (27 received dapagliflozin then placebo and 26 received placebo then dapagliflozin). One patient discontinued during the first treatment period. All patients were included in the analysis. Mean baseline mGFR was 58·3 mL/min per 1·73 m2 (SD 23), median proteinuria was 1110 mg per 24 h (IQR 730–1560), and mean HbA1c was 5·6% (SD 0·4). The difference in mean proteinuria change from baseline between dapagliflozin and placebo was 0·9% (95% CI −16·6 to 22·1; p=0·93). Compared with placebo, mGFR was changed with dapagliflozin treatment by −6·6 mL/min per 1·73 m2 (–9·0 to −4·2; p<0·0001) at week 6. This reduction was fully reversible within 6 weeks after dapagliflozin discontinuation. Compared with placebo, bodyweight was reduced by 1·5 kg (0·03–3·0; p=0·046) with dapagliflozin; changes in systolic and diastolic blood pressure and concentrations of neurohormonal biomarkers did not differ significantly between dapagliflozin and placebo treatment. The numbers of patients who had one or more adverse events during dapagliflozin treatment (17 [32%] of 53) and during placebo treatment (13 [25%] of 52) were similar. No hypoglycaemic events were reported and no deaths occurred. Interpretation: 6-week treatment with dapagliflozin did not affect proteinuria in patients with chronic kidney disease without diabetes, but did induce an acute and reversible decline in mGFR and a reduction in bodyweight. Long-term clinical trials are underway to determine whether SGLT2 inhibitors can safely reduce the rate of major clinical kidney outcomes in patients with chronic kidney disease with and without diabetes. Funding: AstraZeneca