Atomicity and Abstraction for Cross-Blockchain Interactions

A blockchain facilitates secure and atomic transactions between mutually untrusting parties on that chain. Today, there are multiple blockchains with differing interfaces and security properties. Programming in this multi-blockchain world is hindered by the lack of general and convenient abstractions for cross-chain communication and computation. Current cross-chain communication bridges have varied and low-level interfaces, making it difficult to develop portable applications. Current methods for multi-chain atomic transactions are limited in scope to cryptocurrency swaps. This work addresses these issues. We first define a uniform, high-level interface for communication between chains. Building on this interface, we formulate a protocol that guarantees atomicity for general transactions whose operations may span several chains. We formulate and prove the desired correctness and security properties of these protocols. Our prototype implementation is built using the LayerZero cross-chain bridge. Experience with this implementation shows that the new abstractions considerably simplify the design and implementation of multi-chain transactions. Experimental evaluation with multi-chain swap transactions demonstrates performance comparable to that of custom-built implementations

A comparative study of metabolic and hormonal effects of myoinositol vs. metformin in women with polycystic ovary syndrome: a randomised controlled trial

Background: The purpose of the study was to find out which drug is more effective in treatment and improvement of metabolic and hormonal parameters in women with polycystic ovary syndrome (PCOS); Myoinositol or Metformin. This study was conducted since there are very limited studies on the same.Methods: Patients between 15-40 years of age with signs and symptoms of PCOS who attended the outpatient department of obstetrics and gynaecolgy at AVBRH between study period of September, 2012 to August 2014, were subjected to specific investigations to diagnose PCOS. Patients who were diagnosed with PCOS according to the Rotterdam criteria were included in the study group. Patients were randomly allocated to treatment with either myoinositol or metformin. Myoinositol group received 1 g twice daily while Metformin group received 500 mg twice daily for 6 months .The findings and investigations were repeated after 6 months and was compared with the baseline values.Results: Treatment with myoinositol and metformin both decreased body mass index, androgenic features, improved menstrual abnormalities and polycystic ovaries but the Level of insulin resistance as measured by fasting insulin and homeostatic model assessment (HOMA) decreased only on treatment with myoinositol.Conclusions: Myoinositol acts at the level of insulin receptors and is effective in treatment of hyperinsulinemia and insulin resistance, which is the underlying factor leading to the development of polycystic ovary syndrome

Coupling changes in cell shape to chromosome segregation

Animal cells undergo dramatic changes in shape, mechanics and polarity as they progress through the different stages of cell division. These changes begin at mitotic entry, with cell–substrate adhesion remodelling, assembly of a cortical actomyosin network and osmotic swelling, which together enable cells to adopt a near spherical form even when growing in a crowded tissue environment. These shape changes, which probably aid spindle assembly and positioning, are then reversed at mitotic exit to restore the interphase cell morphology. Here, we discuss the dynamics, regulation and function of these processes, and how cell shape changes and sister chromatid segregation are coupled to ensure that the daughter cells generated through division receive their fair inheritance

Cross-cultural adaptation into Punjabi of the English version of the Hospital Anxiety and Depression Scale

BACKGROUND: We wanted to use a Punjabi version of the Hospital Anxiety and Depression Scale (HADS) to enable non-English speaking patients to participate in a clinical trial. The aim of the study was to translate and validate the Hospital Anxiety and Depression Scale into Punjabi. METHODS: The HADS was translated into Punjabi by a multidisciplinary team, verified against the original version, and administered to 73 bilingual patients attending an outpatient clinic. RESULTS: One sample t-tests and the Bland-Altman plots demonstrated acceptable linguistic agreement between the two versions of the HADS. Spearman's rank-order correlation coefficients (p < 0.0001) demonstrate excellent conceptual agreement between each item and its corresponding subscale score, for both versions. Concordance rates revealed that the Punjabi HADS adequately identified borderline cases of anxiety (80.8%), definite cases of anxiety (91.8%) and depression (91.8%), but was less reliable in identifying borderline cases of depression (65.8%). Cronbach alpha coefficients revealed high levels of internal consistency for both the Punjabi and English versions (0.81 and 0.86 for anxiety and 0.71 and 0.85 for depression, respectively). CONCLUSION: The Punjabi HADS is an acceptable, reliable and valid measure of anxiety and depression among physically ill Punjabi speaking people in the United Kingdom

Accuracy and Reliability of Pallor for Detecting Anaemia: A Hospital-Based Diagnostic Accuracy Study

Anaemia is a common disorder. Most health providers in resource poor settings rely on physical signs to diagnose anaemia. We aimed to determine the diagnostic accuracy of pallor for anaemia by using haemoglobin as the reference standard.In May 2007, we enrolled consecutive patients over 12 years of age, able to consent and willing to participate and who had a haemoglobin measurement taken within a day of assessment of clinical pallor from outpatient and medicine inpatient department of a teaching hospital. We did a blind and independent comparison of physical signs (examination of conjunctivae, tongue, palms and nailbed for pallor) and the reference standard (haemoglobin estimation by an electronic cell counter). Diagnostic accuracy was measured by calculating likelihood ratio values and 95% confidence intervals (CI) at different haemoglobin thresholds and area under the receiver operating characteristic curve. Two observers examined a subset of patients (n = 128) to determine the inter-observer agreement, calculated by kappa statistics. We studied 390 patients (mean age 40.1 [SD 17.08] years); of whom 48% were women. The haemoglobin was <7 g/dL in 8% (95% confidence interval, 5, 10) patients; <9 g/dL in 21% (17, 26) patients and <12 g/dL in 64% (60, 70) patients. Among patients with haemoglobin <7 g/dL, presence of severe tongue pallor yielded a LR of 9.87 (2.81, 34.6) and its absence yielded a LR of 0. The tongue pallor outperformed other pallor sites and was also the best discriminator of anaemia at haemoglobin thresholds of 7 g/dL and 9 g/dL (area under the receiver operating characteristic curves (ROC area  = 0.84 [0.77, 0.90] and 0.71[0.64, 0.76]) respectively. The agreement between the two observers for detection of anaemia was poor (kappa values  = 0.07 for conjunctival pallor and 0.20 for tongue pallor).Clinical assessment of pallor can rule out and modestly rule in severe anaemia

Exome Sequencing Implicates Ancestry-Related Mendelian Variation at SYNE1 in Childhood-Onset Essential Hypertension

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope protein 1 (SYNE1), a cardiovascular candidate gene, in 3 of 16 families with early-onset COEH without an antecedent family history. By leveraging exome sequence data from an additional 48 COEH families, 1,700 in-house trios, and publicly available data sets, we demonstrate that compound heterozygous SYNE1 variation in these COEH individuals occurred more often than expected by chance and that this class of biallelic rare variation was significantly enriched among individuals of African genetic ancestry. Using in vitro shRNA knockdown of SYNE1, we show that reduced SYNE1 expression resulted in a substantial decrease in the elasticity of smooth muscle vascular cells that could be rescued by pharmacological inhibition of the downstream RhoA/Rho-associated protein kinase pathway. These results provide insights into the molecular genetics and underlying pathophysiology of COEH and suggest a role for precision therapeutics in the future

A Blood-Based Metabolomic Signature Predictive of Risk for Pancreatic Cancer

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of \u3e13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies

Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients

Recent clinical studies performed in a large number of patients showed that colistin "forgotten" for several decades revived for the management of infections due to multidrug-resistant (MDR) Gram-negative bacteria (GNB) and had acceptable effectiveness and considerably less toxicity than that reported in older publications. Colistin is a rapidly bactericidal antimicrobial agent that possesses a significant postantibiotic effect against MDR Gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The optimal colistin dosing regimen against MDR GNB is still unknown in the intensive care unit (ICU) setting. A better understanding of the pharmacokinetic-pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen. Although pharmacokinetic and pharmacodynamic data in ICU patients are scarce, recent evidence shows that the pharmacokinetics/pharmacodynamics of colistimethate sodium and colistin in critically ill patients differ from those previously found in other groups, such as cystic fibrosis patients. The AUC:MIC ratio has been found to be the parameter best associated with colistin efficacy. To maximize the AUC:MIC ratio, higher doses of colistimethate sodium and alterations in the dosing intervals may be warranted in the ICU setting. In addition, the development of colistin resistance has been linked to inadequate colistin dosing. This enforces the importance of colistin dose optimization in critically ill patients. Although higher colistin doses seem to be beneficial, the lack of colistin pharmacokinetic-pharmacodynamic data results in difficulty for the optimization of daily colistin dose. In conclusion, although colistin seems to be a very reliable alternative for the management of life-threatening nosocomial infections due to MDR GNB, it should be emphasized that there is a lack of guidelines regarding the ideal management of these infections and the appropriate colistin doses in critically ill patients with and without multiple organ failure

Functional selectivity of adenosine receptor ligands

Adenosine receptors are plasma membrane proteins that transduce an extracellular signal into the interior of the cell. Basically every mammalian cell expresses at least one of the four adenosine receptor subtypes. Recent insight in signal transduction cascades teaches us that the current classification of receptor ligands into agonists, antagonists, and inverse agonists relies very much on the experimental setup that was used. Upon activation of the receptors by the ubiquitous endogenous ligand adenosine they engage classical G protein-mediated pathways, resulting in production of second messengers and activation of kinases. Besides this well-described G protein-mediated signaling pathway, adenosine receptors activate scaffold proteins such as β-arrestins. Using innovative and sensitive experimental tools, it has been possible to detect ligands that preferentially stimulate the β-arrestin pathway over the G protein-mediated signal transduction route, or vice versa. This phenomenon is referred to as functional selectivity or biased signaling and implies that an antagonist for one pathway may be a full agonist for the other signaling route. Functional selectivity makes it necessary to redefine the functional properties of currently used adenosine receptor ligands and opens possibilities for new and more selective ligands. This review focuses on the current knowledge of functionally selective adenosine receptor ligands and on G protein-independent signaling of adenosine receptors through scaffold proteins