Synthesis of Imidazo[4,5‐b]quinoxaline Ribonucleosides as Linear Dimensional Analogs of Antiviral Polyhalogenated Benzimidazole Ribonucleosides

We have recently found that 2,5,6‐trichloro‐1‐(β‐D‐ribofuranosyl)benzimidazole (TCRB) and the corresponding 2‐bromo analog have better in vitro activities against HCMV than the clinically used agents ganciclovir and foscarnet. These benzimidazole nucleosides act by a unique mechanism, however, their biological target has not been completely identified. As an approach to probing the target, we have designed imidazo[4,5‐b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole nucleosides to study the spatial limitation of the binding site in the target enzyme. A convenient route was developed for the synthesis of 2‐substituted 6,7‐dichloroimidazo[4,5‐b]quinoxalines involving a reaction of 2,3,6,7‐tetrachloroquinoxaline with ammonia followed by a ring annulation as the key step. This furnished the versatile heterocycle 6,7‐dichloroimidazo[4,5‐b]quinoxalin‐2‐one. Ribosylation of 2‐substituted imidazo[4,5‐b]quinoxalines was influenced by the functional group at the 2‐position and the 2‐one compound was found to smoothly undergo ribosylation. The 2‐one group of the nucleoside was converted into specifically selected 2‐substituted compounds. Evaluation of the compounds for activity against two herpesviruses and for cytotoxicity showed they were less active and/or more cytotoxic than TCRB. We conclude therefore, that the binding pocket on the protein target of TCRB will tolerate some electronic and size changes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112195/1/199800071_ftp.pd

Latent-Variable Synchronous CFGs for Hierarchical Translation

Data-driven refinement of non-terminal categories has been demonstrated to be a reliable technique for improving mono-lingual parsing with PCFGs. In this pa-per, we extend these techniques to learn latent refinements of single-category syn-chronous grammars, so as to improve translation performance. We compare two estimators for this latent-variable model: one based on EM and the other is a spec-tral algorithm based on the method of mo-ments. We evaluate their performance on a Chinese–English translation task. The re-sults indicate that we can achieve signifi-cant gains over the baseline with both ap-proaches, but in particular the moments-based estimator is both faster and performs better than EM.

Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al

The University of California San Francisco, Brain Metastases Stereotactic Radiosurgery (UCSF-BMSR) MRI Dataset

The University of California San Francisco Brain Metastases Stereotactic Radiosurgery (UCSF-BMSR) dataset is a public, clinical, multimodal brain MRI dataset consisting of 560 brain MRIs from 412 patients with expert annotations of 5136 brain metastases. Data consists of registered and skull stripped T1 post-contrast, T1 pre-contrast, FLAIR and subtraction (T1 pre-contrast - T1 post-contrast) images and voxelwise segmentations of enhancing brain metastases in NifTI format. The dataset also includes patient demographics, surgical status and primary cancer types. The UCSF-BSMR has been made publicly available in the hopes that researchers will use these data to push the boundaries of AI applications for brain metastases.Comment: 15 pages, 2 tables, 2 figure

Diagnosis of depression among adolescents – a clinical validation study of key questions and questionnaire

<p>Abstract</p> <p>Background</p> <p>The objective of the study is to improve general practitioners' diagnoses of adolescent depression. Major depression is ranked fourth in the worldwide disability impact.</p> <p>Method/Design</p> <p>Validation of 1) three key questions, 2) SCL-dep6, 3) SCL-10, 4) 9 other SCL questions and 5) WHO-5 in a clinical study among adolescents. The Composite International Diagnostic Interview (CIDI) is to be used as the gold standard interview. The project is a GP multicenter study to be conducted in both Norway and Denmark. Inclusion criteria are age (14–16) and fluency in the Norwegian and Danish language. A number of GPs will be recruited from both countries and at least 162 adolescents will be enrolled in the study from the patient lists of the GPs in each country, giving a total of at least 323 adolescent participants.</p> <p>Discussion</p> <p>The proportion of adolescents suffering from depressive disorders also seems to be increasing worldwide. Early interventions are known to reduce this illness. The earlier depression can be identified in adolescents, the greater the advantage. Therefore, we hope to find a suitable questionnaire that could be recommended for GPs.</p

Evaluating the cost implications of integrating SARS-CoV-2 genome sequencing for infection prevention and control investigation of nosocomial transmission within hospitals

OBJECTIVES: The COG-UK hospital-onset COVID-19 infection (HOCI) trial evaluated the impact of SARS-CoV-2 whole genome sequencing (WGS) on acute infection, prevention, and control (IPC) investigation of nosocomial transmission within hospitals. We estimated the cost implications of using the information from the sequencing reporting tool (SRT), used to determine likelihood of nosocomial infection in IPC practice. METHODS: We conducted a micro-costing approach for SARS-CoV-2 WGS. Data on IPC management resource use and costs were collected from interviews with IPC teams from 14 participating sites and used to assign cost estimates for IPC activities as collected in the trial. Activities included IPC specific actions following a suspicion of healthcare-associated infection (HAI) or outbreak, as well as changes to practice following the return of data via SRT. RESULTS: The mean per sample costs of SARS-CoV-2 sequencing was estimated at £77.10 for rapid and £66.94 for longer turnaround phases. Over the 3 months interventional phases, the total management cost of IPC-defined HAIs and outbreak events across the sites was estimated at £225,070 and £416,447, respectively. Main cost drivers were bed-day lost due to wards closures because of outbreaks followed by outbreak meetings and bed-day lost due to cohorting contacts. Actioning SRTs, the cost of HAIs increased by £5,178 due to unidentified cases and the cost of outbreaks lowered by £11,246 as SRTs excluded hospital outbreaks. CONCLUSIONS: Although, SARS-CoV-2 WGS adds to the total IPC management cost, additional information provided could balance out the additional cost, depending on identified design improvements and effective deployment

Assessing the Brazilian surgical system with six surgical indicators: a descriptive and modelling study

Background: Brazil boasts a health scheme that aspires to provide universal coverage, but its surgical system has rarely been analyzed. In an effort to strengthen surgical systems worldwide, the Lancet Commission on Global Surgery proposed collection of six standardized indicators: two-hour access to surgery, surgical workforce density, surgical volume, perioperative mortality rate (POMR), and protection against impoverishing and catastrophic expenditure. This study aims to characterize the Brazilian surgical health system with these newly devised indicators while gaining understanding on the complexity of the indicators themselves. Methods: Using Brazil’s national healthcare database, commonly reported healthcare variables were used to calculate or simulate the six surgical indicators. Access to surgery was calculated using hospital locations, surgical workforce density was calculated using locations of surgeons, anesthesiologists and obstetricians (SAO), and surgical volume and POMR were identified with surgical procedure codes. The rates of protection against impoverishing and catastrophic expenditure were modelled using cost of inpatient hospitalization and a gamma distribution of incomes based on GINI and GDP/capita. Findings: In 2014, SAO density is 34·7/100,000 population, surgical volume is 4,433 procedures/100,000 people and POMR is 1·71%. 79·4% of surgical patients are protected against impoverishing expenditure and 84·6% were protected against catastrophic expenditure due to surgery each year. Two-hour access to surgery was not able to be calculated from national health data, but a proxy measure suggested that 97·2% of the population has two-hour access to a hospital that may be able to provide surgery. Geographic disparities were seen in all indicators. Interpretation: Brazil‘s public surgical system meets several key benchmarks. Geographic disparities, however, are substantial and raise concerns of equity. Policies should focus on stimulating appropriate geographic allocation of the surgical workforce. In some cases, where benchmarks for each indicator are met, supplemental analysis can further inform our understanding of health systems. This measured and systematic evaluation of surgical systems should be encouraged for all nations seeking to better understand their surgical systems. Funding: There was no funding for this study

Suicidal thoughts and depressive feelings amongst Estonian schoolchildren: effect of family relationship and family structure

Depressive feelings and suicidal ideation in a non-clinical sample of adolescents in Estonia were analysed in the context of family structure, mutual relationships amongst family members and schoolchildren's preferences regarding intimate personal contacts with particular family members. Data from the WHO collaborative study 'Health Behaviour in School-aged Children 2005/2006' (HBSC) were used. A representative sample of schoolchildren aged 11, 13 and 15 years completed the semi-structured questionnaire. The analyses included only adolescents living in households with at least one birth parent. The subjects were 4,389 schoolchildren (2,178 boys and 2,211 girls), who were divided into three groups based on: (1) suicidal thoughts, with or without depressive feelings; (2) depressive feelings; and (3) neither suicidal thoughts nor depressive feelings. Multinomial logistic regression was used. The proportion of depressive feelings increased with age for both boys and girls. Girls expressed depressive feelings more frequently than boys from ages 13 and 15 years, and suicidal thoughts from age 15 years. Self-reported satisfaction with relationships in the family reduced the likelihood of depressive feelings and suicidal thoughts. Good communication with the parents reduced the likelihood of suicidal thoughts in all age groups. Adolescents who were satisfied with their family relationships suffered less frequently from depressive feelings and suicidal thoughts. The best environment for an adolescent was a family with both birth parents. Of the adolescents in 'non-intact' families, those with a step-parent in the family showed suicidal thoughts more frequently than those in single-parent families. Associations between family-related variables and suicidal thoughts were significant even after adjusting for family economic deprivation score

COVID-19 and informal settlements: An urgent call to rethink urban governance

While some countries are nearing or reaching their peak of coronavirus infections, others are only at what seems to be the early stages of the infection curve. Some of these countries, particularly in the Global South, contain some of the world’s largest informal and/or urban settlements and are low resource settings. Given that the last few months have shown us how quickly COVID-19 can push health systems to the brink or overwhelm them, even in high-income countries, it is worrying to think what would happen if the outbreak becomes severe in such contexts