Towards an Understanding of Changing-Look Quasars: An Archival Spectroscopic Search in SDSS

The uncertain origin of the recently-discovered `changing-looking' quasar phenomenon -- in which a luminous quasar dims significantly to a quiescent state in repeat spectroscopy over ~10 year timescales -- may present unexpected challenges to our understanding of quasar accretion. To better understand this phenomenon, we take a first step to building a sample of changing-look quasars with a systematic but simple archival search for these objects in the Sloan Digital Sky Survey Data Release 12. By leveraging the >10 year baselines for objects with repeat spectroscopy, we uncover two new changing-look quasars, and a third discovered previously. Decomposition of the multi-epoch spectra and analysis of the broad emission lines suggest that the quasar accretion disk emission dims due to rapidly decreasing accretion rates (by factors of >2.5), while disfavoring changes in intrinsic dust extinction for the two objects where these analyses are possible. Broad emission line energetics also support intrinsic dimming of quasar emission as the origin for this phenomenon rather than transient tidal disruption events or supernovae. Although our search criteria included quasars at all redshifts and transitions from either quasar-like to galaxy-like states or the reverse, all of the clear cases of changing-look quasars discovered were at relatively low-redshift (z ~ 0.2 - 0.3) and only exhibit quasar-like to galaxy-like transitions.Comment: 15 pages, 8 figures. Updated to accepted versio

Emergency and urgent care capacity in a resource-limited setting: an assessment of health facilities in western Kenya

Objective: Injuries, trauma and non-communicable diseases are responsible for a rising proportion of death and disability in low-income and middle-income countries. Delivering effective emergency and urgent healthcare for these and other conditions in resource-limited settings is challenging. In this study, we sought to examine and characterise emergency and urgent care capacity in a resource-limited setting. Methods: We conducted an assessment within all 30 primary and secondary hospitals and within a stratified random sampling of 30 dispensaries and health centres in western Kenya. The key informants were the most senior facility healthcare provider and manager available. Emergency physician researchers utilised a semistructured assessment tool, and data were analysed using descriptive statistics and thematic coding. Results: No lower level facilities and 30% of higher level facilities reported having a defined, organised approach to trauma. 43% of higher level facilities had access to an anaesthetist. The majority of lower level facilities had suture and wound care supplies and gloves but typically lacked other basic trauma supplies. For cardiac care, 50% of higher level facilities had morphine, but a minority had functioning ECG, sublingual nitroglycerine or a defibrillator. Only 20% of lower level facilities had glucometers, and only 33% of higher level facilities could care for diabetic emergencies. No facilities had sepsis clinical guidelines. Conclusions: Large gaps in essential emergency care capabilities were identified at all facility levels in western Kenya. There are great opportunities for a universally deployed basic emergency care package, an advanced emergency care package and facility designation scheme, and a reliable prehospital care transportation and communications system in resource-limited settings

Acute cellular and vascular responses to photodynamic therapy using EGFR-targeted nanobody-photosensitizer conjugates studied with intravital optical imaging and magnetic resonance imaging

Targeted photodynamic therapy (PDT) has the potential to selectively damage tumor tissue and to increase tumor vessel permeability. Here we characterize the tissue biodistribution of two EGFR-targeted nanobody-photosensitizer conjugates (NB-PS), the monovalent 7D12-PS and the biparatopic 7D12-9G8-PS. In addition, we report on the local and acute phototoxic effects triggered by illumination of these NB-PS which have previously shown to lead to extensive tumor damage. Methods: Intravital microscopy and the skin-fold chamber model, containing OSC-19-luc2-cGFP tumors, were used to investigate: a) the fluorescence kinetics and distribution, b) the vascular response and c) the induction of necrosis after illumination at 1 or 24 h post administration of 7D12-PS and 7D12-9G8-PS. In addition, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of a solid tumor model was used to investigate the microvascular status 2 h after 7D12-PS mediated PDT. Results: Image analysis showed significant tumor colocalization for both NB-PS which was higher for 7D12-9G8-PS. Intravital imaging showed clear tumor cell membrane localization 1 and 2 h after administration of 7D12-9G8-PS, and fluorescence in or close to endothelial cells in normal tissue for both NB-PS. PDT lead to vasoconstriction and leakage of tumor and normal tissue vessels in the skin-fold chamber model. DCE-MRI confirmed the reduction of tumor perfusion after 7D12-PS mediated PDT. PDT induced extensive tumor necrosis and moderate normal tissue damage, which was similar for both NB-PS conjugates. This was significantly reduced when illumination was performed at 24 h com

Gene Expression Profile Identifies Tyrosine Kinase c-Met as a Targetable Mediator of Antiangiogenic Therapy Resistance

PURPOSE: To identify mediators of glioblastoma anti-angiogenic therapy resistance and target these mediators in xenografts. EXPERIMENTAL DESIGN: We performed microarray analysis comparing bevacizumab-resistant glioblastomas (BRGs) to pre-treatment tumors from the same patients. We established novel xenograft models of anti-angiogenic therapy resistance to target candidate resistance mediator(s). RESULTS: BRG microarray analysis revealed upregulation versus pre-treatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pre-treatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met-activated focal adhesion kinase (FAK) and STAT3. We developed two novel xenograft models of anti-angiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pre-treatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met shRNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts. CONCLUSION: These findings support the role of c-Met in survival in hypoxia and invasion, features associated with anti-angiogenic therapy resistance; and growth and therapeutic resistance of xenografts resistant to anti-angiogenic therapy. Therapeutically targeting c-Met could prevent or overcome anti-angiogenic therapy resistance

An Expert Consensus Statement on the Management of Large Chondral and Osteochondral Defects in the Patellofemoral Joint

© The Author(s) 2020. Background: Cartilage lesions of the patellofemoral joint constitute a frequent abnormality. Patellofemoral conditions are challenging to treat because of complex biomechanics and morphology. Purpose: To develop a consensus statement on the functional anatomy, indications, donor graft considerations, surgical treatment, and rehabilitation for the management of large chondral and osteochondral defects in the patellofemoral joint using a modified Delphi technique. Study Design: Consensus statement. Methods: A working group of 4 persons generated a list of statements related to the functional anatomy, indications, donor graft considerations, surgical treatment, and rehabilitation for the management of large chondral and osteochondral defects in the patellofemoral joint to form the basis of an initial survey for rating by a group of experts. The Metrics of Osteochondral Allografts (MOCA) expert group (composed of 28 high-volume cartilage experts) was surveyed on 3 occasions to establish a consensus on the statements. In addition to assessing agreement for each included statement, experts were invited to propose additional statements for inclusion or to suggest modifications of existing statements with each round. Predefined criteria were used to refine statement lists after each survey round. Statements reaching a consensus in round 3 were included within the final consensus document. Results: A total of 28 experts (100% response rate) completed 3 rounds of surveys. After 3 rounds, 36 statements achieved a consensus, with over 75% agreement and less than 20% disagreement. A consensus was reached in 100.00% of the statements relating to functional anatomy of the patellofemoral joint, 88.24% relating to surgical indications, 100.00% relating to surgical technical aspects, and 100.00% relating to rehabilitation, with an overall consensus of 95.5%. Conclusion: This study established a strong expert consensus document relating to the functional anatomy, surgical indications, donor graft considerations for osteochondral allografts, surgical technical aspects, and rehabilitation concepts for the management of large chondral and osteochondral defects in the patellofemoral joint. Further research is required to clinically validate the established consensus statements and better understand the precise indications for surgery as well as which techniques and graft processing/preparation methods should be used based on patient- and lesion-specific factors

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

The Rural Household Multiple Indicator Survey, data from 13,310 farm households in 21 countries

The Rural Household Multiple Indicator Survey (RHoMIS) is a standardized farm household survey approach which collects information on 758 variables covering household demographics, farm area, crops grown and their production, livestock holdings and their production, agricultural product use and variables underlying standard socio-economic and food security indicators such as the Probability of Poverty Index, the Household Food Insecurity Access Scale, and household dietary diversity. These variables are used to quantify more than 40 different indicators on farm and household characteristics, welfare, productivity, and economic performance. Between 2015 and the beginning of 2018, the survey instrument was applied in 21 countries in Central America, sub-Saharan Africa and Asia. The data presented here include the raw survey response data, the indicator calculation code, and the resulting indicator values. These data can be used to quantify on- and off-farm pathways to food security, diverse diets, and changes in poverty for rural smallholder farm households

PDCD1 Polymorphisms May Predict Response to Anti-PD-1 Blockade in Patients With Metastatic Melanoma

A significant number of patients (pts) with metastatic melanoma do not respond to anti-programmed cell death 1 (PD1) therapies. Identifying predictive biomarkers therefore remains an urgent need. We retrospectively analyzed plasma DNA of pts with advanced melanoma treated with PD-1 antibodies, nivolumab or pembrolizumab, for five PD-1 genotype single nucleotide polymorphisms (SNPs): PD1.1 (rs36084323, G>A), PD1.3 (rs11568821, G>A), PD1.5 (rs2227981, C>T) PD1.6 (rs10204225, G>A) and PD1.9 (rs2227982, C>T). Clinico-pathological and treatment parameters were collected, and presence of SNPs correlated with response, progression free survival (PFS) and overall survival (OS). 115 patients were identified with a median follow up of 18.7 months (range 0.26 – 52.0 months). All were Caucasian; 27% BRAF V600 mutation positive. At PD-1 antibody commencement, 36% were treatment-naïve and 52% had prior ipilimumab. The overall response rate was 43%, 19% achieving a complete response. Overall median PFS was 11.0 months (95% CI 5.4 - 17.3) and median OS was 31.1 months (95% CI 23.2 - NA). Patients with the G/G genotype had more complete responses than with A/G genotype (16.5% vs. 2.6% respectively) and the G allele of PD1.3 rs11568821 was significantly associated with a longer median PFS than the AG allele, 14.1 vs. 7.0 months compared to the A allele (p=0.04; 95% CI 0.14 – 0.94). No significant association between the remaining SNPs and responses, PFS or OS were observed. Despite limitations in sample size, this is the first study to demonstrate an association of a germline PD-1 polymorphism and PFS in response to anti-PD-1 therapy in pts with metastatic melanoma. Extrinsic factors like host germline polymorphisms should be considered with tumor intrinsic factors as predictive biomarkers for immune checkpoint regulators

Beyond the ‘East-West’ dichotomy: global variation in cultural models of selfhood

Markus and Kitayama’s (1991) theory of independent and interdependent self-construals had a major influence on social, personality, and developmental psychology by highlighting the role of culture in psychological processes. However, research has relied excessively on contrasts between North American and East Asian samples, and commonly used self-report measures of independence and interdependence frequently fail to show predicted cultural differences. We revisited the conceptualization and measurement of independent and interdependent self-construals in 2 large-scale multinational surveys, using improved methods for cross-cultural research. We developed (Study 1: N = 2924 students in 16 nations) and validated across cultures (Study 2: N = 7279 adults from 55 cultural groups in 33 nations) a new 7-dimensional model of self-reported ways of being independent or interdependent. Patterns of global variation support some of Markus and Kitayama’s predictions, but a simple contrast between independence and interdependence does not adequately capture the diverse models of selfhood that prevail in different world regions. Cultural groups emphasize different ways of being both independent and interdependent, depending on individualism-collectivism, national socioeconomic development, and religious heritage. Our 7-dimensional model will allow future researchers to test more accurately the implications of cultural models of selfhood for psychological processes in diverse ecocultural contexts