Fulvestrant treatment of precocious puberty in girls with McCune-Albright syndrome

BACKGROUND: McCune-Albright Syndrome (MAS) is usually characterized by the triad of precocious puberty (PP), fibrous dysplasia, and café au lait spots. Previous treatments investigated for PP have included aromatase inhibitors and the estrogen receptor modulator, tamoxifen. Although some agents have been partially effective, the optimal pharmacologic treatment of PP in girls with MAS has not been identified. The objective of this study was to evaluate the safety and efficacy of fulvestrant (Faslodex(TM)), a pure estrogen receptor antagonist, in girls with progressive precocious puberty (PP) associated with McCune-Albright Syndrome (MAS). METHODS: In this prospective international multicenter trial, thirty girls ≤ 10 years old with MAS and progressive PP received fulvestrant 4 mg/kg via monthly intramuscular injections for 12 months. Changes in vaginal bleeding, rates of bone age advancement, growth velocity, Tanner staging, predicted adult heights, and uterine and ovarian volumes were measured. RESULTS: Median vaginal bleeding days decreased from 12.0 days per year to 1.0 day per year, with a median change in frequency of -3.6 days, (95% confidence interval (CI) -10.10, 0.00; p = 0.0146). Of patients with baseline bleeding, 74% experienced a ≥50% reduction in bleeding, and 35% experienced complete cessation during the study period (95% CI 51.6%, 89.8%; 16.4%, 57.3%, respectively). Average rates of bone age advancement (ΔBA/ΔCA) decreased from 1.99 pre-treatment to 1.06 on treatment (mean change -0.93, 95% CI -1.43, -0.43; p = 0.0007). No significant changes in uterine volumes or other endpoints or serious adverse events occurred. CONCLUSIONS: Fulvestrant was well tolerated and moderately effective in decreasing vaginal bleeding and rates of skeletal maturation in girls with MAS. Longer-term studies aimed at further defining potential benefits and risks of this novel therapeutic approach in girls with MAS are needed. TRIAL REGISTRATION: NCT0027891

Reefs at Risk: A Map-Based Indicator of Threats to the Worlds Coral Reefs

This report presents the first-ever detailed, map-based assessment of potential threats to coral reef ecosystems around the world. "Reefs at Risk" draws on 14 data sets (including maps of land cover, ports, settle-ments, and shipping lanes), information on 800 sites known to be degraded by people, and scientific expertise to model areas where reef degradation is predicted to occur, given existing human pressures on these areas. Results are an indicator of potential threat (risk), not a measure of actual condition. In some places, particularly where good management is practiced, reefs may be at risk but remain relatively healthy. In others, this indicator underestimates the degree to which reefs are threatened and degraded.Our results indicate that:Fifty-eight percent of the world's reefs are poten-tially threatened by human activity -- ranging from coastal development and destructive fishing practices to overexploitation of resources, marine pollution, and runoff from inland deforestation and farming.Coral reefs of Asia (Southeastern); the most species-rich on earth, are the most threatened of any region. More than 80 percent are at risk (undermedium and high potential threat), and over half are at high risk, primarily from coastal development and fishing-related pressures.Overexploitation and coastal development pose the greatest potential threat of the four risk categories considered in this study. Each, individually, affects a third of all reefs.The Pacific, which houses more reef area than any other region, is also the least threatened. About 60 percent of reefs here are at low risk.Outside of the Pacific, 70 percent of all reefs are at risk.At least 11 percent of the world's coral reefs contain high levels of reef fish biodiversity and are under high threat from human activities. These "hot spot" areas include almost all Philippine reefs, and coral communities off the coasts of Asia, the Comoros, and the Lesser Antilles in the Caribbean.Almost half a billion people -- 8 percent of the total global population -- live within 100 kilometers of a coral reef.Globally, more than 400 marine parks, sanctuaries, and reserves (marine protected areas) contain coral reefs. Most of these sites are very small -- more than 150 are under one square kilometer in size. At least 40 countries lack any marine protected areas for conserving their coral reef systems

Enhanced efficacy and increased long-term toxicity of CNS-directed, AAV-based combination therapy for Krabbe disease

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC) and the progressive accumulation of the toxic metabolite psychosine. We showed previously that central nervous system (CNS)-directed, adeno-associated virus (AAV)2/5-mediated gene therapy synergized with bone marrow transplantation and substrate reduction therapy (SRT) to greatly increase therapeutic efficacy in the murine model of Krabbe disease (Twitcher). However, motor deficits remained largely refractory to treatment. In the current study, we replaced AAV2/5 with an AAV2/9 vector. This single change significantly improved several endpoints primarily associated with motor function. However, nearly all (14/16) of the combination-treated Twitcher mice and all (19/19) of the combination-treated wild-type mice developed hepatocellular carcinoma (HCC). 10 out of 10 tumors analyzed had AAV integrations within the Rian locus. Several animals had additional integrations within or near genes that regulate cell growth or death, are known or potential tumor suppressors, or are associated with poor prognosis in human HCC. Finally, the substrate reduction drug L-cycloserine significantly decreased the level of the pro-apoptotic ceramide 18:0. These data demonstrate the value of AAV-based combination therapy for Krabbe disease. However, they also suggest that other therapies or co-morbidities must be taken into account before AAV-mediated gene therapy is considered for human therapeutic trials

UV-driven Chemistry as a Signpost for Late-stage Planet Formation

The chemical reservoir within protoplanetary disks has a direct impact on planetary compositions and the potential for life. A long-lived carbon-and nitrogen-rich chemistry at cold temperatures (<=50K) is observed within cold and evolved planet-forming disks. This is evidenced by bright emission from small organic radicals in 1-10 Myr aged systems that would otherwise have frozen out onto grains within 1 Myr. We explain how the chemistry of a planet-forming disk evolves from a cosmic-ray/X-ray-dominated regime to an ultraviolet-dominated chemical equilibrium. This, in turn, will bring about a temporal transition in the chemical reservoir from which planets will accrete. This photochemical dominated gas phase chemistry develops as dust evolves via growth, settling and drift, and the small grain population is depleted from the disk atmosphere. A higher gas-to-dust mass ratio allows for deeper penetration of ultraviolet photons is coupled with a carbon-rich gas (C/O > 1) to form carbon-bearing radicals and ions. This further results in gas phase formation of organic molecules, which then would be accreted by any actively forming planets present in the evolved disk.Comment: Accepted to Nature Astronomy, Published Dec 8th 202

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 influence of nativity and neighborhoods on breast cancer stage at diagnosis and survival among California Hispanic women

<p>Abstract</p> <p>Background</p> <p>In the US, foreign-born Hispanics tend to live in socioeconomic conditions typically associated with later stage of breast cancer diagnosis, yet they have lower breast cancer mortality rates than their US-born counterparts. We evaluated the impact of nativity (US- versus foreign-born), neighborhood socioeconomic status (SES) and Hispanic enclave (neighborhoods with high proportions of Hispanics or Hispanic immigrants) on breast cancer stage at diagnosis and survival among Hispanics.</p> <p>Methods</p> <p>We studied 37,695 Hispanic women diagnosed from 1988 to 2005 with invasive breast cancer from the California Cancer Registry. Nativity was based on registry data or, if missing, imputed from case Social Security number. Neighborhood variables were developed from Census data. Stage at diagnosis was analyzed with logistic regression, and survival, based on vital status determined through 2007, was analyzed with Cox proportional hazards regression.</p> <p>Results</p> <p>Compared to US-born Hispanics, foreign-born Hispanics were more likely to be diagnosed at an advanced stage of breast cancer (adjusted odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.09-1.20), but they had a somewhat lower risk of breast cancer specific death (adjusted hazard ratio (HR) = 0.94, 95% CI: 0.90-0.99). Living in low SES and high enclave neighborhoods was associated with advanced stage of diagnosis, while living in a lower SES neighborhood, but not Hispanic enclave, was associated with worse survival.</p> <p>Conclusion</p> <p>Identifying the modifiable factors that facilitate this survival advantage in Hispanic immigrants could help to inform specific interventions to improve survival in this growing population.</p

Selection of Salmonella enterica Serovar Typhi Genes Involved during Interaction with Human Macrophages by Screening of a Transposon Mutant Library

The human-adapted Salmonella enterica serovar Typhi (S. Typhi) causes a systemic infection known as typhoid fever. This disease relies on the ability of the bacterium to survive within macrophages. In order to identify genes involved during interaction with macrophages, a pool of approximately 105 transposon mutants of S. Typhi was subjected to three serial passages of 24 hours through human macrophages. Mutants recovered from infected macrophages (output) were compared to the initial pool (input) and those significantly underrepresented resulted in the identification of 130 genes encoding for cell membrane components, fimbriae, flagella, regulatory processes, pathogenesis, and many genes of unknown function. Defined deletions in 28 genes or gene clusters were created and mutants were evaluated in competitive and individual infection assays for uptake and intracellular survival during interaction with human macrophages. Overall, 26 mutants had defects in the competitive assay and 14 mutants had defects in the individual assay. Twelve mutants had defects in both assays, including acrA, exbDB, flhCD, fliC, gppA, mlc, pgtE, typA, waaQGP, SPI-4, STY1867-68, and STY2346. The complementation of several mutants by expression of plasmid-borne wild-type genes or gene clusters reversed defects, confirming that the phenotypic impairments within macrophages were gene-specific. In this study, 35 novel phenotypes of either uptake or intracellular survival in macrophages were associated with Salmonella genes. Moreover, these results reveal several genes encoding molecular mechanisms not previously known to be involved in systemic infection by human-adapted typhoidal Salmonella that will need to be elucidated

Results of Large-Scale Testing on Effects of Anti-Foam Agent on Gas Retention and Release

The U.S. Department of Energy (DOE) Office of River Protection’s Waste Treatment Plant (WTP) will process and treat radioactive waste that is stored in tanks at the Hanford Site. The waste treatment process in the pretreatment facility will mix both Newtonian and non-Newtonian slurries in large process tanks. Process vessels mixing non-Newtonian slurries will use pulse jet mixers (PJMs), air sparging, and recirculation pumps. An anti-foam agent (AFA) will be added to the process streams to prevent surface foaming, but may also increase gas holdup and retention within the slurry. The work described in this report addresses gas retention and release in simulants with AFA through testing and analytical studies. Gas holdup and release tests were conducted in a 1/4-scale replica of the lag storage vessel operated in the Pacific Northwest National Laboratory (PNNL) Applied Process Engineering Laboratory using a kaolin/bentonite clay and AZ-101 HLW chemical simulant with non-Newtonian rheological properties representative of actual waste slurries. Additional tests were performed in a small-scale mixing vessel in the PNNL Physical Sciences Building using liquids and slurries representing major components of typical WTP waste streams. Analytical studies were directed at discovering how the effect of AFA might depend on gas composition and predicting the effect of AFA on gas retention and release in the full-scale plant, including the effects of mass transfer to the sparge air. The work at PNNL was part of a larger program that included tests conducted at Savannah River National Laboratory (SRNL) that is being reported separately. SRNL conducted gas holdup tests in a small-scale mixing vessel using the AZ-101 high-level waste (HLW) chemical simulant to investigate the effects of different AFAs, their components, and of adding noble metals. Full-scale, single-sparger mass transfer tests were also conducted at SRNL in water and AZ-101 HLW simulant to provide data for PNNL’s WTP gas retention and release modeling

Identification of Conserved and HLA Promiscuous DENV3 T-Cell Epitopes

Anti-dengue T-cell responses have been implicated in both protection and immunopathology. However, most of the T-cell studies for dengue include few epitopes, with limited knowledge of their inter-serotype variation and the breadth of their human leukocyte antigen (HLA) affinity. In order to expand our knowledge of HLA-restricted dengue epitopes, we screened T-cell responses against 477 overlapping peptides derived from structural and non-structural proteins of the dengue virus serotype 3 (DENV3) by use of HLA class I and II transgenic mice (TgM): A2, A24, B7, DR2, DR3 and DR4. TgM were inoculated with peptides pools and the T-cell immunogenic peptides were identified by ELISPOT. Nine HLA class I and 97 HLA class II novel DENV3 epitopes were identified based on immunogenicity in TgM and their HLA affinity was further confirmed by binding assays analysis. A subset of these epitopes activated memory T-cells from DENV3 immune volunteers and was also capable of priming naïve T-cells, ex vivo, from dengue IgG negative individuals. Analysis of inter- and intra-serotype variation of such an epitope (A02-restricted) allowed us to identify altered peptide ligands not only in DENV3 but also in other DENV serotypes. These studies also characterized the HLA promiscuity of 23 HLA class II epitopes bearing highly conserved sequences, six of which could bind to more than 10 different HLA molecules representing a large percentage of the global population. These epitope data are invaluable to investigate the role of T-cells in dengue immunity/pathogenesis and vaccine design. © 2013 Nascimento et al

Health impacts of parental migration on left-behind children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Globally, a growing number of children and adolescents are left behind when parents migrate. We investigated the effect of parental migration on the health of left behind-children and adolescents in low-income and middle-income countries (LMICs). METHODS: For this systematic review and meta-analysis we searched MEDLINE, Embase, CINAHL, the Cochrane Library, Web of Science, PsychINFO, Global Index Medicus, Scopus, and Popline from inception to April 27, 2017, without language restrictions, for observational studies investigating the effects of parental migration on nutrition, mental health, unintentional injuries, infectious disease, substance use, unprotected sex, early pregnancy, and abuse in left-behind children (aged 0-19 years) in LMICs. We excluded studies in which less than 50% of participants were aged 0-19 years, the mean or median age of participants was more than 19 years, fewer than 50% of parents had migrated for more than 6 months, or the mean or median duration of migration was less than 6 months. We screened studies using systematic review software and extracted summary estimates from published reports independently. The main outcomes were risk and prevalence of health outcomes, including nutrition (stunting, wasting, underweight, overweight and obesity, low birthweight, and anaemia), mental health (depressive disorder, anxiety disorder, conduct disorders, self-harm, and suicide), unintentional injuries, substance use, abuse, and infectious disease. We calculated pooled risk ratios (RRs) and standardised mean differences (SMDs) using random-effects models. This study is registered with PROSPERO, number CRD42017064871. FINDINGS: Our search identified 10 284 records, of which 111 studies were included for analysis, including a total of 264 967 children (n=106 167 left-behind children and adolescents; n=158 800 children and adolescents of non-migrant parents). 91 studies were done in China and focused on effects of internal labour migration. Compared with children of non-migrants, left-behind children had increased risk of depression and higher depression scores (RR 1·52 [95% CI 1·27-1·82]; SMD 0·16 [0·10-0·21]), anxiety (RR 1·85 [1·36-2·53]; SMD 0·18 [0·11-0·26]), suicidal ideation (RR 1·70 [1·28-2·26]), conduct disorder (SMD 0·16 [0·04-0·28]), substance use (RR 1·24 [1·00-1·52]), wasting (RR 1·13 [1·02-1·24]) and stunting (RR 1·12 [1·00-1·26]). No differences were identified between left-behind children and children of non-migrants for other nutrition outcomes, unintentional injury, abuse, or diarrhoea. No studies reported outcomes for other infectious diseases, self-harm, unprotected sex, or early pregnancy. Study quality varied across the included studies, with 43% of studies at high or unclear risk of bias across five or more domains. INTERPRETATION: Parental migration is detrimental to the health of left-behind children and adolescents, with no evidence of any benefit. Policy makers and health-care professionals need to take action to improve the health of these young people. FUNDING: Wellcome Trust