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BackgroundMucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients’ phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data.MethodsWe have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease.ResultsWe collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS.ConclusionsMPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.

Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (–0·20, –0·23 to –0·16), levofloxacin (–0·06, –0·09 to –0·04), moxifloxacin (–0·07, –0·10 to –0·04), or bedaquiline (–0·14, –0·19 to –0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Magma transports metals to the Earth’s surface to form ore deposits, but only sulphide-undersaturated magmas were thought to be capable of generating large amounts of ore. Laboratory experiments indicate that large volumes of gold ore can also be generated by sulphide-saturated magma, if the redox conditions of the magma are suitable. Magmas are an important source of noble metals. Metals are transported by magma from deep within the mantle to the shallow crust, where they form subsurface ore deposits 1 , 2 , 3 , 4 , 5 , 6 . The concentration of noble metals in silicate melts has been thought to be controlled by the stability of sulphide minerals in the upper mantle and crust, with only sulphide-undersaturated magmas capable of extracting significant amounts of metals from the mantle 1 , 2 , 3 , 4 , 5 , 6 . Here we present a series of experiments carried out on basaltic and andesitic glasses, melted in the presence of water and sulphur in gold capsules at a pressure of 200 MPa and a temperature of 1,050 °C, under a wide range of redox conditions. We show that gold solubility in silicate melts is highest within a narrow window of redox conditions, characterized by the transformation of sulphide to sulphate species in the magma. Within this redox range, we found that gold was particularly mobile and became dissolved in the silicate melts as a sulphide-bearing component. We suggest that gold-rich magmas can be generated in mantle systems that are sulphide-saturated, as long as they are relatively oxidized. Conditions that are favourable to the mobilization and transport of gold (and presumably other noble metals) may prevail in magmatic systems above subduction zones and in the environments beneath hotspot volcanoes.

Virtual Reality (VR) has emerged as a powerful tool in psychological research, and this technology allows researchers to study a variety of phenomena which would be difficult or impossible to study in a laboratory setting. As VR devices become more accessible and affordable, interest in VR-based research continues to grow. However, integration of VR into psychological research remains limited by a lack of guidance tailored to newcomers in the field. The major obstacles to adopting VR in psychological research stem not only from technical barriers but also from a lack of awareness regarding crucial conceptual and practical considerations. In this context, there is a dearth of resources which are intended for researchers/graduate students without experience using VR. This manuscript outlines key considerations that should be addressed when incorporating VR into a research program.

A review of published and newly measured densities for 40 hydrous silicate glasses indicates that the room-temperature partial molar volume of water is 12.0 +/- 0.5 cm/mol. This value holds for simple or mineral compositions as well as for complex natural glasses, from rhyolite to tephrite compositions, prepared up to 10-20 kbar pressures and containing up to 7 wt% H2O.

Pyruvate kinase (PK) deficiency (PKD) is an autosomal recessive disorder with the typical manifestation of nonspherocytic hemolytic anemia. We analyzed the mutant enzymes of 10 unrelated patients with PKD, whose symptoms ranged from a mild, chronic hemolytic anemia to a severe anemia, by sequence analysis for the presence of alterations in the PKLR gene. In all cases the patients were shown to be compound heterozygous. Eight novel mutations were identified: 458T→C (Ile153Thr), 656T→C (Ile219Thr), 877G→A (Asp293Asn), 991G→A (Asp331Asn), 1055C→A (Ala352Asp), 1483G→A (Ala495Thr), 1649A→T (Asp550Val), and 183‐184ins16bp. This 16 bp duplication produces a frameshift and subsequent stop codon resulting in a drastically reduced mRNA level, and probably in an unstable gene product. Surprisingly, the existence of M2‐type PK could be demonstrated in the patient's red blood cells. The study of different polymorphic sites revealed, with one exception, a strict linkage of the 1705C, 1738T, IVS5(+51)T, T(10) polymorphisms and the presence of 14 ATT repeats in intron 11. Our analyses show the consequences of a distorted structure on enzyme function and we discuss the correlations between the mutations identified and the parameters indicative for enzyme function. Hum Mutat 15:261–272, 2000. © 2000 Wiley‐Liss, Inc.