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Seismology records the presence of various heterogeneities throughout the lower mantle 1 , 2 , but the origins of these signals—whether thermal or chemical—remain uncertain, and therefore much of the information that they hold about the nature of the deep Earth is obscured. Accurate interpretation of observed seismic velocities requires knowledge of the seismic properties of all of Earth’s possible mineral components. Calcium silicate (CaSiO 3 ) perovskite is believed to be the third most abundant mineral throughout the lower mantle. Here we simultaneously measure the crystal structure and the shear-wave and compressional-wave velocities of samples of CaSiO 3 perovskite, and provide direct constraints on the adiabatic bulk and shear moduli of this material. We observe that incorporation of titanium into CaSiO 3 perovskite stabilizes the tetragonal structure at higher temperatures, and that the material’s shear modulus is substantially lower than is predicted by computations 3 – 5 or thermodynamic datasets 6 . When combined with literature data and extrapolated, our results suggest that subducted oceanic crust will be visible as low-seismic-velocity anomalies throughout the lower mantle. In particular, we show that large low-shear-velocity provinces (LLSVPs) are consistent with moderate enrichment of recycled oceanic crust, and mid-mantle discontinuities can be explained by a tetragonal–cubic phase transition in Ti-bearing CaSiO 3 perovskite. Unexpectedly low seismic velocities of CaSiO 3 perovskite in deeply subducted oceanic crust can explain the properties of anomalous continent-sized regions in Earth’s lower mantle.

In this phase 3 study involving patients with HCV genotype 1, 2, 3, 4, or 6 and decompensated cirrhosis, sofosbuvir–velpatasvir with or without ribavirin for 12 weeks or sofosbuvir–velpatasvir for 24 weeks resulted in high rates of sustained virologic response. The number of patients with decompensated cirrhosis caused by chronic infection with the hepatitis C virus (HCV) is projected to rise in the coming decade. 1 For many years, the only treatment option for such patients was liver transplantation. Recently, however, clinical trials of newly approved direct-acting antiviral agents have shown that it is possible to treat HCV infection safely and effectively in patients with decompensated cirrhosis and that successful treatment is associated with early improvement in liver function. 2 – 11 The possible long-term benefits of treatment on existing liver disease remain unknown. The only regimen that is currently approved for the . . .

Black patients with chronic hepatitis C have a higher prevalence of genotype 1 infection and a lower rate of response to treatment. In this prospective study of 100 black and 100 non-Hispanic white patients with chronic hepatitis C (98 percent genotype 1), black patients had a lower rate of response to treatment with peginterferon alfa-2b and ribavirin (19 percent vs. 52 percent, P<0.001). Black patients had a lower rate of response to peginterferon alfa-2b and ribavirin. Hepatitis C virus (HCV) infection is a major cause of liver disease and the most frequent indication for liver transplantation in the United States. 1 The Third National Health and Nutrition Examination Survey estimated that 1.8 percent of the American population had detectable HCV antibodies. 2 This study also found a racial or ethnic variation in rates, with detectable HCV antibodies among 3.2 percent of non-Hispanic blacks and 9.8 percent of non-Hispanic black men 40 to 49 years of age. Recent advances in the treatment of HCV infection have led to improved rates of response. 3 , 4 However, several series reported lower response . . .

The lack of reproducibility of animal experimental results between laboratories, particularly in studies investigating the microbiota, has raised concern among the scientific community. Factors such as environment, stress and sex have been identified as contributors, whereas dietary composition has received less attention. This study firstly evaluated the use of commercially available rodent diets across research institutions, with 28 different diets reported by 45 survey respondents. Secondly, highly variable ingredient, FODMAP (Fermentable Oligo-, Di-, Mono-saccharides And Polyols) and gluten content was found between different commercially available rodent diets. Finally, 40 mice were randomized to four groups, each receiving a different commercially available rodent diet, and the dietary impact on cecal microbiota, short- and branched-chain fatty acid profiles was evaluated. The gut microbiota composition differed significantly between diets and sexes, with significantly different clusters in β-diversity. Total BCFA were highest ( p  = 0.01) and SCFA were lowest ( p  = 0.03) in mice fed a diet lower in FODMAPs and gluten. These results suggest that nutritional composition of commercially available rodent diets impact gut microbiota profiles and fermentation patterns, with major implications for the reproducibility of results across laboratories. However, further studies are required to elucidate the specific dietary factors driving these changes.

This article examines a cervical screening incident from the 1960s and draws lessons for screening policy. Concern about harmful overtreatment of symptomless lesions prompted university gynecologist Herbert Green to study, between 1965 and 1970, a ‘special series’ of 33 women with carcinoma in situ (CIS) who were managed with only limited punch or wedge biopsy. These women were carefully followed up but not treated unless they showed evidence of progression to invasive cancer. This paper examines source documents and subsequent publications in order to ascertain lessons from this incident. In keeping with the 1964 Helsinki Declaration, written consent was not sought. Green published the outcomes for his patients with CIS including the ‘special series.’ A Judicial inquiry (the Cartwright Inquiry) in 1987 concluded that some women had suffered harm and some had died, but numbers and evidence were not clearly stated. Medical case review for the Inquiry identified 25 women with only punch or wedge biopsy; in 21 of these, there were reasons why no further treatment was given; two had developed cervical cancer, and none were recorded as having died. The case review found eight patients, not necessarily in the ‘special series,’ who ‘in retrospect and by 1987 standards’ might have benefited from earlier conisation or hysterectomy. Subsequent claims relating to Green's practice have wrongly stated that as many as one hundred women or more had treatment withheld and over 30 died as a result. These claims are inaccurate. •Cervical cytology screening began, from the late 1940s, without adequate prior evaluation. Ethical principles including informed consent were ignored. Many women suffered harm including loss of fertility and operative death.•Auckland University gynecologist Herbert Green cautioned against harmful overdiagnosis and overtreatment and advocated conisation with careful follow up, in preference to hysterectomy, thereby enabling many young women to preserve their fertility.•During 1965 to 1970 Green practiced, and published about, active monitoring in a ‘special series’ of 33 women with carcinoma in situ initially managed by limited biopsy. By 1974 he advised against this practice, reporting the treatment of 10 women whose lesions had progressed (2 clinical and 8 histological).•A 1987 Judicial Inquiry into practice at National Women’s Hospital Auckland, triggered by a magazine article, led to widely quoted claims that Green had unethically withheld treatment from as many as 100 women, and that up to thirty deaths resulted.•The review of case notes conducted for the Inquiry found only 4 patients where no reason could be found for delayed treatment. Two women managed by limited biopsy were reported to have developed cancer, and none were recorded as having died. The severity of claims made against Green do not stand up to scientific scrutiny.

Patients with primary biliary cholangitis (PBC) who had an inadequate response to ursodiol have few treatment options. Alkaline phosphatase (ALP) and bilirubin levels correlate with the risk of liver transplant or death in PBC patients. Fibroblast growth factor (FGF) 19 is a hormone that acts directly in the liver to regulate bile acid synthesis. We evaluated NGM282, an engineered analogue of FGF19, for the treatment of PBC. In this 28‐day, double‐blind, placebo‐controlled phase 2 trial, 45 PBC patients who had an inadequate response to ursodiol were randomly assigned 1:1:1 to receive subcutaneous daily doses of either NGM282 at 0.3 mg (n = 14), 3 mg (n = 16), or placebo (n = 15). The primary endpoint was a change in ALP from baseline after 28 days of treatment. At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least‐squares mean –51.0 IU/L [standard error (SE) 15.4]) and 3 mg (–66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least‐squares mean differences of –54.3 IU/L (95% confidence interval –104.2 to –4.5; P = 0.0149) and –69.3 IU/L (95% confidence interval –120.5 to –18.3; P = 0.0030), respectively. Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3mg achieved 15% or greater reduction in ALP levels from baseline, compared with 7% (1 of 15) of patients receiving placebo. NGM282 also significantly reduced serum concentrations of transaminases and immunoglobulins. Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups. No worsening of pruritus was observed with NGM282 treatment. Conclusion: NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with PBC. (Hepatology Communications 2018; 00:000‐000) NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with primary biliary cholangitis.

In this study in patients with HCV genotype 1 infection and prior treatment failure, those assigned to 12 weeks or 24 weeks of treatment with ledipasvir and sofosbuvir, with or without ribavirin, had high rates of sustained response (94 to 99% in all groups). Among the estimated 170 million people in the world who have chronic hepatitis C virus (HCV) infection, approximately 60% have the genotype 1 strain of the virus. 1 The treatment of patients infected with HCV genotype 1 is evolving rapidly. 2 – 6 At the end of 2013, the Food and Drug Administration (FDA) approved two new direct-acting antiviral agents for the treatment of HCV infection: the nucleotide polymerase inhibitor sofosbuvir (Gilead Sciences) and the protease inhibitor simeprevir (Janssen Therapeutics). 7 , 8 Among the regimens that have been approved by the FDA for patients with HCV genotype 1 infection who have not had a . . .

Cirrhosis and its related complications remain a prominent global health concern despite advances in understanding and treating the disorder. Early diagnosis and intervention strategies may reduce the impact of cirrhosis; however, it can be difficult for initial point-of-care health care providers to identify and refer patients with cirrhosis due to lack of knowledge and resources. This review examines current diagnostic strategies for cirrhosis and cirrhosis-related complications and the potential benefits of multidisciplinary care for patients with the disorder. A PubMed search of the medical literature was conducted to identify current diagnostic methods and standards and ascertain the impact of multidisciplinary care on patients with cirrhosis. Screening of patients at risk for cirrhosis has been recommended by several professional and governmental organizations. Unfortunately, identification of early-stage cirrhosis remains challenging despite development of novel calculations for risk (eg, aspartate transaminase-to-platelet count ratio) that use values from common, noninvasive laboratory tests to determine the extent of liver disease. Abnormal liver function test results and alterations in serum liver enzyme markers (eg, alanine and aspartate transaminases) may suggest cirrhosis in patients with chronic liver disease; however, they are not definitive. Liver biopsy is the gold standard for diagnosis and staging of cirrhosis, but its cost, invasiveness, and risk of complications have prompted the development of noninvasive tests (eg, elastography). Primary care physicians should be aware of the signs and symptoms of cirrhosis-related complications, particularly portal hypertension, and refer patients to specialists for further evaluation when warranted. Patients at risk for cirrhosis should be screened and the underlying etiologic factor(s) of the liver disease treated or appropriately managed when possible. Primary care physicians should be aware of the signs and symptoms of cirrhosis and its related complications and adopt a low threshold for referral to a specialist when the condition is suspected. An integrated, multidisciplinary approach to care between specialists and primary care physicians may improve early detection of cirrhosis and its related complications and strengthen management strategies.