High exposure of global tree diversity to human pressure.

Safeguarding Earth's tree diversity is a conservation priority due to the importance of trees for biodiversity and ecosystem functions and services such as carbon sequestration. Here, we improve the foundation for effective conservation of global tree diversity by analyzing a recently developed database of tree species covering 46,752 species. We quantify range protection and anthropogenic pressures for each species and develop conservation priorities across taxonomic, phylogenetic, and functional diversity dimensions. We also assess the effectiveness of several influential proposed conservation prioritization frameworks to protect the top 17% and top 50% of tree priority areas. We find that an average of 50.2% of a tree species' range occurs in 110-km grid cells without any protected areas (PAs), with 6,377 small-range tree species fully unprotected, and that 83% of tree species experience nonnegligible human pressure across their range on average. Protecting high-priority areas for the top 17% and 50% priority thresholds would increase the average protected proportion of each tree species' range to 65.5% and 82.6%, respectively, leaving many fewer species (2,151 and 2,010) completely unprotected. The priority areas identified for trees match well to the Global 200 Ecoregions framework, revealing that priority areas for trees would in large part also optimize protection for terrestrial biodiversity overall. Based on range estimates for >46,000 tree species, our findings show that a large proportion of tree species receive limited protection by current PAs and are under substantial human pressure. Improved protection of biodiversity overall would also strongly benefit global tree diversity.

New semi-dwarfing alleles with increased coleoptile length by gene editing of gibberellin 3-oxidase 1 using CRISPR-Cas9 in barley (Hordeum vulgare L.).

The green revolution was based on genetic modification of the gibberellin (GA) hormone system with "dwarfing" gene mutations that reduces GA signals, conferring shorter stature, thus enabling plant adaptation to modern farming conditions. Strong GA-related mutants with shorter stature often have reduced coleoptile length, discounting yield gain due to their unsatisfactory seedling emergence under drought conditions. Here we present gibberellin (GA) 3-oxidase1 (GA3ox1) as an alternative semi-dwarfing gene in barley that combines an optimal reduction in plant height without restricting coleoptile and seedling growth. Using large-scale field trials with an extensive collection of barley accessions, we showed that a natural GA3ox1 haplotype moderately reduced plant height by 5-10 cm. We used CRISPR/Cas9 technology, generated several novel GA3ox1 mutants and validated the function of GA3ox1. We showed that altered GA3ox1 activities changed the level of active GA isoforms and consequently increased coleoptile length by an average of 8.2 mm, which could provide essential adaptation to maintain yield under climate change. We revealed that CRISPR/Cas9-induced GA3ox1 mutations increased seed dormancy to an ideal level that could benefit the malting industry. We conclude that selecting HvGA3ox1 alleles offers a new opportunity for developing barley varieties with optimal stature, longer coleoptile and additional agronomic traits.

Genome architecture and diverged selection shaping pattern of genomic differentiation in wild barley.

Divergent selection of populations in contrasting environments leads to functional genomic divergence. However, the genomic architecture underlying heterogeneous genomic differentiation remains poorly understood. Here, we de novo assembled two high-quality wild barley (Hordeum spontaneum K. Koch) genomes and examined genomic differentiation and gene expression patterns under abiotic stress in two populations. These two populations had a shared ancestry and originated in close geographic proximity but experienced different selective pressures due to their contrasting micro-environments. We identified structural variants that may have played significant roles in affecting genes potentially associated with well-differentiated phenotypes such as flowering time and drought response between two wild barley genomes. Among them, a 29-bp insertion into the promoter region formed a cis-regulatory element in the HvWRKY45 gene, which may contribute to enhanced tolerance to drought. A single SNP mutation in the promoter region may influence HvCO5 expression and be putatively linked to local flowering time adaptation. We also revealed significant genomic differentiation between the two populations with ongoing gene flow. Our results indicate that SNPs and small SVs link to genetic differentiation at the gene level through local adaptation and are maintained through divergent selection. In contrast, large chromosome inversions may have shaped the heterogeneous pattern of genomic differentiation along the chromosomes by suppressing chromosome recombination and gene flow. Our research offers novel insights into the genomic basis underlying local adaptation and provides valuable resources for the genetic improvement of cultivated barley.

Relative growth rate (RGR) and other confounded variables: mathematical problems and biological solutions.

BACKGROUND: Relative growth rate (RGR) has a long history of use in biology. In its logged form, RGR = ln[(M + ΔM)/M], where M is size of the organism at the commencement of the study, and ΔM is new growth over time interval Δt. It illustrates the general problem of comparing non-independent (confounded) variables, e.g. (X + Y) vs. X. Thus, RGR depends on what starting M(X) is used even within the same growth phase. Equally, RGR lacks independence from its derived components, net assimilation rate (NAR) and leaf mass ratio (LMR), as RGR = NAR × LMR, so that they cannot legitimately be compared by standard regression or correlation analysis. FINDINGS: The mathematical properties of RGR exemplify the general problem of 'spurious' correlations that compare expressions derived from various combinations of the same component terms X and Y. This is particularly acute when X >> Y, the variance of X or Y is large, or there is little range overlap of X and Y values among datasets being compared. Relationships (direction, curvilinearity) between such confounded variables are essentially predetermined and so should not be reported as if they are a finding of the study. Standardizing by M rather than time does not solve the problem. We propose the inherent growth rate (IGR), lnΔM/lnM, as a simple, robust alternative to RGR that is independent of M within the same growth phase. CONCLUSIONS: Although the preferred alternative is to avoid the practice altogether, we discuss cases where comparing expressions with components in common may still have utility. These may provide insights if (1) the regression slope between pairs yields a new variable of biological interest, (2) the statistical significance of the relationship remains supported using suitable methods, such as our specially devised randomization test, or (3) multiple datasets are compared and found to be statistically different. Distinguishing true biological relationships from spurious ones, which arise from comparing non-independent expressions, is essential when dealing with derived variables associated with plant growth analyses.

Fossil pollen resolves origin of the South African Proteaceae as transcontinental not transoceanic.

BACKGROUND AND AIMS: The prevailing view from the areocladogenesis of molecular phylogenies is that the iconic South African Cape Proteaceae (subfamily Proteoideae) arrived from Australia across the Indian Ocean in the Upper Cretaceous (100‒65 million years ago, Ma). Since fossil pollen indicates that the family probably arose in North-West Africa during the early Cretaceous, an alternative view is that it migrated to the Cape from North-Central Africa. The plan therefore was to collate fossil pollen records throughout Africa to determine if they are consistent with an African (para-autochthonous) origin for the Cape Proteaceae, and to seek further support from other paleo-disciplines. METHODS: Palynology (identity, date and location of records), molecular phylogeny and chronogram preparation, biogeography of plate tectonics, and paleo-atmospheric and ocean circulation models. KEY RESULTS: Our collation of the rich assemblage of Proteaceae palynomorphs stretching back to 107 Ma (Triorites africaensis) in North-West Africa showed its progressive overland migration to the Cape by 75‒65 Ma. No key palynomorphs recorded in Australia-Antarctica have morphological affinities with African fossils but specific clade assignment of the preMiocene records is not currently possible. The Cape Proteaceae encompass three molecular-based clades (tribes) whose most-recent apparent ancestors are sisters to those in Australia. However, our chronogram shows that the major Adenanthos/Leucadendron-related clade, originating 54‒34 Ma, would have 'arrived' too late as species with Proteaceae affinities were already present ~20 My earlier. The Franklandia/Protea-related clade arose 118‒81 Ma so its distinctive pollen should have been the foundation for the scores of palynomorphs recorded at 100‒80 Ma but it was not. Also, the prevailing winds and ocean currents trended away from South Africa rather than towards, as the 'out-of-Australia' hypothesis requires. Based on the evidence assembled here, we list three points favouring an Australian origin and nine against; four points favouring an Antarctic origin and seven against; and nine points favouring a North-Central African origin and three against. CONCLUSIONS: We conclude that a gradual migration of the Proteaceae from North-Central Africa southeast→south→southwest to the Cape and surrounds occurred via adaptation and speciation during the period 90‒70 Ma. We caution that incorrect conclusions may be drawn from literal interpretations of molecular phylogenies that neglect the fossil record and do not recognize the possible confounding effects of selection under matched environments leading to parallel evolution and extinction of bona fide sister clades.

Protective Effects of Lactobacillus gasseri against High-Cholesterol Diet-Induced Fatty Liver and Regulation of Host Gene Expression Profiles.

Fatty liver is one of the most pervasive liver diseases worldwide. Probiotics play an important role in the progression of liver disease, but their effects on host regulation are poorly understood. This study investigated the protective effects of lactobacillus gasseri (L. gasseri) against high-cholesterol diet (HCD)-induced fatty liver injury using a zebrafish larvae model. Liver pathology, lipid accumulation, oxidative stress and hepatic inflammation were evaluated to demonstrate the changes in a spectrum of hepatic injury. Moreover, multiple indexes on host gene expression profiles were comprehensively characterized by RNA screening. The results showed that treatment with L. gasseri ameliorated HCD-induced morphological and histological alterations, lipid regulations, oxidative stress and macrophage aggregation in the liver of zebrafish larvae. Furthermore, the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that the core pathways of L. gasseri regulation were interleukin-17 (IL-17) signaling, phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, the regulation of lipolysis and adipocytes and fatty acid elongation and estrogen signaling. The genes at key junction nodes, hsp90aa1.1, kyat3, hsd17b7, irs2a, myl9b, ptgs2b, cdk21 and papss2a were significantly regulated by L. gasseri administration. To conclude, the current research extends our understanding of the protective effects of L. gasseri against fatty liver and provides potential therapeutic options for fatty liver treatment.

Whole-genome assembly and resequencing reveal genomic imprint and key genes of rapid domestication in narrow-leafed lupin.

Shifting from a livestock-based protein diet to a plant-based protein diet has been proposed as an essential requirement to maintain global food sustainability, which requires the increased production of protein-rich crops for direct human consumption. Meanwhile, the lack of sufficient genetic diversity in crop varieties is an increasing concern for sustainable food supplies. Countering this concern requires a clear understanding of the domestication process and dynamics. Narrow-leafed lupin (Lupinus angustifolius L.) has experienced rapid domestication and has become a new legume crop over the past century, with the potential to provide protein-rich seeds. Here, using long-read whole-genome sequencing, we assembled the third-generation reference genome for the narrow-leafed lupin cultivar Tanjil, comprising 20 chromosomes with a total genome size of 615.8 Mb and contig N50 = 5.65 Mb. We characterized the original mutation and putative biological pathway resulting in low seed alkaloid level that initiated the recent domestication of narrow-leafed lupin. We identified a 1133-bp insertion in the cis-regulatory region of a putative gene that may be associated with reduced pod shattering (lentus). A comparative analysis of genomic diversity in cultivars and wild types identified an apparent domestication bottleneck, as precisely predicted by the original model of the bottleneck effect on genetic variability in populations. Our results identify the key domestication genetic loci and provide direct genomic evidence for a domestication bottleneck, and open up the possibility of knowledge-driven de novo domestication of wild plants as an avenue to broaden crop plant diversity to enhance food security and sustainable low-carbon emission agriculture.

Pancreatic involvement in Erdheim-Chester disease: a case report and review of the literature.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by infiltration of lipid-laden foamy macrophages within different tissues. Clinical manifestations of ECD are highly heterogeneous. Bone lesions are found in 80%-95% of patients, while extraosseous lesions usually involve the cardiovascular system, retroperitoneum, central nervous system (CNS), and skin. Pancreatic involvement in ECD has barely been reported. CASE PRESENTATION: A 29-year-old female initially presented with menoxenia, diabetes insipidus and diabetes mellitus. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) revealed hypermetabolic foci in the bilateral frontal lobe, saddle area, and pancreas. A 99mTc-MDP bone scrintigraphy scan revealed symmetrical increased uptake in distal femoral and proximal tibial metaphysis, which was confirmed to be osteosclerosis by high-resolution peripheral quantitative computed tomography. The patient underwent incomplete resection of the sellar mass. Histological examination of biopsies showed histiocytic aggregates, which were positive for S100 and negative for CD1a and CD207 on immunohistochemistry. Enhanced abdominal CT scan showed hypointense nodules within the body and tail of the pancreas. Endoscopic ultrasonography guided fine-needle aspiration (EUS-FNA) found no evidence of malignancy. She was diagnosed with ECD and treated with high-dose IFN-α. Repeated examinations at three-and eight-months post treatment revealed markedly reduction of both intracranial and pancreatic lesions. CONCLUSIONS: ECD is a rare histiocytic neoplasm that can involve almost every organ, whereas pancreatic involvement has barely been reported to date. Here, we present the rare case of pancreatic lesions in ECD that responded well to interferon-α. We further reviewed reports of pancreatic involvement in histiocytic disorders and concluded the characteristics of such lesions to help diagnosis and treatment, in which these lesions mimicked pancreatic adenocarcinoma and caused unnecessary invasive surgeries.

Genomic structural equation modelling provides a whole-system approach for the future crop breeding.

KEY MESSAGE: Using genomic structural equation modelling, this research demonstrates an efficient way to identify genetically correlating traits and provides an effective proxy for multi-trait selection to consider the joint genetic architecture of multiple interacting traits in crop breeding. Breeding crop cultivars with optimal value across multiple traits has been a challenge, as traits may negatively correlate due to pleiotropy or genetic linkage. For example, grain yield and grain protein content correlate negatively with each other in cereal crops. Future crop breeding needs to be based on practical yet accurate evaluation and effective selection of beneficial trait to retain genes with the best agronomic score for multiple traits. Here, we test the framework of whole-system-based approach using structural equation modelling (SEM) to investigate how one trait affects others to guide the optimal selection of a combination of agronomically important traits. Using ten traits and genome-wide SNP profiles from a worldwide barley panel and SEM analysis, we revealed a network of interacting traits, in which tiller number contributes positively to both grain yield and protein content; we further identified common genetic factors affecting multiple traits in the network of interaction. Our method demonstrates an efficient way to identify genetically correlating traits and underlying pleiotropic genetic factors and provides an effective proxy for multi-trait selection within a whole-system framework that considers the joint genetic architecture of multiple interacting traits in crop breeding. Our findings suggest the promise of a whole-system approach to overcome challenges such as the negative correlation of grain yield and protein content to facilitating quantitative and objective breeding decisions in future crop breeding.

Fire-mediated germination syndromes in Leucadendron (Proteaceae) and their functional correlates.

A mechanistic understanding of fire-driven seedling recruitment is essential for effective conservation management of fire-prone vegetation, such as South African fynbos, especially with rare and threatened taxa. The genus Leucadendron (Proteaceae) is an ideal candidate for comparative germination studies, comprising 85 species with a mixture of contrasting life-history traits (killed by fire vs able to resprout; serotinous vs geosporous) and seed morphologies (nutlets vs winged achenes). Individual and combined effects of heat and smoke on seed germination of 40 species were quantified in the laboratory, and Bayesian inference applied to distinguish biologically meaningful treatment effects from non-zero, but biologically trivial, effects. Three germination syndromes were identified based on whether germination was dependent on, enhanced by, or independent of direct fire cues (heat and smoke). Seed storage location was the most reliable predictor of germination syndromes, with soil-stored seeds c. 80% more likely to respond to direct fire cues (primarily smoke) than canopy-stored seeds. Notable exceptions were L. linifolium, with an absolute requirement for smoke to germinate (the third serotinous species so reported), and two other serotinous species with smoke-enhanced germination. Nutlet-bearing species, whether serotinous or geosporous, were c. 70% more likely to respond to fire cues than winged seeds, but there was no evidence for an effect of phylogeny or persistence strategy on germination. This comprehensive account of seed germination characteristics and identification of germination syndromes and their predictors, supports propagation, conservation and restoration initiatives in this iconic fynbos genus and other fire-prone shrubs with canopy or soil-stored seeds.

Gene-set association and epistatic analyses reveal complex gene interaction networks affecting flowering time in a worldwide barley collection.

Single-marker genome-wide association studies (GWAS) have successfully detected associations between single nucleotide polymorphisms (SNPs) and agronomic traits such as flowering time and grain yield in barley. However, the analysis of individual SNPs can only account for a small proportion of genetic variation, and can only provide limited knowledge on gene network interactions. Gene-based GWAS approaches provide enormous opportunity both to combine genetic information and to examine interactions among genetic variants. Here, we revisited a previously published phenotypic and genotypic data set of 895 barley varieties grown in two years at four different field locations in Australia. We employed statistical models to examine gene-phenotype associations, as well as two-way epistasis analyses to increase the capability to find novel genes that have significant roles in controlling flowering time in barley. Genetic associations were tested between flowering time and corresponding genotypes of 174 putative flowering time-related genes. Gene-phenotype association analysis detected 113 genes associated with flowering time in barley, demonstrating the unprecedented power of gene-based analysis. Subsequent two-way epistasis analysis revealed 19 pairs of gene×gene interactions involved in controlling flowering time. Our study demonstrates that gene-based association approaches can provide higher capacity for future crop improvement to increase crop performance and adaptation to different environments.

Clinical characteristics and the long-term outcome of patients with atypical POEMS syndrome variant with undetectable monoclonal gammopathy.

The diagnosis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome requires polyneuropathy and monoclonal plasma cell proliferation as two mandatory criteria. Our aim was to summarize clinical manifestations and treatment responses of POEMS variants with no evidence of monoclonal gammopathy. We queried all medical documentation of patients referred to Peking Union Medical College Hospital from August 2012 to July 2017, and reviewed the clinical and laboratory features of 13 patients with atypical POEMS syndrome with undetectable monoclonal gammopathy, and compared to prototypes published. The prevalence of polyneuropathy, organomegaly, skin changes, and extravascular fluid overload were 100%, 100%, 92%, and 100%, respectively. Other clinical manifestations, such as endocrinopathy, pulmonary hypertension, papilledema, thrombocytosis, and polycythemia affected similar percentages of patients as seen in prototypes. POEMS variants enrolled had a median serum vascular endothelial growth factor (VEGF) level of 4998 pg/ml (range 2155-11,029 pg/ml). Long-term follow-up found that all 12 patients received autologous stem cell transplant, melphalan-based therapy or lenalidomide/thalidomide-based therapy obtained clinical improvement, of which eight experienced decreased levels of VEGF by 50% or back to normal. The median progression-free survival was 101.5 months. Our findings raised a variant of POEMS syndrome variants with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting plasma cell.

Evaluating heart function in patients with POEMS syndrome.

AIMS: Our aim is to investigate the characterized echocardiographic cardiac measurements of POEMS syndrome and determine its relationship with clinical manifestations. METHODS AND RESULTS: The cross-sectional study included 27 treatment-naïve patients with newly diagnosed POEMS syndrome and 26 age- and sex-matched healthy volunteers. Information of clinical manifestations, serological tests, pulmonary function tests, and both conventional echocardiograph and tissue Doppler imaging (TDI) were collected and analyzed. Pearson's correlation coefficient was used for determining the related clinical and echocardiographic parameters. Compared to healthy people, left ventricular (LV) mass index (LVMI) was elevated in patients with POEMS syndrome (41.3 ± 11.0 g/m2.7 , P < .05). LV systolic dysfunction was found by decreased mitral S' (9.0 ± 2.2 m/sec, P < .01), and diastolic dysfunction by mitral E'/A' (1.10 ± 0.42, P < .05), E/E' (8.69 ± 4.06, P < .001) on lateral, and E/E' (7.90 ± 3.28, P = .133) on septal mitral annulus. The presence of decreased tricuspid annular plane systolic excursion (TAPSE) (22.2 ± 3.5 mm, P < .01) and lateral tricuspid S' (11.1 ± 1.8 m/sec, P < .05) suggested deterioration of right ventricular (RV) systolic function. Parameters obtained from standard echocardiograph (tricuspid E/A ratio and DT) and TDI ((lateral tricuspid annulus E'/A' and E/E') indicated reduced RV diastolic function. Pulmonary hypertension (PH) was presented in six patients. Correlation analysis suggested that PH was related to total lung capacity (TLC) and diffusion capacity of carbon monoxide (DLCO). CONCLUSION: Echocardiographic measurements found that there was elevation of LVMI, pulmonary artery hypertension, and subclinical impairment of systolic and diastolic functions of both the right and left heart in patients with POEMS syndrome.

Environmental drivers and genomic architecture of trait differentiation in fire-adapted Banksia attenuata ecotypes.

Trait divergence between populations is considered an adaptive response to different environments, but to what extent this response is accompanied by genetic differentiation is less clear since it may be phenotypic plasticity. In this study, we analyzed phenotypic variation between two Banksia attenuata growth forms, lignotuberous (shrub) and epicormic resprouting (tree), in fire-prone environments to identify the environmental factors that have driven this phenotypic divergence. We linked genotype with phenotype and traced candidate genes using differential gene expression analysis. Fire intervals determined the phenotypic divergence between growth forms in B. attenuata. A genome-wide association study identified 69 single nucleotide polymorphisms, putatively associated with growth form, whereas no growth form- or phenotype-specific genotypes were identified. Genomic differentiation between the two growth forms was low (Fst = 0.024). Differential gene expression analysis identified 37 genes/transcripts that were differentially expressed in the two growth forms. A small heat-shock protein gene, associated with lignotuber presence, was differentially expressed in the two forms. We conclude that different fire regimes induce phenotypic polymorphism in B. attenuata, whereas phenotypic trait divergence involves the differential expression of a small fraction of genes that interact strongly with the disturbance regime. Thus, phenotypic plasticity among resprouters is the general strategy for surviving varying fire regimes.

Cost-effectiveness analysis of intensive hypertension control in China.

China has the largest population of adults with hypertension in the world. Recent clinical trials have shown that intensive hypertension control can help patients achieve lower blood pressure and reduce the incidence of major cardiovascular disease (CVD) events, but this level of hypertension control also incurs additional costs to patients and society and may result in a substantial increase in adverse events. The objective of this study is to assess the cost-effectiveness of intensive hypertension control to inform health policymakers and health care delivery systems in China in their decision-making regarding hypertension treatment strategies. We developed a Markov based simulation model of hypertension to assess the impact of intensive and standard hypertension control strategies for the Chinese population who are diagnosed with hypertension. Model parameters were estimated based on the best available data and the literature. We projected that intensive hypertension control would avert about 2.2 million coronary heart disease events and 4.4 million stroke events for all hypertensive patients in China in 10 years compared to standard hypertension control. The incremental cost-effectiveness ratio (ICER) for intensive hypertension control was estimated at 7876 CNY per quality-adjusted life year (QALY) compared to standard hypertension control. Intensive hypertension control would be more cost-effective than standard hypertension control in China. Our findings indicated that China should consider expanding intensive hypertension control among hypertensive patients given its great potential in preventing CVD.

Direct-Acting Antiviral Agents for Patients With Hepatitis C Virus Genotype 1 Infection Are Cost-Saving.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective in treatment of hepatitis C virus (HCV) genotype 1 infection, but their cost and value have been debated. We performed a systematic review of published cost-effectiveness analyses of DAAs, synthesized their results with updated drug prices, and calculated the maximum price at which DAA therapy for HCV genotype 1 infection is cost-effective (increased quality-adjusted life-years [QALYs] and increased cost that the society is willing to pay) and cost-saving (increased QALYs and decreased costs). METHODS: We conducted a systematic review of the PubMed, Medline, EMBASE, Cochrane library, EconLit, Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database, Health Technology Assessment, and Tufts University databases for cost-effectiveness analyses published from 2011 through 2015. Our analysis included cost effectiveness of DAAs versus previous standard-of-care regimens (peginterferon and ribavirin, boceprevir and telaprevir), or no treatment, performed for patients with HCV genotype 1 infection. We excluded studies that were not written in English or those that did not report QALYs. Reported incremental cost-effectiveness ratios (ICERs) and treatment costs for each comparison were extracted; the threshold price was estimated for each analysis in which regimens were found to be cost-effective (ICER ≤$100,000/QALY) or cost-saving (ICER <$0), those that decreased costs and increased QALYs. RESULTS: We identified 24 cost-effectiveness studies that reported 170 ICERs for combinations of 11 drugs, from 11 countries. Of those, 81 ICERs were determined for first-generation DAAs (boceprevir and telaprevir) and 89 ICERs were determined for second-generation DAAs (drugs approved after the first-generation DAAs) as a primary intervention. The median threshold prices at which first-generation and second-generation DAAs became cost-effective were estimated as $120,100 (interquartile range, $90,700-$176,800) and $227,200 (interquartile range, $142,800-$355,800), respectively. At the discounted price of $60,000, a total of 71% of the analyses found second-generation DAAs to be cost-saving and 22% to be cost-effective. CONCLUSIONS: In a systematic review, we found treatment of HCV genotype 1 infection with second-generation DAAs to be cost-effective when they cost less than and $227,200; these drugs produced cost savings at current discounts.

Detection of MYD88 L265P and WHIM-like CXCR4 mutation in patients with IgM monoclonal gammopathy related disease.

A broad spectrum of diseases are associated with IgM monoclonal gammopathy, including Waldenstrom macroglobulinemia (WM), various types of B cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), primary amyloidosis (AL), and monoclonal gammopathy of undetermined significance (MGUS); these are called IgM monoclonal gammopathy related diseases (IgM-RD). We investigated MYD88 L265P and WHIM-like CXCR4 mutations in various IgM-RD. Patients with serum immunofixation electrophoresis confirmed IgM monoclonal gammopathy who had enough material for DNA extraction and presented between January 2008 and October 2016 at Peking Union Medical College Hospital were enrolled in this cohort. We performed real-time allele-specific-polymerase chain reaction and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutations. One hundred and twelve patients (64 male and 48 female patients) were included in this retrospective study. The median age at diagnosis was 62 years (range, 30-84 years). In total, 64 patients (57.1%) carried the MYD88 L265P mutation and 14 patients (12.5%) carried the CXCR4 WHIM-like mutation. We identified the MYD88 L265P somatic variant in cases with WM (39/42), MGUS (8/18), NHL (14/41, including 4/13 diffuse large B cell lymphoma (DLBCL), 1/8 mucosa-associated lymphoid tissue, 3/6 splenic marginal zone lymphoma (SMZL), 1/4 chronic lymphocytic leukemia, 2/3 nodal marginal zone lymphoma (NMZL), 1/2 mantle cell lymphoma, 1 Burkitt lymphoma, and 1 B cell NHL that could not be classified), primary AL (2/2), and IgM-PN (1/1). The mutation was absent in five patients with Cryoglobulinemia, two with primary cold agglutinin disease and one with MM. The CXCR4 WHIM-like mutation was present in 10/42 patients with WM, 3/41 with NHL (1 DLBCL, 1 SMZL, and 1 NMZL), and 1/18 patients with IgM MGUS. Among the patients with NHL, those with the mutated MYD88 L265P genotype were younger and had lower level of IgG and IgA than the patients with the wild-type genotype. Patients with the mutated MYD88 L265P genotype with WM and MZL were compared. More male patients, higher levels of IgM and lower levels of LDH were found in the WM group. There was no significant difference in overall survival between the two groups. We present a study of the prevalence of the MYD88 L265P mutation and CXCR4 WHIM-like mutation in IgM RD. The MYD88 L265P mutation may play a key role in the pathogenesis of IgM monoclonal gammopathies. It would be interesting in the future to use MYD88 mutation status to differentiate among diseases.

Prevention of Hepatitis C by Screening and Treatment in U.S. Prisons.

BACKGROUND: The prevalence of hepatitis C virus (HCV) in U.S. prisoners is high; however, HCV testing and treatment are rare. Infected inmates released back into society contribute to the spread of HCV in the general population. Routine hepatitis screening of inmates followed by new therapies may reduce ongoing HCV transmission. OBJECTIVE: To evaluate the health and economic effect of HCV screening and treatment in prisons on the HCV epidemic in society. DESIGN: Agent-based microsimulation model of HCV transmission and progression of HCV disease. DATA SOURCES: Published literature. TARGET POPULATION: Population in U.S. prisons and general community. TIME HORIZON: 30 years. PERSPECTIVE: Societal. INTERVENTIONS: Risk-based and universal opt-out hepatitis C screening in prisons, followed by treatment in a portion of patients. OUTCOME MEASURES: Prevention of HCV transmission and associated disease in prisons and society, costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and total prison budget. RESULTS OF BASE-CASE ANALYSIS: Implementing risk-based and opt-out screening could diagnose 41,900 to 122,700 new HCV cases in prisons in the next 30 years. Compared with no screening, these scenarios could prevent 5500 to 12,700 new HCV infections caused by released inmates, wherein about 90% of averted infections would have occurred outside of prisons. Screening could also prevent 4200 to 11,700 liver-related deaths. The ICERs of screening scenarios were $19,600 to $29,200 per QALY, and the respective first-year prison budget was $900 to $1150 million. Prisons would require an additional 12.4% of their current health care budget to implement such interventions. RESULTS OF SENSITIVITY ANALYSIS: Results were sensitive to the time horizon, and ICERs otherwise remained less than $50,000 per QALY. LIMITATION: Data on transmission network, reinfection rate, and opt-out HCV screening rate are lacking. CONCLUSION: Universal opt-out HCV screening in prisons is highly cost-effective and would reduce HCV transmission and HCV-associated diseases primarily in the outside community. Investing in U.S. prisons to manage hepatitis C is a strategic approach to address the current epidemic. PRIMARY FUNDING SOURCE: National Institutes of Health.

Molecular epidemiology of hepatitis C infections in Ningxia, China: genotype, phylogeny and mutation analysis.

BACKGROUND: Current prevalence and genotype distribution of hepatitis C virus (HCV) infection remain unknown in Ningxia, northwest China. METHODS: From June to December 2013, 13,022 individuals were screened in Ningxia HIV/AIDS Sentinel Surveillance System, with their demographic features collected and serum samples tested for HCV antibody. Sero-positive drug users were further subjected to sequencing of NS5B and Core regions of HCV. RESULTS: The anti-HCV prevalence was 0.34 % among individuals without history of drug use, while it was 15.80 % among drug users. Of 79 NS5B sequences amplified from drug users, 64 (81.0 %) were male and 51 (64.0 %) were injection drug users (IDUs). Subtype 3a (40.5 %) and 1b (25.3 %) were the most predominant subtypes, followed in frequency by 3b (10.1 %) and 2a (7.6 %). Subtype distribution has no significant difference between injection and non-injection drug users. Based on phylogeographic analysis, HCV strains in Ningxia IDUs were mainly originated from two sites, Yunnan province (in southwest China bordering Myanmar, also known as Burma) and Xinjiang Autonomous Region (in northwest China on the border of Central Asia), which are the two major drug trafficking originates in China. Previously reported drug-resistance mutations were also scanned in this treatment-naïve population. Amino acid substitutions (C316N) associated with direct anti-viral agents (DAA) resistance were identified in the NS5B region in seven samples. CONCLUSION: This study is the first to reveal the existence of multiple genotypes of HCV in Ningxia, an inland province in northwest China, suggesting the rapid spreading of the virus.