Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy

BACKGROUND: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). METHODS: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. RESULTS: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06). CONCLUSIONS: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230

Predictions from Lattice QCD

In the past year, we calculated with lattice QCD three quantities that were unknown or poorly known. They are the $q^2$ dependence of the form factor in semileptonic $D\to Kl\nu$ decay, the decay constant of the $D$ meson, and the mass of the $B_c$ meson. In this talk, we summarize these calculations, with emphasis on their (subsequent) confirmation by experiments.Comment: v1: talk given at the International Conference on QCD and Hadronic Physics, Beijing, June 16-20, 2005; v2: poster presented at the XXIIIrd International Symposium on Lattice Field Theory, Dublin, July 25-3

Insufficient Rest or Sleep and Its Relation to Cardiovascular Disease, Diabetes and Obesity in a National, Multiethnic Sample

BACKGROUND: A new question on insufficient rest/sleep was included in the 2008 Behavioral Risk Factor Surveillance System (BRFSS) for the 50 states, District of Columbia, and three US territories. No previous study, however, has examined perceived insufficient rest/sleep in relation to cardiovascular disease (CVD) or diabetes mellitus. We examined the association between self-reported insufficient rest/sleep and CVD, diabetes, and obesity in a contemporary sample of US adults. METHODS: Multiethnic, nationally representative, cross-sectional survey (2008 BRFSS) participants were >20 years of age (n=372, 144, 50% women). Self-reported insufficient rest/sleep in the previous month was categorized into four groups: zero, 1-13, 14-29, and 30 days. There were five outcomes: 1) any CVD, 2) coronary heart disease (CHD), 3) stroke, 4) diabetes mellitus, and 5) obesity (body mass index≥30 kg/m2). We employed multivariable logistic regression to calculate odds ratio (OR), (95% confidence interval (CI), of increasing categories of insufficient rest/sleep, taking zero days of insufficient rest/sleep as the referent category. PRINCIPAL FINDINGS: Insufficient rest/sleep was found to be associated with 1) any CVD, 2) CHD, 3) stroke, 4) diabetes mellitus, and 5) obesity, in separate analyses. Compared to those reporting zero days of insufficient sleep (referent), the OR (95% CI) associated with all 30 days of insufficient sleep was 1.67 (1.55-1.79) for any cardiovascular disease, 1.69(1.56-1.83) for CHD, 1.51(1.36-1.68) for stroke, 1.31(1.21-1.41) for diabetes, and 1.51 (1.43-1.59) for obesity. CONCLUSIONS: In a multiethnic sample of US adults, perceived insufficient rest/sleep was found to be independently associated with CHD, stroke, diabetes mellitus and obesity

Awe and Wonder in Scientific Practice: Implications for the Relationship Between Science and Religion

This paper examines the role of awe and wonder in scientific practice. Drawing on evidence from psychological research and the writings of scientists and science communicators, I argue that awe and wonder play a crucial role in scientific discovery. They focus our attention on the natural world, encourage open-mindedness, diminish the self (particularly feelings of self-importance), help to accord value to the objects that are being studied, and provide a mode of understanding in the absence of full knowledge. I will flesh out implications of the role of awe and wonder in scientific discovery for debates on the relationship between science and religion. Abraham Heschel argued that awe and wonder are religious emotions because they reduce our feelings of self-importance, and thereby help to cultivate the proper reverent attitude towards God. Yet metaphysical naturalists such as Richard Dawkins insist that awe and wonder need not lead to any theistic commitments for scientists. The awe some scientists experience can be regarded as a form of non-theistic spirituality, which is neither a reductive naturalism nor theism. I will attempt to resolve the tension between these views by identifying some common ground

Evolution of HIV virulence in response to widespread scale up of antiretroviral therapy: a modeling study

There are global increases in the use of HIV antiretroviral therapy (ART), guided by clinical benefits of early ART initiation and the efficacy of treatment as prevention of transmission. Separately, it has been shown theoretically and empirically that HIV virulence can evolve over time; observed virulence levels may reflect an adaptive balance between infected lifespan and per-contact transmission rate. However, the potential effects of widespread ART usage on HIV virulence are unknown. To predict these effects, we used an agent-based stochastic model to simulate evolutionary trends in HIV virulence, using set point viral load as a proxy for virulence. We calibrated our model to prevalence and incidence trends of South Africa. We explored two distinct ART scenarios: (1) ART initiation based on HIV-infected individuals reaching a CD4 count threshold; and (2) ART initiation based on individual time elapsed since HIV infection (a scenario that mimics “universal testing and treatment” (UTT) aspirations). In each case, we considered a range in population uptake of ART. We found that HIV virulence is generally unchanged in scenarios of CD4-based initiation. However, with ART initiation based on time since infection, virulence can increase moderately within several years of ART rollout, under high coverage levels and early treatment initiation (albeit within the context of epidemics that are rapidly decreasing in size). Sensitivity analyses suggested the impact of ART on virulence is relatively insensitive to model calibration. Our modeling study suggests that increasing HIV virulence driven by UTT is likely not a major public health concern, but should be monitored in sentinel surveillance, in a manner similar to transmitted resistance to antiretroviral drugs

Bacterial porin disrupts mitochondrial membrane potential and sensitizes host cells to apoptosis

The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (delta psi m). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of delta psi m. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce delta psi m loss and apoptosis, demonstrating that dissipation of delta psi m is a requirement for cell death caused by neisserial infection

The Cobalamin-Binding Protein in Zebrafish Is an Intermediate between the Three Cobalamin-Binding Proteins in Human

In humans, three soluble extracellular cobalamin-binding proteins; transcobalamin (TC), intrinsic factor (IF), and haptocorrin (HC), are involved in the uptake and transport of cobalamin. In this study, we investigate a cobalamin-binding protein from zebrafish (Danio rerio) and summarize current knowledge concerning the phylogenetic evolution of kindred proteins. We identified a cobalamin binding capacity in zebrafish protein extracts (8.2 pmol/fish) and ambient water (13.5 pmol/fish) associated with a single protein. The protein showed resistance toward degradation by trypsin and chymotrypsin (like human IF, but unlike human HC and TC). The cobalamin analogue, cobinamide, bound weaker to the zebrafish cobalamin binder than to human HC, but stronger than to human TC and IF. Affinity for another analogue, adenosyl-pseudo-cobalamin was low compared with human HC and TC, but high compared with human IF. The absorbance spectrum of the purified protein in complex with hydroxo-cobalamin resembled those of human HC and IF, but not TC. We searched available databases to further explore the phylogenies of the three cobalamin-binding proteins in higher vertebrates. Apparently, TC-like proteins are the oldest evolutionary derivatives followed by IF and HC (the latter being present only in reptiles and most but not all mammals). Our findings suggest that the only cobalamin-binding protein in zebrafish is an intermediate between the three human cobalamin binders. These findings support the hypothesis about a common ancestral gene for all cobalamin-binding proteins in higher vertebrates

Usefulness of primary care electronic networks to assess the incidence of chlamydia, diagnosed by general practitioners

Background: Chlamydia is the most common curable sexually transmitted infection (STI) in the Netherlands. The majority of chlamydia diagnoses are made by general practitioners (GPs). Baseline data from primary care will facilitate the future evaluation of the ongoing large population-based screening in the Netherlands. The aim of this study was to assess the usefulness of electronic medical records for monitoring the incidence of chlamydia cases diagnosed in primary care in the Netherlands. Methods. In the electronic records of two regional and two national networks, we identified chlamydia diagnoses by means of ICPC codes (International Classification of Primary Care), laboratory results in free text and the prescription of antibiotics. The year of study was 2007 for the two regional networks and one national network, for the other national network the year of study was 2005. We calculated the incidence of diagnosed chlamydia cases per sex, age group and degree of urbanization. Results: A large diversity was observed in the way chlamydia episodes were coded in the four different GP networks and how easily information concerning chlamydia diagnoses could be extracted. The overall incidence ranged from 103.2/100,000 to 590.2/100,000. Differences were partly related to differences between patient populations. Nevertheless, we observed similar trends in the incidence of chlamydia diagnoses in all networks and findings were in line with earlier reports. Conclusions: Electronic patient records, originally intended for individual patient care in general practice, can be an additional source of data for monitoring chlamydia incidence in primary care and can be of use in assessing the future impact of population-based chlamydia screening programs. To increase the usefulness of data we recommend more efforts to standardize registration by (specific) ICPC code and laboratory results across the existing GP networks

Viral population estimation using pyrosequencing

The diversity of virus populations within single infected hosts presents a major difficulty for the natural immune response as well as for vaccine design and antiviral drug therapy. Recently developed pyrophosphate based sequencing technologies (pyrosequencing) can be used for quantifying this diversity by ultra-deep sequencing of virus samples. We present computational methods for the analysis of such sequence data and apply these techniques to pyrosequencing data obtained from HIV populations within patients harboring drug resistant virus strains. Our main result is the estimation of the population structure of the sample from the pyrosequencing reads. This inference is based on a statistical approach to error correction, followed by a combinatorial algorithm for constructing a minimal set of haplotypes that explain the data. Using this set of explaining haplotypes, we apply a statistical model to infer the frequencies of the haplotypes in the population via an EM algorithm. We demonstrate that pyrosequencing reads allow for effective population reconstruction by extensive simulations and by comparison to 165 sequences obtained directly from clonal sequencing of four independent, diverse HIV populations. Thus, pyrosequencing can be used for cost-effective estimation of the structure of virus populations, promising new insights into viral evolutionary dynamics and disease control strategies.Comment: 23 pages, 13 figure

A Recurrent Stop-Codon Mutation in Succinate Dehydrogenase Subunit B Gene in Normal Peripheral Blood and Childhood T-Cell Acute Leukemia

BACKGROUND: Somatic cytidine mutations in normal mammalian nuclear genes occur during antibody diversification in B lymphocytes and generate an isoform of apolipoprotein B in intestinal cells by RNA editing. Here, I describe that succinate dehydrogenase (SDH; mitochondrial complex II) subunit B gene (SDHB) is somatically mutated at a cytidine residue in normal peripheral blood mononuclear cells (PBMCs) and T-cell acute leukemia. Germ line mutations in the SDHB, SDHC or SDHD genes cause hereditary paraganglioma (PGL) tumors which show constitutive activation of homeostatic mechanisms induced by oxygen deprivation (hypoxia). PRINCIPAL FINDINGS: To determine the prevalence of a mutation identified in the SDHB mRNA, 180 samples are tested. An SDHB stop-codon mutation c.136C>T (R46X) is present in a significant fraction (average = 5.8%, range = less than 1 to 30%, n = 52) of the mRNAs obtained from PBMCs. In contrast, the R46X mutation is present in the genomic DNA of PBMCs at very low levels. Examination of the PBMC cell-type subsets identifies monocytes and natural killer (NK) cells as primary sources of the mutant transcript, although lesser contributions also come from B and T lymphocytes. Transcript sequence analyses in leukemic cell lines derived from monocyte, NK, T and B cells indicate that the mutational mechanism targeting SDHB is operational in T-cell acute leukemia. Accordingly, substantial levels (more than 3%) of the mutant SDHB transcripts are detected in five of 20 primary childhood T-cell acute lymphoblastic leukemia (T-ALL) bone marrow samples, but in none of 20 B-ALL samples. In addition, distinct heterozygous SDHB missense DNA mutations are identified in Jurkat and TALL-104 cell lines which are derived from T-ALLs. CONCLUSIONS: The identification of a recurrent, inactivating stop-codon mutation in the SDHB gene in normal blood cells suggests that SDHB is targeted by a cytidine deaminase enzyme. The SDHB mutations in normal PBMCs and leukemic T cells might play a role in cellular pre-adaptation to hypoxia