The NCCN Guidelines for Breast Cancer Screening and Diagnosis have been developed to facilitate clinical decision making. This manuscript discusses the diagnostic evaluation of individuals with suspected breast cancer due to either abnormal imaging and/or physical findings. For breast cancer screening recommendations, please see the full guidelines on NCCN.org.

Research on future-oriented mental time travel (FMTT) is highly active yet somewhat unruly. I believe this is due, in large part, to the complexity of both the tasks used to test FMTT and the concepts involved. Extraordinary care is a necessity when grappling with such complex and perplexing metaphysical constructs as self and time and their co-instantiation in memory. In this review, I first discuss the relation between future mental time travel and types of memory (episodic and semantic). I then examine the nature of both the types of self-knowledge assumed to be projected into the future and the types of temporalities that constitute projective temporal experience. Finally, I argue that a person lacking episodic memory should nonetheless be able to imagine a personal future by virtue of (1) the fact that semantic, as well as episodic, memory can be self-referential, (2) autonoetic awareness is not a prerequisite for FMTT, and (3) semantic memory does, in fact, enable certain forms of personally oriented FMTT. WIREs Cogn Sci 2013, 4:63-79. doi: 10.1002/wcs.1210 For further resources related to this article, please visit the WIREs website.

Advances to the equilibrium-point (EP) theory and solutions to several classical problems of action and perception are suggested and discussed. Among them are (1) the posture-movement problem of how movements away from a stable posture can be made without evoking resistance of posture-stabilizing mechanisms resulting from intrinsic muscle and reflex properties; (2) the problem of kinesthesia or why our sense of limb position is fairly accurate despite ambiguous positional information delivered by proprioceptive and cutaneous signals; (3) the redundancy problems in the control of multiple muscles and degrees of freedom. Central to the EP hypothesis is the notion that there are specific neural structures that represent spatial frames of reference (FRs) selected by the brain in a task-specific way from a set of available FRs. The brain is also able to translate or/and rotate the selected FRs by modifying their major attributes-the origin, metrics, and orientation-and thus substantially influence, in a feed-forward manner, action and perception. The brain does not directly solve redundancy problems: it only limits the amount of redundancy by predetermining where, in spatial coordinates, a task-specific action should emerge and allows all motor elements, including the environment, to interact to deliver a unique action, thus solving the redundancy problem (natural selection of action). The EP theory predicts the existence of specific neurons associated with the control of different attributes of FRs and explains the role of mirror neurons in the inferior frontal gyrus and place cells in the hippocampus. WIREs Cogni Sci 2011 2 287-304 DOI: 10.1002/wcs.108 For further resources related to this article, please visit the WIREs website.

BACKGROUND

The performance of routine and supplemental immunization activities is usually measured by the administrative method: dividing the number of doses distributed by the size of the target population. This method leads to coverage estimates that are sometimes impossible (e.g., vaccination of 102% of the target population), and are generally inconsistent with the proportion found to be vaccinated in Demographic and Health Surveys (DHS). We describe a method that estimates the fraction of the population accessible to vaccination activities, as well as within-campaign inefficiencies, thus providing a consistent estimate of vaccination coverage.

RESULTS

We developed a likelihood framework for estimating the effective coverage of vaccination programs using cross-sectional surveys of vaccine coverage combined with administrative data. We applied our method to measles vaccination in three African countries: Ghana, Madagascar, and Sierra Leone, using data from each country's most recent DHS survey and administrative coverage data reported to the World Health Organization. We estimate that 93% (95% CI: 91, 94) of the population in Ghana was ever covered by any measles vaccination activity, 77% (95% CI: 78, 81) in Madagascar, and 69% (95% CI: 67, 70) in Sierra Leone. "Within-activity" inefficiencies were estimated to be low in Ghana, and higher in Sierra Leone and Madagascar. Our model successfully fits age-specific vaccination coverage levels seen in DHS data, which differ markedly from those predicted by naïve extrapolation from country-reported and World Health Organization-adjusted vaccination coverage.

CONCLUSIONS

Combining administrative data with survey data substantially improves estimates of vaccination coverage. Estimates of the inefficiency of past vaccination activities and the proportion not covered by any activity allow us to more accurately predict the results of future activities and provide insight into the ways in which vaccination programs are failing to meet their goals. Please see later in the article for the Editors' Summary.

A lack of consensus exists with regards to the relative rates of NRAS and BRAF mutations in the radial (RGP) and vertical (VGP) growth phases of individual melanoma tumors. This study was conducted to test the hypothesis that mutations are acquired with progression from RGP to VGP. Using laser capture microdissection, pure tumor DNA was obtained from 15 in situ melanomas, and from the RGP and VGP of 29 invasive tumors. NRAS exon 2 and BRAF exon 15 DNA were amplified by PCR and sequenced. Mutations were present in 6 of 15 in situ melanomas (40%). Of 29 invasive tumors, 16 exhibited RGP mutations (55.2%); 22 showed VGP mutations (75.9%). Paired RGP/VGP mutation analysis revealed a trend toward discordance in the distribution of mutations, favoring VGP localization (P=0.07). Of 15 samples, 12 with mutations in both phases had an increased proportion of mutated DNA in the VGP, measured on DNA chromatograms (P=0.08). Limitations of this study include a relatively small sample cohort selected for technical reasons from a larger population, presenting the risk of selection bias. These concerns notwithstanding our findings support the hypothesis that NRAS and BRAF mutations increase with tumor progression from superficial to invasive disease. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclub.

BACKGROUND

Expansion of the CGG trinucleotide repeat in the 5'-untranslated region of the FMR1, fragile X mental retardation 1, gene results in suppression of protein expression for this gene and is the underlying cause of Fragile X syndrome. In unaffected individuals, the FMRP protein, together with two additional paralogues (Fragile X Mental Retardation Syndrome-related Protein 1 and 2), associates with mRNA to form a ribonucleoprotein complex in the nucleus that is transported to dendrites and spines of neuronal cells. It is thought that the fragile X family of proteins contributes to the regulation of protein synthesis at sites where mRNAs are locally translated in response to stimuli.

RESULTS

Here, we report the X-ray crystal structures of the non-canonical nuclear localization signals of the FXR1 and FXR2 autosomal paralogues of FMRP, which were determined at 2.50 and 1.92 Å, respectively. The nuclear localization signals of the FXR1 and FXR2 comprise tandem Tudor domain architectures, closely resembling that of UHRF1, which is proposed to bind methylated histone H3K9.

CONCLUSIONS

The FMRP, FXR1 and FXR2 proteins comprise a small family of highly conserved proteins that appear to be important in translational regulation, particularly in neuronal cells. The crystal structures of the N-terminal tandem Tudor domains of FXR1 and FXR2 revealed a conserved architecture with that of FMRP. Biochemical analysis of the tandem Tudor domains reveals their ability to preferentially recognize trimethylated peptides in a sequence-specific manner.

BACKGROUND

This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

BACKGROUND

Venous thrombosis is a common disease with a high mortality rate shortly after the event. However, details on long-term mortality in these patients are lacking. The aim of this study was to determine long-term mortality in a large cohort of patients with venous thrombosis.

RESULTS

4,947 patients from the Multiple Environmental and Genetic Assessment study of risk factors for venous thrombosis (MEGA study) with a first nonfatal venous thrombosis or pulmonary embolism and 6,154 control individuals without venous thrombosis, aged 18 to 70 years, were followed up for 8 years. Death and causes of death were retrieved from the Dutch death registration. Standardized mortality ratios (SMRs) were calculated for patients compared with control individuals. Several subgroups were studied as well. 736 participants (601 patients and 135 controls) died over a follow-up of 54,948 person-years. The overall mortality rate was 22.7 per 1,000 person-years (95% CI 21.0-24.6) for patients and 4.7 per 1,000 person-years (95% CI 4.0-5.6) for controls. Patients with venous thrombosis had a 4.0-fold (95% CI 3.7-4.3) increased risk of death compared with controls. The risk remained increased up to 8 years after the thrombotic event, even when no additional comorbidities were present. The highest risk of death was found for patients with additional malignancies (SMR 5.5, 95% CI 5.0-6.1). Main causes of death were diseases of the circulatory system, venous thrombosis, and malignancies. Main limitation was a maximum age of 70 at time of inclusion for the first event. Therefore results can not be generalized to those in the highest age categories.

CONCLUSIONS

Patients who experienced a first venous thrombosis had an increased risk of death which lasted up to 8 years after the event, even when no comorbidities were present at time of thrombosis. Future long-term clinical follow-up could be beneficial in these patients. Please see later in the article for the Editors' Summary.

BACKGROUND

Suboptimal medicine use is a global public health problem. For 35 years the World Health Organization (WHO) has promoted essential medicines policies to improve quality use of medicines (QUM), but evidence of their effectiveness is lacking, and uptake by countries remains low. Our objective was to determine whether WHO essential medicines policies are associated with better QUM.

RESULTS

We compared results from independently conducted medicines use surveys in countries that did versus did not report implementation of WHO essential medicines policies. We extracted survey data on ten validated QUM indicators and 36 self-reported policy implementation variables from WHO databases for 2002-2008. We calculated the average difference (as percent) for the QUM indicators between countries reporting versus not reporting implementation of specific policies. Policies associated with positive effects were included in a regression of a composite QUM score on total numbers of implemented policies. Data were available for 56 countries. Twenty-seven policies were associated with better use of at least two percentage points. Eighteen policies were associated with significantly better use (unadjusted p<0.05), of which four were associated with positive differences of 10% or more: undergraduate training of doctors in standard treatment guidelines, undergraduate training of nurses in standard treatment guidelines, the ministry of health having a unit promoting rational use of medicines, and provision of essential medicines free at point of care to all patients. In regression analyses national wealth was positively associated with the composite QUM score and the number of policies reported as being implemented in that country. There was a positive correlation between the number of policies (out of the 27 policies with an effect size of 2% or more) that countries reported implementing and the composite QUM score (r=0.39, 95% CI 0.14 to 0.59, p=0.003). This correlation weakened but remained significant after inclusion of national wealth in multiple linear regression analyses. Multiple policies were more strongly associated with the QUM score in the 28 countries with gross national income per capita below the median value (US$2,333) (r=0.43, 95% CI 0.06 to 0.69, p=0.023) than in the 28 countries with values above the median (r=0.22, 95% CI -0.15 to 0.56, p=0.261). The main limitations of the study are the reliance on self-report of policy implementation and measures of medicine use from small surveys. While the data can be used to explore the association of essential medicines policies with medicine use, they cannot be used to compare or benchmark individual country performance.

CONCLUSIONS

WHO essential medicines policies are associated with improved QUM, particularly in low-income countries. Please see later in the article for the Editors' Summary.

We retrospectively reviewed 12 patients with spinal tuberculosis of the thoracic and lumbar spine who had radical débridement, anterior decompression, interbody arthrodesis with an anterior interbody titanium cage, and autologous bone grafts, combined with a standardized perioperative antituberculous regimen. Their mean age was 55.1 years and they were observed for a mean of 65.3 months. Indications for surgery included epidural abscess, structural destruction with instability, progressive kyphosis, and/or neurologic deterioration. Kyphotic deformity was corrected from a mean of 24.6 degrees (range, 15 degrees-32 degrees) to a mean of 10 degrees (range, 4 degrees-18 degrees). Tuberculous infection was controlled and bony fusion was achieved in all patients. No recurrence of infection or construct failure was recorded. All patients were safely mobilized within the first postoperative week; back pain fully resolved in eight patients and improved in the remaining four. We conclude that radical débridement followed by anterior stabilization with a titanium cage and bone grafting is a reasonable alternative for tuberculous spondylitis requiring surgical treatment. It enables accurate and lasting deformity correction and provides adequate stability to allow early mobilization. The presence of a titanium cage in an area of mycobacterial infection did not preclude infection control or lead to recurrence.

METHODS

Therapeutic study. Level IV (case series). Please see Guidelines for Authors for a complete description of levels of evidence.

BACKGROUND

Financial ties between health professionals and industry may unduly influence professional judgments and some researchers have suggested that widening disease definitions may be one driver of over-diagnosis, bringing potentially unnecessary labeling and harm. We aimed to identify guidelines in which disease definitions were changed, to assess whether any proposed changes would increase the numbers of individuals considered to have the disease, whether potential harms of expanding disease definitions were investigated, and the extent of members' industry ties.

RESULTS

We undertook a cross-sectional study of the most recent publication between 2000 and 2013 from national and international guideline panels making decisions about definitions or diagnostic criteria for common conditions in the United States. We assessed whether proposed changes widened or narrowed disease definitions, rationales offered, mention of potential harms of those changes, and the nature and extent of disclosed ties between members and pharmaceutical or device companies. Of 16 publications on 14 common conditions, ten proposed changes widening and one narrowing definitions. For five, impact was unclear. Widening fell into three categories: creating "pre-disease"; lowering diagnostic thresholds; and proposing earlier or different diagnostic methods. Rationales included standardising diagnostic criteria and new evidence about risks for people previously considered to not have the disease. No publication included rigorous assessment of potential harms of proposed changes. Among 14 panels with disclosures, the average proportion of members with industry ties was 75%. Twelve were chaired by people with ties. For members with ties, the median number of companies to which they had ties was seven. Companies with ties to the highest proportions of members were active in the relevant therapeutic area. Limitations arise from reliance on only disclosed ties, and exclusion of conditions too broad to enable analysis of single panel publications.

CONCLUSIONS

For the common conditions studied, a majority of panels proposed changes to disease definitions that increased the number of individuals considered to have the disease, none reported rigorous assessment of potential harms of that widening, and most had a majority of members disclosing financial ties to pharmaceutical companies. Please see later in the article for the Editors' Summary.

The classic [MN55] confusion matrix experiment (16 consonants, white noise masker) was repeated by using computerized procedures, similar to those of Phatak and Allen (2007). ["Consonant and vowel confusions in speech-weighted noise," J. Acoust. Soc. Am. 121, 2312-2316]. The consonant scores in white noise can be categorized in three sets: low-error set [/m/, /n/], average-error set [/p/, /t/, /k/, /s/, /[please see text]/, /d/, /g/, /z/, /Z/], and high-error set /f/theta/b/, /v/, /E/,/theta/]. The consonant confusions match those from MN55, except for the highly asymmetric voicing confusions of fricatives, biased in favor of voiced consonants. Masking noise cannot only reduce the recognition of a consonant, but also perceptually morph it into another consonant. There is a significant and systematic variability in the scores and confusion patterns of different utterances of the same consonant, which can be characterized as (a) confusion heterogeneity, where the competitors in the confusion groups of a consonant vary, and (b) threshold variability, where confusion threshold [i.e., signal-to-noise ratio (SNR) and score at which the confusion group is formed] varies. The average consonant error and errors for most of the individual consonants and consonant sets can be approximated as exponential functions of the articulation index (AI). An AI that is based on the peak-to-rms ratios of speech can explain the SNR differences across experiments.

Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The ability to efficiently modify the genome using CRISPR technology has rapidly revolutionized biology and genetics and will soon transform medicine. Duchenne muscular dystrophy (DMD) represents one of the first monogenic disorders that has been investigated with respect to CRISPR-mediated correction of causal genetic mutations. DMD results from mutations in the gene encoding dystrophin, a scaffolding protein that maintains the integrity of striated muscles. Thousands of different dystrophin mutations have been identified in DMD patients, who suffer from a loss of ambulation followed by respiratory insufficiency, heart failure, and death by the third decade of life. Using CRISPR to bypass DMD mutations, dystrophin expression has been efficiently restored in human cells and mouse models of DMD. Here, we review recent progress toward the development of possible CRISPR therapies for DMD and highlight opportunities and potential obstacles in attaining this goal. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

In principle, to achieve the most natural and harmonious rejuvenation of the face, all changes that result from the aging process should be corrected. Traditionally, soft tissue lifting and redraping have constituted the cornerstone of most facial rejuvenation procedures. Changes in the facial skeleton that occur with aging and their impact on facial appearance have not been well appreciated. Accordingly, failure to address changes in the skeletal foundation of the face may limit the potential benefit of any rejuvenation procedure. Correction of the skeletal framework is increasingly viewed as the new frontier in facial rejuvenation. It currently is clear that certain areas of the facial skeleton undergo resorption with aging. Areas with a strong predisposition to resorption include the midface skeleton, particularly the maxilla including the pyriform region of the nose, the superomedial and inferolateral aspects of the orbital rim, and the prejowl area of the mandible. These areas resorb in a specific and predictable manner with aging. The resultant deficiencies of the skeletal foundation contribute to the stigmata of the aging face. In patients with a congenitally weak skeletal structure, the skeleton may be the primary cause for the manifestations of premature aging. These areas should be specifically examined in patients undergoing facial rejuvenation and addressed to obtain superior aesthetic results.

METHODS

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Please see the Author Video associated with this article. Background: A multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C) has recently been described. Objective: To evaluate imaging findings of MIS-C associated with COVID-19. Subjects and Methods: Imaging studies and medical records of sixteen patients (0-20 years) admitted with MIS-C were retrospectively reviewed. Thoracic imaging studies were evaluated for parenchymal, mediastinal and hilar, and cardiovascular abnormalities. Abdominal imaging studies were evaluated for abnormalities of solid viscera, hollow viscera, peritoneum, as well as the mesentery and retroperitoneum. Studies were reviewed independently by two radiologists, and disagreements were resolved by a third, senior radiologist. Results: Sixteen patients were included (10 male and 6 female; 20 months - 20 years). All 16 patients presented with fever. Other presenting signs and symptoms included: vomiting (12; 75%), abdominal pain (11; 69%), rash (10;62.5%), conjunctivitis (8;50%), diarrhea (7;44%), headache (6;37.5%), and sore throat (5;31%). Shortness of breath and cough were each present in one patient. Chest radiograph demonstrated cardiomegaly (10; 62.5%), congestive heart failure or pulmonary edema (9; 56%), atelectasis (9; 56%), pleural effusions (7; 44%), adult respiratory distress syndrome (2; 12.5%) and pneumonia (1; 6%). Absolute interobserver agreement was 69-100%. Eight patients (50%) were evaluated for PE (6 [75%] by CT angiography [CTA] and 2 [25%] by ventilation/perfusion scintigraphy). In 2 (25%), CTA demonstrated a segmental PE. Abdominal imaging findings (US and CT) included small volume ascites (6; 38%), hepatomegaly (6; 38%), echogenic kidneys (5; 31%), bowel wall thickening (3; 19%), gallbladder wall thickening (3; 19%), mesenteric lymphadenopathy (2; 13%), splenomegaly (1; 6%), and bladder wall thickening (1; 6%). The frequencies of findings based on all the reviewed modalities were: cardiomegaly (12; 75%), pleural effusion (10; 63%) and atelectasis (10; 63%). 15 patients (94%) were discharged home (length of hospital stay 3-20 days). There were no mortalities. Conclusion: MIS-C associated with COVID-19 is characterized predominantly by cardiovascular abnormalities, though also solid visceral organ, gallbladder, and bowel abnormalities as well as ascites, reflecting a multisystemic inflammatory process. Clinical Impact: The constellation of imaging findings in the setting of COVID-19 may alert pediatric radiologists to the diagnosis of MIS-C prior to rapid deterioration of patients.

Adult hippocampal neurogenesis (AHN) has intrigued neuroscientists for decades. Several lines of evidence show that adult-born neurons in the hippocampus are functionally integrated and contribute to cognitive function, in particular learning and memory processes. Biological properties of immature hippocampal neurons indicate that these cells are more easily excitable compared with mature neurons, and demonstrate enhanced structural plasticity. The structure in which adult-born hippocampal neurons are situated-the dentate gyrus-is thought to contribute to hippocampus function by disambiguating similar input patterns, a process referred to as pattern separation. Several ideas about AHN function have been put forward; currently there is good evidence in favor of a role for AHN in pattern separation. This function of AHN may be understood within a 'representational-hierarchical' view of brain organization. WIREs Cogn Sci 2014, 5:573-587. doi: 10.1002/wcs.1304 For further resources related to this article, please visit the WIREs website.

BACKGROUND

The authors have declared no conflicts of interest for this article.

The ultimate goal of drug delivery is to increase the bioavailability and reduce the toxic side effects of the active pharmaceutical ingredient (API) by releasing them at a specific site of action. In the case of antitumor therapy, association of the therapeutic agent with a carrier system can minimize damage to healthy, nontarget tissues, while limit systemic release and promoting long circulation to enhance uptake at the cancerous site due to the enhanced permeation and retention effect (EPR). Stimuli-responsive systems have become a promising way to deliver and release payloads in a site-selective manner. Potential carrier systems have been derived from a wide variety of materials, including inorganic nanoparticles, lipids, and polymers that have been imbued with stimuli-sensitive properties to accomplish triggered release based on an environmental cue. The unique features in the tumor microenvironment can serve as an endogenous stimulus (pH, redox potential, or unique enzymatic activity) or the locus of an applied external stimulus (heat or light) to trigger the controlled release of API. In liposomal carrier systems triggered release is generally based on the principle of membrane destabilization from local defects within bilayer membranes to effect release of liposome-entrapped drugs. This review focuses on the literature appearing between November 2008-February 2016 that reports new developments in stimuli-sensitive liposomal drug delivery strategies using pH change, enzyme transformation, redox reactions, and photochemical mechanisms of activation. WIREs Nanomed Nanobiotechnol 2017, 9:e1450. doi: 10.1002/wnan.1450 For further resources related to this article, please visit the WIREs website.

Functional annotation of genomes is a prerequisite for contemporary basic and applied genomic research, yet farmed animal genomics are deficient in such annotation. To address this, the FAANG (Functional Annotation of Animal Genomes) Consortium is producing genome-wide data sets on RNA expression, DNA methylation, and chromatin modification, as well as chromatin accessibility and interactions. In addition to informing our understanding of genome function, including comparative approaches to elucidate constrained sequence or epigenetic elements, these annotation maps will improve the precision and sensitivity of genomic selection for animal improvement. A scientific community-driven effort has already created a coordinated data collection and analysis enterprise crucial for the success of this global effort. Although it is early in this continuing process, functional data have already been produced and application to genetic improvement reported. The functional annotation delivered by the FAANG initiative will add value and utility to the greatly improved genome sequences being established for domesticated animal species. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

twilight is a Bioconductor compatible package for analysing the statistical significance of differentially expressed genes. It is based on the concept of the local false discovery rate (FDR), a generalization of the frequently used global FDR. twilight implements the heuristic search algorithm for estimating the local FDR introduced in our earlier work. In addition to the raw significance measures, it produces diagnostic plots, which provide insight into the extent of differential expression across genes.

BACKGROUND

http://www.bioconductor.org

BACKGROUND

stefanie.scheid@molgen.mpg.de

BACKGROUND

Please visit our software webpage on http://compdiag.molgen.mpg.de/software.

BACKGROUND

Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.

RESULTS

Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.

CONCLUSIONS

FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors' Summary.

BACKGROUND

Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.

RESULTS

We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38-4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16-2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19-3.03) than for atopic asthma (1.37, 95% CI 0.89-2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11-1.79) per 0.5 kg and 2.25 (95% CI 1.23-4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.

CONCLUSIONS

Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary.

3' processing is an essential step in the maturation of all messenger RNAs (mRNAs) and is a tightly coupled two-step reaction: endonucleolytic cleavage at the poly(A) site is followed by the addition of a poly(A) tail, except for metazoan histone mRNAs, which are cleaved but not polyadenylated. The recognition of a poly(A) site is coordinated by the sequence elements in the mRNA 3' UTR and associated protein factors. In mammalian cells, three well-studied sequence elements, UGUA, AAUAAA, and GU-rich, are recognized by three multisubunit factors: cleavage factor I(m) (CFI(m) ), cleavage and polyadenylation specificity factor (CPSF), and cleavage stimulation factor (CstF), respectively. In the yeast Saccharomyces cerevisiae, UA repeats and A-rich sequence elements are recognized by Hrp1p and cleavage factor IA. Structural studies of protein-RNA complexes have helped decipher the mechanisms underlying sequence recognition and shed light on the role of protein factors in poly(A) site selection and 3' processing machinery assembly. In this review we focus on the interactions between the mRNA cis-elements and the protein factors (CFI(m) , CPSF, CstF, and homologous factors from yeast and other eukaryotes) that define the poly(A) site. WIREs RNA 2011 2 732-747 DOI: 10.1002/wrna.88 For further resources related to this article, please visit the WIREs website.

BACKGROUND

To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur.

RESULTS

We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th-95th percentile, to provide an indication of the uncertainty in the estimates. We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th-95th centiles, 83,300-217,700) while causing potentially 253 intussusception deaths (76-689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000-281,500) while potentially causing 547 intussusception deaths (237-1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700-63,700) and cause an additional 294 (161-471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%-25% children, beyond the 63%-73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes.

CONCLUSIONS

Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths. Please see later in the article for the Editors' Summary.