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Over the course of an individual's lifetime, normal human cells accumulate mutations.sup.1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage.sup.2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma. The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues., Author(s): Luiza Moore [sup.1] [sup.2] , Alex Cagan [sup.1] , Tim H. H. Coorens [sup.1] , Matthew D. C. Neville [sup.1] , Rashesh Sanghvi [sup.1] , Mathijs A. Sanders [sup.1] [...]

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing.sup.1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals. Somatic mutations obtained from laser microdissected biopsies of human tissues are used to reconstruct the developmental phylogenies of these tissues back to the zygote., Author(s): Tim H. H. Coorens [sup.1] , Luiza Moore [sup.1] [sup.2] , Philip S. Robinson [sup.1] [sup.3] , Rashesh Sanghvi [sup.1] , Joseph Christopher [sup.1] [sup.3] [sup.4] , James Hewinson [...]

Global concern over widely documented declines in pollinators.sup.1-3 has led to the identification of anthropogenic stressors that, individually, are detrimental to bee populations.sup.4-7. Synergistic interactions between these stressors could substantially amplify the environmental effect of these stressors and could therefore have important implications for policy decisions that aim to improve the health of pollinators.sup.3,8,9. Here, to quantitatively assess the scale of this threat, we conducted a meta-analysis of 356 interaction effect sizes from 90 studies in which bees were exposed to combinations of agrochemicals, nutritional stressors and/or parasites. We found an overall synergistic effect between multiple stressors on bee mortality. Subgroup analysis of bee mortality revealed strong evidence for synergy when bees were exposed to multiple agrochemicals at field-realistic levels, but interactions were not greater than additive expectations when bees were exposed to parasites and/or nutritional stressors. All interactive effects on proxies of fitness, behaviour, parasite load and immune responses were either additive or antagonistic; therefore, the potential mechanisms that drive the observed synergistic interactions for bee mortality remain unclear. Environmental risk assessment schemes that assume additive effects of the risk of agrochemical exposure may underestimate the interactive effect of anthropogenic stressors on bee mortality and will fail to protect the pollinators that provide a key ecosystem service that underpins sustainable agriculture. A meta-analysis of studies in which bees were exposed to combinations of agrochemicals, nutritional stressors and/or parasites revealed evidence for synergistic effects on mortality when bees were exposed to multiple agrochemicals at field-realistic levels., Author(s): Harry Siviter [sup.1] [sup.2] , Emily J. Bailes [sup.1] [sup.3] [sup.4] , Callum D. Martin [sup.1] , Thomas R. Oliver [sup.1] [sup.4] [sup.5] , Julia Koricheva [sup.1] , Ellouise [...]

Purpose.--Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods.--An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including preanalytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results.--The literature search identified 1338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusions.--The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens, and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity or clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, reevaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice. doi: 10.5858/arpa.2018-0901-SA, INTRODUCTION The use of assays that assess genomic variants in circulating tumor DNA (ctDNA) is increasing in the oncology clinical setting, despite uncertainties surrounding preanalytical considerations, analytical validity, and clinical [...]

Introduction. In the equatorial Pacific Ocean, the El Nino-Southern Oscillation substantially affects atmospheric and oceanic conditions on interannual time scales. The central and eastern equatorial Pacific fluctuates between anomalously warm [...]

Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTNI-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST., Introduction Netrins are a family of extracellular proteins that regulate cell migration and survival during development and adulthood. The first member, netrin-1, was identified as a secreted protein mediating axon [...]

High-resolution time-of-flight measurements of H atom products from photolysis of phenol, 4-methylphenol, 4-fluorophenol, and thiophenol, at many UV wavelengths ([[lambda].sub.phot]), have allowed systematic study of the influence of ring substituents and the heteroatom on the fragmentation dynamics. All dissociate by X--H (X = O, S) bond fission after excitation at their respective [S.sub.1]([sup.1][pi][[pi].sup.*])-[S.sub.0] origins and at all shorter wavelengths. The achieved kinetic energy resolution reveals population of selected vibrational levels of the various phenoxyl and thiophenoxyl coproducts, providing uniquely detailed insights into the fragmentation dynamics. Dissociation in all cases is deduced to involve nuclear motion on the [sup.1][pi][[sigma].sup.*] potential energy surface (PES). The route to accessing this PES, and the subsequent dynamics, is seen to be very sensitive to [[lambda].sub.phot] and substitution of the heteroatom. In the case of the phenols, dissociation after excitation at long [[lambda].sub.phot] is rationalized in terms of radiationless transfer from [S.sub.1] to [S.sub.0] levels carrying sufficient O--H stretch vibrational energy to allow coupling via the conical intersection between the So and [sup.1][pi][[sigma].sup.*] PESs at longer O--H bond lengths. In contrast, H + [C.sub.6][H.sub.5]O([X.sup.2][B.sub.1]) products formed after excitation at short [[lambda].sub.phot] exhibit anisotropic recoil-velocity distributions, consistent with prompt dissociation induced by coupling between the photoprepared [sup.1][pi][[pi].sup.*] excited state and the [sup.1][pi][[sigma].sup.*] PES. The fragmentation dynamics of thiophenol at all [[lambda].sub.phot] matches the latter behavior more closely, reflecting the different relative dispositions of the [sup.1][pi][[pi].sup.*] and [sup.1][pi][[sigma].sup.*] PESs. Additional insights are provided by the observed branching into the ground ([X.sup.2][B.sub.1]) and first excited ([sup.2][B.sub.2]) states of the resulting [C.sub.6][H.sub.5]S radicals. photofragment translational spectroscopy | nonadiabatic | dissociation dynamics

One of the most dynamic areas of health policy is the transition of Medicaid programs to managed care and market competition. Maryland has been a leader in this trend, initiating three different systems of managed care for the Medicaid population during the 1990s as it searched for an ideal plan. The Maryland experience illustrates the complex new demands that policy makers are facing. Health plans are expected not only to deliver budgetary savings, but also to improve the quality of their services and guarantee a place for safety-net providers in their delivery systems. As a result, there is a sizable gap between the original savings projected for the new Maryland system and its actual capacity for cost containment. The apparent collision between economic assumptions and political realities, however, may point the way to a constructive synthesis - a form of managed care that balances economy with important community, professional, and personal values.

The number of American and Canadian first-year pediatric residents has been increasing. More foreign graduates are qualifying at higher residency levels. The percentage of woman pediatric residents now stands at 64%. Med/peds training programs have fewer residents but are growing rapidly. The percentage of pediatricians choosing general practice has grown from 60% in 1992 to 67% in 1995. Neonatal-perinatal medicine and pediatric emergency medicine are the most popular subspecialties. Most subspecialists other than neonatal-perinatal specialists choose academic practice settings. Only 45% of neonatal-perinatal specialists do so., ABBREVIATIONS. ABP, American Board of Pediatrics, ITE, intraining examination; US, United States; med / peds, medicine / pediatrics; AMG, American medical school graduate; LCME, Liaison Committee for Medical Education, AOA, [...]

Technical skills in diagnosis and treatment must be verified before residents in pediatrics are permitted to take a certifying examination in pediatrics. In 1986, the American Board of Pediatrics (ABP) listed 101 technical procedures that could be taught in pediatric training programs. A survey showed that 72 of 101 listed technical procedures, ranging from arterial puncture and intubation to incision and drainage of an abscess, were considered essential by 162 of 231 pediatric program directors. Although residents who were surveyed felt competent in their ability to perform the majority of the 72 essential procedures, more than 25 percent of residents reported a lack of experience with some of them. The technical skills considered essential by practicing pediatricians were assessed by a survey of 500 general pediatricians, of which 35 percent responded. Eighty percent of responding pediatricians considered 49 of the 72 technical skills to be essential, whereas 24 skills were classified as absolutely necessary, and seven skills were considered unnecessary by more than half of the responding pediatricians. These findings suggest that the 24 technical skills considered to be absolutely essential by practicing physicians should be taught in pediatric programs. The ability to perform these 24 skills should be confirmed and recorded. (Consumer Summary produced by Reliance Medical Information, Inc.)

THOMAS R. OLIVER looks at the national debate over health care reform of a decade ago and congressional policy decisions on the issue. He analyzes why Congress rejected proposals to stimulate broad competition in the financing and delivery of health care services and instead enacted a more narrow system to regulate hospital costs for the Medicare program.

This article examines the history of efforts to add prescription drug coverage to the Medicare program. It identifies several important patterns in policymaking over four decades. First, prescription drug coverage has usually been tied to the fate of broader proposals for Medicare reform. Second, action has been hampered by divided government, federal budget deficits, and ideological conflict between those seeking to expand the traditional Medicare program and those preferring a greater role for private health care companies. Third, the provisions of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 reflect earlier missed opportunities. Policymakers concluded from past episodes that participation in the new program should be voluntary, with Medicare beneficiaries and taxpayers sharing the costs. They ignored lessons from past episodes, however, about the need to match expanded benefits with adequate mechanisms for cost containment. Based on several new circumstances in 2003, the article demonstrates why there was a historic opportunity to add a Medicare prescription drug benefit and identify challenges to implementing an effective policy.

A comprehensive framework was devised to evaluate the State Children's Health Insurance Program (SCHIP) established in 1997. The framework relies on a number of potential measures and data sources for reviewing the program information recorded by states in SCHIP applications, particularly their strategic objectives and proposed performance measures. The analysis reveals that the states propose a wide range of objectives and measures and that there is considerable variation among the states. Overall, states' SCHIP plans tend to stress program enrollment and access to services but fail to emphasize the type and quality of services children receive once they are enrolled in the program. A broader conceptual framework is needed for policy makers, advocates, and researchers to make a full assessment of state goals and SCHIP performance.