Utilization of ACP CPT codes among high-need Medicare beneficiaries in 2017: A brief report

IMPORTANCE: Medicare beneficiaries with high medical needs can benefit from Advance Care Planning (ACP). Medicare reimburses clinical providers for ACP discussions, but it is unknown whether high-need beneficiaries are receiving this service. OBJECTIVE: To compare rates of billed ACP discussions among a cohort of high-need Medicare beneficiaries with the non-high-needs Medicare population. DESIGN: Retrospective analysis of Medicare Fee-for-Service (FFS) claims in 2017 comparing high-need beneficiaries (seriously ill, frail, ESRD, and disabled) with non-high need beneficiaries. SETTING: Nationally representative FFS Medicare 20% sample. PARTICIPANTS: Medicare beneficiaries were assigned to one of the following classifications: seriously ill (65+), frail (65+), seriously ill and frail (65+); non-high need (65+); end stage renal disease (ESRD) or disabled ( \u3c 65). All participants had data available for years 2016-2017. EXPOSURE: Receipt of a billed ACP discussion, CPT codes 99497 or 99498. MAIN OUTCOME AND MEASURE: Rates of billed ACP visits were compared between high-need patients and non-high-need patients. Rates were adjusted for the 65+ population for sex, age, race/ethnicity, Charlson comorbidity index, Medicare/Medicaid dual eligibility status, and Hospital Referral Region. RESULTS: Among the 65+ groups, those most likely to have a billed ACP discussion included seriously ill and frail (5.2%), seriously ill (4.2%), and frail (3.3%). Rates remained consistent after adjusting (4.5%, 4.0%, 3.1%, respectively). Each subgroup differed significantly (p \u3c .05) from non-high need beneficiaries (2.3%) in both unadjusted and adjusted analyses. Among the \u3c 65 high need groups, the rates were 2.7% for ESRD and 1.3% for the disabled (the latter p \u3c .05 compared with non-high needs). CONCLUSIONS AND RELEVANCE: While rates of billed ACP discussions varied among patient groups with high medical needs, overall they were relatively low, even among a cohort of patients for whom ACP may be especially relevant

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance

Exploring provision for children identified with special educational needs: an international review of policy and practice

This project aimed to create a descriptive map of international research which explores the notion of the continuum of educational provision for children with special educational needs. It also aimed to determine and examine the nature of how the continuum of provision is conceptualised, operationalised and enacted in a sample of selected countries. Commissioned by the National Council for Special Education, it also identified implications for the development of provision within the Irish context. The research involved a systematic identification and thematic review of theory, identifying and examining literature associated with the conceptualisation of the continuum; it examined the policy and provision across 55 administrations as publically reported, primarily to international agencies; it carried out more detailed examination of policy and practice in 10 countries using a survey and vignette study; and it involved a series of interviews with a range of individuals in a range of settings in four countries with differing approaches to supporting children with special educational needs. This paper outlines the overall findings of the research. It focuses in particular upon the need to change how we think about provision associated with continua, recognising the lack of international coherence in approaches to support for pupils with special educational needs. It identifies in particular the opportunities presented by a reconceptualisation of the class and the management of class resources, and the role key personnel can play in creating links between diverse services

Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity

TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5α but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations

Self-oligomerization Regulates Stability of Survival Motor Neuron Protein Isoforms by Sequestering an SCF\u3csup\u3eSlmb\u3c/sup\u3e Degron

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers

Human cerebral malaria and Plasmodium falciparum genotypes in Malawi

<p>Abstract</p> <p>Background</p> <p>Cerebral malaria, a severe form of <it>Plasmodium falciparum </it>infection, is an important cause of mortality in sub-Saharan African children. A Taqman 24 Single Nucleotide Polymorphisms (SNP) molecular barcode assay was developed for use in laboratory parasites which estimates genotype number and identifies the predominant genotype.</p> <p>Methods</p> <p>The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with cerebral malaria.</p> <p>Results</p> <p>Single genotypes were shared between the peripheral blood, the brain, and other tissues of cerebral malaria patients, while malaria-infected patients who died of non-malarial causes had mixed genetic signatures in tissues examined. Children with retinopathy-positive cerebral malaria had significantly less complex infections than those without retinopathy (OR = 3.7, 95% CI [1.51-9.10]).The complexity of infections significantly decreased over the malaria season in retinopathy-positive patients compared to retinopathy-negative patients.</p> <p>Conclusions</p> <p>Cerebral malaria patients harbour a single or small set of predominant parasites; patients with incidental parasitaemia sustain infections involving diverse genotypes. Limited diversity in the peripheral blood of cerebral malaria patients and correlation with tissues supports peripheral blood samples as appropriate for genome-wide association studies of parasite determinants of pathogenicity.</p

SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.

Since the publication of the Society for Immunotherapy of Cancer\u27s (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients

Risk of advanced fibrosis in first-degree relatives of with nonalcoholic liver disease

Peer reviewe

Developing a matrix to identify and prioritise research recommendations in HIV Prevention

BACKGROUND: HIV prevention continues to be problematic in the UK, as it does globally. The UK Department of Health has a strategic direction with greater focus on prevention as part of its World Class Commissioning Programme. There is a need for targeted evidence-based prevention initiatives. This is an exploratory study to develop an evidence mapping tool in the form of a matrix: this will be used to identify important gaps in contemporary HIV prevention evidence relevant to the UK. It has the potential to aid prioritisation in future research.METHODS: Categories for prevention and risk groups were developed for HIV prevention in consultation with external experts. These were used as axes on a matrix tool to map evidence. Systematic searches for publications on HIV prevention were undertaken using electronic databases for primary and secondary research undertaken mainly in UK, USA, Canada, Australia and New Zealand, 2006-9. Each publication was screened for inclusion then coded. The risk groups and prevention areas in each paper were counted: several publications addressed multiple risk groups. The counts were exported to the matrix and clearly illustrate the concentrations and gaps of literature in HIV prevention.RESULTS: 716 systematic reviews, randomised control trials and other primary research met the inclusion criteria for HIV prevention. The matrix identified several under researched areas in HIV prevention.CONCLUSIONS: This is the first categorisation system for HIV prevention and the matrix is a novel tool for evidence mapping. Some important yet under-researched areas have been identified in HIV prevention evidence: identifying the undiagnosed population; international adaptation; education; intervention combinations; transgender; sex-workers; heterosexuals and older age groups.<br/