WH2 and proline-rich domains of WASP-family proteins collaborate to accelerate actin filament elongation.

WASP-family proteins are known to promote assembly of branched actin networks by stimulating the filament-nucleating activity of the Arp2/3 complex. Here, we show that WASP-family proteins also function as polymerases that accelerate elongation of uncapped actin filaments. When clustered on a surface, WASP-family proteins can drive branched actin networks to grow much faster than they could by direct incorporation of soluble monomers. This polymerase activity arises from the coordinated action of two regulatory sequences: (i) a WASP homology 2 (WH2) domain that binds actin, and (ii) a proline-rich sequence that binds profilin-actin complexes. In the absence of profilin, WH2 domains are sufficient to accelerate filament elongation, but in the presence of profilin, proline-rich sequences are required to support polymerase activity by (i) bringing polymerization-competent actin monomers in proximity to growing filament ends, and (ii) promoting shuttling of actin monomers from profilin-actin complexes onto nearby WH2 domains. Unoccupied WH2 domains transiently associate with free filament ends, preventing their growth and dynamically tethering the branched actin network to the WASP-family proteins that create it. Collaboration between WH2 and proline-rich sequences thus strikes a balance between filament growth and tethering. Our work expands the number of critical roles that WASP-family proteins play in the assembly of branched actin networks to at least three: (i) promoting dendritic nucleation; (ii) linking actin networks to membranes; and (iii) accelerating filament elongation

Psychotropic Medication Use among Medicare Beneficiaries Following Traumatic Brain Injury

Objectives—To characterize psychotropic medication use before and after traumatic brain injury (TBI) hospitalization among older adults. A secondary objective is to determine how receipt of indicated pharmacologic treatment for anxiety and post-traumatic stress disorder (PTSD) differs following TBI. Design—Retrospective cohort Setting—United States Participants—Medicare beneficiaries age ≥65 hospitalized with TBI 2006-2010 with continuous drug coverage for 12 months before and after TBI (n=60,276). Measurements—We obtained monthly psychotropic medication use by drug class and specific drugs from Medicare Part D drug event files. International Classification of Disease, 9th Edition CM, codes were used to define anxiety (300.0x) and PTSD (309.81). Results—Average monthly prevalence of psychotropic medication use among all patients hospitalized for TBI was 44.8%; antidepressants comprised 73%. Prevalence of psychotropic medication use increased from 2006-2010. Following TBI, psychotropic medication use increased slightly (odds ratio (OR) 1.05; 95% confidence interval (CI) 1.03, 1.06.) Tricyclic antidepressant use decreased post-TBI (OR 0.76; 95% CI 0.73, 0.79) while use of the sedating antidepressants mirtazapine (OR 1.31; 95% CI 1.25, 1.37) and trazadone (OR 1.11; 95% CI 1.06, 1.17) increased. Antipsychotic (OR 1.15; 95% CI 1.12, 1.19) use also increased post-TBI. Beneficiaries newly diagnosed with anxiety (OR 0.42; 95% CI 0.36, 0.48) and/or PTSD (OR 0.39; 95% CI 0.18, 0.84) post-TBI were less likely to receive indicated pharmacologic treatment. Conclusions—Older adults hospitalized with TBI have a high prevalence of psychotropic medication use yet are less likely to receive indicated pharmacological treatment for newly diagnosed anxiety and PTSD following TBI

Seshat: The Global History Databank

The vast amount of knowledge about past human societies has not been systematically organized and, therefore, remains inaccessible for empirically testing theories about cultural evolution and historical dynamics. For example, what evolutionary mechanisms were involved in the transition from the small-scale, uncentralized societies, in which humans lived 10,000 years ago, to the large-scale societies with an extensive division of labor, great differentials in wealth and power, and elaborate governance structures of today? Why do modern states sometimes fail to meet the basic needs of their populations? Why do economies decline, or fail to grow? In this article, we describe the structure and uses of a massive databank of historical and archaeological information, Seshat: The Global History Databank. The data that we are currently entering in Seshat will allow us and others to test theories explaining how modern societies evolved from ancestral ones, and why modern societies vary so much in their capacity to satisfy their members’ basic human needsPeer reviewedFinal Published versio

Cost-Effectiveness of Second-Line Chemotherapy/Biologics among Elderly Metastatic Colon Cancer Patients

INTRODUCTION: Advancements in chemotherapy treatment have improved the clinical management of metastatic colon cancer (mCC) patients. An increasing number of elderly mCC patients receive various combinations of regimens in second-line chemotherapy/biologics treatment (Tx2) after first-line treatment (Tx1) to prolong survival and/or palliate symptoms, but these regimens have higher costs. This analysis investigated the survival benefit and incremental cost associated with Tx2 among elderly mCC patients. METHODS: Elderly (aged ≥66 years) SEER-Medicare patients diagnosed with mCC in 2003–2007 were identified and followed until death or the end of 2009. Cox regression and partitioned least squares regression were utilized to obtain the survival benefit and incremental cost associated with Tx2 within a 5-year study period. A time-varying model was used to reduce bias due to sequential ordering of Tx1 and Tx2. The regressions controlled for patient demographic characteristics, clinical variables, and a proxy for poor performance. Bootstrapping was used to generate 95% confidence intervals (CI). RESULTS: Of the 3,266 elderly mCC patients who received Tx1, 2,744 (84%) died within the observation period; 1,440 (44%) received Tx2. The survival benefit associated with receipt of Tx2 was 0.33 years (95% CI 0.19–0.43), and the associated incremental cost was $40,888 (95$123,903 per life year gained (95% CI 9,600–216,082). CONCLUSION: The estimated survival benefit of receiving second-line chemotherapy/biologics was about 4 months, which is consistent with evidence from clinical trials. This improved survival was associated with an ICER that exceeds the traditional threshold. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-014-0134-8) contains supplementary material, which is available to authorized users

Profile scaling in decay of nanostructures

The flattening of a crystal cone below its roughening transition is studied by means of a step flow model. Numerical and analytical analyses show that the height profile, h(r,t), obeys the scaling scenario dh/dr = F(r t^{-1/4}). The scaling function is flat at radii r<R(t) \sim t^{1/4}. We find a one parameter family of solutions for the scaling function, and propose a selection criterion for the unique solution the system reaches.Comment: 4 pages, RevTex, 3 eps figure

BEACON:A Summary Framework to Overcome Potential Reimbursement Hurdles

Objective To provide a framework for addressing payers' criteria during the development of pharmaceuticals.Methods A conceptual framework was presented to an international health economic expert panel for discussion. A structured literature search (from 2010 to May 2015), using the following databases in Ovid: Medline((R)) and Medline((R)) In-Process (PubMed), Embase (Ovid), EconLit (EBSCOhost) and the National Health Service Economic Evaluation Database (NHS EED), and a 'grey literature' search, were conducted to identify existing criteria from the payer perspective. The criteria assessed by existing frameworks and guidelines were collated; the most commonly reported criteria were considered for inclusion in the framework. A mnemonic was conceived as a memory aide to summarise these criteria.Results Overall, 41 publications were identified as potentially relevant to the objective. Following further screening, 26 were excluded upon full-text review on the basis of no framework presented (n = 13), redundancy (n = 11) or abstract only (n = 2). Frameworks that captured criteria developed for or utilised by the pharmaceutical industry (n = 5) and reimbursement guidance (n = 10) were reviewed. The most commonly identified criteria-unmet need/patient burden, safety, efficacy, quality-of-life outcomes, environment, evidence quality, budget impact and comparator-were incorporated into the summary framework. For ease of communication, the following mnemonic was developed: BEACON (Burden/target population, Environment, Affordability/value, Comparator, Outcomes, Number of studies/quality of evidence).Conclusions The BEACON framework aims to capture the 'essence' of payer requirements by addressing the most commonly described criteria requested by payers regarding the introduction of a new pharmaceutical.</p

Patient-centric structural determinants of adherence rates among asthma populations: Exploring the potential of patient activation and encouragement tool TRUSTR to improve adherence

Background: Lack of adherence with prescribed medications among the asthma populations exacerbates health outcomes and increases social and economic costs. Objectives: The proposed study aims to model patient-centric structural determinants of adherence rates among asthma patients and explore the potential of mobile health apps such as the TRUSTR platform to improve adherence using its power of monetary and non-monetary chatbotting and non-monetary nudges. Following specific hypotheses are tested: (1) Patient attributes, such as their age and medical condition, have significant effect on their adherence with the prescribed treatment plans. (2) Behavioral nudging with rewards and engagement via mobile health apps will increase adherence rates. Methods: The patient population (N = 37 359) consists of commercially insured patients with asthma who have been identified from administrative claims in the HealthCore Integrated Research Database (HIRD) between April 1, 2018 and March 31, 2019. Two Structural Equation Models (SEMs) are estimated to quantify direct, indirect, and total effect sizes of age and medical condition on proportion of days covered (PDC) and medical possession ratio (MPR), mediated by patient medical and pharmacy visits. Fourteen additional SEMs were estimated to lateralize TRUSTR findings and conduct sensitivity analysis. Results: HIRD data reveal mean adherence rate of 59% (standard deviation (SD) 29%) for PDC and 58% for MPR (SD 36%). Key structural findings from SEMs derived from the HIRD dataset indicate that each additional year in the age of the patient has a positive total effect on the adherence rate. Patients with poor medical condition are likely to have lower adherence rate, but this direct effect is countered by mediating variables. Further, each additional reward and higher engagement with a mobile app is likely to have a positive total effect on increasing the adherence rate. Conclusions: HIRD data reveal mean adherence rate of 59% (SD 29%), providing the evidence for the opportunity to increase adherence rate by around 40%. Statistical modeling results reveal structural determinants, such as the opportunity to nudge, are higher among younger patients, as they have higher probability of being non-adherent. Methodologically, lateralization approach demonstrates the potential to capture real-world evidence beyond clinical data and merge it with clinical data

Molecular clock-like evolution of human immunodeficiency virus type 1

AbstractThe molecular clock hypothesis states that the rate of nucleotide substitution per generation is constant across lineages. If generation times were equal across lineages, samples obtained at the same calendar time would have experienced the same number of generations since their common ancestor. However, if sequences are not derived from contemporaneous samples, differences in the number of generations may be misinterpreted as variation in substitution rates and hence may lead to false rejection of the molecular clock hypothesis. A recent study has called into doubt the validity of clock-like evolution for HIV-1, using molecular sequences derived from noncontemporaneous samples. However, after separating their within-individual data according to sampling time, we found that what appeared to be nonclock-like behavior could be attributed, in most cases, to noncontemporaneous sampling, with contributions also likely to derive from recombination. Natural selection alone did not appear to obscure the clock-like evolution of HIV-1