Pointed-end capping by tropomodulin3 negatively regulates endothelial cell motility

Actin filament pointed-end dynamics are thought to play a critical role in cell motility, yet regulation of this process remains poorly understood. We describe here a previously uncharacterized tropomodulin (Tmod) isoform, Tmod3, which is widely expressed in human tissues and is present in human microvascular endothelial cells (HMEC-1). Tmod3 is present in sufficient quantity to cap pointed ends of actin filaments, localizes to actin filament structures in HMEC-1 cells, and appears enriched in leading edge ruffles and lamellipodia. Transient overexpression of GFP–Tmod3 leads to a depolarized cell morphology and decreased cell motility. A fivefold increase in Tmod3 results in an equivalent decrease in free pointed ends in the cells. Unexpectedly, a decrease in the relative amounts of F-actin, free barbed ends, and actin-related protein 2/3 (Arp2/3) complex in lamellipodia are also observed. Conversely, decreased expression of Tmod3 by RNA interference leads to faster average cell migration, along with increases in free pointed and barbed ends in lamellipodial actin filaments. These data collectively demonstrate that capping of actin filament pointed ends by Tmod3 inhibits cell migration and reveal a novel control mechanism for regulation of actin filaments in lamellipodia

Disease-modifying drug initiation patterns in commercially insured multiple sclerosis patients: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>The goal of this research was to compare the demographics, clinical characteristics and treatment patterns for newly diagnosed multiple sclerosis (MS) patients in a commercial managed care population who received disease-modifying drug (DMD) therapy versus those not receiving DMD therapy.</p> <p>Methods</p> <p>A retrospective cohort study using US administrative healthcare claims identified individuals newly diagnosed with MS (no prior MS diagnosis 12 months prior using ICD-9-CM 340) and ≥ 18 years old during 2001-2007 to characterize them based on demographics, clinical characteristics, and pharmacologic therapy for one year prior to and a minimum of one year post-index. The index date was the first MS diagnosis occurring in the study period. Follow-up of subjects was done by ICD-9-CM code identification and not by actual chart review. Multivariate analyses were conducted to adjust for confounding variables.</p> <p>Results</p> <p>Patients were followed for an average of 35.7 ± 17.5 months after their index diagnosis. Forty-three percent (n = 4,462) of incident patients received treatment with at least one of the DMDs during the post-index period. Treated patients were primarily in the younger age categories of 18-44 years of age, with DMD therapy initiated an average of 5.3 ± 9.1 months after the index diagnosis. Once treatment was initiated, 27.7% discontinued DMD therapy after an average of 17.6 ± 14.6 months, and 16.5% had treatment gaps in excess of 60 days.</p> <p>Conclusions</p> <p>Nearly 60% of newly-diagnosed MS patients in this commercial managed care population remained untreated while over a quarter of treated patients stopped therapy and one-sixth experienced treatment gaps despite the risk of disease progression or a return of pre-treatment disease activity.</p

Spreading in Social Systems: Reflections

In this final chapter, we consider the state-of-the-art for spreading in social systems and discuss the future of the field. As part of this reflection, we identify a set of key challenges ahead. The challenges include the following questions: how can we improve the quality, quantity, extent, and accessibility of datasets? How can we extract more information from limited datasets? How can we take individual cognition and decision making processes into account? How can we incorporate other complexity of the real contagion processes? Finally, how can we translate research into positive real-world impact? In the following, we provide more context for each of these open questions.Comment: 7 pages, chapter to appear in "Spreading Dynamics in Social Systems"; Eds. Sune Lehmann and Yong-Yeol Ahn, Springer Natur

Total knee replacement after high tibial osteotomy: Time-to-event analysis and predictors

© 2021 Joule Inc. or its licensors. BACKGROUND: An important aim of high tibial osteotomy (HTO) is to prevent or delay the need for total knee replacement (TKR). We sought to estimate the frequency and timing of conversion from HTO to TKR and the factors associated with it. METHODS: We prospectively evaluated patients with osteoarthritis (OA) of the knee who underwent medial opening wedge HTO from 2002 to 2014 and analyzed the cumulative incidence of TKR in July 2019. The presence or absence of TKR on the HTO limb was identified from the orthopedic surgery reports and knee radiographs contained in the electronic medical records for each patient at London Health Sciences Centre. We used cumulative incidence curves to evaluate the primary outcome of time to TKR. We used multivariable Cox proportional hazards analysis to assess potential preoperative predictors including radiographic disease severity, malalignment, correction size, pain, sex, age, body mass index (BMI) and year of surgery. RESULTS: Among 556 patients who underwent 643 HTO procedures, the cumulative incidence of TKR was 5% (95% confidence interval [CI] 3%–7%) at 5 years and 21% (95% CI 17%–26%) at 10 years. With the Cox proportional hazards multivariable model, the following preoperative factors were significantly associated with an increased rate of conversion: radiographic OA severity (adjusted hazard ratio [HR] 1.96, 95% CI 1.12–3.45), pain (adjusted HR 0.85, 95% CI 0.75–0.96)], female sex (adjusted HR 1.67, 95% CI 1.08–2.58), age (adjusted HR 1.50 per 10 yr, 95% CI 1.17–1.93) and BMI (adjusted HR 1.31 per 5 kng/m2, 95% CI 1.12–1.53). INTERPRETATION: We found that 79% of knees did not undergo TKR within 10 years after undergoing medial opening wedge HTO. The strongest predictor of conversion to TKR is greater radiographic disease at the time of HTO

General Practitioners' views on the provision of nicotine replacement therapy and bupropion.

BACKGROUND: Nicotine replacement therapies (NRT) and a new drug, bupropion, are licensed in several countries as aids to smoking cessation. General practitioners (GPs) play a crucial role in recommending or prescribing these medications. In the UK there has been discussion about whether the medications should be reimbursable by the National Health Service (NHS). This study assessed English GPs' attitudes towards reimbursement of NRT and bupropion. METHODS: Postal survey of a randomly selected national sample of GPs; 376 GPs completed the questionnaire after one reminder; effective response rate: 53%. There was no difference between the responses of GPs who responded to the initial request and those who responded only after a reminder suggesting minimal bias due to non-response. RESULTS: Attitudes of GPs were remarkably divided on most issues relating to the medications. Forty-three percent thought that bupropion should not be on NHS prescription while 42% thought that it should be (15% did not know); Fifty percent thought that NRT should not be on NHS prescription while 42% thought it should be (8% did not know). Requiring that smokers attend behavioural support programmes to be eligible to receive the medications on NHS prescription made no appreciable difference to the GPs' views. GPs were similarly divided on whether having the medications reimbursable would add unacceptably to their workload or offer a welcome opportunity to discuss smoking with their patients. A principal components analysis of responses to the individual questions on NRT and bupropion revealed that GPs' attitudes could be understood in terms of a single 'pro-con' dimension accounting for 53% of the total variance which made no distinction between the two medications. CONCLUSIONS: GPs in England appear to be divided in their attitudes to medications to aid smoking cessation and appear not to discriminate in their views between different types of medication or different aspects of their use. This suggests that their attitudes are generated by quite fundamental values. Addressing these values may be important in encouraging GPs to adhere more closely to national and international guidelines