Wireless Sensing of Lower Lip and Thumb-Index Finger ‘Ramp-and-Hold’ Isometric Force Dynamics in a Small Cohort of Unilateral MCA Stroke: Discussion of Preliminary Findings

Automated wireless sensing of force dynamics during a visuomotor control task was used to rapidly assess residual motor function during finger pinch (right and left hand) and lower lip compression in a cohort of seven adult males with chronic, unilateral middle cerebral artery (MCA) stroke with infarct confirmed by anatomic magnetic resonance imaging (MRI). A matched cohort of 25 neurotypical adult males served as controls. Dependent variables were extracted from digitized records of ‘ramp-and-hold’ isometric contractions to target levels (0.25, 0.5, 1, and 2 Newtons) presented in a randomized block design; and included force reaction time, peak force, and dF/dtmax associated with force recruitment, and end-point accuracy and variability metrics during the contraction hold-phase (mean, SD, criterion percentage ‘on-target’). Maximum voluntary contraction force (MVCF) was also assessed to establish the force operating range. Results based on linear mixed modeling (LMM, adjusted for age and handedness) revealed significant patterns of dissolution in fine force regulation among MCA stroke participants, especially for the contralesional thumb-index finger followed by the ipsilesional digits, and the lower lip. For example, the contralesional thumb-index finger manifest increased reaction time, and greater overshoot in peak force during recruitment compared to controls. Impaired force regulation among MCA stroke participants during the contraction hold-phase was associated with significant increases in force SD, and dramatic reduction in the ability to regulate force output within prescribed target force window (±5% of target). Impaired force regulation during contraction hold-phase was greatest in the contralesional hand muscle group, followed by significant dissolution in ipsilateral digits, with smaller effects found for lower lip. These changes in fine force dynamics were accompanied by large reductions in the MVCF with the LMM marginal means for contralesional and ipsilesional pinch forces at just 34.77% (15.93 N vs. 45.82 N) and 66.45% (27.23 N vs. 40.98 N) of control performance, respectively. Biomechanical measures of fine force and MVCF performance in adult stroke survivors provide valuable information on the profile of residual motor function which can help inform clinical treatment strategies and quantitatively monitor the efficacy of rehabilitation or neuroprotection strategies

Barriers and facilitators to HPV vaccination in primary care practices: A mixed methods study using the Consolidated Framework for Implementation Research

Abstract Background In the United States, the effective, safe huma papilloma virus (HPV) vaccine is underused and opportunities to prevent cancer continue to be missed. National guidelines recommend completing the 2–3 dose HPV vaccine series by age 13, well before exposure to the sexually transmitted virus. Accurate characterization of the facilitators and barriers to full implementation of HPV vaccine recommendations in the primary care setting could inform effective implementation strategies. Methods We used the Consolidated Framework for Implementation Research (CFIR) to systematically investigate and characterize factors that influence HPV vaccine use in 10 primary care practices (16 providers) using a concurrent mixed methods design. The CFIR was used to guide collection and analysis of qualitative data collected through in-person semi-structured interviews with the primary care providers. We analyzed HPV vaccine use with data abstracted from medical charts. Constructs that most strongly influenced vaccine use were identified by integrating the qualitative and quantitative data. Results Of the 72 CFIR constructs assessed, seven strongly distinguished and seven weakly distinguished between providers with higher versus lower HPV vaccine coverage. The majority of strongly distinguishing constructs were facilitators and were related to characteristics of the providers (knowledge and beliefs; self-efficacy; readiness for change), their perception of the intervention (relative advantage of vaccinating younger vs. older adolescents), and their process to deliver the vaccine (executing). Additional weakly distinguishing constructs that were facilitators were from outer setting (peer pressure; financial incentives), inner setting (networks and communications and readiness for implementation) and process (planning; engaging, and reflecting and evaluating). Two strongly distinguishing constructs were barriers to use, one from the intervention (adaptability of the age of initiation) and the other from outer setting (patient needs and resources). Conclusions Using CFIR to systematically examine the use of this vaccine in independent primary care practices enabled us to identify facilitators and barriers at the provider, interpersonal and practice level that need to be addressed in future efforts to increase vaccine use in such settings. Our findings suggest that implementation strategies that target the provider and help them to address multi-level barriers to HPV vaccine use merit further investigation

The Archaeology of Native American Persistence at Mission San José

Archaeological investigations at Mission San José in Fremont, California, have revealed large areas of the mission landscape, including portions of two adobe dwellings in the mission’s Native American neighborhood. Preliminary synthesis of previous and ongoing research at Mission San José focuses on the implications of archaeological evidence for understanding the persistence of indigenous cultural practices under missionization. Materials considered include flaked stone artifacts, shell and glass beads, modified ceramic disks, and faunal and floral remains. Our findings suggest that native people rearticulated various practices within the mission, but did so in ways that were consistent with existing traditions and cultural knowledge

Development of a composite model derived from cardiopulmonary exercise tests to predict mortality risk in patients with mild-to-moderate heart failure

Objective: Cardiopulmonary exercise testing (CPET) is used to predict outcome in patients with mild-to-moderate heart failure (HF). Single CPET-derived variables are often used, but we wanted to see if a composite score achieved better predictive power. Methods: Retrospective analysis of patient records at the Department of Cardiology, Castle Hill Hospital, Kingston-upon-Hull. 387 patients [median (25th-75th percentile)] [age 65 (56-72) years; 79% males; LVEF 34 (31-37) %] were included. Patients underwent a symptomlimited, maximal CPET on a treadmill. During a median follow up of 8.6 ± 2.1 years in survivors, 107 patients died. Survival models were built and validated using a hybrid approach between the bootstrap and Cox regression. Nine CPET-derived variables were included. Z-score defined each variable's predictive strength. Model coefficients were converted to a risk score. Results: Four CPET-related variables were independent predictors of all-cause mortality in the survival model: the presence of exertional oscillatory ventilation (EOV), increasing slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope), decreasing oxygen uptake efficiency slope (OUES), and an increase in the lowest ventilatory equivalent for carbon dioxide (VEqCO2 nadir). Individual predictors of mortality ranged from 0.60 to 0.71 using Harrell’s C-statistic, but the optimal combination of EOV + VE/VCO2 slope + OUES + VEqCO2 nadir reached 0.75. The Hull CPET risk score had a significantly higher area under the curve (0.78) when compared to the Heart Failure Survival Score (AUC=0.70;

Does warfarin prevent deep venous thrombosis in high-risk patients?

Warfarin (Coumadin) is effective in preventing deep venous thrombosis (DVT) among patients with a history of DVT. Conventional dosing and longer durations are the most effective, but the ideal length of therapy is unknown (strength of recommendation [SOR]: A, based on large randomized controlled trials and meta-analysis). Warfarin is useful in preventing DVT in patients with cancer, specifically those treated with chemotherapy (SOR: B, based on small randomized controlled trials). Warfarin may be effective in preventing DVT in immobilized patients such as those with trauma, spinal cord injury, or stroke (SOR: B, based on an underpowered randomized controlled trial and uncontrolled studies)

Iterative approach to computational enzyme design

A general approach for the computational design of enzymes to catalyze arbitrary reactions is a goal at the forefront of the field of protein design. Recently, computationally designed enzymes have been produced for three chemical reactions through the synthesis and screening of a large number of variants. Here, we present an iterative approach that has led to the development of the most catalytically efficient computationally designed enzyme for the Kemp elimination to date. Previously established computational techniques were used to generate an initial design, HG-1, which was catalytically inactive. Analysis of HG-1 with molecular dynamics simulations (MD) and X-ray crystallography indicated that the inactivity might be due to bound waters and high flexibility of residues within the active site. This analysis guided changes to our design procedure, moved the design deeper into the interior of the protein, and resulted in an active Kemp eliminase, HG-2. The cocrystal structure of this enzyme with a transition state analog (TSA) revealed that the TSA was bound in the active site, interacted with the intended catalytic base in a catalytically relevant manner, but was flipped relative to the design model. MD analysis of HG-2 led to an additional point mutation, HG-3, that produced a further threefold improvement in activity. This iterative approach to computational enzyme design, including detailed MD and structural analysis of both active and inactive designs, promises a more complete understanding of the underlying principles of enzymatic catalysis and furthers progress toward reliably producing active enzymes

A cryptic cycle in haematopoietic niches promotes initiation of malaria transmission and evasion of chemotherapy

Blood stage human malaria parasites may exploit erythropoietic tissue niches and colonise erythroid progenitors; however, the precise influence of the erythropoietic environment on fundamental parasite biology remains unknown. Here we use quantitative approaches to enumerate Plasmodium infected erythropoietic precursor cells using an in vivo rodent model of Plasmodium berghei. We show that parasitised early reticulocytes (ER) in the major sites of haematopoiesis establish a cryptic asexual cycle. Moreover, this cycle is characterised by early preferential commitment to gametocytogenesis, which occurs in sufficient numbers to generate almost all of the initial population of circulating, mature gametocytes. In addition, we show that P. berghei is less sensitive to artemisinin in splenic ER than in blood, which suggests that haematopoietic tissues may enable origins of recrudescent infection and emerging resistance to antimalarials. Continuous propagation in these sites may also provide a mechanism for continuous transmission and infection in malaria endemic regions

Rapid and sensitive insulated isothermal PCR for point-of-need feline leukaemia virus detection

Objectives: Feline leukaemia virus (FeLV), a gamma retrovirus, causes diseases of the feline haematopoietic system that are invariably fatal. Rapid and accurate testing at the point-of-need (PON) supports prevention of virus spread and management of clinical disease. This study evaluated the performance of an insulated isothermal PCR (iiPCR) that detects proviral DNA, and a reverse transcription (RT)-iiPCR that detects both viral RNA and proviral DNA, for FeLV detection at the PON. Methods: Mycoplasma haemofelis, feline coronavirus, feline herpesvirus, feline calicivirus and feline immunodeficiency virus were used to test analytical specificity. In vitro transcribed RNA, artificial plasmid, FeLV strain American Type Culture Collection VR-719 and a clinical FeLV isolate were used in the analytical sensitivity assays. A retrospective study including 116 clinical plasma and serum samples that had been tested with virus isolation, real-time PCR and ELISA, and a prospective study including 150 clinical plasma and serum samples were implemented to evaluate the clinical performances of the iiPCR-based methods for FeLV detection. Results: Ninety-five percent assay limit of detection was calculated to be 16 RNA and five DNA copies for the RT-iiPCR, and six DNA copies for the iiPCR. Both reactions had analytical sensitivity comparable to a reference real-time PCR (qPCR) and did not detect five non-target feline pathogens. The clinical performance of the RT-iiPCR and iiPCR had 98.82% agreement (kappa[κ] = 0.97) and 100% agreement (κ = 1.0), respectively, with the qPCR (n = 85). The agreement between an automatic nucleic extraction/RT-iiPCR system and virus isolation to detect FeLV in plasma or serum was 95.69% (κ = 0.95) and 98.67% (κ = 0.85) in a retrospective (n = 116) and a prospective (n = 150) study, respectively. Conclusions and relevance: These results suggested that both RT-iiPCR and iiPCR assays can serve as reliable tools for PON FeLV detection

Dread and latency impacts on a VSL for cancer risk reduction

We propose a structural relationship between the value of preventing a statistical cancer fatality and the value of statistical life (VSL) for risks of an instantaneous road accident fatality. This relationship incorporates a context effect reflecting both the illness or ‘morbidity’ associated with cancer fatality and the ‘dread’ or horror associated with the prospect of eventual death from cancer, as well as a latency effect that captures the discounting likely to arise because the onset of the symptoms of cancer typically occurs after some delay. We use a Risk-Risk trade-off study to validate this model by directly estimating the influence of context and latency effects upon the relative size of the VSL for cancer and for road accidents, confirming that both effects are significant and estimating their size using regression analysis. We show that morbidity accounts for the majority of the context premium. We use the elicited coefficients to reconstruct VSL estimates for a range of cancers characterised by their latency and morbidity periods