High anti-tumor activity of a novel alpha-fetoprotein-maytansinoid conjugate targeting alpha-fetoprotein receptors in colorectal cancer xenograft model.

The alpha-fetoprotein receptor (AFPR) is a novel target for cancer therapeutics. It is expressed on most cancers and myeloid derived suppressor cells (MDSCs) but generally absent on normal tissues. Studies were performed to investigate the use of recombinant human AFP (ACT-101) conjugated with maytansinoid toxins for targeted toxin delivery to cancer. Four structurally different ACT-101-maytansinoid conjugates containing cleavable glutathione sensitive linkers were initially investigated in a mouse xenograft model of colorectal cancer. Reduction in tumor volume was seen for all four conjugates compared to control (p < 0.05). The anti-tumor effects of the conjugate selected for further development (ACT-903) persisted after treatment discontinuation, with tumors becoming undetectable in 9 of 10 mice, and all 10 mice surviving through Day 60 with no obvious signs of toxicity. A follow-up study performed in the same model compared the effects of single intravenous doses of ACT-903 (10-50 mg/kg) to that of control groups receiving vehicle or ACT-101. A significant reduction of tumor burden compared to control was achieved in the 40 and 50 mg/kg dose groups. Survival was significantly prolonged in these 2 groups (40 mg/kg (p < 0.0001); 50 mg/kg (p = 0.0037). Free maytansine blood levels at 4 h were 0.008% of the dose, indicating stability of the conjugate in circulation as was expected based on in vitro plasma stability studies. No obvious signs of toxicity were seen in any of the treated groups. Observed efficacy and excellent tolerability of ACT-903 in these xenograft models support advancing the development of ACT-903 toward clinical use.

Clinical application of risk assessment in PAH: Expert center APRN recommendations.

Performing longitudinal and consistent risk assessments for patients with pulmonary arterial hypertension (PAH) is important to help guide treatment decisions to achieve early on and maintain a low-risk status and improve patient morbidity and mortality. Clinical gestalt or expert perception alone may over or underestimate a patient's risk status. Indeed, regular and continued use of validated risk assessment tools more accurately predict patients' survival. Effective PAH risk assessments are often underutilized even though many seasoned clinicians will attest to using these tools routinely. We present recommendations based on real-world experience in varied clinical practice settings around the United States for overcoming barriers to facilitate regular, serial formal risk assessment. Expert advanced practice provider clinicians from mid to large-size medical centers collaborated to formulate recommendations based on multiple discourses and discussions. Enlisting the help of support staff, such as medical assistants and nurses, to fill in available risk parameters in risk assessment tools can save time for providers and increase efficiency, as can technology-based solutions such as integrating risk assessments into electronic medical records. Modified, abbreviated risk assessment tools can be applied to a patient's clinical scenario when all of a patient's data are not available to complete a more comprehensive assessment. Initial discussions regarding the overall meaning and prognostic importance of risk scores may assist patients to take on a more active role in terms of informed decision-making regarding their care. A collaborative approach can help clinics establish consistent use of risk assessment.

Association of Peripheral Serum MicroRNAs With Persistent Phantom Limb Pain in Individuals With Amputation.

OBJECTIVE: Individuals with major limb amputation(s) frequently experience phantom limb sensations, which are described as vivid impressions of either parts or entire missing limb(s). Despite the high incidence and prevalence of phantom limb pain, the underlying pathophysiology of phantom limb pain remains poorly understood. The objective of this study was to evaluate a possible role of microRNAs in the pathophysiology of phantom limb pain. DESIGN: Adults with acquired limb amputation and varying degrees of phantom limb pain consented to provide clinical data and blood samples. One hundred forty participants with single or multiple limb amputation(s) were enrolled. The Visual analog scale and neuropathic pain symptom inventory were administered to evaluate the pain. Serum samples were analyzed for microRNA expression and bioinformatic analysis was performed. RESULTS: Sixty-seven participants did not experience phantom limb pain, whereas 73 participants experienced varying severities of phantom limb pain measured on a pain scale. Linear regression analysis suggested that the time since amputation is inversely related to severity of the pain. A significantly increased expression of 16 microRNAs was observed in participants experiencing phantom limb pain. Bioinformatic analysis shows a possible role of these microRNAs in regulating genes expressed in peripheral neuropathy. CONCLUSIONS: This study provides the first evidence of association of microRNA in phantom limb pain.

Characteristics of phantom limb pain in U.S. civilians and service members.

OBJECTIVES: The population of Americans with limb loss is on the rise, with a different profile than in previous generations (e.g., greater incidence of amputation due to diabetes). This study aimed to identify the key characteristics of phantom limb sensation (PLS) and pain (PLP) in a current sample of Americans with limb loss. METHODS: This cross-sectional study is the first large-scale (n=649) study on PLP in the current population of Americans with limb loss. A convenience sample of military and civilian persons missing one or more major limbs was surveyed regarding their health history and experience with phantom limb phenomena. RESULTS: Of the participants surveyed, 87% experienced PLS and 82% experienced PLP. PLS and PLP typically first occurred immediately after amputation (47% of cases), but for a small percentage (3-4%) onset did not occur until over a year after amputation. Recent PLP severity decreased over time (ß=0.028, 95% CI: -0.05-0.11), but most participants reported PLP even 10 years after amputation. Higher levels of recent PLP were associated with telescoping (ß=0.123, 95% CI: 0.04-0.21) and higher levels of pre-amputation pain (ß=0.104, 95% CI: 0.03-0.18). Those with congenitally missing limbs experienced lower levels of recent PLP (t (37.93)=3.93, p<0.01) but there were no consistent differences in PLP between other amputation etiologies. CONCLUSIONS: Phantom limb phenomena are common and enduring. Telescoping and pre-amputation pain are associated with higher PLP. Persons with congenitally missing limbs experience lower levels of PLP than those with amputation(s), yet PLP is common even in this subpopulation.

Clinical evaluation of the refined clothespin relocation test: A pilot study.

BACKGROUND: The refined clothespin relocation test is a test used to evaluate the performance of a prosthesis user by analysing the compensatory motions and time to complete a grasping and placement exercise. The test has been studied previously with a motion capture laboratory and has now been adapted for a clinical setting. A comparison of prosthesis user to an able-bodied group is needed to determine efficacy as an assessment tool. OBJECTIVE: To modify the previous refined clothespin relocation test and assess whether it can distinguish between able-bodied and prosthesis users. STUDY DESIGN: Comparative analysis. METHODS: Forty-two able-bodied subjects and three prosthesis users completed the adapted refined clothespin relocation test protocol. Average refined clothespin relocation test scores describing the degree of compensatory movements and the time to complete the protocol were compared using a Mann-Whitney U-test. RESULTS: A significant difference was found in the refined clothespin relocation test score between the able-bodied (Md = 65.32, n = 42) and prosthesis users (Md = 23.07, n = 3) with a medium effect size (p < 0.001, r = 0.43). CONCLUSION: Prosthesis users demonstrated larger compensations and longer completion times, as reflected in the refined clothespin relocation test final score. The refined clothespin relocation test has the potential to be a useful clinical tool to assess user performance on a functional task. CLINICAL RELEVANCE: This preliminary study demonstrates that the adapted protocol can distinguish between the two groups based on refined clothespin relocation test score. A future multi-centre study is required using multiple raters and comparing it with the existing outcome measures to validate the refined clothespin relocation test and determine inter-rater reliability.

Phantom motor execution as a treatment for phantom limb pain: protocol of an international, double-blind, randomised controlled clinical trial.

INTRODUCTION: Phantom limb pain (PLP) is a chronic condition that can greatly diminish quality of life. Control over the phantom limb and exercise of such control have been hypothesised to reverse maladaptive brain changes correlated to PLP. Preliminary investigations have shown that decoding motor volition using myoelectric pattern recognition, while providing real-time feedback via virtual and augmented reality (VR-AR), facilitates phantom motor execution (PME) and reduces PLP. Here we present the study protocol for an international (seven countries), multicentre (nine clinics), double-blind, randomised controlled clinical trial to assess the effectiveness of PME in alleviating PLP. METHODS AND ANALYSIS: Sixty-seven subjects suffering from PLP in upper or lower limbs are randomly assigned to PME or phantom motor imagery (PMI) interventions. Subjects allocated to either treatment receive 15 interventions and are exposed to the same VR-AR environments using the same device. The only difference between interventions is whether phantom movements are actually performed (PME) or just imagined (PMI). Complete evaluations are conducted at baseline and at intervention completion, as well as 1, 3 and 6 months later using an intention-to-treat (ITT) approach. Changes in PLP measured using the Pain Rating Index between the first and last session are the primary measure of efficacy. Secondary outcomes include: frequency, duration, quality of pain, intrusion of pain in activities of daily living and sleep, disability associated to pain, pain self-efficacy, frequency of depressed mood, presence of catastrophising thinking, health-related quality of life and clinically significant change as patient's own impression. Follow-up interviews are conducted up to 6 months after the treatment. ETHICS AND DISSEMINATION: The study is performed in agreement with the Declaration of Helsinki and under approval by the governing ethical committees of each participating clinic. The results will be published according to the Consolidated Standards of Reporting Trials guidelines in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03112928; Pre-results.

Motion Normalized Proportional Control for Improved Pattern Recognition-Based Myoelectric Control.

This paper describes two novel proportional control algorithms for use with pattern recognition-based myoelectric control. The systems were designed to provide automatic configuration of motion-specific gains and to normalize the control space to the user's usable dynamic range. Class-specific normalization parameters were calculated using data collected during classifier training and require no additional user action or configuration. The new control schemes were compared to the standard method of deriving proportional control using a one degree of freedom Fitts' law test for each of the wrist flexion/extension, wrist pronation/supination and hand close/open degrees of freedom. Performance was evaluated using the Fitts' law throughput value as well as more descriptive metrics including path efficiency, overshoot, stopping distance and completion rate. The proposed normalization methods significantly outperformed the incumbent method in every performance category for able bodied subjects (p < 0.001) and nearly every category for amputee subjects. Furthermore, one proposed method significantly outperformed both other methods in throughput (p < 0.0001), yielding 21% and 40% improvement over the incumbent method for amputee and able bodied subjects, respectively. The proposed control schemes represent a computationally simple method of fundamentally improving myoelectric control users' ability to elicit robust, and controlled, proportional velocity commands.

Safety, tolerability, and efficacy of overnight switching from sildenafil to tadalafil in patients with pulmonary arterial hypertension.

AIMS: Tadalafil, a once-daily phosphodiesterase type 5 inhibitor (PDE-5I), offers clinicians an alternative to sildenafil, a 3-times-daily (t.i.d.) PDE-5I for treatment of pulmonary arterial hypertension (PAH). However, there are limited data describing the risks and benefits or recommended methodology of switching patients from sildenafil to tadalafil. METHODS: Chart reviews were conducted on all World Health Organization group 1 patients on sildenafil for ≥ 3 months who transitioned to tadalafil with documented clinic visits and 6-min walk tests on both drugs. Most patients were transitioned by discontinuing sildenafil after the evening dose and initiating tadalafil 40 mg/day the next day. Data collected included demographics, PAH etiology, diagnostic hemodynamics, 6-min walk distance (6MWD), PDE-5I side effects, and concomitant medications. Data on B-type natriuretic peptide (BNP) levels were available for most patients also receiving endothelin receptor antagonists (ERAs). RESULTS: Medical records from 98 patients were evaluated. Most patients (92%) were on sildenafil for > 1 year, and 78% were receiving sildenafil 80-100 mg t.i.d. Ninety-seven percent of patients (95/98) were successfully transitioned and maintained on 40 mg/day. With a mean duration on tadalafil therapy of 243 ± 127 days at the time of analysis, 6MWD was unchanged. Patient-reported adverse events included headache (4%) and heartburn (2%). There was minimal change in BNP levels in the subset of patients receiving an ERA concomitantly. CONCLUSIONS: Transition from sildenafil to tadalafil 40 mg/day appears feasible without clinical deterioration or intolerable side effects. This study provides guidance to physicians considering transition from sildenafil to tadalafil for selecting patients.

Determining skill level in myoelectric prosthesis use with multiple outcome measures.

To obtain more insight into how the skill level of an upper-limb myoelectric prosthesis user is composed, the current study aimed to (1) portray prosthetic handling at different levels of description, (2) relate results of the clinical level to kinematic measures, and (3) identify specific parameters in these measures that characterize the skill level of a prosthesis user. Six experienced transradial myoelectric prosthesis users performed a clinical test (Southampton Hand Assessment Procedure [SHAP]) and two grasping tasks. Kinematic measures were end point kinematics, joint angles, grasp force control, and gaze behavior. The results of the clinical and kinematic measures were in broad agreement with each other. Participants who scored higher on the SHAP showed overall better performance on the kinematic measures. They had smaller movement times, had better grip force control, and needed less visual attention on the hand. The results showed that time was a key parameter in prosthesis use and should be one of the main focus aspects of rehabilitation. The insights from this study are useful in rehabilitation practice because they allow therapists to specifically focus on certain parameters that may result in a higher level of skill for the prosthesis user.

Survey of upper limb prosthesis users in Sweden, the United Kingdom and Canada.

BACKGROUND: As part of the process of improving prosthetic arms, it is important to obtain the opinions of the user population. OBJECTIVES: To identify factors that should be focused on to improve prosthesis provision. STUDY DESIGN: Postal questionnaire. METHODS: The questionnaire was sent to 292 adults (aged 18 to 70 years) with upper-limb loss or absence at five centres (four in Europe) Participants were identified as regular attendees of the centres. RESULTS: This questionnaire received a response from 180 users (response rate 62%) of different types of prosthetic devices. Responses showed that the type of prosthesis generally used was associated with gender, level of loss and use for work (Pearson chi-square, p-values below 0.05). The type of prosthesis was not associated with cause, side, usage (length per day, sports or driving) or reported problems. The findings did not identify any single factor requiring focus for the improvement of prostheses or prosthetic provision. CONCLUSIONS: Every part of the process of fitting a prosthesis can be improved, which will have an effect for some of the population who use their devices regularly. There is, however, no single factor that would bring greater improvement to all users. CLINICAL RELEVANCE: Based on information gained from a broad range of prosthesis users, no single aspect of prosthetic provision will have a greater impact on the use of upper limb prostheses than any other. Efforts to improve the designs of prosthetic systems can cover any aspect of provision.

Comparing hiking, mountain biking and horse riding impacts on vegetation and soils in Australia and the United States of America.

Hiking, horse riding and mountain biking are popular in protected areas in Australia and the United States of America. To help inform the often contentious deliberations about use of protected areas for these three types of activities, we review recreation ecology research in both countries. Many impacts on vegetation, soils and trails are similar for the three activities, although there can be differences in severity. Impacts include damage to existing trails, soil erosion, compaction and nutrification, changes in hydrology, trail widening, exposure of roots, rocks and bedrock. There can be damage to plants including reduction in vegetation height and biomass, changes in species composition, creation of informal trails and the spread of weeds and plant pathogens. Due to differences in evolutionary history, impacts on soil and vegetation can be greater in Australia than in the USA. There are specific social and biophysical impacts of horses such as those associated with manure and urine, grazing and the construction and use of tethering yards and fences. Mountain bike specific impacts include soil and vegetation damage from skidding and the construction of unauthorised trails, jumps, bridges and other trail technical features. There are gaps in the current research that should be filled by additional research: (1) on horse and mountain bike impacts to complement those on hiking. The methods used need to reflect patterns of actual usage and be suitable for robust statistical analysis; (2) that directly compares types and severity of impacts among activities; and (3) on the potential for each activity to contribute to the spread of weeds and plant pathogens. Additional research will assist managers and users of protected areas in understanding the relative impacts of these activities, and better ways to manage them. It may not quell the debates among users, managers and conservationists, but it will help put it on a more scientific footing.

Impacts of recreation and tourism on plant biodiversity and vegetation in protected areas in Australia.

This paper reviews recent research into the impact of recreation and tourism in protected areas on plant biodiversity and vegetation communities in Australia. Despite the international significance of the Australian flora and increasing visitation to protected areas there has been limited research on recreational and tourism impacts in Australia. As overseas, there are obvious direct impacts of recreation and tourism such as clearing of vegetation for infrastructure or damage from trampling, horse riding, mountain biking and off road vehicles. As well, there are less obvious but potentially more severe indirect impacts. This includes self-propagating impacts associated with the spread of some weeds from trails and roads. It also includes the severe impact on native vegetation, including many rare and threatened plants, from spread of the root rot fungus Phytopthora cinnamomi. This review highlights the need for more recreational ecology research in Australia.

Vegetation associated with different walking track types in the Kosciuszko alpine area, Australia.

Tourism infrastructure such as walking tracks can have negative effects on vegetation including in mountain regions. In the alpine area around continental Australia's highest mountain, Mt Kosciuszko (2228 m), there is a range of walking tracks (paved, gravel and raised steel mesh surfaces) in addition to an extensive network of informal/non-hardened tracks. Vegetation characteristics were compared between track types on/under tracks, on the track verge, and in the adjacent native vegetation. For a raised steel mesh walkway there was no difference in vegetation under the walkway, on the verge, and 3m away. In contrast, for a non-hardened track there was 35% bare ground on the track surface but no other detectable impacts. Gravel and paved tracks had distinct verges largely comprising bare ground and exotic species. For non-hardened tracks there was an estimated 270 m2 of disturbance per km of track. For wide gravel tracks the combined area of bare ground, exotic plants and gravel was estimated as 4290 m2 per km, while for narrow gravel tracks it was estimated as 2940 m2 per km. For paved tracks there was around 2680 m2 per km of damage. In contrast, there was no detectable effect of raised steel mesh walkway on vegetation highlighting some of the benefits of this surface over other track types.

The interaction of testosterone and breeding phase on the reproductive behavior and use of space of male zebra finches.

It is well known that androgens play a critical role in mediating the reproductive behavior of males. However, many laboratory experiments that examined the effects of testosterone in male songbirds typically limited their investigations to the early phase of breeding. We sought to determine the influence of testosterone on social behavior, pair bonding, nesting, and use of space in captive zebra finch (Taeniopygia guttata) males as a function of breeding stage (pre-laying, incubation, and nestling phases). Fourteen males were released into an aviary with 14 females and allowed to breed for 7 weeks. Half of the males were given testosterone implants and half were given control implants. During the pre-laying phase, testosterone-implanted males spent significantly more time in nesting activities than control birds and more time elapsed from starting to build a nest to when their mates initiated egg-laying. During the incubation phase, testosterone-implanted subjects spent significantly more time in female-directed and undirected singing. Use of space varied between hormone conditions depending upon breeding phase: there was no difference during pre-laying, but during the incubation and nestling phases, testosterone-implanted subjects used significantly more space. This significant increase in "home range" during the latter phase of the breeding cycle coincides with results from field studies on other species. These results underscore the importance of considering breeding phase in assessing the behavioral sensitivity to hormones.

Prehatch entrainment of circadian rhythms in the domestic chick using different light regimes.

The onset of circadian rhythms in many animals occurs during prenatal development. We conducted four experiments, using the domestic chick as a model, to assess when these rhythms can first be entrained and the type of light zeitgeber necessary. In Experiment 1, the presence of circadian rhythms was assessed using tonic immobility, an antipredator behavior, whereas in Experiments 2 to 4 body temperature was studied. We demonstrate that (a) circadian rhythms can be entrained during the late stage of the chick's 21-day incubation period (prehatch Days 13-18), (b) only 1 day of light cues [12:12 hr light:dark (12L:12D)] on prehatch Day 13 is necessary for entrainment, and (c) short bouts of light, which simulate the light cues embryos typically experience during natural incubation, can act as zeitgebers although they are not as effective as 12L:12D. The onset of entrainment is earlier than predicted and suggests that the brain structures mediating circadian rhythms mature sooner than proposed by previous research.