Trials Of Short Duration Research Articles

P036 EXPLORING EARLY-RESPONSIVE PHARMACODYNAMIC BIOMARKERS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE (IBD)

The generation of high-quality pilot data that leads to “go/no-go decisions” regarding new or repurposed drugs is often problematic, particularly with a high placebo response rate. In short duration trials, pharmacodynamic (PD) biomarkers can demonstrate proof-of-concept of drug action that may or may not be bridged to clinical outcomes. We sought to identify early-changing PD biomarkers in patients with IBD. Clinical scores and serum were obtained at baseline and after 1–2 weeks of corticosteroids in 5 IBD patients. Using the SOMAscan assay, 45 published chronic steroid and infliximab-responsive proteins were evaluated. All were log-transformed and normality verified using the Shapiro-Wilk test. Pre- to post- treatment comparisons were performed using a paired t-test (p<0.01). Label-free proteome profiling using mass spectrometry was performed. Thirteen proteins responded consistently to 1–2 weeks of corticosteroids. These included biomarkers previously shown to be responsive in pediatric IBD patients after 2 doses of infliximab (CCL23, carnosinase, p-cadherin, CCL25, testican-2, AGT, and FAM3B) and after longer courses of corticosteroid therapy (AGT, afamin, GHBP, CCL22, MMP12, PROT C, Ly9). Four were detected by label-free mass spectrometry (AGT, afamin, PROT C, and carnosinase). Most are involved in regulation of inflammation, immune homeostasis, and extracellular matrix binding. In this small sample, change in some biomarkers correlated with short-term clinical response (carnosinase, testican-2, FAM3B). We have identified treatment-responsive proteins in IBD patients after several weeks of steroids, after 2 doses of infliximab, and within 1–2 weeks of treatment with steroids; these biomarkers may be useful for screening trials of anti-inflammatory drugs. For selection of candidates to study in larger, controlled trials, short-duration biomarker-based trials would be beneficial for patients.

Vitamin K supplementation for cystic fibrosis.

Cystic fibrosis is a genetic disorder which can lead to multiorgan dysfunction. Malabsorption of fat and fat-soluble vitamins (A, D, E, K) may occur and can cause subclinical deficiencies of some of these vitamins. Vitamin K is known to play an important role in both blood coagulation and bone formation. Supplementation with vitamin K appears to be one way of addressing the deficiency, but there is very limited agreement on the appropriate dose and frequency of use of these supplements. This is an updated version of the review. To assess the effects of vitamin K supplementation in people with cystic fibrosis and to determine the optimal dose and route of administration of vitamin K for both routine and therapeutic use. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 30 January 2017. Randomised and quasi-randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in children or adults diagnosed with cystic fibrosis (by sweat test or genetic testing). Two authors independently screened papers, extracted trial details and assessed their risk of bias. Two trials (total of 32 participants) each lasting one month were included in the review and were assessed as having a moderate risk of bias. One was a dose-ranging parallel group trial in children (aged 8 to 18 years); and the other (with an older cohort) had a cross-over design comparing supplements to no treatment, but no separate data were reported for the first intervention period. Neither of the trials addressed any of the primary outcomes (coagulation, bone formation and quality of life). Both trials reported the restoration of serum vitamin K and undercarboxylated osteocalcin levels to the normal range after one month of daily supplementation with 1 mg of vitamin K. Evidence from randomised controlled trials on the benefits of routine vitamin K supplementation for people with CF is currently weak and limited to two small trials of short duration. However, no harm was found and until further evidence is available, the present recommendations should be adhered to.

Antidepressant-Induced Acute Liver Injury: A Case-Control Study in an Italian Inpatient Population.

Pre-marketing clinical trials show that antidepressant-induced liver injury seems to be a rare adverse event. Because of short follow-up trial duration, the incidence of liver injury due to antidepressant use could be underestimated. We aimed to quantify the risk of acute liver injury associated with antidepressant use through a case-control analysis among an inpatient population. A multicenter study was carried out in nine Italian hospitals from October 2010 to January 2014, within the DILI-IT (Drug-Induced Liver Injury in Italy) study project. After exclusion of all patients with a clear competing cause of liver injury, cases were defined as adults admitted to the hospital with a diagnosis of acute liver injury, while controls had any other acute clinical condition not related to the liver. Antidepressant exposure was evaluated within 90days prior to the date of the first sign/symptom of liver injury. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated as a measure of risk estimates for liver injury. We included 17 cases exposed to antidepressants matched to 99 controls. According to the features of liver injury, all cases showed symptomatic liver function test abnormalities at hospital admission, with the main signs/symptoms represented by fatigue, nausea, asthenia, or dark urine. Citalopram was the antidepressant mostly involved in the increase of liver enzymes, mainly alanine aminotransferase. Compared with non-use, current use of antidepressants was associated with a significantly increased risk of liver injury (adjusted OR, ORADJ, 1.84; 95% CI 1.02-3.32). Specifically, an increased, but not significant, risk of developing liver injury was observed for citalopram, a selective serotonin-reuptake inhibitor (ORADJ 1.82; 95% CI 0.60-5.53). The use of antidepressants is not as safe in terms of liver injury as expected; instead, the risk of antidepressant-induced liver injury is likely underestimated. The lack of significance does not reflect the absence of risk, but rather suggests the need to evaluate it in a wider setting of antidepressant users.

The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder

A Cochrane systematic review on immediate-release methylphenidate for adults with attention deficit hyperactivity disorder (ADHD) was withdrawn from the Cochrane Library on 26 May 2016 after substantial criticism of its...

Rapid target foraging with reach or gaze: The hand looks further ahead than the eye.

Real-world tasks typically consist of a series of target-directed actions and often require choices about which targets to act on and in what order. Such choice behavior can be assessed from an optimal foraging perspective whereby target selection is shaped by a balance between rewards and costs. Here we evaluated such decision-making in a rapid movement foraging task. On a given trial, participants were presented with 15 targets of varying size and value and were instructed to harvest as much reward as possible by either moving a handle to the targets (hand task) or by briefly fixating them (eye task). The short trial duration enabled participants to harvest about half the targets, ensuring that total reward was due to choice behavior. We developed a probabilistic model to predict target-by-target harvesting choices that considered the rewards and movement-related costs (i.e., target distance and size) associated with the current target as well as future targets. In the hand task, in comparison to the eye task, target choice was more strongly influenced by movement-related costs and took into account a greater number of future targets, consistent with the greater costs associated with arm movement. In both tasks, participants exhibited near-optimal behaviour and in a constrained version of the hand task in which choices could only be based on target positions, participants consistently chose among the shortest movement paths. Our results demonstrate that people can rapidly and effectively integrate values and movement-related costs associated with current and future targets when sequentially harvesting targets.

Tailored Communication Within Mobile Apps for Diabetes Self-Management: A Systematic Review.

BackgroundThe prevalence of diabetes is increasing and with the requirements for self-management and risk of late complications, it remains a challenge for the individual and society. Patients can benefit from support from health care personnel in their self-management, and the traditional communication between patients and health care personnel is changing. Smartphones and apps offer a unique platform for communication, but apps with integrated health care personnel communication based on patient data are yet to be investigated to provide evidence of possible effects.ObjectiveOur goal was to systematically review studies that aimed to evaluate integrated communication within mobile apps for tailored feedback between patients with diabetes and health care personnel in terms of (1) study characteristics, (2) functions, (3) study outcomes, (4) effects, and (5) methodological quality.MethodsA systematic literature search was conducted following our International Prospective Register of Systematic Reviews (PROSPERO) protocol, searching for apps with integrated communication for persons with diabetes tested in a controlled trial in the period 2008 to 2016. We searched the databases PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central, Excerpta Medica database (EMBASE), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform. The search was closed in September 2016. Reference lists of primary articles and review papers were assessed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and we applied the Cochrane risk of bias tool to assess methodological quality.ResultsWe identified 2822 citations and after duplicate removal, we assessed 1128 citations. A total of 6 papers were included in this systematic review, reporting on data from 431 persons participating in small trials of short duration. The integrated communication features were mostly individualized as written non–real-time feedback. The number of functions varied from 2 to 9, and blood glucose tracking was the most common. HbA1c was the most common primary outcome, but the remaining reported outcomes were not standardized and comparable. Because of both the heterogeneity of the included trials and the poor methodological quality of the studies, a meta-analysis was not possible. A statistically significant improvement in the primary measure of outcome was found in 3 of the 6 included studies, of which 2 were HbA1c and 1 was mean daytime ambulatory blood pressure. Participants in the included trials reported positive usability or feasibility postintervention in 5 out of 6 trials. The overall methodological quality of the trials was, however, scored as an uncertain risk of bias.ConclusionsThis systematic review highlights the need for more trials of higher methodological quality. Few studies offer an integrated function for communication and feedback from health care personnel, and the research field represents an area of heterogeneity with few studies of highly rigorous methodological quality. This, in combination with a low number of participants and a short follow-up, is making it difficult to provide reliable evidence of effects for stakeholders.

CORRECTIONS.

EDITORIALS Hallucinations Predict Relapse After Discontinuation of Risperidone in Patients With Alzheimer’s Disease and Psychosis or Agitation Helen Lavretsky, M.D., M.S. An article in this issue by Patel and colleagues (1) provides new evidence of the predictors of relapse after discontinuing anti- psychotic medications in older adults with Alzheimer’s disease and psychosis or agitation. This is a post hoc analysis following the initial publication of the multicenter Antipsychotic Dis- continuation in Alzheimer’s Disease trial results, which indi- cated that patients who responded to risperidone over 16 weeks of open-label treatment showed a twofold to fourfold higher risk of relapse 16–32 weeks after discontinuation of risperidone compared with continuation on risperidone (2). In the present study, the researchers examined the associa- tions between neuropsychiatric symptoms, both at study base- line and immediately after open risperidone treatment, and the likelihood of relapse after subsequent randomization to con- tinued risperidone treatment or discontinuation to placebo. Of 180 patients with Alzheimer’s disease and symptoms of agita- tion or psychosis who received treatment with risperidone for 16 weeks, 110 responded and were randomly assigned to 1) continue risperidone for 32 weeks, 2) continue risperidone for 16 weeks followed by a switch to placebo for 16 weeks, or 3) switch to placebo for 32 weeks. Compared with patients who had mild hallucinations or no hallucinations at baseline, patients with severe hallucinations showed a higher likelihood of relapse (hazard ratio52.96, 95% CI51.52, 5.76; p50.001). This effect was present for the subsample of patients with auditory hallucina- tions but not those with visual hallucinations. Among patients with baseline hallucinations, 13 of 17 (76.5%) who discontinued risperidone relapsed, compared with 10 of 26 (38.5%) who continued risperidone (p,0.02). This group difference remained for severe (77.8%) compared with mild (36%) hallucinations (p50.02). Neuropsychiatric Inventory domain scores after the initial open-treatment phase prior to randomization were not as- sociated with relapse. The authors conclude with a caution that physicians must be mindful of the potential for relapse in patients with Alzheimer’s disease who present with severe hallucinations at baseline, particularly auditory hallucinations. The study results provide important information that could contribute to guidelines for discontinuation of antipsychotics in patients with Alzheimer’s disease and related dementing illnesses (3). With the global aging trend, our society is deal- ing with rising rates of Alzheimer’s disease and other forms of dementia that currently afflict an estimated 5.4 million Am J Psychiatry 174:4, April 2017 individuals in the United States, 96% of whom are over 65 years of age (Alzheimer’s Facts and Figures, 2016; http://m.alz.org/ facts-and-figures.asp). As of 2016, the aggregated cost of care for all individuals with Alzheimer’s disease and other dementias is estimated at $236 billion, with 68% of the cost covered by Medicare and Medicaid (Alzheimer’s Facts and Figures, 2016). Besides cognitive decline, noncognitive behavioral symptoms or neuropsychiatric symptoms (4) accompany dementia in 80%290% of patients and are associated with excess morbidity and mortality as well as more suffering on the part of both patients and caregivers (5, 6). Nonetheless, compared with in- vestments made to develop pharmacotherapy for cognitive symptoms, systematic efforts to improve the use of medications to treat noncognitive behavioral symptoms have been modest. While numerous stud- ies have provided vari- The study results provide ous degrees of efficacy for important information noncognitive behavioral that could contribute symptoms for a wide va- to guidelines for riety of medications, in- discontinuation of cluding antipsychotics, there is still limited evi- antipsychotics in patients dence to provide guid- with Alzheimer’s disease and ance on their continuous related dementing illnesses. use (7, 8). For individuals who have a good response to antipsychotics, withdrawal from them has been associated with significant relapse (2). At the same time, the efficacy of antipsychotics has been called into question by reports suggesting that the existing evidence is based on trials of short duration that use small samples and varying assessment instruments and often show a high placebo response (9). The use of antipsychotics in dementia is com- plicated by a variety of concerning side effects, including ex- trapyramidal symptoms (particularly tardive dyskinesia [10]), hyperglycemia, diabetes mellitus, weight gain, increases in serum lipid levels, and cardiovascular effects (11, 12). A review of the literature found a 1.3- to 2-fold increased risk of cere- brovascular accidents in case-control studies of elderly pa- tients on antipsychotics, which was highest in the first weeks of treatment and among those who had certain risk factors, such as higher age, cognitive impairment, and vascular disease (11). A review of 17 studies on antipsychotics in individuals with ajp.psychiatryonline.org

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obese Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females and is often associated with a number of cardiometabolic disorders such as central obesity, dyslipidaemia, hypertension, insulin resistance, hyperinsulinaemia, glucose intolerance and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a gut hormone secreted after a meal, enhances glucosestimulated insulin secretion and additionally suppresses appetite and gastric motility. Most studies found impaired GLP-1 kinetics in obese individuals, whereas small studies in PCOS reported reduced, normal or even elevated GLP-1 levels. Apart from their efficacy in patients with T2DM, some GLP-1 receptor agonists (GLP-1 RAs) have been successfully tested in terms of both efficiency and safety in obese individuals without diabetes and liraglutide 3 mg once daily has been approved as an antiobesity drug in the USA and the European Union. Recently, some small trials of short duration using GLP-1 RAs as monotherapy or combined with metformin in obese PCOS women showed positive results regarding weight reduction and a decrease in testosterone levels but without significant effects on insulin levels, insulin sensitivity and menstrual patterns. Longer term studies with more patients and higher doses of liraglutide (as this drug is already approved for obese individuals) are required to determine the precise indications of GLP-1 RAs in PCOS and to evaluate safety issues.

Prepotent motor activity and inhibitory control demands in different variants of the go/no-go paradigm.

Inhibitory control enables humans to stop prepotent motor activity, and is commonly studied using go/no-go or stop-signal tasks. In stop-signal tasks, prepotent motor activity is elicited by delaying stop signals relative to go signals. In go/no-go tasks, however, trials include only one signal-go or no-go. Hence, prepotent motor activity has to be ensured differently-for example, by using rare no-go trials and short trial durations. However, a literature survey shows that ∼40% of studies use equiprobable go/no-go trials and ∼20% use long stimulus-stimulus intervals (> 4 s). It is unclear whether such slow-paced, equiprobable go/no-go tasks elicit prepotent motor activity and probe inhibitory control. We recorded EEG during four go/no-go tasks, varying in no-go probability and trial duration. We quantified prepotent motor activity on successfully inhibited no-go trials using the lateralized readiness potential. Only fast-paced go/no-go tasks with rare no-go trials reliably evoked such activity. We then used a stop-signal task and independent component analysis to isolate an established neural signature of inhibitory control, and investigated this signature's activity across the go/no-go tasks. Across tasks, increased prepotent motor activity on individual no-go trials was accompanied by greater frontocentral P3 amplitudes, confirming it as an index of inhibition. Crucially, this inhibition-related activity showed a 75% reduction in slow-paced, equiprobable go/no-go tasks compared to fast-paced, rare no-go versions. Therefore, since many common go/no-go task configurations do not reliably evoke prepotent motor activity, their inhibitory requirements are greatly reduced. This has major implications for the usage of go/no-go tasks in psychological experiments.

Tolerability of cariprazine in the treatment of acute bipolar I mania: A pooled post hoc analysis of 3 phase II/III studies

BackgroundAtypical antipsychotics have broad-spectrum efficacy against core symptoms of acute mania/mixed states in bipolar disorder; however, they are associated with clinically significant adverse effects (AEs). MethodsThis post hoc analysis evaluated the safety and tolerability of the atypical antipsychotic cariprazine in the treatment of adult patients with acute manic/mixed episodes of bipolar I disorder. Data were taken from three 3-week randomized, double-blind, placebo-controlled, flexible-dose trials of cariprazine 3–12mg/d. Patient subgroups categorized by modal daily dose (3–6mg/d; 9–12mg/d) were used to assess dose response. ResultsThe pooled safety population comprised 1065 patients (placebo=442; cariprazine 3–6mg/d=263; cariprazine 9–12mg/d=360). More cariprazine- than placebo-treated patients reported double-blind treatment-emergent AEs; the overall AE incidence was similar among cariprazine-dose groups. AEs reported in ≥5% of cariprazine patients overall with at least twice the incidence of placebo were akathisia, extrapyramidal symptoms, restlessness, and vomiting. The incidence of SAEs was low and similar between the placebo- and cariprazine-treatment groups. Metabolic parameter changes were small and generally similar between cariprazine and placebo groups; mean increases in fasting glucose levels were greater with cariprazine (3–6mg/d=6.6mg/dL; 9–12mg/d=7.2mg/dL) than placebo (1.7mg/dL). Mean weight change was 0.54kg and 0.17kg for cariprazine and placebo, respectively; weight increase ≥7% was <3% in all treatment groups. Cariprazine was not associated with clinically meaningful changes in electrocardiogram parameters. LimitationsPost hoc analysis, flexible-dose design, short trial duration. ConclusionCariprazine was generally safe and well-tolerated in patients with manic/mixed episodes associated with bipolar I disorder.

Feasibility of placebo-controlled trial designs for new CFTR modulator evaluation

BackgroundNew CFTR modulators are in development that sponsors anticipate will be comparable or superior to approved modulators. Testing these agents for efficacy will require either placebo-controlled or active-comparator trials. MethodsWe surveyed US CF physicians and their patients eligible to receive approved modulators or their families for willingness to participate in placebo-controlled modulator trials of varying duration. ResultsInterest in placebo-controlled trials of short duration (2–4weeks) was greatest, with few respondents, particularly among patient respondents, willing to consider 6month studies. Patients/families with access to approved modulators were consistently less interested in placebo-controlled modulator trials of any duration. ConclusionsSample size and interpretability advantages of placebo-controlled trials outweigh alternative active-comparator trials, but must consider physician and patient thresholds for forgoing treatment with approved modulators. Enrollment will be most feasible for short-duration trials and those conducted among populations without access to approved modulators.

Multi-Component Interventions and Cognitive Health: A Scoping Review.

Single-component interventions for modifiable risk factors to improve cognitive function in older adults have limited impacts. Multi-component interventions may be more effective. The current review describes randomized trials of multi-component interventions, and reports the state of the evidence to protect the cognitive health and reduce the risk of cognitive decline among middle-aged and older adults. Two hundred seventy-nine studies were found through electronic databases, 30 full-text reviews were completed, and six studies were identified for final selection. Findings suggest that a multi-component approach is promising compared to single-component interventions. Most multi-component intervention studies found improvement in at least one domain of cognitive function. However, the quality of multi-component studies was largely fair or poor primarily due to small samples and short trial durations. There is a need for more rigorous studies of multi-component interventions and to refine the knowledge on the specific interventions that optimize prevention domains. [Journal of Gerontological Nursing, 43(5), 39-48.].

OP131 Cost-Effectiveness Of Dexamethasone And Adalimumab For Uveitis

INTRODUCTION:Uveitis is inflammation inside the eye whose underlying cause may be infectious or non-infectious. The objective of our study was to assess the cost-effectiveness of the dexamethasone implant and adalimumab compared with current practice (immunosuppressants and systemic corticosteroids) in patients with non-infectious intermediate, posterior or pan-uveitis.METHODS:A Markov model was built to estimate costs and benefits of the interventions. Systematic reviews were performed to identify the relevant evidence. Quality of life data collected in three key randomized-controlled trials (1-3) was used to estimate the interventions effectiveness compared with the trials comparator arms, which consisted of placebo plus limited current practice (LCP). An indirect treatment comparison between adalimumab and dexamethasone was considered inappropriate due to lack of necessary evidence. For adalimumab, patients with active and inactive uveitis were considered separately. Due to the short duration of the trials, the rate of blindness, an important complication of uveitis, was highly uncertain. Substantial exploratory analyses were therefore undertaken. The analysis was performed from the perspective of the National Health Service (NHS) and Personal Social Services (PSS). Costs were calculated based on standard United Kingdom sources.RESULTS:The estimated incremental cost-effectiveness (ICER) of dexamethasone compared with LCP was GBP19,509 per quality-adjusted life year (QALY) gained. The estimated ICER of adalimumab compared with LCP was GBP94,523 and GBP317,547 per QALY in patients with active and inactive uveitis respectively. The factors with the largest impact upon the ICERs were the rate of blindness and the proportion of cases of blindness avoided by interventions.CONCLUSIONS:Dexamethasone and adalimumab resulted in health gains, but at significant extra costs, especially adalimumab which is unlikely to be considered a cost-effective use of NHS resources. The results of the analysis are highly uncertain due to the limited availability of evidence on: the comparative effectiveness of dexamethasone, adalimumab and current practice; the effectiveness of treatments in avoiding blindness; and, the effectiveness of interventions in different subgroups.

Time for action versus action in time: time estimation differs between motor preparation and execution

ABSTRACTTheories relating to time perception and motor performance predict very different temporal distortions depending on the synchronisation or succession of temporal processing and motor behaviour. However, our knowledge about the temporal difference between motor preparation and execution is still scarce. In order to expand on prior studies, two different time reproduction tasks were utilised to measure motor preparation and motor execution. We found that motor preparation of a planned action allows participants to complete the time reproduction task more accurately and, in short duration trials, less variably than for motor execution. Furthermore, under-reproduction was found in motor preparation compared to motor execution, which may be caused by increased temporal information processing. According to the attentional gate theory, more attention allocated to time processing and reduced motor distraction leads to less temporal distortion in the motor preparation. The findings are also important for designing to study consciousness, temporal and visual processing.

Using Bayesian Adaptive Trial Designs for Comparative Effectiveness Research: A Virtual Trial Execution.

Bayesian and adaptive clinical trial designs offer the potential for more efficient processes that result in lower sample sizes and shorter trial durations than traditional designs. To explore the use and potential benefits of Bayesian adaptive clinical trial designs in comparative effectiveness research. Virtual execution of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) as if it had been done according to a Bayesian adaptive trial design. Comparative effectiveness trial of antihypertensive medications. Patient data sampled from the more than 42000 patients enrolled in ALLHAT with publicly available data. Number of patients randomly assigned between groups, trial duration, observed numbers of events, and overall trial results and conclusions. The Bayesian adaptive approach and original design yielded similar overall trial conclusions. The Bayesian adaptive trial randomly assigned more patients to the better-performing group and would probably have ended slightly earlier. This virtual trial execution required limited resampling of ALLHAT patients for inclusion in RE-ADAPT (REsearch in ADAptive methods for Pragmatic Trials). Involvement of a data monitoring committee and other trial logistics were not considered. In a comparative effectiveness research trial, Bayesian adaptive trial designs are a feasible approach and potentially generate earlier results and allocate more patients to better-performing groups. National Heart, Lung, and Blood Institute.

Medication Safety

Medication Safety

Neural Network Model of Vestibular Nuclei Reaction to Onset of Vestibular Prosthetic Stimulation.

The vestibular system incorporates multiple sensory pathways to provide crucial information about head and body motion. Damage to the semicircular canals, the peripheral vestibular organs that sense rotational velocities of the head, can severely degrade the ability to perform activities of daily life. Vestibular prosthetics address this problem by using stimulating electrodes that can trigger primary vestibular afferents to modulate their firing rates, thus encoding head movement. These prostheses have been demonstrated chronically in multiple animal models and acutely tested in short-duration trials within the clinic in humans. However, mainly, due to limited opportunities to fully characterize stimulation parameters, there is a lack of understanding of “optimal” stimulation configurations for humans. Here, we model possible adaptive plasticity in the vestibular pathway. Specifically, this model highlights the influence of adaptation of synaptic strengths and offsets in the vestibular nuclei to compensate for the initial activation of the prosthetic. By changing the synaptic strengths, the model is able to replicate the clinical observation that erroneous eye movements are attenuated within 30 minutes without any change to the prosthetic stimulation rate. Although our model was only built to match this time point, we further examined how it affected subsequent pulse rate modulation (PRM) and pulse amplitude modulation (PAM). PAM was more effective than PRM for nearly all stimulation configurations during these acute tests. Two non-intuitive relationships highlighted by our model explain this performance discrepancy. Specifically, the attenuation of synaptic strengths for afferents stimulated during baseline adaptation and the discontinuity between baseline and residual firing rates both disproportionally boost PAM. Comodulation of pulse rate and amplitude has been experimentally shown to induce both excitatory and inhibitory eye movements even at high baseline stimulation rates. We also modeled comodulation and found synergistic combinations of stimulation parameters to achieve equivalent output to only amplitude modulation. This may be an important strategy to reduce current spread and misalignment. The model outputs reflected observed trends in clinical testing and aspects of existing vestibular prosthetic literature. Importantly, the model provided insight to efficiently explore the stimulation parameter space, which was helpful, given limited available patient time.

Clinical drug research in chronic central neurodegenerative disorders

ABSTRACTSeveral compounds developed the treatment of Alzheimer’s disease and Parkinson’s disease have been clinically unsuccessful. Suggested reasons for these failures have included heterogeneous symptom expression, inappropriate assessment of effects, safety and tolerability hurdles, short duration of disease-modifying trials, recruiting pressure on study centers, administrative and bureaucratic overload, and pooling results from trial centers in different health care systems with differing quality and therapeutic concepts. The solution to these problems will include reducing the costs of drug development, with a concomitant reduction of approval hurdles. Trial designs are influenced by ethics committees, health care officials, political administrations, and research scientists. None have direct contact with the treated patients. Approval of novel therapeutic agents lies in the remit of health care officials, whereby price plays a more dominant role than therapeutic efficacy. Patients and prescribing physicians, however, are better placed to act as arbiters of the efficacy, risks, and overall value of a new drug in practice.

Planting microcuttings: An innovative method for establishing a willow vegetation cover

The standard approach to establishing woody species such as willows in phytoremediation and ecological engineering is based on planting either unrooted rods or cuttings. Whether planted by hand or mechanically, this approach is usually time-consuming and expensive, and sometimes results in uncompleted projects. In this short-duration trial, we assessed a new method for propagating two common willow species (Salix viminalis L. and Salix miyabeana Seemen) using microcuttings of different sizes (i.e. 1, 2 and 5cm-long). Best results were obtained with 5cm-long cuttings, in terms of resprouting rate (average 100%), number of shoots (average 8.9) and shoot length (average 11.5cm after 41 days), although there were significant differences according to species, with S. viminalis sprouting faster and better than S. miyabeana. These results, although preliminary, provide a new, more rapid and economical avenue for willow propagation for restoration or other environmental purposes.

Anatomic Clinical Trial Endpoints for Nonexudative Age-Related Macular Degeneration

To review the role of anatomic endpoints in clinical trials for the study of nonexudative age-related macular degeneration (AMD) with an emphasis on a novel composite endpoint for the study of emerging therapies for intermediate AMD (iAMD). Unlike clinical trials for exudative AMD, it is impractical to use the change in visual acuity (VA) as a primary endpoint for the study of nonexudative AMD. By the time VA has been lost in nonexudative AMD, proof-of-concept early-stage clinical trials would take years to run, and drug development would be a near impossible task. Surrogate endpoints are needed that reliably predict future vision loss and can be easily measured. Anatomic changes that correlate with disease progression in nonexudative AMD offer the greatest promise as primary endpoints. In preparation for this review, the electronic PubMed database was searched for relevant research pertaining to anatomic endpoints for the study of nonexudative AMD. Paper selection was based on our knowledge of the field with the goal to be as inclusive as possible. Whenever possible, recent review articles and results from large clinical trials, preferably with outcomes from many years of follow-up were favored over trials of short duration. The most commonly used anatomic endpoint for the study of late, nonexudative AMD is the growth of geographic atrophy (GA). The advantages of studying GA include the appreciation that its enlargement through the foveal center leads to significant vision loss through the availability of natural history studies, the understanding that prevention of this growth would preserve vision in the future, the ability to reliably measure GA using different imaging strategies, and the development appropriate statistical tools that reliably predict the growth of GA over time. The major disadvantage of using GA is that significant, irreversible disease progression has already occurred. The use of drusen volume as a predictor of disease progression and the use of a composite endpoint that incorporates drusen growth, formation of GA, and formation of neovascularization offers an opportunity to study therapies at an earlier stage of AMD with a greater likelihood of preserving better vision over a lifetime. Anatomic endpoints for the study of nonexudative AMD are needed to accelerate drug development, and the availability of optical coherence tomography algorithms capable of reliably measuring drusen morphology offer the best opportunity to study therapies for iAMD.