Improving With Practice: A Neural Model of Mathematical Development

The ability to improve in speed and accuracy as a result of repeating some task is an important hallmark of intelligent biological systems. Although gradual behavioral improvements from practice have been modeled in spiking neural networks, few such models have attempted to explain cognitive development of a task as complex as addition. In this work, we model the progression from a counting-based strategy for addition to a recall-based strategy. The model consists of two networks working in parallel: a slower basal ganglia loop and a faster cortical network. The slow network methodically computes the count from one digit given another, corresponding to the addition of two digits, whereas the fast network gradually “memorizes” the output from the slow network. The faster network eventually learns how to add the same digits that initially drove the behavior of the slower network. Performance of this model is demonstrated by simulating a fully spiking neural network that includes basal ganglia, thalamus, and various cortical areas. Consequently, the model incorporates various neuroanatomical data, in terms of brain areas used for calculation and makes psychologically testable predictions related to frequency of rehearsal. Furthermore, the model replicates developmental progression through addition strategies in terms of reaction times and accuracy, and naturally explains observed symptoms of dyscalculia.     

A novel customizable modular bioreactor system for whole-heart cultivation under controlled 3D biomechanical stimulation

In the last decade, cardiovascular tissue engineering has made great progress developing new strategies for regenerative medicine applications. However, while tissue engineered heart valves are already entering the clinical routine, tissue engineered myocardial substitutes are still restrained to experimental approaches. In contrast to the heart valves, tissue engineered myocardium cannot be repopulated in vivo because of its biological complexity, requiring elaborate cultivation conditions ex vivo. Although new promising approaches—like the whole-heart decellularization concept—have entered the myocardial tissue engineering field, bioreactor technology needed for the generation of functional myocardial tissue still lags behind in the sense of user-friendly, flexible and low cost systems. Here, we present a novel customizable modular bioreactor system that can be used for whole-heart cultivation. Out of a commercially obtainable original equipment manufacturer platform we constructed a modular bioreactor system specifically aimed at the cultivation of decellularized whole-hearts through perfusion and controlled 3D biomechanical stimulation with a simple but highly flexible operation platform based on LabVIEW^®. The modular setup not only allows a wide range of variance regarding medium conditioning under controlled 3D myocardial stretching but can also easily be upgraded for e.g. electrophysiological monitoring or stimulation, allowing for a tailor-made low-cost myocardial bioreactor system.     

Efficacy of bupropion and predictors of successful outcome in a sample of French smokers: a randomized placebo-controlled trial

BACKGROUND: Previous published studies assessed the efficacy of bupropion in smoking cessation only in North American populations of smokers. Results of therapeutic drug trials are not always directly applicable in other populations. AIMS: To confirm the efficacy of bupropion in smoking cessation in European smokers. DESIGN: A multi-centre, randomized, double-blind placebo-controlled trial. SETTING: Seventy-four smoking cessation out-patient clinics in France. PARTICIPANTS: The study included 509 smokers motivated to quit smoking. Intervention Subjects were randomized to either slow-release bupropion 150 mg b.i.d. (B) or to placebo (Pl) in a 2 : 1 ratio, treated for 7 weeks, and followed-up for 26 weeks. MEASUREMENTS: Main outcome measure: 6 months' point prevalence abstinence, determined by self-report and expired air carbon monoxide measurement. Secondary outcome measures: weeks 4-7 and weeks 4-26 continuous abstinence rates, craving, withdrawal symptoms, weight and cigarette consumption in smokers unable to quit. Adverse events were recorded systematically. FINDINGS: Six months' point prevalence abstinence rates were 31% and 16%[odds ratio = 2.3, confidence interval (CI) 95%: 1.4-3.7] in the B and Pl groups, respectively. Continuous abstinence rates were 41% (B) and 21% (P) with OR = 2.5 (CI 95%: 1.6-3.9) for weeks 4-7, and 25% (B) and 13% (P) with OR = 2.2 (CI 95%: 1.3-3.6) for weeks 4-26, respectively. Craving decreased significantly more with B than with Pl during treatment period, but there was no difference for total withdrawal symptoms score. Abstinent subjects gained significantly less weight at week 7 with B than with Pl. Low level of nicotine dependence, high motivation, absence of smoking-related disease, long duration of previous quit attempts, male gender, low level of current alcohol problems and living as a couple were predictive of successful cessation. With the exception of marital status, no interaction was observed between any of these predictive factors and the efficacy of bupropion. More of those who continued smoking in the B group than the P group reduced their consumption by at least 50%. CONCLUSIONS: Sustained-release bupropion is efficacious as an aid to smoking cessation in European smokers. No outcome predictors were identified that might indicate that certain subgroups of smokers would benefit more than others from treatment with bupropion.     

Effectiveness of braces designed using computer-aided design and manufacturing (CAD/CAM) and finite element simulation compared to CAD/CAM only for the conservative treatment of adolescent idiopathic scoliosis: a prospective randomized controlled trial

Purpose

Clinical assessment of immediate in-brace effect of braces designed using CAD/CAM and FEM vs. only CAD/CAM for conservative treatment of AIS, using a randomized blinded and controlled study design.

Methods

Forty AIS patients were prospectively recruited and randomized into two groups. For 19 patients (control group), the brace was designed using a scan of patient’s torso and a conventional CAD/CAM approach (CtrlBrace). For the 21 other patients (test group), the brace was additionally designed using finite element modeling (FEM) and 3D reconstructions of spine, rib cage and pelvis (NewBrace). The NewBrace design was simulated and iteratively optimized to maximize the correction and minimize the contact surface and material.

Results

Both groups had comparable age, sex, weight, height, curve type and severity. Scoliosis Research Society standardized criteria for bracing were followed. Average Cobb angle prior to bracing was 27° and 28° for main thoracic (MT) and lumbar (L) curves, respectively, for the control group, while it was 33° and 28° for the test group. CtrlBraces reduced MT and L curves by 8° (29 %) and 10° (40 %), respectively, compared to 14° (43 %) and 13° (46 %) for NewBraces, which were simulated with a difference inferior to 5°. NewBraces were 50 % thinner and had 20 % less covering surface than CtrlBraces.

Conclusion

Braces designed with CAD/CAM and 3D FEM simulation were more efficient and lighter than standard CAD/CAM TLSO’s at first immediate in-brace evaluation. These results suggest that long-term effect of bracing in AIS may be improved using this new platform for brace fabrication.

Trial registration

NCT02285621.

     

Patient dose considerations for routine megavoltage cone-beam CT imaging

Megavoltage cone-beam CT (MVCBCT), the recent addition to the family of in-room CT imaging systems for image-guided radiation therapy (IGRT), uses a conventional treatment unit equipped with a flat panel detector to obtain a three-dimensional representation of the patient in treatment position. MVCBCT has been used for more than two years in our clinic for anatomy verification and to improve patient alignment prior to dose delivery. The objective of this research is to evaluate the image acquisition dose delivered to patients for MVCBCT and to develop a simple method to reduce the additional dose resulting from routine MVCBCT imaging. Conventional CT scans of phantoms and patients were imported into a commercial treatment planning system (TPS: Phillips, Pinnacle) and an arc treatment mimicking the MVCBCT acquisition process was generated to compute the delivered acquisition dose. To validate the dose obtained from the TPS, a simple water-equivalent cylindrical phantom with spaces for MOSFETs and an ion chamber was used to measure the MVCBCT image acquisition dose. Absolute dose distributions were obtained by simulating MVCBCTs of 9 and 5 monitor units (MU) on pelvis and head and neck patients, respectively. A compensation factor was introduced to generate composite plans of treatment and MVCBCT imaging dose. The article provides a simple equation to compute the compensation factor. The developed imaging compensation method was tested on routinely used clinical plans for prostate and head and neck patients. The quantitative comparison between the calculated dose by the TPS and measurement points on the cylindrical phantom were all within 3%. The dose percentage difference for the ion chamber placed in the center of the phantom was only 0.2%. For a typical MVCBCT, the dose delivered to patients forms a small anterior-posterior gradient ranging from 0.6 to 1.2 cGy per MVCBCT MU. MVCBCT acquisitions in the pelvis and head and neck areas deliver slightly more dose than current portal imaging but render soft tissue information for positioning. Overall, the additional dose from daily 9 MU MVCBCTs of prostate patients is small compared to the treatment dose (<4%). Dose-volume histograms of compensated plans for pelvis and head and neck patients imaged daily with MVCBCT showed no additional dose to the target and small increases at low doses. The results indicate that the dose delivered for MVCBCT imaging can be precisely calculated in the TPS and therefore included in the treatment plan. This allows simple plan compensations, such as slightly reducing the treatment dose, to minimize the total dose received by critical structures from daily positioning with MVCBCT. The proposed compensation factor reduces the number of MU per treatment beam per fraction. Both the number of fractions and the beam arrangement are kept unchanged. Reducing the imaging volume in the cranio-caudal direction can further reduce the dose delivered for MVCBCT. This is a useful feature to eliminate the imaging dose to the eyes or to focus on a specific region of interest for alignment.     

Osteogenic progenitor cells in rat bone marrow stromal populations exhibit self-renewal in culture

Marrow stromal cells are a heterogeneous population, comprising a variety of lineages including osteogenic cells. In the presence of ascorbic acid, sodium beta-glycerophosphate, and dexamethasone, rat bone marrow stromal cells form discrete nodules of mineralized, bonelike tissue. We used nodule formation by rat bone marrow stromal cells to assay for the self-renewal capacity of osteogenic progenitor cell populations. Cultures were subcultured every 5 days up to six times. Osteogenesis was assayed from second to sixth subcultures by counting the number and measuring the areas of mineralized nodules formed in cultures grown with 10(-8) mol/L dexamethasone. Nodule number and area decreased progressively between second and sixth subcultures. Alkaline phosphatase activity associated with individual cells and measured videodensitometrically decreased exponentially between the second and sixth subculture. The number of cells with alkaline phosphatase activity also decreased with progressive subculturing. The proportions of 3H-thymidine-labeled cells after continuous labeling from the beginning of the culture period showed 90% labeling for cells with alkaline phosphatase activity and fibroblastlike cells. Cultures labeled for only the first 3 days exhibited higher labeling of alkaline phosphatase-positive cells than fibroblastlike cells (P less than .05). Cultures that were flash-labeled at the end of the culture period demonstrated low labeling indices for cells with alkaline phosphatase activity and up to 10-fold higher labeling indices for fibroblastlike cells. Separate cultures treated with a cytocidal dose of high specific activity 3H-thymidine did not form nodules. These results indicate that osteogenic progenitor cells or another cell type required for nodules to develop must divide early in culture if nodule formation is to occur, and that osteoprogenitor cells express a limited capacity for self-renewal.     

Upfront DPYD Genotyping and Toxicity Associated with Fluoropyrimidine-Based Concurrent Chemoradiotherapy for Oropharyngeal Carcinomas: A Work in Progress

Simple SummaryThe combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas. DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines. Upfront screening for the DPYD*2A allele has been available in the province of Québec, Canada, since March 2017. This study aimed to determine the effect of upfront genotyping on the incidence of grade ≥3 toxicities. We included 181 patients in the analysis. Extended screening for three supplemental at-risk DPYD variants was also retrospectively performed in August 2019. The DPYD*2A, c.2846A>T and c.1236G>A polymorphisms were associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can thus identify patients in whom 5-FU-related toxicity should be avoided.AbstractBackground: 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related toxicities in patients harboring at-risk DPYD polymorphisms. Methods: The studied population included consecutive patients with locoregionally advanced oropharyngeal carcinoma treated with carboplatin and 5-FU-based CRT one year before and after the implementation of upfront DPYD*2A genotyping. We aimed to determine the effect of DPYD genotyping on grade ≥3 toxicities. Results: 181 patients were analyzed (87 patients before and 94 patients following DPYD*2A screening). Of the patients, 91% (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of six additional patients with alternative DPYD variants (two c.2846A>T and four c.1236G>A mutations). Grade ≥3 toxicities occurred in 71% of the patients before DPYD*2A screening versus 62% following upfront genotyping (p = 0.18). When retrospectively analyzing additional non-DPYD*2A variants, the relative risks for mucositis (RR 2.36 [1.39–2.13], p = 0.0063), dysphagia (RR 2.89 [1.20–5.11], p = 0.019), and aspiration pneumonia (RR 13 [2.42–61.5)], p = 0.00065) were all significantly increased. Conclusion: The DPYD*2A, c.2846A>T, and c.1236G>A polymorphisms are associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can identify patients in whom 5-FU-related toxicity should be avoided.     

Carbamates and Benzodiazepines have different effects on detoxified alcoholics' sleep polygraphy

We showed in a previous work that tetrabamate (molecular complex composed of febarbamate, difebarbamate and phenobarbital) induced delta sleep in alcoholics, compared to diazepam. The aim of the present study was to test the hypothesis that the effect of tetrabamate on delta sleep was due to the carbamate part of the drug. We compared the effects of diazepam, tetrabamate, and meprobamate on 32 recently detoxified alcoholic inpatients' sleep polygraphy. Except for sleep duration and wake after sleep onset, tetrabamate and meprobamate groups had a similar polygraphic profile, in contrast to diazepam. Compared to the diazepam group, tetrabamate and meprobamate groups showed a decrease in stage 2 and an increase in stage 4. The effects of tetrabamate and meprobamate on stage 4, compared to diazepam, had comparable amplitudes. We propose the hypothesis that carbamates exert their action on delta sleep through an antagonist effect on 5HT-2 or histamine H1 receptors.