Prediction of continuous and discrete kinetic parameters in horses from inertial measurement units data using recurrent artificial neural networks.

Vertical ground reaction force (GRFz) measurements are the best tool for assessing horses' weight-bearing lameness. However, collection of these data is often impractical for clinical use. This study evaluates GRFz predicted using data from body-mounted IMUs and long short-term memory recurrent neural networks (LSTM-RNN). Twenty-four clinically sound horses, equipped with IMUs on the upper-body (UB) and each limb, walked and trotted on a GRFz measuring treadmill (TiF). Both systems were time-synchronised. Data from randomly selected 16, 4, and 4 horses formed training, validation, and test datasets, respectively. LSTM-RNN with different input sets (All, Limbs, UB, Sacrum, or Withers) were trained to predict GRFz curves or peak-GRFz. Our models could predict GRFz shapes at both gaits with RMSE below 0.40 N.kg-1. The best peak-GRFz values were obtained when extracted from the predicted curves by the all dataset. For both GRFz curves and peak-GRFz values, predictions made with the All or UB datasets were systematically better than with the Limbs dataset, showing the importance of including upper-body kinematic information for kinetic parameters predictions. More data should be gathered to confirm the usability of LSTM-RNN for GRFz predictions, as they highly depend on factors like speed, gait, and the presence of weight-bearing lameness.

Improving gait classification in horses by using inertial measurement unit (IMU) generated data and machine learning.

For centuries humans have been fascinated by the natural beauty of horses in motion and their different gaits. Gait classification (GC) is commonly performed through visual assessment and reliable, automated methods for real-time objective GC in horses are warranted. In this study, we used a full body network of wireless, high sampling-rate sensors combined with machine learning to fully automatically classify gait. Using data from 120 horses of four different domestic breeds, equipped with seven motion sensors, we included 7576 strides from eight different gaits. GC was trained using several machine-learning approaches, both from feature-extracted data and from raw sensor data. Our best GC model achieved 97% accuracy. Our technique facilitated accurate, GC that enables in-depth biomechanical studies and allows for highly accurate phenotyping of gait for genetic research and breeding. Our approach lends itself for potential use in other quadrupedal species without the need for developing gait/animal specific algorithms.

Fraser syndrome without cryptophthalmos: Two cases.

Fraser syndrome (MIM#219000) is an autosomal recessive disorder, characterized by the association of cryptophthtalmos, syndactyly of the four extremities, urinary tract abnormalities and laryngo-tracheal anomalies. This condition is due to homozygous or compound heterozygous mutations in the FRAS/FREM complex genes: FRAS1, FREM2 and GRIP1. Here we report two atypical cases of Fraser syndrome due to mutations in the FRAS1 gene without cryptophthalmos. The first proband had syndactyly of three extremities, bilateral nostril coloboma, dysplastic ears with bilateral conductive hearing loss, blepharophimosis and lacrimal duct abnormalities. FRAS1 sequencing identified two pathogenic compound heterozygous variants: a nonsense variant in exon 70 and a missense variant in exon 24. The second proband had membranous syndactyly of the four extremities, left renal agenesis, laryngeal and ano-rectal malformations, dysplastic ears and bilateral conductive hearing loss. FRAS1 sequencing identified a pathogenic homozygous variant in the last exon of the gene. This first description of molecularly confirmed cases with Fraser syndrome without cryptophthalmos could contribute to further delineation of the clinical spectrum of Fraser syndrome, especially for possible phenotypically milder cases. Larger cohorts are required to try to refer the hypothesis of genotype-phenotype correlation.

Genetic Obesity and Bariatric Surgery Outcome in 1014 Patients with Morbid Obesity.

BACKGROUND: Mutations in the leptin-melanocortin pathway genes are known to cause monogenic obesity. The prevalence of these gene mutations and their effect on weight loss response after bariatric surgery are still largely unknown. OBJECTIVE: To determine the prevalence of genetic obesity in a large bariatric cohort and evaluate their response to bariatric surgery. METHODS: Mutation analysis of 52 obesity-associated genes. Patient inclusion criteria were a BMI > 50 kg/m2, an indication for revisional surgery or an early onset of obesity (< 10 years of age). RESULTS: A total of 1014 patients were included, of whom 30 (3%) were diagnosed with genetic obesity, caused by pathogenic heterozygous mutations in either MC4R, POMC, PCSK1, SIM1, or PTEN. The percentage total body weight loss (%TBWL) after Roux-en-Y gastric bypass (RYGB) surgery was not significantly different for patients with a mutation in MC4R, POMC, and PCSK1 compared with patients lacking a molecular diagnosis. Of the confirmed genetic obesity cases, only patients with MC4R mutations receiving a sleeve gastrectomy (SG) showed significantly lower %TBWL compared with patients lacking a molecular diagnosis, during 2 years of follow-up. CONCLUSIONS: In this cohort of morbid obese bariatric patients, an estimated prevalence of monogenic obesity of 3% is reported. Among these patients, the clinical effects of heterozygous mutations in POMC and PCSK1 do not interfere with the effectiveness of most commonly performed bariatric procedures within the first 2 years of follow-up. Patients with MC4R mutations achieved superior weight loss after primary RYGB compared with SG.

[Genetic obesity: new diagnostic options]. / Genetische obesitas.

- Obesity is an important risk factor for morbidity and premature death, as well as a contributing factor to psychosocial problems. The incidence of obesity has increased dramatically over the last few decades.- Obesity is considered to be a multifactorial condition in which both environmental factors and genetic factors play a part.- In approximately 5% of patients with morbid obesity, a monogenic cause can be identified. Mutations in the MC4R gene are the most frequently occurring monogenic cause of obesity.- The department of Genetics at the VU University Medical Center Amsterdam offers morbidly obese patients a diagnostic analysis of 50 obesity-associated genes. - An underlying obesity-associated genetic defect can influence patient response to certain treatments. Therefore, if the gene defect is known, it can be taken into account when considering treatment options.- The understanding of the genetics of obesity will significantly contribute to research into the development of personalized treatment options.

Validation of distal limb mounted inertial measurement unit sensors for stride detection in Warmblood horses at walk and trot.

BACKGROUND: Inertial measurement unit (IMU) sensor-based techniques are becoming more popular in horses as a tool for objective locomotor assessment. OBJECTIVES: To describe, evaluate and validate a method of stride detection and quantification at walk and trot using distal limb mounted IMU sensors. STUDY DESIGN: Prospective validation study comparing IMU sensors and motion capture with force plate data. METHODS: A total of seven Warmblood horses equipped with metacarpal/metatarsal IMU sensors and reflective markers for motion capture were hand walked and trotted over a force plate. Using four custom built algorithms hoof-on/hoof-off timing over the force plate were calculated for each trial from the IMU data. Accuracy of the computed parameters was calculated as the mean difference in milliseconds between the IMU or motion capture generated data and the data from the force plate, precision as the s.d. of these differences and percentage of error with accuracy of the calculated parameter as a percentage of the force plate stance duration. RESULTS: Accuracy, precision and percentage of error of the best performing IMU algorithm for stance duration at walk were 28.5, 31.6 ms and 3.7% for the forelimbs and -5.5, 20.1 ms and -0.8% for the hindlimbs, respectively. At trot the best performing algorithm achieved accuracy, precision and percentage of error of -27.6/8.8 ms/-8.4% for the forelimbs and 6.3/33.5 ms/9.1% for the hindlimbs. MAIN LIMITATIONS: The described algorithms have not been assessed on different surfaces. CONCLUSIONS: Inertial measurement unit technology can be used to determine temporal kinematic stride variables at walk and trot justifying its use in gait and performance analysis. However, precision of the method may not be sufficient to detect all possible lameness-related changes. These data seem promising enough to warrant further research to evaluate whether this approach will be useful for appraising the majority of clinically relevant gait changes encountered in practice.

Solving a cold case of haemolysis: back to the basics.

Membrane disorders comprise an important group of inherited haemolytic anaemias. Diagnostic work-up starts with examination of the blood smear, followed by osmotic gradient ektacytometry. In special cases DNA analysis is performed to confirm the diagnosis. For this purpose a next-generation sequencing-based method has been developed. The combination of these techniques established the correct diagnosis in a case of haemolytic anaemia of unknown cause.

A double hit implicates DIAPH3 as an autism risk gene.

Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a 'double-hit' compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.

The neuropathology of hereditary congenital facial palsy vs Möbius syndrome.

OBJECTIVE: To characterize the neuropathology of hereditary congenital facial palsy. METHODS: The authors compared brainstem pathology of three members of one family with autosomal dominant congenital facial palsy to that in three age-matched controls. The neuropathologic findings of the familial patients were compared with those of patients with Möbius syndrome. RESULTS: The authors observed a marked decrease in the number of neurons in the facial motor nucleus with corresponding small facial nerve remnants. In the patients with congenital facial palsy the number of facial motoneurons ranged between 280 and 1,680 as compared to 5,030 and 8,700 for controls. No signs of neuronal degeneration or necrosis with neuronal loss, gliosis, or calcifications were present. There were no other abnormalities of the rhombencephalon and its associated structures. The corticospinal tracts were fully developed. In contrast, Möbius syndrome is part of a more complex congenital anomaly of the posterior fossa with hypoplasia of the entire brainstem, including the traversing long tracts, with signs of neuronal degeneration and other congenital brain abnormalities. CONCLUSION: Neuropathologic findings confirm clinical observations that hereditary congenital facial palsy and Möbius syndrome are two different entities with a different pathogenesis.

Automated attention flags in chronic disease care planning.

OBJECTIVES: To assess the value of computerised decision support in the management of chronic respiratory disease by comparing agreement between three respiratory specialists, general practitioners (care coordinators), and decision support software. METHODS: Care guidelines for two chronic obstructive pulmonary disease projects of the SA HealthPlus Coordinated Care Trial were formulated. Decision support software, Care Plan On-Line (CPOL), was created to represent the intent of these guidelines via automated attention flags to appear in patients' electronic medical records. For a random sample of 20 patients with care plans, decisions about the use of nine additional services (eg, smoking cessation, pneumococcal vaccination) were compared between the respiratory specialists, the patients' GPs and the CPOL attention flags. RESULTS: Agreement among the specialists was at the lower end of moderate (intraclass correlation coefficient [ICC], 0.48; 95% CI, 0.39-0.56), with a 20% rate of contradictory decisions. Agreement with recommendations of specialists was moderate to poor for GPs (kappa, 0.49; 95% CI, 0.33-0.66) and moderate to good for CPOL (kappa, 0.72; 95% CI, 0.55-0.90). CPOL agreement with GPs was moderate to poor (kappa, 0.41; 95% CI, 0.24-0.58). GPs were less likely than specialists or CPOL to decide in favour of an additional service (P<0.001). CPOL was 87% accurate as an indicator of specialist decisions. It gave a 16% false-positive rate according to specialist decisions, and flagged 61% of decisions where GPs said No and specialists said Yes. CONCLUSIONS: Automated decision support may provide GPs with improved access to the intent of guidelines; however, further investigation is required.