Voice Analysis to Differentiate the Dopaminergic Response in People With Parkinson's Disease.

Humans' voice offers the widest variety of motor phenomena of any human activity. However, its clinical evaluation in people with movement disorders such as Parkinson's disease (PD) lags behind current knowledge on advanced analytical automatic speech processing methodology. Here, we use deep learning-based speech processing to differentially analyze voice recordings in 14 people with PD before and after dopaminergic medication using personalized Convolutional Recurrent Neural Networks (p-CRNN) and Phone Attribute Codebooks (PAC). p-CRNN yields an accuracy of 82.35% in the binary classification of ON and OFF motor states at a sensitivity/specificity of 0.86/0.78. The PAC-based approach's accuracy was slightly lower with 73.08% at a sensitivity/specificity of 0.69/0.77, but this method offers easier interpretation and understanding of the computational biomarkers. Both p-CRNN and PAC provide a differentiated view and novel insights into the distinctive components of the speech of persons with PD. Both methods detect voice qualities that are amenable to dopaminergic treatment, including active phonetic and prosodic features. Our findings may pave the way for quantitative measurements of speech in persons with PD.

High-Resolution Motor State Detection in Parkinson's Disease Using Convolutional Neural Networks.

Patients with advanced Parkinson's disease regularly experience unstable motor states. Objective and reliable monitoring of these fluctuations is an unmet need. We used deep learning to classify motion data from a single wrist-worn IMU sensor recording in unscripted environments. For validation purposes, patients were accompanied by a movement disorder expert, and their motor state was passively evaluated every minute. We acquired a dataset of 8,661 minutes of IMU data from 30 patients, with annotations about the motor state (OFF,ON, DYSKINETIC) based on MDS-UPDRS global bradykinesia item and the AIMS upper limb dyskinesia item. Using a 1-minute window size as an input for a convolutional neural network trained on data from a subset of patients, we achieved a three-class balanced accuracy of 0.654 on data from previously unseen subjects. This corresponds to detecting the OFF, ON, or DYSKINETIC motor state at a sensitivity/specificity of 0.64/0.89, 0.67/0.67 and 0.64/0.89, respectively. On average, the model outputs were highly correlated with the annotation on a per subject scale (r = 0.83/0.84; p < 0.0001), and sustained so for the highly resolved time windows of 1 minute (r = 0.64/0.70; p < 0.0001). Thus, we demonstrate the feasibility of long-term motor-state detection in a free-living setting with deep learning using motion data from a single IMU.

A Multi-Layer Gaussian Process for Motor Symptom Estimation in People With Parkinson's Disease.

The assessment of Parkinson's disease (PD) poses a significant challenge, as it is influenced by various factors that lead to a complex and fluctuating symptom manifestation. Thus, a frequent and objective PD assessment is highly valuable for effective health management of people with Parkinson's disease (PwP). Here, we propose a method for monitoring PwP by stochastically modeling the relationships between wrist movements during unscripted daily activities and corresponding annotations about clinical displays of movement abnormalities. We approach the estimation of PD motor signs by independently modeling and hierarchically stacking Gaussian process models for three classes of commonly observed movement abnormalities in PwP including tremor, (non-tremulous) bradykinesia, and (non-tremulous) dyskinesia. We use clinically adopted severity measures as annotations for training the models, thus allowing our multi-layer Gaussian process prediction models to estimate not only their presence but also their severities. The experimental validation of our approach demonstrates strong agreement of the model predictions with these PD annotations. Our results show that the proposed method produces promising results in objective monitoring of movement abnormalities of PD in the presence of arbitrary and unknown voluntary motions, and makes an important step toward continuous monitoring of PD in the home environment.

Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo.

Mitochondrial redox signals have a central role in neuronal physiology and disease. Here we describe a new optical approach to measure fast redox signals with single-organelle resolution in living mice that express genetically encoded redox biosensors in their neuronal mitochondria. Moreover, we demonstrate how parallel measurements with several biosensors can integrate these redox signals into a comprehensive characterization of mitochondrial function. This approach revealed that axonal mitochondria undergo spontaneous 'contractions' that are accompanied by reversible redox changes. These contractions are amplified by neuronal activity and acute or chronic neuronal insults. Multiparametric imaging reveals that contractions constitute respiratory chain-dependent episodes of depolarization coinciding with matrix alkalinization, followed by uncoupling. In contrast, permanent mitochondrial damage after spinal cord injury depends on calcium influx and mitochondrial permeability transition. Thus, our approach allows us to identify heterogeneity among physiological and pathological redox signals, correlate such signals to functional and structural organelle dynamics and dissect the underlying mechanisms.

Prioritizing diabetes nutrition recommendations based on evidence.

Recommendations for carbohydrate, protein, dietary fat, micronutrients, and alcohol are classified according the level of available evidence based on the American Diabetes Association evidence grading system. The grading of recommendations can be used to prioritize nutrition care as those graded A are the most robust and can be emphasized first. Strong evidence suggests that the total amount of carbohydrate in meals (or snacks) is more important than the source or type. All persons with diabetes can benefit from basic information concerning carbohydrate foods, portion sizes, and amounts to select for meals. Patients on intensive (physiological) insulin therapy or insulin pumps can adjust their bolus insulin according to the amount of carbohydrate they plan to ingest. Therefore, the first priority is to identify a food/meal plan that can be used to integrate an insulin regimen into the person's lifestyle. Nutrition therapy for type 2 diabetes progresses from prevention of obesity or weight gain to improving insulin resistance to contributing to improved metabolic control. Research supports nutrition therapy as an effective therapy in reaching treatment goals for glycemia, lipids, and blood pressure. Monitoring of outcomes is essential to assess the outcomes of lifestyle interventions and/or to determine if changes in medication(s) are necessary.

Evolution of diabetes medical nutrition therapy.

Research supports the importance of medical nutrition therapy in achieving diabetes treatment goals. For persons requiring insulin therapy, the first priority is to integrate an insulin regimen into the patient's lifestyle. For type 2 diabetes, the priority is to focus on lifestyle strategies (that is, nutrition and exercise) that will improve metabolic outcomes at diagnosis and as the disease progresses. Patients with diabetes need nutrition recommendations that are supported by scientific evidence and that can be easily understood and translated into everyday life. To achieve positive outcomes, a coordinated team effort that provides continued education and support is essential.

Carbohydrate and diabetes: is the source or the amount of more importance?

There have been two approaches to examining the effects of carbohydrate on postprandial glycemia: 1) studies designed to determine the glycemic response of foods containing carbohydrate, regardless of the source, i.e., starch, sugar, or fiber (glycemic index [GI] of carbohydrates), and 2) studies comparing the glycemic response to equivalent amounts of starches or sugars. A number of food factors determine the glycemic response to carbohydrates: food form, digestibility, cooking, sugars, type of starch, presence of antinutrients, and second meal or lente effect. In people with diabetes, the severity of glucose intolerance and premeal glucose concentrations also influence the glycemic response. The GI attempts to classify individual foods (50-g portions) by the extent to which they raise blood glucose levels compared with a standard (reference carbohydrate), initially glucose and in later studies bread. Acute glycemic responses differ, however, when meals containing low GI foods are compared to meals containing high GI foods long term (measured by fructosamine or hemoglobin A1c), the outcomes are mixed. If there is an effect from the GI of foods on glycemia, it is modest at best. In other studies, when sucrose is substituted for a variety of starches--in meals or snacks and both acutely and for up to 6 weeks--the glycemic response is similar if the total amount of carbohydrate is similar. Therefore, the recommendation for persons with diabetes in regard to the glycemic effect of carbohydrates is that the total amount of carbohydrate in meals or snacks is more important than the source or type and is the first priority in the planning of meals or snacks. This has led to the implementation of carbohydrate counting, in which foods are listed as carbohydrate choices based on the amount and not the source of the carbohydrate.

Transcriptional activation of the granulocyte-macrophage colony-stimulating factor receptor gene in cell mutants.

Retroviral insertional mutagenesis has proven to be a powerful in vivo approach for identifying genetic mutations involved in tumorigenesis or developmental abnormalities. Applying this approach to an in vitro system, where experimental design can be readily manipulated, would greatly increase its efficacy. In this study, we sought to determine whether retroviral insertional mutagenesis could be used to isolate cell mutants, in which the transcriptional activation of a receptor gene has occurred. Cells of the myeloid progenitor cell line FDC-P1(M), which do not express the alpha receptor subunit (GMRalpha) for granulocyte-macrophage colony-stimulating factor (GM-CSF), were infected and selected for growth in GM-CSF. Over 100 mutants were isolated at a frequency up to ninefold higher than that of uninfected controls. Expression of GMRalpha in these mutants was confirmed by blocking proliferation with GM-CSF antibodies, detection of high-affinity receptors, and Northern blot analysis. Significantly, in 7/18 mutants analyzed, gross DNA rearrangements had occurred in the GMRalpha locus. These rearrangements were demonstrated to be due to intergenic rearrangements, juxtaposing an active enhancer/promoter upstream of the GMRalpha gene. In one mutant it could be demonstrated that the wild-type allele was also expressed, providing evidence that secondary mutations had occurred. The implications of these results for retroviral insertional mutagenesis are discussed.

Managing obesity in patients with comorbidities.

Type 2 diabetes, cardiovascular disease, and hypertension are comorbities associated with obesity. Treatment and prevention strategies for these comorbidities of obesity are often assumed to be the same-weight loss. Although many persons may lose weight initially, recidivism is a major concern. Therefore, medical nutrition therapy for obese persons with comorbidities should be refocused from weight loss to attaining and maintaining metabolic parameters--normal blood glucose levels, optimal lipid levels, and blood pressure levels within normal limits. Moderate weight loss is only one lifestyle strategy that can be recommended. Research has also supported other lifestyle strategies, including becoming more physically fit. In type 2 diabetes, a restricted energy diet even without weight loss, spacing of meals throughout the day, and fat intake modifications have been shown to improve glycemia. Dyslipidemia can be improved by reducing or changing the fat content of the diet. Blood pressure levels can be reduced by a diet high in fruits and vegetables and low in fat. Research is underway to determine if weight loss can prevent chronic disease; however, once comorbidities are present, lifestyle strategies should be directed toward the improvement of metabolic parameters associated with the comorbidity.

Protein, diabetes, and nephropathy.

Evidence suggests that a low-protein diet (0.8 g/kg) is beneficial in persons with diabetes with the onset of macroalbuminuria. Despite problems with existing studies, preliminary evidence suggests that vegetable proteins are not detrimental to renal function and may be used to supplement or replace animal proteins.

Lifestyle modifications for diabetes management.

Nutrition therapy and physical activity can assist persons with diabetes to achieve metabolic goals. Several lifestyle strategies can be used. Monitoring metabolic parameters, including blood glucose, glycated hemoglobin, lipids, blood pressure, and body weight, as well as assessing for quality of life are essential to determine whether treatment goals are being achieved by lifestyle changes. If not, adjustments in the overall management plan need to be made.

Protein: metabolism and effect on blood glucose levels.

Insulin is required for carbohydrate, fat, and protein to be metabolized. With respect to carbohydrate from a clinical standpoint, the major determinate of the glycemic response is the total amount of carbohydrate ingested rather than the source of the carbohydrate. This fact is the basic principle of carbohydrate counting for meal planning. Fat has little, if any, effect on blood glucose levels, although a high fat intake does appear to contribute to insulin resistance. Protein has a minimal effect on blood glucose levels with adequate insulin. However, with insulin deficiency, gluconeogenesis proceeds rapidly and contributes to an elevated blood glucose level. With adequate insulin, the blood glucose response in persons with diabetes would be expected to be similar to the blood glucose response in persons without diabetes. The reason why protein does not increase blood glucose levels is unclear. Several possibilities might explain the response: a slow conversion of protein to glucose, less protein being converted to glucose and released than previously thought, glucose from protein being incorporated into hepatic glycogen stores but not increasing the rate of hepatic glucose release, or because the process of gluconeogenesis from protein occurs over a period of hours and glucose can be disposed of if presented for utilization slowly and evenly over a long time period.

Effectiveness of medical nutrition therapy provided by dietitians in the management of non-insulin-dependent diabetes mellitus: a randomized, controlled clinical trial.

OBJECTIVE: To assess the effect of medical nutrition therapy (MNT) provided by dietitians on medical and clinical outcomes for adults with non-insulin-dependent diabetes mellitus (NIDDM), and to compare MNT administered according to practice guidelines nutrition care (PGC) to MNT administered with basic nutrition care (BC). DESIGN: A prospective, randomized, controlled clinical trial of two levels of MNT on metabolic control in persons newly diagnosed with or currently under treatment for NIDDM was conducted at diabetes centers in three states (Minnesota, Florida, and Colorado). BC consisted of a single visit with a dietitian; PGC involved an initial visit with a dietitian followed by two visits during the first 6 weeks of the study period. Data were collected at entry to the study and at 3 and 6 months. SUBJECTS: Results are reported for 179 men and women aged 38 to 76 years: 85 assigned randomly to BC and 94 to PGC. This represents 72% of the 247 subjects enrolled. An additional 62 adults with NIDDM at one site who had no contact with a dietitian were identified as a nonrandom comparison group. OUTCOMES: Medical outcome measures included fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and serum lipid levels. Clinical outcomes included weight, body mass index, waist-to-hip ratio, and changes in medical therapy. STATISTICAL ANALYSES: Initial analysis of the discrete variables was done using the chi 2 statistic with Yates' correction. Initial analysis of continuous variables was done by analysis of variance. The changes in variables between time periods were analyzed by paired t test, and comparisons between groups were analyzed using a t test for independent groups. RESULTS: At 6 months, PGC resulted in significant improvements in blood glucose control as indicated by FPG and HbA1c levels and BC resulted in significant improvements in HbA1c level. Participants assigned to the PGC group had a mean FPG level at 6 months that was 10.5% lower than the level at entry, and those in the BC group had a 5.3% lower value. Among subjects who had diabetes for longer than 6 months, those who received PGC had a significantly better HbA1c level at 3 months compared with those receiving BC. The comparison group showed no improvement in glycemic control over a comparable 6 months. PGC subjects had significant improvements in cholesterol values at 6 months, and subjects in both the PGC and the BC groups had significant weight loss. CONCLUSIONS: MNT provided by dietitians resulted in significant improvements in medical and clinical outcomes in both the BC and PGC groups and is beneficial to persons with NIDDM. Persons with a duration of diabetes longer than 6 months tended to do better with PGC than with BC. Because of the upward trend in glucose levels after 3 months, ongoing MNT by dietitians is important for long-term metabolic control.

Cost-effectiveness of medical nutrition therapy provided by dietitians for persons with non-insulin-dependent diabetes mellitus.

OBJECTIVE: To conduct a cost analysis and cost-effectiveness study based on a randomized clinical trial of basic nutrition care (BC) and practice guidelines nutrition care (PGC) provided by dietitians in outpatient clinics. DESIGN: Subjects with non-insulin-dependent diabetes mellitus (NIDDM) from three states (Minnesota, Florida, Colorado) were randomly assigned to a group receiving BC or a group receiving PGC for a 6-month clinical trial. Along with data about medical and clinical outcomes, data about cost resources were collected. The cost-effectiveness of PGC compared with BC was calculated using per-patient costs and glycemic outcomes for the 6 months of the study. A net cost-effectiveness ratio comparing BC and PGC, including the cost savings resulting from changes in medical therapy, was also calculated. SUBJECTS: The study reports on a sample of 179 subjects with NIDDM between the ages of 38 and 76 years who completed the clinical trial. RESULTS: Patients in the PGC group experienced a mean 1.1 +/- 2.8 mmol/L decrease in fasting plasma glucose level 6 months after entry to the study, for a total per-patient cost of $112. PGC costs included one glycated hemoglobin assay used by the dietitian to evaluate nutrition outcomes. Patients in the BC group experienced a mean 0.4 +/- 2.7 mmol/L decrease, for a total per-patient cost of $42. In the PGC group, 17 persons had changes in therapy, which yielded an average 12-month cost savings prorated for all patients of $31.49. In contrast, in the BC group, 9 persons had changes in therapy, for an average 12-month prorated cost savings of $3.13. Each unit of change in fasting plasma glucose level from entry to the 6-month follow-up can be achieved with an investment of $5.75 by implementing BC or of $5.84 by implementing PGC. If net costs are considered (per-patient costs--cost savings due to therapy changes), the cost-effectiveness ratios become $5.32 for BC and $4.20 for PGC, assuming the medical changes in therapy were maintained for 12 months. APPLICATIONS: These findings suggest that individualized nutrition interventions can be delivered by experienced dietitians with a reasonable investment of resources. Cost-effectiveness is enhanced when dietitians are engaged in active decision making about intervention alternatives based on the patient's needs.

Practice guidelines for medical nutrition therapy provided by dietitians for persons with non-insulin-dependent diabetes mellitus. International Diabetes Center.

Nutrition practice guidelines define a systematic approach for medical nutrition therapy (MNT) provided by dietitians and are derived from scientific evidence and expert opinion. Nutrition practice guidelines for persons with non-insulin-dependent diabetes mellitus (NIDDM) can be implemented for those with newly diagnosed or previously diagnosed NIDDM at the first visit to a dietitian for initial or ongoing MNT. The guidelines apply to patients treated with MNT alone, MNT and oral glucose-lowering agents, or MNT and insulin. They provide a framework to assist the dietitian in the assessment, intervention (nutrition prescription, education, goal setting), and evaluation of outcomes for MNT. Minimum referral data for clinical decision making and outcome criteria are defined. Basic nutrition care is defined as one visit with the dietitian. Nutrition practice guidelines care consists of a series of visits with the dietitian. At the second follow-up visit, the dietitian assesses what has been accomplished with the nutrition interventions. If the patient has implemented the nutrition recommendations to the best of his or her ability and has not achieved the treatment goals, the dietitian should notify the physician and recommend that changes in medical management are needed. Ongoing nutrition care is recommended at 6-month to 1-year intervals for both basic and practice guidelines care.

Practice guidelines for nutrition care by dietetics practitioners for outpatients with non-insulin-dependent diabetes mellitus: consensus statement.

In summary, nutrition practice guidelines for dietitians who provide outpatient care for persons with NIDDM provide a roadmap for nutrition care that allows for consistency in individualized care. A field test that compares care according to practice guidelines with usual or basic care can provide evidence, based on medical, education/behavior, and cost outcomes, that practice guidelines are not only reasonable and realistic but also effective.