Adherence of Clinical Practice Guidelines for Oropharyngeal Dysphagia in Parkinson Disease to Trustworthy Standards: A Systematic Survey.

Despite the high prevalence and burden of dysphagia in Parkinson disease (PD), the availability and trustworthiness of clinical practice guidelines (CPGs) regarding its assessment and management remains uncertain. The objective of this study is to appraise the quality of CPGs for dysphagia in PD. We searched OVID Medline, Embase, CINAHL and SpeechBite from January 2011 to July 2023 for guidance documents addressing screening, referral, monitoring, assessment, or management of dysphagia in PD. We additionally conducted an informal search of web pages of relevant professional societies and government organizations. Paired reviewers independently screened studies, and for relevant guidance documents, abstracted data and assessed their quality using the National Guideline Clearinghouse Extent of Adherence to Trustworthy Standards instrument. Thirteen CPGs proved eligible. Of these, eight (62%) were developed by professional societies. Overall, CPGs were deemed low quality. Eleven (85%) CPGs reported funding sources, and nine (69%) reported conflicts of interest. Five (35%) guidance documents included a methodologist, four (30%) included patient partners, four (30%) described study selection processes, and two (15%) clearly described relevant benefits and harms. Regarding dysphagia-specific recommendations, less than half of guidance documents met standards for trustworthiness; six (46%) provided a synthesis of available evidence, eight (54%) specified strength of recommendations, and two (15%) articulated unambiguous recommendations. Limited guidance exists regarding screening, monitoring and referral for dysphagia in PD. Existing guidance frequently fails to meet standards for trustworthiness. International, multidisciplinary, evidence-based practice guidelines with adequate methodological and patient partner involvement are needed.

Dysphagia in Open Partial Horizontal Laryngectomy Type IIa: Quantitative Analysis of Videofluoroscopy using the ASPEKT Method.

Open Partial Horizontal Laryngectomy (OPHL) Type IIa surgery is a conservative surgical technique used in the treatment of laryngeal carcinomas. In this pilot study, we aimed to characterize swallowing function and physiology in a series of patients after OPHL Type IIa surgery through comparison to healthy reference values for quantitative measures for videofluoroscopy. We performed retrospective quantitative analysis of videofluoroscopy recordings of thin liquid swallows for a preliminary sample of 10 male patients. Each videofluoroscopy clip was rated in triplicate by trained blinded raters according to the ASPEKT Method (Analysis of Swallowing Physiology: Events, Kinematics and Timing). This preliminary sample of patients with previous OPHL surgery showed functional airway protection, with only 2 patients showing incomplete laryngeal vestibule closure (LVC) and associated airway invasion. However, the majority of patients (90%) showed prolonged latencies to LVC and upper esophageal sphincter (UES) opening. Prolonged durations of LVC and UES opening were also noted, but these were in the direction of compensation rather than impairment. Reduced pharyngeal area at rest was seen in 70% of the sample, and all patients showed poor pharyngeal constriction. Post-swallow residue was a prominent finding in ≥ 75% of these patients. In particular, reduced or absent constriction of the hypopharynx in the region of the pyriform sinuses was noted as a characteristic of swallowing in this sample. The data from these patients suggest that despite functional airway protection, severe swallowing dysfunction involving poor pharyngeal constriction and bolus clearance may be likely after OPHL surgery.

A Tutorial on Diagnostic Benefit and Radiation Risk in Videofluoroscopic Swallowing Studies.

The videofluoroscopic swallowing study (VFSS) is a key tool in assessing swallowing function. As with any diagnostic procedure, the probable benefits of the study must be weighed against possible risks. The probable benefit of VFSS is an accurate assessment of swallowing function, enabling patient management decisions potentially leading to improved patient health status and quality of life. A possible (though highly unlikely) risk in VFSS is carcinogenesis, arising from the use of ionizing radiation. Clinicians performing videofluoroscopic swallowing studies should be familiar with both sides of the risk benefit equation in order to determine whether the study is medically justified. The intent of this article is to provide the necessary background for conversations about benefit and risk in videofluoroscopic swallowing studies.

Food-Grade Activated Charcoal for Contrast-Enhanced Photoacoustic Imaging of Aspiration: A Phantom Study.

Aspiration pneumonia has the highest attributable mortality of all medical complications post-stroke, or in individuals with progressive neurological diseases. For optimum health outcomes for individuals with dysphagia, a non-invasive and convenient method for objectively detecting aspiration is needed. This study introduces a potential new aspiration screening method based on photoacoustic imaging (PAI), a medical imaging technology that measures the optical contrast of tissue rather than mechanical or elastic properties. In this preliminary study, a tissue-mimicking neck phantom was designed to test the performance of PAI for aspiration screening with a charcoal solution as a contrast agent. A 1064 nm wavelength light source was illuminated on the anterior of the neck phantom to induce the photoacoustic effect. The resulting photoacoustic signal of the charcoal contrast in the mock trachea was detected by a linear transducer array with a 2.25 MHz central ultrasound frequency. The phantom results showed that charcoal solution at 10 mg/ml exhibited strong photoacoustic signals when flowing into the phantom trachea. By overlaying the photoacoustic signals of the charcoal contrast on top of the ultrasound image, we were able to simultaneously visualize the movement of food contrast and a cross-section of tissue structures during mock swallowing. Moreover, we confirmed the ability to detect the flow of charcoal contrast at a small bolus volume of ~ 7 µl through the phantom, suggesting high sensitivity to detect small aspiration events. The study suggests that PAI holds promise to be developed as an aspiration detection tool with charcoal powder as a contrast agent.

Endoscopic evaluation of pharyngeal and laryngeal sensation in patients with chronic obstructive pulmonary disease (COPD): A cross-sectional study.

OBJECTIVE: To describe and compare the findings of endoscopic sensory assessment in COPD patients and healthy controls. DESIGN: A prospective cross-sectional study. SETTING: Otorhinolaryngology outpatient clinic at a university hospital. PARTICIPANTS: 27 adults with COPD and 11 age-matched healthy controls. MAIN OUTCOME MEASURES: Group differences in light touch endoscopic tests of pharyngeal and laryngeal sensation, controlling for pooled salivary secretions in the pharynx and laryngo-pharyngeal reflux as measured by the Reflux Finding Score (RFS). RESULTS: A significant difference in laryngeal sensation was found between the study groups (P = .047), with reduced laryngeal sensation in the COPD patients. Additionally, a significant relationship was found between impaired oropharyngeal sensation and the presence of pooled salivary secretions in the pharynx (P = .018), especially in the pyriform sinuses (P = .012). No differences in the frequency of abnormal RFSs were found between groups. CONCLUSION: Individuals with COPD were significantly more likely to present with impaired laryngeal sensation. Additionally, impaired sensation in the oropharynx was associated with pooled salivary secretions in the pharynx.

The Effect of Lingual Resistance Training Interventions on Adult Swallow Function: A Systematic Review.

Lingual resistance training has been proposed as an intervention to improve decreased tongue pressure strength and endurance in patients with dysphagia. However, little is known about the impact of lingual resistance training on swallow physiology. This systematic review scrutinizes the available evidence regarding the effects of lingual resistance training on swallowing function in studies using Videofluoroscopic Swallowing Studies (VFSS) with adults. Seven articles met the inclusion criteria and underwent detailed review for study quality, data extraction, and planned meta-analysis. Included studies applied this intervention to a stroke and brain injury patient populations or to healthy participants, applied different training protocols, and used a number of outcome measures, making it difficult to generalize results. Lingual resistance training protocols included anterior and posterior tongue strengthening, accuracy training, and effortful press against hard palate with varying treatment durations. VFSS protocols typically included a thin barium stimulus along with one other consistency to evaluate the effects of the intervention. Swallowing measures included swallow safety, efficiency, and temporal measures. Temporal measures significantly improved in one study, while safety improvements showed mixed results across studies. Reported improvements in swallowing efficiency were limited to reductions in thin liquid barium residue in two studies. Overall, the evidence regarding the impact of lingual resistance training for dysphagia is mixed. Meta-analysis was not possible due to differences in methods and outcome measurements across studies. Reporting all aspects of training and details regarding VFSS protocols is crucial for the reproducibility of these interventions. Future investigations should focus on completing robust analyses of swallowing kinematics and function following tongue pressure training to determine efficacy for swallowing function.

Correction to: An Exploratory Study of Hyoid Visibility, Position, and Swallowing-Related Displacement in a Pediatric Population.

This letter notifies the readers of the Dysphagia journal of an error in the original published version of this manuscript, describing hyoid position during swallowing in children using an available pediatric dataset. A previously available open source spreadsheet tool had been used to calculate the position of the hyoid bone on lateral view videofluoroscopic images. An error in the mathematical formula built into the spreadsheet resulted in a reversal of reported results for measures of peak hyoid position in the X and Y planes of measurement. This erratum provides corrections to the results and interpretations of the original manuscript.

Corrigendum to "Challenges to assumptions regarding oral shear rate during oral processing and swallowing based on sensory testing with thickened liquids" [Food Hydrocolloids 84C (2018) 173-180].

[This corrects the article PMC6367734.].

An Exploratory Study of Hyoid Visibility, Position, and Swallowing-Related Displacement in a Pediatric Population.

Hyoid position and swallowing-related displacement has been studied in healthy adults and adults with dysphagia, but research is limited in children. The aim of this study was to investigate feasibility of visualizing and measuring position and swallowing-related displacement of the hyoid bone in children. We explored relationships between hyoid displacement, age and aspiration risk scores. Pediatric swallowing data were extracted from a videofluoroscopy database containing recordings from 133 children aged 9 days to 21 years (mean 36 months, SD 3 years) referred for videofluoroscopy due to concerns regarding their feeding. Children presented with varying etiologies: neurological, structural, respiratory, and other diagnoses. Still shot images were extracted for the frame of hyoid peak position and a frame showing the hyoid at rest. Pixel-based image analysis software was used to measure hyoid position in three directions (X = anterior, Y = superior, XY = hypotenuse) relative to C4 vertebra. Difference between rest and peak position was used to measure hyoid displacement (X, Y and XY). The hyoid was not visible in children < 9 months, but could be reliably visualized and measured in 49 children. Descriptive statistics were collected for hyoid parameters. Age was significantly associated with rest (Y and XY) and peak (Y and XY) hyoid position parameters as well as anterior displacement. No significant associations were observed between hyoid parameters and aspiration risk scores. This study successfully explored hyoid visibility, position and swallowing-related displacement in a pediatric population. Hyoid can be reliably visualized and tracked through videofluoroscopy in children > 9 months of age.

Characterizing the Flow of Thickened Barium and Non-barium Liquid Recipes Using the IDDSI Flow Test.

The use of thickened liquids for dysphagia management has become wide-spread. Videofluoroscopy is commonly used to determine dysphagia severity and to evaluate the effectiveness of interventions, including texture modification, but this requires the use of radio-opaque contrast media. In order for the results of a videofluoroscopy to have validity with respect to confirming swallowing safety and efficiency on different liquid consistencies, it is important to understand the flow characteristics of the contrast media used and how the flow of these stimuli compares to the flow of liquids that are provided outside the assessment context. In this study, we explored the flow characteristics of 20% w/v barium and non-barium stimuli prepared using starch and gum thickeners to reach the slightly, mildly and moderately thick liquid categories defined by the International Dysphagia Diet Standardisation Initiative (IDDSI). Our goal was to identify recipes that would produce stimuli with stable flow properties over a 3 h time frame post mixing. Thickener concentration was titrated to achieve matching flow (i.e., IDDSI Flow Test results within a 1 ml range) across the four stimulus types (non-barium starch, non-barium gum, barium starch, barium gum) within each IDDSI level. The combination of barium and thickeners resulted in further thickening, particularly with starch-based thickening agents. A probe of the influence of refrigeration showed no difference in flow measures between chilled and room temperature stimuli over a 3-h time frame. Overall, recipes with stable flow over three hours were identified for all barium and non-barium liquids tested.

Development of a Non-invasive Device for Swallow Screening in Patients at Risk of Oropharyngeal Dysphagia: Results from a Prospective Exploratory Study.

Oropharyngeal dysphagia is prevalent in several at-risk populations, including post-stroke patients, patients in intensive care and the elderly. Dysphagia contributes to longer hospital stays and poor outcomes, including pneumonia. Early identification of dysphagia is recommended as part of the evaluation of at-risk patients, but available bedside screening tools perform inconsistently. In this study, we developed algorithms to detect swallowing impairment using a novel accelerometer-based dysphagia detection system (DDS). A sample of 344 individuals was enrolled across seven sites in the United States. Dual-axis accelerometry signals were collected prospectively with simultaneous videofluoroscopy (VFSS) during swallows of liquid barium stimuli in thin, mildly, moderately and extremely thick consistencies. Signal processing classifiers were trained using linear discriminant analysis and 10,000 random training-test data splits. The primary objective was to develop an algorithm to detect impaired swallowing safety with thin liquids with an area under receiver operating characteristic curve (AUC) > 80% compared to the VFSS reference standard. Impaired swallowing safety was identified in 7.2% of the thin liquid boluses collected. At least one unsafe thin liquid bolus was found in 19.7% of participants, but participants did not exhibit impaired safety consistently. The DDS classifier algorithms identified participants with impaired thin liquid swallowing safety with a mean AUC of 81.5%, (sensitivity 90.4%, specificity 60.0%). Thicker consistencies were effective for reducing the frequency of penetration-aspiration. This DDS reached targeted performance goals in detecting impaired swallowing safety with thin liquids. Simultaneous measures by DDS and VFSS, as performed here, will be used for future validation studies.

The Relationship between Texture-Modified Diets, Mealtime Duration, and Dysphagia Risk in Long-Term Care.

Many long-term care (LTC) residents have an increased risk for dysphagia and receive texture-modified diets. Dysphagia has been shown to be associated with longer mealtime duration, and the use of texture-modified diets has been associated with reduced nutritional intake. The current study aimed to determine if the degree of diet modification affected mealtime duration and to examine the correlation between texture-modified diets and dysphagia risk. Data were collected from 639 LTC residents, aged 62-102 years. Nine meal observations per resident provided measures of meal duration, consistencies consumed, coughing and choking, and assistance provided. Dysphagia risk was determined by identifying residents who coughed/choked at meals, were prescribed thickened fluids, and/or failed a formal screening protocol. Degree of texture modification was derived using the International Dysphagia Diet Standardization Initiative Functional Diet Scale. There was a significant association between degree of diet modification and dysphagia risk (P < 0.001). However, there was no association between diet modifications and mealtime duration, even when the provision of physical assistance was considered. Some residents who presented with signs of swallowing difficulties were not prescribed a texture-modified diet. Swallowing screening should be performed routinely in LTC to monitor swallowing status and appropriateness of diet prescription. Physical assistance during meals should be increased.

Prevalence and Characteristics Associated with Modified Texture Food Use in Long Term Care: An Analysis of Making the Most of Mealtimes (M3) Project.

Purpose: To describe the prevalence and characteristics of modified-texture food (MTF) consumers when applying standard diet terminology. Methods: Making the Most of Mealtimes (M3) is a cross-sectional multi-site study including 32 long-term care (LTC) homes located in 4 Canadian provinces. Resident characteristics were collected from health records using a defined protocol and extraction form. Since homes used 67 different terms to describe MTFs, diets were recategorized using the International Dysphagia Diet Standardization Initiative Framework as a basis for classification. Results: MTFs were prescribed to 47% (n = 298) of participants (n = 639) and prevalence significantly differed among provinces (P < 0.0001). Various resident characteristics were significantly associated with use of MTFs: dysphagia and malnutrition risk, dementia diagnosis, prescription of oral nutritional supplements; lower body weight and calf circumference; greater need for physical assistance with eating; poor oral health status; and dependence in all activities of daily living. Conclusions: This is the first study that used a diverse sample of LTC residents to determine prevalence of MTF use and described consumers. The prevalence of prescribed MTFs was high and diverse across provinces in Canada. Residents prescribed MTFs were more vulnerable than residents on regular texture diets. These findings add value to our understanding of MTF consumers.

Prevalence of inadequate micronutrient intakes of Canadian long-term care residents.

This study determines the prevalence of inadequate micronutrient intakes consumed by long-term care (LTC) residents. This cross-sectional study was completed in thirty-two LTC homes in four Canadian provinces. Weighed and estimated food and beverage intake were collected over 3 non-consecutive days from 632 randomly selected residents. Nutrient intakes were adjusted for intra-individual variation and compared with the Dietary Reference Intakes. Proportion of participants, stratified by sex and use of modified (MTF) or regular texture foods, with intakes below the Estimated Average Requirement (EAR) or Adequate Intake (AI), were identified. Numbers of participants that met these adequacy values with use of micronutrient supplements was determined. Mean age of males (n 197) was 85·2 (sd 7·6) years and females (n 435) was 87·4 (sd 7·8) years. In all, 33 % consumed MTF; 78·2 % (males) and 76·1 % (females) took at least one micronutrient pill. Participants on a MTF had lower intake for some nutrients (males=4; females=8), but also consumed a few nutrients in larger amounts than regular texture consumers (males=4; females =1). More than 50 % of participants in both sexes and texture groups consumed inadequate amounts of folate, vitamins B6, Ca, Mg and Zn (males only), with >90 % consuming amounts below the EAR/AI for vitamin D, E, K, Mg (males only) and K. Vitamin D supplements resolved inadequate intakes for 50-70 % of participants. High proportions of LTC residents have intakes for nine of twenty nutrients examined below the EAR or AI. Strategies to improve intake specific to these nutrients are needed.

Creation and Initial Validation of the International Dysphagia Diet Standardisation Initiative Functional Diet Scale.

OBJECTIVE: To assess consensual validity, interrater reliability, and criterion validity of the International Dysphagia Diet Standardisation Initiative Functional Diet Scale, a new functional outcome scale intended to capture the severity of oropharyngeal dysphagia, as represented by the degree of diet texture restriction recommended for the patient. DESIGN: Participants assigned International Dysphagia Diet Standardisation Initiative Functional Diet Scale scores to 16 clinical cases. Consensual validity was measured against reference scores determined by an author reference panel. Interrater reliability was measured overall and across quartile subsets of the dataset. Criterion validity was evaluated versus Functional Oral Intake Scale (FOIS) scores assigned by survey respondents to the same case scenarios. Feedback was requested regarding ease and likelihood of use. SETTING: Web-based survey. PARTICIPANTS: Respondents (N=170) from 29 countries. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Consensual validity (percent agreement and Kendall τ), criterion validity (Spearman rank correlation), and interrater reliability (Kendall concordance and intraclass coefficients). RESULTS: The International Dysphagia Diet Standardisation Initiative Functional Diet Scale showed strong consensual validity, criterion validity, and interrater reliability. Scenarios involving liquid-only diets, transition from nonoral feeding, or trial diet advances in therapy showed the poorest consensus, indicating a need for clear instructions on how to score these situations. The International Dysphagia Diet Standardisation Initiative Functional Diet Scale showed greater sensitivity than the FOIS to specific changes in diet. Most (>70%) respondents indicated enthusiasm for implementing the International Dysphagia Diet Standardisation Initiative Functional Diet Scale. CONCLUSIONS: This initial validation study suggests that the International Dysphagia Diet Standardisation Initiative Functional Diet Scale has strong consensual and criterion validity and can be used reliably by clinicians to capture diet texture restriction and progression in people with dysphagia.

Challenges to assumptions regarding oral shear rate during oral processing and swallowing based on sensory testing with thickened liquids.

For people with dysphagia, or difficulty swallowing, thickened liquids are used to slow bolus flow to make them easier to control. For these liquids, the oral shear rate of 50 s-1 has been adopted as the standard at which viscosity measurements are taken. However, there is evidence to suggest that other shear rates may be more appropriate to model the processes in the mouth and throat. This research compared the sensory and rheological properties of xanthan gum, guar gum, and carboxymethyl cellulose thickened liquids that had been matched for apparent viscosity at 50 s-1 to assess the validity of the current shear rate standard. Properties of gums were observed at various viscosity levels based on the International Dysphagia Diet Standardisation Initiative (IDDSI) framework. Textural sensory characteristics of samples were quantified using magnitude estimation scaling and a trained descriptive panel, while rheological measurements were taken at shear rates of 1 to 1000 s-1. Perceived slipperiness of the gums was found to be driven by thickness level at low viscosity levels, but affected by the shear thinning behavior of the gums at higher viscosity levels. Although the liquids had been matched for apparent viscosity at 50 s-1, panelists could distinguish both the perceived viscosities of the gums and their ease of swallowing, suggesting that 50 s-1 is neither appropriate to model the oral nor pharyngeal shear rates. A single oral shear rate could not be predicted from the data, and it is proposed that panelists evaluated oral viscosity using different methods at different viscosity levels. Based on the sensory data, the pharyngeal shear rate during swallowing appears to lie above 50 s-1.

Sensory characteristics of liquids thickened with commercial thickeners to levels specified in the International Dysphagia Diet Standardization Initiative (IDDSI) framework.

Sensory characteristics are important for the acceptance of thickened liquids, but those of liquids thickened to the new standards put forth by the International Dysphagia Diet Standardization Initiative (IDDSI) are unknown. This research sought to identify and rate the perception of important sensory properties of liquids thickened to levels specified in the IDDSI framework. Samples were made with water, with and without added barium sulfate, and were thickened with a cornstarch or xanthan gum based thickener. Samples were characterized using projective mapping/ultra-flash profiling to identify important sample attributes, and then with trained descriptive analysis panels to characterize those attributes in non-barium and barium thickened liquids. Three main groups of attributes were observed. Taste and flavor attributes decreased in intensity with increasing thickener. Thickener specific attributes included graininess and chalkiness for the cornstarch thickened samples, and slipperiness for the xanthan gum samples. Within the same type of thickener, ratings of thickness-related attributes (perceived viscosity, adhesiveness, manipulation, and swallowing) at different IDDSI levels were significantly different from each other. However, in non-barium samples, cornstarch samples were perceived as thicker than xanthan gum samples even though they had similar apparent viscosities at 50 s-1. On the other hand, the two thickeners had similar perceived thickness in the barium samples even though the apparent viscosities of cornstarch samples were higher than those of the xanthan gum samples. In conclusion, IDDSI levels can be distinguished based on sensory properties, but these properties may be affected by the type of thickener and medium being thickened.

A Preliminary Videofluoroscopic Investigation of Swallowing Physiology and Function in Individuals with Oculopharyngeal Muscular Dystrophy (OPMD).

Dysphagia is one of the primary symptoms experienced by individuals with Oculopharyngeal Muscular Dystrophy (OPMD). However, we lack understanding of the discrete changes in swallowing physiology that are seen in OPMD, and the resulting relationship to impairments of swallowing safety and efficiency. This study sought to describe the pathophysiology of dysphagia in a small sample of patients with OPMD using a videofluoroscopy examination (VFSS) involving 3 × 5 mL boluses of thin liquid barium (22% w/v). The aim of this study is to extend what is known about the pathophysiology of dysphagia in OPMD, by quantifying changes in swallow timing, kinematics, safety, and efficiency, measured from VFSS. This study is a secondary analysis of baseline VFSS collected from 11 adults (4 male), aged 48-62 (mean 57) enrolled in an industry-sponsored phase 2 therapeutic drug trial. Blinded raters scored the VFSS recordings for safety [Penetration-Aspiration Scale (PAS)], efficiency [Normalized Residue Ratio Scale (NRRS)], timing [Pharyngeal Transit Time (PTT), Swallow Reaction Time (SRT), Laryngeal Vestibule Closure Reaction Time (LVCrt), Upper Esophageal Sphincter Opening Duration (UESD)], and kinematics (hyoid movement, pharyngeal constriction, UES opening width). Impairment thresholds from existing literature were defined to characterize swallowing physiology and function. Further, Fisher's Exact tests and Pearson's correlations were used to conduct a preliminary exploration of associations between swallowing physiology (e.g., kinematics, timing) and function (i.e., safety, efficiency). Compared to published norms, we identified significant differences in the degree of maximum pharyngeal constriction, hyoid movement distance and speed, as well as degree and timeliness of airway closure. Unsafe swallowing (PAS ≥ 3) was seen in only 3/11 patients. By contrast, clinically significant residue (i.e., NRRS scores ≥ 0.09 vallecular; ≥ 0.2 pyriform) was seen in 7/11 patients. Fisher's Exact tests revealed associations between prolonged SRT, PTT, and unsafe swallowing. Weak associations were also identified between post-swallow residue and poor pharyngeal constriction during the swallow. Detailed analysis of swallowing physiology in this series of adults with OPMD aligns with impaired muscular function (e.g., reduced pharyngeal constriction, incomplete laryngeal vestibule closure) associated with the disease, and primary functional challenges with swallow efficiency. Further work is needed to explore a greater range of food and liquid textures, and to identify additional physiological mechanisms underlying swallowing impairment in OPMD.