Retinopathy develops at similar glucose levels but higher HbA1c levels in people with black African ancestry compared to white European ancestry: evidence for the need to individualize HbA1c interpretation.

AIMS: To examine the association of HbA1c and glucose levels with incident diabetic retinopathy according to black African or white European ancestry. METHODS: In this retrospective cohort study of 202 500 US Veterans with diabetes (2000-2014), measures included HbA1c , outpatient random serum/plasma glucose, and incident retinopathy [conversion from negative to ≥2 positive evaluations (ICD-9 codes), without a subsequent negative]. RESULTS: At baseline, the study population had a mean age of 59.3 years, their mean BMI was 31.9 kg/m2 , HbA1c level was 57 mmol/mol (7.4%) and glucose level was 8.8 mmol/l, and 77% were of white European ancestry (white individuals) and 21% of black African ancestry (black individuals). HbA1c was 0.3% higher in black vs white individuals (P < 0.001), adjusting for baseline age, sex, BMI, estimated glomerular filtration rate (eGFR), haemoglobin, and average systolic blood pressure and glucose. Over 11 years, incident retinopathy occurred in 9% of black and 7% of white individuals, but black individuals had higher HbA1c , glucose, and systolic blood pressure (all P < 0.001); adjusted for these factors, incident retinopathy was reduced in black vs white individuals (P < 0.001). The population incidence of retinopathy (7%) was associated with higher mean baseline HbA1c in individuals with black vs white ancestry [63 mmol/mol (7.9%) vs 58 mmol/mol (7.5%); P < 0.001)], but with similar baseline glucose levels (9.0 vs 9.0 mmol/l; P = 0.660, all adjusted for baseline age, sex and BMI). CONCLUSIONS: Since retinopathy occurs at higher HbA1c levels in black people for a given level of average plasma glucose, strategies may be needed to individualize the interpretation of HbA1c measurements.

Impact of mismatches in HbA1c vs glucose values on the diagnostic classification of diabetes and prediabetes.

AIMS: To determine whether HbA1c mismatches (HbA1c levels that are higher or lower than expected for the average glucose levels in different individuals) could lead to errors if diagnostic classification is based only on HbA1c levels. METHODS: In a cross-sectional study, 3106 participants without known diabetes underwent a 75-g oral glucose tolerance test (fasting glucose and 2-h glucose) and a 50-g glucose challenge test (1-h glucose) on separate days. They were classified by oral glucose tolerance test results as having: normal glucose metabolism; prediabetes; or diabetes. Predicted HbA1c was determined from the linear regression modelling the relationship between observed HbA1c and average glucose (mean of fasting glucose and 2-h glucose from the oral glucose tolerance test, and 1-h glucose from the glucose challenge test) within oral glucose tolerance test groups. The haemoglobin glycation index was calculated as [observed - predicted HbA1c ], and divided into low, intermediate and high haemoglobin glycation index mismatch tertiles. RESULTS: Those participants with higher mismatches were more likely to be black, to be men, to be older, and to have higher BMI (all P<0.001). Using oral glucose tolerance test criteria, the distribution of normal glucose metabolism, prediabetes and diabetes was similar across mismatch tertiles; however, using HbA1c criteria, the participants with low mismatches were classified as 97% normal glucose metabolism, 3% prediabetes and 0% diabetes, i.e. mostly normal, while those with high mismatches were classified as 13% normal glucose metabolism, 77% prediabetes and 10% diabetes, i.e. mostly abnormal (P<0.001). CONCLUSIONS: Measuring only HbA1c could lead to under-diagnosis in people with low mismatches and over-diagnosis in those with high mismatches. Additional oral glucose tolerance tests and/or fasting glucose testing to complement HbA1c in diagnostic classification should be performed in most individuals.

Racial differences in performance of HbA1c for the classification of diabetes and prediabetes among US adults of non-Hispanic black and white race.

AIM: To characterize differences between black and white people in optimal HbA1c thresholds for diagnoses of diabetes and prediabetes. METHODS: Data were included from the National Health and Nutrition Examination Survey, 2005-2014. Black and white adults (age 18-70 years) who underwent an oral glucose tolerance test and had available fasting plasma glucose, 2-h plasma glucose and HbA1c measurements were eligible for inclusion. Diabetes or prediabetes status was defined by fasting plasma glucose and 2-h plasma glucose using American Diabetes Association criteria. Classification of diabetes, prediabetes and dysglycaemia by HbA1c was evaluated for a range of HbA1c thresholds, with optimal thresholds defined as those values that maximized the sum of sensitivity and specificity (Youden's index). RESULTS: In 5324 black (32.3%) and white (67.7%) individuals, Youden's index (optimal) thresholds for HbA1c were ≥42 mmol/mol (6.0%) and ≥39 mmol/mol (5.7%) for discriminating diabetes vs non-diabetes, ≥ 44 mmol/mol (6.2%) and ≥39 mmol/mol (5.7%) for discriminating diabetes vs prediabetes (excluding normoglycaemia), ≥39 mmol/mol (5.7%) and ≥37 mmol/mol (5.5%) for discriminating dysglycaemia vs normoglycaemia, and ≥39 mmol/mol (5.7%) and ≥37 mmol/mol (5.5%) for discriminating prediabetes vs normoglycaemia (excluding diabetes), in black and white people, respectively. CONCLUSIONS: Consistently higher optimal HbA1c thresholds in black people than in white people suggest a need to individualize HbA1c relative to glucose levels if HbA1c is used to diagnose diabetes and prediabetes.

SSB taxes and diet quality in US preschoolers: estimated changes in the 2010 Healthy Eating Index.

BACKGROUND: Taxing sugar-sweetened beverages (SSBs) has been proposed as a strategy to combat child obesity. Yet it is unclear how a tax on SSBs might influence the overall quality of diet in preschool children. Thus, we use simulated price increases and the 2010 Healthy Eating Index (HEI-2010) to explore the relationship between SSB taxes and diet quality in preschool children. METHODS: Price and purchase data from the 2009-2012 Nielsen Homescan Panel and a two-part marginal effects model were used to estimate relative changes in purchases with a 20% increase in the price of SSBs. Demand elasticities were applied to dietary intake data for children ages 2-5 years from the National Health and Nutrition Examination Survey (2009-2010 and 2011-2012) to estimate the impact of a 20% SSB tax on dietary intake and quality (HEI-2010). RESULTS: A 20% increase in the price of SSBs was associated with lower total caloric intake (-28 kcal d-1 , p < 0.01), caloric intake from juice drinks (-20 kcal d-1 , p < 0.01), added sugars (-4.1 servings d-1 , p = 0.03), refined grains (-0.63 servings d-1 , p < 0.01) and total meat (-0.56 servings d-1 , p < 0.01). Beneficial decreases in empty calories and refined grains were offset by unfavourable changes in fatty acid profile, total protein, vegetables and fruit, such that total HEI scores (0-100 range) were not meaningfully changed with a 20% increase in SSB price (difference: -0.85, p < 0.01). CONCLUSIONS: A 20% tax on SSBs could decrease caloric intake, and intakes of added sugars and SSBs, but may not improve diet quality as an isolated intervention among US preschool children.

In vivo markers of inflammatory response in recent-onset schizophrenia: a combined study using [(11)C]DPA-713 PET and analysis of CSF and plasma.

Several lines of evidence suggest aberrant immune response in schizophrenia, including elevated levels of cytokines. These cytokines are thought to be produced by activated microglia, the innate immune cells of the central nervous system. However, increase in translocator protein 18 kDa (TSPO), a marker of activated glia, has not been found in patients with chronic schizophrenia using second-generation radiotracers and positron emission tomography (PET)-based neuroimaging. In this study we focused on patients with recent onset of schizophrenia (within 5 years of diagnosis). Quantified levels of TSPO in the cortical and subcortical brain regions using the PET-based radiotracer [(11)C]DPA-713 were compared between the patients and healthy controls. Markers of inflammation, including interleukin 6 (IL-6), were assessed in the plasma and cerebrospinal fluid (CSF) in these participants. We observed no significant change in the binding of [(11)C]DPA-713 to TSPO in 12 patients with recent onset of schizophrenia compared with 14 controls. Nevertheless, the patients with recent onset of schizophrenia showed a significant increase in IL-6 in both plasma (P<0.001) and CSF (P=0.02). The CSF levels of IL-6 were significantly correlated with the levels of IL-6 in plasma within the total study population (P<0.001) and in patients with recent onset of schizophrenia alone (P=0.03). Our results suggest that increased levels of IL-6 may occur in the absence of changed TSPO PET signal in the brains of medicated patients with recent onset of schizophrenia. Future development of PET-based radiotracers targeting alternative markers of glial activation and immune response may be needed to capture the inflammatory signature present in the brains of patients with early-stage disease.

Ten-year beverage intake trends among US preschool children: rapid declines between 2003 and 2010 but stagnancy in recent years.

BACKGROUND: It has been previously reported that total energy intake among US preschool children (ages 2-5 years) decreased between 2003-2004 and 2009-2010. However, little is known about how intakes of beverages among US preschoolers (ages 2-5 years) changed from 2003-2004 to 2011-2012. OBJECTIVES: This paper examines changes in intakes of key beverages during this period, as well as how eating location (at home or away from home) and source (store vs. others) may have contributed to these changes. METHODS: Cross-sectional day one dietary data among children ages 2-5 years from the National Health and Nutrition Examination Survey 2003-2004, 2005-2006, 2007-2008, 2009-2010 and 2011-2012 were used. Survey-weighted mean intakes by survey year, eating location and source were computed for total sugar-sweetened beverages (SSBs), milks, 100% juice, low/no-calorie beverages, 10 key beverages, total beverages and total foods. Means were compared using two-tailed z-tests with Bonferroni corrections (α < 0.05). RESULTS: Between 2003-2004 and 2011-2012, among 2-5 year olds, total caloric intake fell by 132 kcal d(-1) , with intakes of beverages falling by 55 kcal d(-1) . Decreases in intakes of total SSBs (-57 kcal d(-1) ), fruit-flavoured or juice drinks containing <100% juice (juice drinks) (-37 kcal d(-1) ), caloric soft drinks (-13 kcal d(-1) ) and >1% fat, low-sugar milk (-42 kcal d(-1) ) were among the major changes. By eating location, total beverage intake at home fell by 73 kcal d(-1) . By source, total beverage intake from stores fell by 106 kcal d(-1) . Changes in intakes occurred primarily between 2003-2004 and 2009-2010, as there were no significant differences in beverage intakes between 2009-2010 and 2011-2012. Intakes of total calories (+49 kcal d(-1) ) and calories from foods (+53 kcal d(-1) ) trended upward between 2009-2010 and 2011-2012, but changes were not significant. CONCLUSIONS: These findings suggest improvements in the diets of preschoolers between 2003-2004 and 2009-2010, of which stores were a major contributor.

Resistance to botulinum toxin injections for spasmodic dysphonia.

A known complication of botulinum toxin injections in the treatment of dystonia has been the occasional development of resistance. This has been seen primarily with patients who receive injections for torticollis. We report on 2 patients who, after several years of receiving injections for spasmodic dysphonia, developed clinical resistance by failing to have expected voice improvement after receiving laryngeal reinjection. One of the 2 patients demonstrated antibodies to botulinum toxin by mouse neutralization bioassay. The second patient had negative bioassay results but had no clinical response to the test toxin injection of facial muscles. These cases demonstrate that, although uncommon, resistance to botulinum toxin injections can occur in the treatment of spasmodic dysphonia. We offer suggestions to limit this complication.

Advances and refinements in phonosurgery.

Scientific discovery, technological advances, and improved outcomes assessment have resulted in advances and refinements in phonosurgery. Three areas of substantial evolution are phonomicrosurgery, laryngeal framework surgery, and the use of implantable materials in vocal folds. Discovery of the importance of the superficial layers of the lamina propria has led to increased use of more limited medial microflap approaches and less frequent use of the classic lateral cordotomy flap approach. Alternative approaches to managing vocal fold scarring defects have addressed the separation of body and cover and provided suitable lamina propria replacement. Approaches to sulcus vocalis have been refined to address type II (linear vergeture) and type III (focal invasive pit) sulcus, where there is loss of lamina propria, while still recognizing the common nonpathological type I (physiological) sulcus. Technological advancements such as photodynamic therapy, tuned dye lasers, and laryngeal microdebridement have augmented the armamentarium for mechanical removal of laryngeal papillomata. Careful infusion-assisted microexcision and adjunctive medical management have been refined and made more effective. Laryngeal framework surgery has embraced the development of Silastic, hydroxylapatite, expanded polytetrafluoroethylene, and titanium shims. Anatomical studies have helped to improve operative precision and safety, and have led to inventive variations in arytenoid repositioning that improve closure of the posterior subunit. Vocal fold augmentation by injection has been facilitated by innovative use of the rigid telescope and intraoperative videostroboscopy. Anatomical studies have focused on the infrafold region and rheological studies have attempted to match viscoelastic properties of injectable substances to those of vocal fold tissues. Alloplastic materials such as Teflon have been largely supplanted by newer bioimplantables such as fat, collagen, and fascia.

Muscle fiber-type changes induced by botulinum toxin injection in the rat larynx.

This study examined muscle fiber-type alterations after single or multiple botulinum toxin (BT) injections to better understand possible morphologic changes induced by therapeutic BT injections in patients with spasmodic dysphonia. Muscle fiber staining was accomplished in rat intrinsic laryngeal muscles with antibodies to specific myosin heavy chains. Results indicated that the typical baseline distributions of type II muscle fibers (ie, types IIa, IIb, IIx, and IIL) were altered by BT injection, while no change was observed in type I fibers. Embryonic fibers were observed only along the needle insertion site at 7 days post BT injection. Although inferences from these animal data to human neuromuscular function must be made with caution, our findings provide insight into the possible cellular and molecular changes characterizing BT-injected muscles.

Influence of computed tomography on pretherapeutic tumor staging in head and neck cancer patients.

Refinements in radiographic techniques have resulted in increased use of radiographic studies in the evaluation of patients with head and neck cancer over the past 20 years. To assess the impact of such studies, we compared tumor clinical stages based solely on physical-examination findings with those obtained with the addition of CT findings. This study was accomplished through case review of 81 head and neck cancer patients who underwent CT after preliminary TNM-stage assignment as determined on the basis of physical examination alone. In this cohort, 44 patients (54%) had a change in assigned clinical stage. We reviewed individual anatomic sites to determine where CT was found to be most useful in modifying tumor stage. Changes in tumor and nodal stage were found across all major sites of the head and neck. Tumors of the hypopharynx were the most likely to change stage (90%) on the basis of CT findings, whereas tumors of the glottic larynx were least likely to undergo a change in stage (16%). The therapeutic implications of these findings are discussed in the context of the published literature.

Physiologic assessment of botulinum toxin effects in the rat larynx.

OBJECTIVE: Botulinum toxin (BT) is a currently used treatment for spasmodic dysphonia (SD) and other related focal dystonias. The goal of this study is to provide a basis for using the rat larynx to objectively assess physiological and histological effects of BT. STUDY DESIGN: Dosages and volumes of BT injection were varied and three physiological parameters were measured. These measures included: optical density of PAS-stained laryngeal muscle after electrical stimulation, which is an indirect measure of denervation, spontaneous laryngeal muscle activity, and laryngeal movement. METHODS: A new microlaryngoscopic technique was developed, which made it possible to observe and manipulate the rat larynx endoscopically. Laryngeal movement and electromyographic (EMG) measures were made prior to injection and 3 days following BT injections of various dosages and volumes. Optical density measures were made 3 days after injection. RESULTS: Significant reductions in vocal fold motion and spontaneous laryngeal muscle activity as a function of increased BT dosage were observed. In addition, the optical density of PAS-stained laryngeal muscle after electrical stimulation was increased following BT injection. Significant volume effects in optical density were observed in the lateral thyroarytenoid and lateral cricoarytenoid muscles on the contralateral side. CONCLUSIONS: The rat laryngeal model is suitable for assessing BT effects. In addition, the three physiological variables provided useful and reliable measures of laryngeal function. It is the authors' intention to use the rat laryngeal model to further examine the physiological and histological effects of BT with the goal of developing new methods for the treatment of patients with SD and other focal dystonias.

Increased acute and chronic mitotic activity in rat laryngeal muscles after botulinum toxin injection.

OBJECTIVES: To characterize the acute and chronic cellular effects of botulinum toxin (BT) injection into rat laryngeal muscles. A complete characterization of these effects is important because patients with focal dystonias of the head and neck are commonly treated with BT injection. Further, potential muscular changes in the larynx must be carefully delineated owing to the critical phonatory and airway protective functions of these muscles. STUDY DESIGN: The acute and chronic cellular effects of BT injection were studied using 5'-bromo 2'-deoxyuridine (BrdU) following single and repeated BT injection into rat laryngeal muscles. BrdU is incorporated into mitotically active nuclei such that changes in cell proliferative behavior following BT injection can be monitored. RESULTS: Increased mitotic activity was detected in the tissue samples studied following BT injection. Differences in the times of the peak distribution of BrdU-labeled cells in each laryngeal muscle were observed. This may be related to the diffusion effects of BT. Prolonged muscle fiber changes, including splitting, were also observed as the result of repeated BT injection. CONCLUSIONS: The results of this study suggest that BT may induce a proliferative response in muscle tissue.

The histologic fate of autologous collagen injected into the canine vocal fold.

Collagen is a functionally essential component of the five-layered structure of the vocal fold. Soluble bovine collagen has previously been shown to be an effective injectable bioimplant for vocal fold defects, paralysis, and, especially, scarred larynges. Although bovine collagen appears to be well tolerated, the concern for possible adverse immunologic responses has deterred approval from the Food and Drug Administration for its clinical use in the larynx. Currently we are investigating the use of injectable autologous collagen for vocal fold augmentation. The purpose of this study is to examine the histologic fate of autologous collagen injected into the canine vocal fold at multiple intervals after injection. An ellipse of skin measuring 3 x 6 cm was harvested from each of three dogs and processed into a naturally cross-linked injectable solution of collagen (Autologen). This autologous collagen was injected into one vocal fold and a control injection of buffer solution was injected contralaterally. The injections were well tolerated and no dog appeared to suffer any immediate or delayed ill effects. The dog larynges were harvested 1, 3, and 6 months after collagen injection and examined grossly and histologically. Injected autologous collagen material persisted in these experimental animals and appeared to be well tolerated. Based on this preliminary study, we anticipate autologous collagen to be at least as suitable as bovine chemically cross-linked collagen as an injectable bioimplant for vocal fold augmentation. It may also have the advantage of added safety and stability.

Planned postradiotherapy neck dissection in patients with advanced head and neck cancer.

BACKGROUND: Metastatic neck nodes in patients with squamous cell carcinoma of the head and neck are most commonly managed by surgery, radiotherapy, or combined-modality therapy. For combined-modality cases, the sequencing of surgery and radiotherapy is generally guided by which modality is considered preferable for treatment of the primary tumor. A postradiotherapy neck dissection is often considered for those patients with > N1 disease in which the primary is treated with radiotherapy alone. METHODS: Between February 1991 and October 1995, 25 patients with node-positive squamous cell carcinoma of the head and neck were treated with planned unilateral (n = 22) or bilateral (n = 3) neck dissection following high-dose radiotherapy. The primary tumor sites included: tongue base (n = 11), tonsil (n = 6), nasopharynx (n = 3), pyriform sinus (n = 2), supraglottic larynx, (n = 1), soft palate (n = 1), and unknown head and neck primary (n = 1). The specific nodal stage breakdown of the 28 individual neck dissections (25 patients) was N1 (n = 1), N2A (n = 5), N2B (n = 15), N3 (n = 7). RESULTS: Nineteen of the 28 neck dissections (68%) demonstrated no evidence of residual carcinoma. Of the nine positive neck dissections, six revealed malignant cells in a single nodal echelon. The 1- and 2-year rate of neck control in all 25 patients was 100% and 93%, respectively. The 1- and 2-year disease-specific survival for all 25 patients was 83% and 60%, respectively. With a minimum follow-up of 2 years, 64% of the 25 patients remain alive with no evidence of disease or dead of non-cancer causes. CONCLUSION: In this series of postradiotherapy neck dissections, two thirds of the dissections demonstrated no evidence of residual tumor (19/28, or 68%). However, there was not a direct correlation between pretreatment nodal size (neck staging), radiation dose delivered, and the likelihood of achieving a cancer-free neck dissection. Only one of 28 postradiotherapy neck dissections identified tumor outside of nodal stations II-IV. The predictable pattern of residual disease in pathologically positive cases suggests that a selective neck dissection encompassing levels II-IV may be appropriate in a majority of patients.

An anatomic study of the rat larynx: establishing the rat model for neuromuscular function.

The gross and microscopic anatomy of the rat larynx was studied with particular attention to myology and neuromuscular structures to further validate it as a model to evaluate morphologic and functional changes induced by botulinum injection. A laryngeal alar cartilage (LAIC), alar cricoarytenoid (ACA) muscle, and a superior cricoarytenoid muscle (SCA) were identified as anatomic structures not previously described. Two portions (medial and lateral) of the thyroarytenoid muscle (TA) were distinguished. The function of the ACA was suggested to be similar to the aryepiglottis muscle in humans and the function of the SCA was suggested to be similar to the human interarytenoid muscle. The predominant pattern of motor endplate (MEP) distribution in rat laryngeal muscles (posterior cricoarytenoid, lateral cricoarytenoid, cricothyroid, and SCA) was to have MEPs concentrated mostly at the midbelly of muscle where they were distributed throughout the cross-sectional area of the midbelly. The TA and ACA differed from this pattern. The lateral TA had MEPs concentrated at the anterior third of its belly and those of the medial TA were located at the midbelly. Motor endplates in the ACA were located mostly at the posterior portion of muscle. Muscle fiber-typing showed subtle differences between the intrinsic laryngeal muscles. Fast fibers were predominant in the rat laryngeal muscles. This study supports the expanded use of rats in studies of laryngeal neuromuscular function and disease in humans.

Transoral electromyographic recordings in botulinum toxin-injected rat larynges.

Objective assessment of muscle function following botulinum toxin injections in laryngeal muscles is difficult in human subjects. We developed a rat laryngeal model for the study of botulinum toxin injection. A new laryngoscopic technique has made it possible to observe the rat larynx endoscopically and to obtain electromyographic measurements during and after injection of toxin. The electromyographic interference pattern, fibrillation potentials, and vocal fold movement were used for analyzing dose and volume effects of injected toxin. We conclude that the lowest dosage able to produce the maximal duration of functional laryngeal impairment is 0.07 U in a volume of 0.4 microL. This model will enable us to obtain physiologic and histologic parameters that can be used to assess the selection of optimal treatment regimens with botulinum toxin for the treatment of patients with spasmodic dysphonia.

Manual circumlaryngeal therapy for functional dysphonia: an evaluation of short- and long-term treatment outcomes.

Manual circumlaryngeal therapy (manual laryngeal musculoskeletal tension reduction) was used to treat 25 consecutive functional dysphonia patients. Pre- and post-treatment audio recordings of connected speech and sustained vowel samples were submitted to auditory-perceptual and acoustical analysis to assess the immediate and long-term effects of a single treatment session. To complement audio recordings, subjects were interviewed in follow-up regarding the stability of treatment effects. Pre- and post-treatment comparisons demonstrated significant voice improvements. No significant differences were observed between post-treatment measures, suggesting that vocal gains were maintained. Interviews revealed 68% of subjects reported occasional partial recurrences, typically less than 4 days in duration, which resolved spontaneously. These results replicate and extend previous research suggesting the utility of manual circumlaryngeal therapy for functional voice disorders.

Correlation between vocal functions and glottal measurements in patients with unilateral vocal fold paralysis.

Observations and analysis of glottal characteristics are critical in choosing the best modality for surgery in patients with unilateral vocal fold paralysis (UVP). This study suggests that multiple glottal characteristics influence the vocal product in patients with UVP. In addition to the horizontal position of the paralyzed vocal fold (deviation from the midline), the glottal area, degree of bowing of the paralyzed and contralateral vocal folds, maximum separation between vocal folds, compensatory glottal maneuvers, and the vertical glottic closure plane significantly influenced the quality of the voice. Clinicians should be aware of these observations to facilitate treatment planning and assessment of the results of surgical procedures used to improve voice quality in cases of UVP.