Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial.

BACKGROUND: Obesity is strongly associated with prevalence of obstructive sleep apnea (OSA), and weight loss has been shown to reduce disease severity. OBJECTIVE: To investigate whether liraglutide 3.0 mg reduces OSA severity compared with placebo using the primary end point of change in apnea-hypopnea index (AHI) after 32 weeks. Liraglutide's weight loss efficacy was also examined. SUBJECTS/METHODS: In this randomized, double-blind trial, non-diabetic participants with obesity who had moderate (AHI 15-29.9 events h(-1)) or severe (AHI ⩾30 events h(-1)) OSA and were unwilling/unable to use continuous positive airway pressure therapy were randomized for 32 weeks to liraglutide 3.0 mg (n=180) or placebo (n=179), both as adjunct to diet (500 kcal day(-1) deficit) and exercise. Baseline characteristics were similar between groups (mean age 48.5 years, males 71.9%, AHI 49.2 events h(-1), severe OSA 67.1%, body weight 117.6 kg, body mass index 39.1 kg m(-2), prediabetes 63.2%, HbA1c 5.7%). RESULTS: After 32 weeks, the mean reduction in AHI was greater with liraglutide than with placebo (-12.2 vs -6.1 events h(-1), estimated treatment difference: -6.1 events h(-1) (95% confidence interval (CI), -11.0 to -1.2), P=0.0150). Liraglutide produced greater mean percentage weight loss compared with placebo (-5.7% vs -1.6%, estimated treatment difference: -4.2% (95% CI, -5.2 to -3.1%), P<0.0001). A statistically significant association between the degree of weight loss and improvement in OSA end points (P<0.01, all) was demonstrated post hoc. Greater reductions in glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) were seen with liraglutide versus placebo (both P<0.001). The safety profile of liraglutide 3.0 mg was similar to that seen with doses ⩽1.8 mg. CONCLUSIONS: As an adjunct to diet and exercise, liraglutide 3.0 mg was generally well tolerated and produced significantly greater reductions than placebo in AHI, body weight, SBP and HbA1c in participants with obesity and moderate/severe OSA. The results confirm that weight loss improves OSA-related parameters.

Development of a diagnostic rule for identifying radiographic osteoarthritis in people with first metatarsophalangeal joint pain.

OBJECTIVE: To develop a diagnostic rule for the identification of radiographic osteoarthritis (OA) of the first metatarsophalangeal joint (MTPJ) in people with first MTPJ pain. DESIGN: Symptoms and clinical observations were documented in 181 people with first MTPJ pain, and the presence of OA was confirmed using plain film radiography. Diagnostic test statistics were calculated to assess the ability of symptoms and clinical observations to identify radiographic OA. Multivariate logistic regression was used to develop two diagnostic models: a statistically optimal model and a simplified clinical model. RESULTS: Multivariate logistic regression identified pain duration greater than 25 months, the presence of a dorsal exostosis, hard-end feel, crepitus and less than 64° of first MTPJ dorsiflexion to be significantly associated with radiographic OA. The statistically optimal model and clinical model performed similarly, with the areas under the receiver operating characteristics curves being 0.87 (95% confidence interval [CI] 0.81-0.93) and 0.87 (95% CI 0.80-0.93), respectively, and the percentage of cases correctly classified being 86.2 and 85.6, respectively. A cut-off score of ≥3 using the clinical model resulted in a sensitivity of 88%, specificity of 71%, accuracy of 84%, positive likelihood ratio of 3.07 and negative likelihood ratio of 0.17. CONCLUSIONS: In people with first MTPJ pain, a model consisting of five clinical observations can accurately identify the presence or absence of radiographic OA. The application of this diagnostic rule may assist clinical decision making and potentially reduce the need for referral for radiographs.

Foot structure and function in older people with radiographic osteoarthritis of the medial midfoot.

OBJECTIVE: To investigate whether foot structure and dynamic foot function differ between older people with and without radiographically confirmed osteoarthritis (OA) of the talo-navicular joint (TNJ) and navicular-first cuneiform joint (N1(st)CJ). METHOD: Dorso-plantar and lateral weighbearing foot radiographs (right feet) were obtained from 205 older people aged 61-94 years, and the presence of OA in the TNJ and N1(st)CJ was determined using a standardized atlas. Foot structure was assessed using a clinical measure (the arch index [AI]) and two radiographic measures (calcaneal inclination angle [CIA] and calcaneal-first metatarsal angle [C1MA]). Dynamic plantar pressure assessment during walking was undertaken using the Tekscan MatScan system. RESULTS: Thirty-five participants exhibited radiographic OA in the TNJ and N1(st)CJ. There were no significant differences between the groups in relation to age, sex, weight or walking velocity. Compared to those without OA in these joints, those with OA had significantly flatter feet, as evidenced by larger AI (0.26+/-0.05 vs 0.25+/-0.05, P=0.02), smaller CIA (18.5+/-6.3 vs 21.3+/-5.4 degrees, P<0.01) and larger C1MA (137.0+/-9.3 vs 132.4+/-8.0 degrees, P<0.01), and exhibited significantly higher maximum forces in the midfoot (15.2+/-7.3 vs 11.2+/-7.0 kg, P<0.01; 36% increase). CONCLUSION: Older people with radiographic OA of the TNJ and N1(st)CJ exhibit flatter feet and increased loading of the plantar midfoot when walking. Excessive loading of the midfoot may predispose to OA by increasing dorsal compressive forces, although prospective studies are required to confirm whether this relationship is causal.

Radiographic evaluation of foot osteoarthritis: sensitivity of radiographic variables and relationship to symptoms.

OBJECTIVES: To evaluate a radiographic atlas for grading foot osteoarthritis (OA) in relation to the relative sensitivity of different radiographic and views and features, and to examine the relationship between radiographic OA and foot symptoms. METHODS: Weightbearing dorso-plantar (DP) and lateral foot radiographs were obtained from 197 people (126 women and 71 men) aged 62-94 years (mean age 75.9, standard deviation [SD] 6.6). The prevalence of OA in five joints (the first metatarsophalangeal joint [1st MPJ], the first cuneo-metatarsal joint [1st CMJ], the second cuneo-metatarsal joint [2nd CMJ], the navicular-first cuneiform joint [N1st CJ] and the talo-navicular joint [TNJ]) was then determined using both views in combination (as recommended in the atlas), or by using either view in isolation. Associations between radiographic OA in individual foot joints and symptoms were then explored. RESULTS: Joint-specific prevalence of OA using both DP and lateral views was 1st MPJ (42.4%), 1st CMJ (22.6%), 2nd CMJ (60.2%), N1st CJ (39.1%) and TNJ (32.7%). Using only the DP view detected almost all cases of 1st MPJ OA (94.6%), however, the sensitivity was lower for the other joints (31.0-60.7%). Using only the lateral view detected almost all cases of OA (83.8 to 86.9%), with the exception of the 1st MPJ and 1st CMJ (50.9% and 60.7%, respectively). Using either osteophytes (OP) alone or joint space narrowing (JSN) alone showed low sensitivity for all joints (14.3-63.0%), with the exception of OP alone in the DP view for the 1st MPJ and JSN in the lateral view for the 2nd CMJ (83.8% and 84.0%, respectively). Radiographic OA in individual foot joints and the total number of joints affected were both moderately associated with foot symptoms. CONCLUSION: Epidemiological and clinical studies should incorporate observation of both OP and JSN from both DP and lateral views to determine the presence of OA in the foot, as the number of cases detected is reduced if only one radiographic feature or view is used. Radiographic foot OA is common in older people and is moderately associated with foot symptoms.

Radiographic classification of osteoarthritis in commonly affected joints of the foot.

OBJECTIVE: To develop a radiographic atlas for the classification of osteoarthritis (OA) in commonly affected joints of the foot based on observations of osteophytes and joint space narrowing, and to assess its intra- and inter-examiner reliability. DESIGN: Weightbearing dorso-plantar and lateral foot radiographs from people aged over 65 years were examined, and an atlas was developed incorporating characteristic OA features of five foot joints: the first metatarsophalangeal joint, the first cuneo-metatarsal joint (1(st) CMJ), the second cuneo-metatarsal (2(nd) CMJ), the navicular-first cuneiform joint and the talonavicular joint. To assess the reliability of the atlas, two examiners independently rated 50 radiographs on two separate occasions. RESULTS: Observations using the atlas demonstrated moderate to excellent reliability within examiners (percentage agreement from 86 to 99% and weighted kappa from 0.45 to 0.95), and, with the exception of joint space narrowing of the 2(nd) CMJ from the lateral projection, fair to excellent reliability between examiners (percentage agreement from 86 to 97% and weighted kappa from 0.32 to 0.87). Intra-class correlation coefficients for the overall foot OA score (representing the sum of observations for all joints from both feet) ranged between 0.83 and 0.89 for intra-examiner comparisons, and between 0.72 and 0.74 for inter-examiner comparisons. CONCLUSION: Radiographic features of OA in commonly affected foot joints can be documented with high levels of agreement within examiners and moderate levels of agreement between examiners. Provided single examiners or consensus gradings are used, the atlas appears to be a useful tool to assist in the standardization of foot OA assessment for epidemiological and clinical studies.

Plantar pressures are higher under callused regions of the foot in older people.

BACKGROUND: Mechanically induced hyperkeratotic lesions (corns and calluses) are among the most common foot problems in older people. However, their aetiology is not well understood. AIM: To compare the magnitude of pressures generated under the foot when walking in older people with and without plantar calluses. METHODS: Peak plantar pressure measurements were obtained from 292 participants (99 men and 193 women) aged 62-96 years (mean +/- SD 77.6 +/- 6.9) recruited from a retirement village and a university health sciences clinic. Comparisons were then made between callused and noncallused regions of the foot. RESULTS: In total, 151 participants (52%) had at least one plantar callus. Those with plantar calluses were more likely to be female, have moderate to severe hallux valgus, and at least one lesser toe deformity. Regional peak plantar pressures were significantly higher in people with calluses under the second metatarsophalangeal joint (2.34 +/- 0.46 vs. 2.12 +/- 0.51 kg/cm(2), P = 0.001), the third to fifth metatarsophalangeal joints (1.71 +/- 0.46 vs. 1.50 +/- 0.51 kg/cm(2), P = 0.009) and the hallux (1.40 +/- 0.34 vs. 1.23 +/- 0.47 kg/cm(2), P = 0.007) compared with people without calluses under these sites. CONCLUSION: Plantar pressures are significantly higher under callused regions of the foot in older people. Raised pressure may play a role in the development of plantar calluses by accelerating the turnover rate of keratinocytes in the epidermis. Future studies should focus on evaluating the efficacy of pressure-relieving interventions in the prevention and treatment of keratotic disorders in older people.

Zolpidem reduces the sleep disturbance of jet lag.

OBJECTIVE: To determine the degree to which zolpidem 10 mg would reduce the sleep disruption associated with rapid, eastward transatlantic travel. BACKGROUND: Subsequent to rapid transmeridian travel, individuals often complain of jet lag which includes transient disturbances in sleep patterns, alertness, appetite and mood. Disturbed sleep and impaired alertness appear to be the most debilitating symptoms of jet lag. METHODS: This multi-center, double-blind randomized, placebo-controlled, parallel-groups study involved 138 adult (mean age 44.9 years) experienced travelers while on their regular eastward transatlantic assignments originating in the US and crossing 5-9 time zones. Subjects were normal sleepers when not traveling and had to have traveled overseas at least twice during the last 24 months. Subjects were randomized to zolpidem 10 mg or placebo for three (optionally four) consecutive nights starting with the first nighttime sleep after travel. Sleep was assessed with daily questionnaires. RESULTS: A total of 130 subjects completed the study. Compared to placebo, zolpidem was associated with significantly improved sleep (statistically significant differences at nights indicated) longer total sleep time (night 1), reduced number of awakenings (nights 1 and 2), and improved sleep quality (nights 1, 2 and 3). Zolpidem was not associated with improvement in sleep latency. No unexpected or serious adverse events were reported and the most common adverse event was headache in both groups (9.2 and 17.6% for placebo and zolpidem, respectively). CONCLUSION: In seasoned travelers, zolpidem 10 mg produced significant improvement in sleep following rapid transmeridian travel.

Work-shift period and weight change.

The present study was done to determine whether weight gain was more prevalent in workers on late shifts than in those on day shifts. A questionnaire about changes in weight, food intake, exercise, and sleep since starting the job on the current shift was given to day-shift and late-shift (evening and night) hospital workers. Data were analyzed for 85 subjects, 36 of whom worked during the day shift and 49 the late shift. The late-shift group reported a mean weight gain of 4.3 kg, which was greater than the mean weight gain of 0.9 kg for the day-shift group (P = 0.02). There were, however, no significant differences in current body mass index (26.7 +/- 5.4 SD) between groups. There was a trend for late-shift workers to report eating more since beginning the later shift (P = 0.06). When combined with those reporting exercising less (P = NS), this trend became significant (P = 0.04). Late-shift workers reported eating fewer meals (1.9 +/- 0.9 SD) than the day-shift workers (2.5 +/- 0.9; P = 0.002). In addition, late-shift workers reported eating the last daily meal later (mean = 22:27, or 10:27 PM) than day-shift workers (17:52 or 5:52 PM; P < 0.00005). Late-shift workers also reported more naps (P = 0.01) and longer naps (P = 0.05) during the work week than did day-shift workers. The reported changes in eating, exercise, and sleep may contribute to the increased weight gain of late-shift workers.

Quality of life in people with insomnia.

OBJECTIVE: To determine whether subjects with insomnia report greater reductions in quality of life (QoL) than subjects without insomnia when assessed with self-report instruments. METHODS: Questionnaires were completed by individuals recruited through media advertisements and screened with a structured telephone interview. Data obtained from 261 individuals with insomnia (INS group) were compared with those of 101 individuals with no sleep complaint, or controls (CTL group). RESULTS: Subjects in the INS group obtained lower mean sum scores on the Medical Outcomes Study Cognitive Scale than did subjects in the CTL group (25.34 +/- 0.34 vs 31.91 +/- 0.58, t = 9.53, p < 0.0001). The INS group also obtained lower mean scores on all subscales of the SF-36 Questionnaire compared with those in the CTL group (each, p < 0.0001 or lower), indicating impairments across multiple QoL domains. Psychiatric assessment revealed that subjects in the INS group obtained significantly higher mean item scores than subjects in the control group on the Zung Depression Scale (2.22 +/- 0.03 vs. 1.52 +/- 0.03, p < 0.0001) and the Zung Anxiety Scale (1.96 +/- 0.02 vs. 1.40 +/- 0.04, p < 0.0001). In addition, subjects in the INS group reported significantly greater impairments in specific QoL domains on the QoL inventory, and the Work and Daily Activities Inventory. No differences were observed between subjects in the INS group who were receiving treatment for insomnia versus those who were untreated. CONCLUSIONS: The results of this study indicate that significant QoL impairments are associated with insomnia.

The Taskforce 2000 survey on medical education in sleep and sleep disorders.

Previous research has shown evidence of a widening gap between scientific research and clinical teaching in sleep and sleep disorders. To address the deficiencies in current medical education in sleep, the Taskforce 2000 was established by the American Sleep Disorders Association. The present study was undertaken to assess the teaching activities, needs and interests of the membership of the two largest professional sleep societies (American Sleep Disorders Association and Sleep Research Society). Survey instruments included a brief, 5-item postcard survey, which was mailed to all members, followed by an in-depth, 34-item questionnaire, which was completed by 158 respondents from the intitial postcard survey (N = 808). Results indicated that the majority of respondents (65.2%) are currently involved in teaching sleep to medical students or postgraduate trainees, although the average amount of teaching time was only 2.1 hours for undergraduate and 4.8 hours for graduate education in sleep. Teaching of sleep laboratory procedures and clinical evaluation of sleep-disordered patients is limited at either an undergraduate or postgraduate level. The major deficiencies noted were the lack of time in the medical curriculum and the need for better resources and teaching facilities. A large majority of respondents indicated their willingness to be involved in sleep education for physicians, and rated this a high priority for the professional organization.

Postprandial sleep in healthy men.

Twenty-one healthy men between 18 and 30 years of age were studied to determine the effects of midday food intake on sleep. Twelve subjects were administered liquid carbohydrate meals at lunchtime on 2 consecutive days. Subjects slept on 22 of the 24 study days for an average of 93 minutes during 3 hours of postprandial polysomnographic recording. Nine subjects were used as controls and were deprived of a lunch meal. Six of the nine subjects slept for an average of 30 minutes during the postprandial period. This time was significantly shorter than that of subjects in the meal condition (p < 0.005). There was no difference in latency to sleep onset following food intake between the two study groups. The results of this study suggest that lunchtime food intake does not promote the initiation of sleep, but that it does increase the duration of sleep episodes occurring during the postprandial period.

The relationship between daytime and nighttime food intake in an obese night-eater.

Some obese individuals consume food during awakenings from nighttime sleep. Three studies were conducted on a 28-year-old morbidly obese male with chronic sleeping complaints and insignificant weight loss, despite self-reported daily caloric restriction: I. For 3 mo, the subject recorded food intake for 24-h periods. Mean daytime intake was 1286 kcal +/- 386 (SD), and mean nighttime intake was 1036 kcal +/- 487 (SD). Caloric values of daytime and nighttime intake were negatively correlated, r = -0.22, df= 82, p < .05. II. Seven consecutive 24-h food intake recordings were obtained with an automated formula dispenser when the subject was an inpatient on a metabolic ward and received ad libitum formula as his sole food source. Mean daytime intake was 1245 +/- 662 (SD), and mean nighttime intake was 231 +/- 236 (SD). There was a non-significant negative correlation between daytime and nighttime intake, r = -0.32, df = 5, NS. III. The subject underwent polysomnographic studies on 2 non-consecutive nights, following the administration of either a low (600 kcal) or high (1800 kcal) daytime caloric condition. The subject, upon awakening from nighttime sleep, could eat from a platter of sandwich quarters placed at his bedside. The addition of 1200 kcal to daytime intake decreased nighttime intake by 654 kcal, or by 55% of the additional calories delivered during the day. The three studies (I, II, and III) show that daytime food intake can be negatively correlated with nighttime intake, and that daytime intake can influence nighttime intake in a documented obese night-eater.

Postprandial sleep and thermogenesis in normal men.

Twelve normal male subjects were given low- (16.77 kj/kg) and high- (54.49 kj/kg) calorie liquid carbohydrate lunch meals on 4 days, during which measures of sleep EEG, thermogenesis (heat production), core body temperature, and skin surface temperature were obtained. On 2 days subjects were required to remain awake, and on 2 days sleep was allowed. Both meals were administered in each condition. On the days that subjects were instructed to remain awake, thermogenesis was significantly greater following high-calorie meals than low-calorie meals, and both meal conditions produced levels of thermogenesis that were greater than those observed when sleep was allowed. When given the opportunity, 11 of 12 subjects slept following both low- and high-calorie meals. There was no difference between meal conditions in the total minutes or percent of stages 1, 2, 3/4, or rapid eye movement (REM) sleep following meals. However, the onset of postprandial sleep episodes was associated with the peak of the postprandial rise in thermogenesis, and the occurrence of sleep was followed by precipitous and statistically significant declines in thermogenesis and core body temperature, as well as increases in skin surface temperature. These data suggest that postprandial sleep is associated with rises in thermogenesis, and that its occurrence decreases postprandial heat production and body temperature.

Trait-state artifacts and the diagnosis of personality disorders.

The multiaxial nature of DSM-III has stimulated interest in the personality disorders. There are also indications that it has produced an increase in their diagnosis. However, there is clinical and psychometric evidence that a personality evaluation undertaken while a patient is in a dysphoric mental state may distort or misrepresent traits, the so-called trait-state problem in personality assessment. The present study appears to be the first to investigate this phenomenon with a clinical interview rather than with personality tests. It examined the effect of anxiety, depression, and level of global impairment on the diagnosis of personality disorder and the assessment of the criteria for the individual Axis II disorders. Eighty-four patients, most of whom had current Axis I diagnoses, were evaluated by seven experienced clinicians with a new semistructured interview, the Personality Disorder Examination. The sample evidenced a trend toward acknowledging fewer maladaptive personality traits at follow-up than at entry. There was no evidence, however, that anxiety or depression had affected either the diagnosis of a personality disorder or the criteria associated with most of the individual personality disorders.

Early onset and accumulation of REM sleep in depression: a study of the phase-advance hypothesis.

Twenty-two depressed subjects who met criteria for major depressive disorder were grouped according to their initial REM latency. Subjects with short (less than or equal to 60 min) initial REM latency were separated from those with normal (greater than 60 min) initial REM latency. Subjects with short initial REM latency were found to have earlier onsets to at least two subsequent REM periods. The number of minutes of REM sleep accumulated were also plotted against elapsed time after sleep onset. The short-latency group accumulated REM sleep earlier than, but at about the same rate as, the normal latency group. These data support the phase-advance hypothesis of REM sleep in depression.

Subjective ratings of the characteristics and sequelae of good and poor sleep in normals.

Forty normal subjects completed a general screening inventory and two post-sleep questionnaires (PSQs). One PSQ was self-administered after a good night of sleep and one after a poor night of sleep. Responses to a subset of items from both nights were factor-analyzed. Varimax rotation yielded four factors that were interpreted as (a) Dysphoria (b) Cognitive Inefficiency and Sleepiness (c) Motor Impairment and (d) Social Discomfort. Night-to-night comparisons of subjects' estimates of sleep parameters reveal that poor sleep is associated with longer sleep latency, a greater number of awakenings, less total sleep time, and more difficulty initiating and maintaining sleep than good sleep. Mean scores for each generated factor of the PSQ also differed significantly between nights, suggesting that a greater degree of disturbance is associated with poor sleep. The implications of these data as well as the reliability of subjective ratings of sleep quality and post-sleep experiences are discussed.