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PURPOSE: The effect of mandibular advancement device therapy on daytime sleepiness remains unclear. Here, we evaluate the effect of a mandibular advancement device on daytime sleepiness using the Karolinska Sleepiness Scale.

METHODS: We randomized 88 snoring patients with an apnea-hypopnea index < 30 and daytime sleepiness to a mandibular advancement device or a sham device for four months. The Karolinska Sleepiness Scale, which measures grades of sleepiness from 1 (very alert) to 9 (very sleepy), was used for seven consecutive days, four times each day. The results were analyzed with quantile regression at quartiles controlling for baseline, age, body mass index (kg/m²), sex, apnea-hypopnea index, and full-time work.

RESULTS: The Karolinska Sleepiness Scale score was lower with the mandibular advancement device than with the sham device at specific time intervals. The positive effect of mandibular advancement device therapy occurred at wake up and before lunch during the whole week and before lunch on weekdays at the middle quartile. The adjusted differences between the interventions favored mandibular advancement device therapy by almost one unit and normalized the Karolinska Sleepiness Scale scores at wake up and before lunch. In addition, there were positive effects of mandibular advancement device therapy before dinner at the highest quartile during the whole week, on weekdays, and on the weekend.

CONCLUSION: Mandibular advancement devices used for snoring and sleep apnea reduce daytime sleepiness, particularly at wake up and before lunch, but provide some benefit before dinner.

Context: There is a considerable diagnostic delay in acromegaly, contributing to increased morbidity. Voice changes due to orofacial and laryngeal changes are common in acromegaly.

Objective: Our aim was to explore the use of digital voice analysis as a biomarker for acromegaly using broad acoustic analysis and machine learning.

Methods: Voice recordings from patients with acromegaly and matched controls were collected using a mobile phone at Swedish university hospitals. Anthropometric and clinical data and the Voice Handicap Index (VHI) were assessed. Digital voice analysis of a sustained and stable vowel [a] resulted in 3274 parameters, which were used for training of machine learning models classifying the speaker as “acromegaly” or “control.” The machine learning models were trained with 76% of the data and the remaining 24% was used to assess their performance. For comparison, voice recordings of 50 pairs of participants were assessed by 12 experienced endocrinologists.

Results: We included 151 Swedish patients with acromegaly (13% biochemically active and 10% newly diagnosed) and 139 matched controls. The machine learning model identified patients with acromegaly more accurately (area under the receiver operating curve [ROC AUC] 0.84) than experienced endocrinologists (ROC AUC 0.69). Self-reported voice problems were more pronounced in patients with acromegaly than matched controls (median VHI 6 vs 2, P < .01) with higher prevalence of clinically significant voice handicap (VHI ≥20: 22.5% vs 3.6%).

Conclusion: Digital voice analysis can identify patients with acromegaly from short voice recordings with high accuracy. Patients with acromegaly experience more voice disorders than matched controls.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) within sub-Saharan Africa (SSA) is increasing. Despite the pathophysiology of T2D differing by ethnicity and sex, risk stratification and guidelines for the prevention of T2D are generic, relying on evidence from studies including predominantly Europeans. Accordingly, this study aims to develop ethnic-specific and sex-specific risk prediction models for the early detection of dysglycaemia (impaired glucose tolerance and T2D) to inform clinically feasible, culturally acceptable and cost-effective risk management and prevention strategies using dietary modification in SSA and European populations.

METHODS AND ANALYSIS: This multinational collaboration will include the prospective cohort data from two African cohorts, the Middle-Aged Soweto Cohort from South Africa and the Research on Obesity and Diabetes among African Migrants Prospective cohort from Ghana and migrants living in Europe, and a Swedish cohort, the Pre-Swedish CArdioPulmonary bioImage Study. Targeted proteomics, as well as targeted and untargeted metabolomics, will be performed at baseline to discover known and novel ethnic-specific and sex-specific biomarkers that predict incident dysglycaemia in the different longitudinal cohorts. Dietary patterns that explain maximum variation in the biomarker profiles and that associate with dysglycaemia will be identified in the SSA and European cohorts and used to build the prototypes for dietary interventions to prevent T2D. A comparative cost-effectiveness analysis of the dietary interventions will be estimated in the different populations. Finally, the perceptions of at-risk participants and healthcare providers regarding ethnic-specific and sex-specific dietary recommendations for the prevention of T2D will be assessed using focus group discussions and in-depth interviews in South Africa, Ghana, Germany (Ghanaian migrants) and Sweden.

ETHICS AND DISSEMINATION: Ethical clearance has been obtained from all participating sites. The study results will be disseminated at scientific conferences and in journal publications, and through community engagement events and diabetes organisations in the respective countries.

Objective: To explore depot-specific functional aspects of adipose tissue, examining the putative role for menopause and HIV status on insulin sensitivity (SI) and beta-cell function in Black South African women.

Methods: Women (n = 92) from the Middle-Aged Soweto Cohort, including premenopausal HIV-negative women (n = 21); premenopausal women living with HIV (LWH; n = 11); postmenopausal HIV-negative women (n = 42); and postmenopausal women LWH (n = 18) underwent the following tests: body composition (dual-energy x-ray absorptiometry); fasting bloods for sex hormones, inflammation, and adipokines; frequently sampled intravenous glucose tolerance test for SI and beta-cell function (disposition index, DI); abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT) biopsies for cell size, and mRNA expression of adipokines, inflammation, and estrogen receptors (ER).

Results: Depot-specific associations between gene expression and insulin parameters did not differ by HIV or menopause status. Pooled analysis showed significant models for SI (P = .002) and DI (P = .003). Higher SI was associated with lower leptin and CD11c expression in aSAT and higher adiponectin in gSAT. Higher DI was associated with higher aSAT and gSAT expression of adiponectin, lipoprotein lipase, ER alpha, and PPAR gamma, and lower leptin in aSAT. Women LWH had higher expression of adiponectin and lower expression of leptin in both aSAT (P = .002 and P = .005) and gSAT (P = .004 and P = .002), respectively, and a larger proportion of smaller cells in aSAT (P < .001).

Conclusion: Insulin sensitivity and beta-cell function were distinctively associated with aSAT and gSAT. While menopause did not influence these relationships, HIV had a significant effect on adipose tissue, characterized by variations in cell size distribution and transcript levels within the depots.

BACKGROUND: This study examined whether sick leave due to severe stress (stress leave) and duration of leave are associated with future cancer risk.

METHODS: We conducted a matched case-control study using complete-population data from Swedish national registers (2005 to 2018), including 516,678 primary cancer cases and 2,357,433 matched controls. Odds ratios (OR) were calculated by conditional logistic regression and adjusted for pre-specified confounders.

RESULTS: Stress leave of any duration, reported to the Swedish Social Insurance Register, was associated with a slightly increased cancer risk, with the highest risk estimate for 1-30 versus 0 days (adjusted OR 1.05, 95% CI 1.02-1.09). In men, a clear exposure-response trend was present. We observed increased risks of prostate cancer (adjusted OR for > 90 days: 1.10, 95% CI 1.01-1.20) and cervical cancer (adjusted OR for > 90 days: 1.11, 95% CI 1.05-1.17, including cancer in situ). In etiology-based analyses, a positive association was found for smoking-related cancers, and the risk relationship for non-cervical HPV-related cancers was similar to that for cervical cancer. Risk estimates were above one for several types of stress in relation to overall cancer risk, including an exposure-response trend for acute stress reactions (p-trend 4.0 × 10-4) but a null association for post-traumatic stress disorder.

CONCLUSIONS: Stress leave was associated with a modestly higher risk of cancer overall and prostate and cervical cancers specifically. Regardless of whether the link is biological or reflective of lifestyle mediators or for cervical cancer, lower participation in screening, these findings suggest a potential relevance of severe stress for cancer prevention.

Objectives: The adipocyte-derived hormone leptin has been associated with the pathogenesis of cardiovascular disease. The mechanisms underlying this association are unclear but may relate to effects on the vascular endothelium. Our aim was to explore the effects of leptin on endothelial vasomotor and fibrinolytic function in healthy volunteers and patients with coronary artery disease.

Design: The vascular effects of leptin were assessed infusing recombinant human leptin in healthy volunteers during measuring vasomotor response by venous occlusion plethysmography. Additionally, circulating levels of leptin were analysed in relation to endothelial dysfunction in patients with established coronary artery disease.

Results: In healthy male volunteers, intra-arterial infusion of recombinant human leptin (80, 800 and 8,000 ng/min; n = 10) did not affect basal forearm blood flow, plasma tissue plasminogen activator (tPA) or plasminogen activator inhibitor type 1 concentrations (all p > 0.05). However, during concomitant co-infusion with leptin (800 ng/min; n = 10), drug-induced vasodilatation was reduced (p = 0.001), and tPA activity increased (p = 0.002). In patients with coronary artery disease, those with the high plasma leptin levels had reduced drug-induced vasodilatation (p < 0.001), and increased net release of tPA antigen and activity (p < 0.001 and p = 0.03, respectively) compared to those with low levels. The study has been registered retrospectively at Clinical Trials with number NCT04374500.

Conclusion: Intrabrachial leptin infusion did not affect the basal vascular tone, whereas acute and chronic hyperleptinemia was associated with blunted vasoreactivity in healthy volunteers, and in patients with coronary artery disease.

Objective: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.

Methods: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1−7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale.

Results: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.

Conclusion: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted.

Objective: The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1-40 and Aβ1-42 concentrations in individuals with T2D and matched controls.

Methods: Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1-40, Aβ1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1-40 and Aβ1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration.

Results: At baseline, Aβ1-40 and Aβ1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1-40: p = 0.034, Aβ1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group.

Conclusions: Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.

Context: Adrenal insufficiency (AI) is usually diagnosed by low plasma cortisol levels following a short Synacthen test (SST). Most plasma cortisol is bound to corticosteroid-binding globulin, which is increased by estrogen in combined estrogen-progestin oral contraceptives (COCs). Women with AI using COCs are therefore at risk of having an apparently normal plasma cortisol level during SST, which would not adequately reflect AI.

Objective: To test whether salivary cortisol or cortisone during SST is more robust against the COC effect and to calculate the lower reference limits (LRLs) for these to be used as tentative diagnostic cutoffs to exclude AI.

Methods: Forty-one healthy women on COCs and 46 healthy women without exogenous estrogens performed an SST with collection of plasma and salivary samples at 0, 30, and 60 min after Synacthen injection. The groups were compared using regression analysis with age as covariate and the LRLs were calculated parametrically.

Results: SST-stimulated plasma cortisol levels were significantly higher in the COC group versus controls, while mean salivary cortisol and cortisone levels were slightly lower in the COC group. Importantly, COC use did not significantly alter LRLs for salivary cortisol or cortisone. The smallest LRL difference between groups was seen for salivary cortisone.

Conclusion: Salivary cortisol and especially salivary cortisone are considerably less affected by COC use than plasma cortisol during SST. Due to similar LRLs, a common cutoff for salivary cortisol and cortisone during SST can be used to exclude AI in premenopausal women irrespective of COC use.

Objectives: To investigate longitudinal changes in SHBG and free testosterone (free T) levels among Black middle-aged African men, with and without coexistent HIV, and explore associations with incident dysglycaemia and measures of glucose metabolism.

Design: This longitudinal study enrolled 407 Black South African middle-aged men, comprising primarily 322 men living without HIV (MLWOH) and 85 men living with HIV (MLWH), with normal fasting glucose at enrollment. Follow-up assessments were conducted after 3.1 ± 1.5 years.

Methods: At baseline and follow-up, SHBG, albumin, and total testosterone were measured and free T was calculated. An oral glucose tolerance test at follow-up determined dysglycaemia (impaired fasting glucose, impaired glucose tolerance, type 2 diabetes) and glucose metabolism parameters including insulin sensitivity (Matsuda index), insulin resistance (homeostasis model assessment of insulin resistance), and beta(β)cell function (disposition index). The primary analysis focussed on MLWOH, with a subanalysis on MLWH to explore whether associations in MLWOH differed from MLWH.

Results: The prevalence of dysglycaemia at follow-up was 17% (n = 55) in MLWOH. Higher baseline SHBG was associated with a lower risk of incident dysglycaemia (odds ratio 0.966; 95% confidence interval 0.945-0.987) and positively associated with insulin sensitivity (β = 0.124, P < .001) and β-cell function (β = 0.194, P = .001) at follow-up. Free T did not predict dysglycaemia. In MLWH, dysglycaemia prevalence at follow-up was 12% (n = 10). Neither baseline SHBG nor free T were associated with incident dysglycaemia and glucose metabolism parameters in MLWH.

Conclusion: SHBG levels predict the development of dysglycaemia in middle-aged African men but do not exhibit the same predictive value in MLWH.