Host and Environmental Factors Influencing Individual Human Cytokine Responses.

Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral, and non-microbial metabolic stimuli in 534 healthy subjects. In this first study, we show a strong impact of non-genetic host factors (e.g., age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies. PAPERCLIP.

Imaging fetal anatomy.

Due to advancements in ultrasound techniques, the focus of antenatal ultrasound screening is moving towards the first trimester of pregnancy. The early first trimester however remains in part, a 'black box', due to the size of the developing embryo and the limitations of contemporary scanning techniques. Therefore there is a need for images of early anatomical developmental to improve our understanding of this area. By using new imaging techniques, we can not only obtain better images to further our knowledge of early embryonic development, but clear images of embryonic and fetal development can also be used in training for e.g. sonographers and fetal surgeons, or to educate parents expecting a child with a fetal anomaly. The aim of this review is to provide an overview of the past, present and future techniques used to capture images of the developing human embryo and fetus and provide the reader newest insights in upcoming and promising imaging techniques. The reader is taken from the earliest drawings of da Vinci, along the advancements in the fields of in utero ultrasound and MR imaging techniques towards high-resolution ex utero imaging using Micro-CT and ultra-high field MRI. Finally, a future perspective is given about the use of artificial intelligence in ultrasound and new potential imaging techniques such as synchrotron radiation-based CT to increase our knowledge regarding human development.

Growth differentiation factor 15 is not modified after weight loss induced by liraglutide in South Asians and Europids with type 2 diabetes mellitus.

Glucagon-like peptide-1 receptor (GLP-1R) agonists induce weight loss in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanism is unclear. Recently, the mechanism by which metformin induces weight loss could be explained by an increase in growth differentiation factor 15 (GDF15), which suppresses appetite. Therefore, we aimed to investigate whether the GLP-1R agonist liraglutide modifies plasma GDF15 levels in patients with T2DM. GDF15 levels were measured in plasma samples obtained from Dutch Europids and Dutch South Asians with T2DM before and after 26 weeks of treatment with daily liraglutide (n = 44) or placebo (n = 50) added to standard care. At baseline, circulating GDF15 levels did not differ between South Asians and Europids with T2DM. Treatment with liraglutide, compared to placebo, decreased body weight, but did not modify plasma GDF15 levels in all patients, or when data were split by ethnicity. Also, the change in plasma GDF15 levels after treatment with liraglutide did not correlate with changes in body weight or HbA1c levels. In addition, the dose of metformin used did not correlate with baseline plasma GDF15 levels. Compared to placebo, liraglutide treatment for 26 weeks does not modify plasma GDF15 levels in Dutch Europid or South Asian patients with T2DM. Thus, the weight loss induced by liraglutide is likely explained by other mechanisms beyond the GDF15 pathway. HIGHLIGHTS: What is the central question of this study? Growth differentiation factor 15 (GDF15) suppresses appetite and is increased by metformin: does the GLP-1R agonist liraglutide modify plasma GDF15 levels in patients with type 2 diabetes mellitus (T2DM)? What is the main finding and its importance? Plasma GDF15 levels did not differ between South Asians and Europids with T2DM and were not modified by 26 weeks of liraglutide in either ethnicity. Moreover, there was no correlation between the changes in plasma GDF15 levels and dosage of metformin administered, changes in body weight or HbA1c levels. The appetite-suppressing effect of liraglutide is likely exerted via pathways other than GDF15.

Unraveling a Major Burden of Orofacial Clefts Analyses: Classification of Cleft Palate Fistulas by Cleft Surgeons.

OBJECTIVE: The objective of this study was to investigate how cleft surgeons classify palatal fistulas. We focused on three different anatomical locations (ie, hard palate, soft palate, junction hard/soft palate) to analyze agreement/disagreement at various anatomical locations. DESIGN: Cross-sectional survey study. PARTICIPANTS: Participants in an international webinar that focused on palatal fistula treatment were included. INTERVENTION: Participants were presented with a survey pre- and post-webinar. MAIN OUTCOMES: Frequency of used classification systems for classifying oronasal fistulas and the inter-rater reliability of the Pittsburgh classification system. RESULTS: A total of 141 participants completed the questionnaires prior to the webinar and 109 participants completed the survey after the webinar. In total, four classification systems were used (ie, Pittsburgh, Pakistan Comprehensive Fistula Classification [PCFC], anatomical and 'other'). The Pittsburgh classification was the most commonly used system in all cases. However, Pittsburgh inter-rater reliability was low (κ = 0.136 pre-webinar, and κ = 0.174 post-webinar). Surprisingly, a substantial shift was observed from the anatomical to Pittsburgh classification after the webinar, indicating increased awareness of the usability of the Pittsburgh classification system. CONCLUSIONS: This study demonstrates a large heterogeneity with regards to the classification of cleft palate fistulas. Interestingly, a shift was observed from the anatomical to Pittsburgh classification after the webinar. However, the inter-rater reliability for using the Pittsburgh classification was low. Classifying palatal fistulas in a homogenous fashion could enhance comparison of primary palate repair and could improve treatment of palatal fistulas.

Differences in analysis and treatment of upper airway obstruction in Robin sequence across different countries in Europe.

The goal of this study was to explore the availability of diagnostic and treatment options for managing upper airway obstruction (UAO) in infants with Robin Sequence (RS) in Europe. Countries were divided in lower- (LHECs, i.e., PPP per capita < $4000) and higher-health expenditure countries (HHECs, i.e., PPP per capita ≥ $4000). An online survey was sent to European healthcare professionals who treat RS. The survey was designed to determine the availability of diagnostic tools such as arterial blood gas analysis (ABG), pulse oximetry, CO2 analysis, polysomnography (PSG), and sleep questionnaires, as well as to identify the used treatment options in a specific center. Responses were received from professionals of 85 centers, originating from 31 different countries. It was equally challenging to provide care for infants with RS in both LHECs and HHECs (3.67/10 versus 2.65/10, p = 0.45). Furthermore, in the LHECs, there was less access to ABG (85% versus 98%, p = 0.03), CO2 analysis (45% versus 70%, p = 0.03), and PSG (54% versus 93%, p < 0.01). There were no significant differences in the accessibility concerning pulse oximetry, sleep questionnaires, home saturation monitoring, nasopharyngeal tubes, Tuebingen plates, and mandibular distraction.    Conclusion: This study demonstrates a large difference in available care for infants with RS throughout Europe. LHECs have less access to diagnostic tools in RS when compared to HHECs. There is, however, no difference in the availability of treatment modalities between LHECs and HHECs. What is Known: • Patients with Robin sequence (RS) require complex and multidisciplinary care. They can present with moderate to severe upper airway obstruction (UAO). There exists a large variety in the use of diagnostics for both UAO treatment indications and evaluations. In most cases, conservative management of UAO in RS is sufficient. Patients with UAO that persist despite conservative management ultimately need surgical intervention. To determine which intervention is best suitable for the individual RS patient, the level of UAO needs to be determined through diagnostic testing. • There is a substantial variation among institutions across Europe for both diagnostics and treatment options in UAO. A standardized, internationally accepted protocol for the assessment and management of UAO in RS could guide healthcare professionals in the timing of assessment and indications to prevent escalation of UAO. Creating such a protocol might be a challenge, as there are large financial differences between countries in Europe (e.g., health expenditure per capita in purchasing power parity in international dollars ranges from $600 to over $8500). What is New: • There is a substantial variation in the availability of objective diagnostic tools between European countries. Arterial blood gas analysis, CO2 analysis and polysomnography are not equally accessible for lower-healthcare expenditure countries (LHECs) compared to higher-healthcare expenditure countries (HHECs). These differences are not only limited to availability; there is also a difference in quality of these diagnostic tools. Surprisingly, there is no difference in access to treatment tools between LHECs and HHECs. • There is national heterogeneity in access to tools for diagnosis and treatment of RS, which suggests centralization of health care, showing that specialized care is only available in tertiary centers. By centralization of care for RS infants, diagnostics and treatment can be optimized in the best possible way to create a uniform European protocol and ultimately equal care across Europe. Learning what is necessary for adequate monitoring could lead to better allocation of resources, which is especially important in a low-resource setting.

Identifying Risk Factors for Recurrence After Cubital Tunnel Release.

PURPOSE: This study investigated specific risk factors for recurrent surgery of ulnar nerve entrapment (ie, ipsilateral clinical symptoms within 5 years after initial cubital tunnel release [CuTR]) in a large cohort. We hypothesized that recurrence is associated with lifestyle variables (eg, smoking, drinking alcohol, a high body mass index [BMI]) or comorbidities). METHODS: A retrospective cohort study was performed using the Current Procedural Terminology codes for all patients who underwent CuTR between January 2012 and November 2018. Demographic data, including sex, age, weight, height, BMI, comorbidities, smoking, and alcohol consumption, were collected. The primary outcome was the need for revision surgery after initial CuTR. Univariate and multivariate analyses were performed to identify potential risk factors for revision surgery. RESULTS: Of the 678 patients who underwent CuTR, 120 patients (18%) needed revision surgery within 5 years. Sixty-six patients required subfascial transposition (55%) and 47 patients (39%) received in situ releases. Also, sex, BMI, smoking, alcohol consumption, and comorbidities (except for spinal disc herniation) were similar between the primary and revision subgroup. Age at first occurrence was significantly lower in the revision group (48 years for revision vs 52 years for primary surgery). Moreover, cervical spinal disc herniation was associated with revision surgery (13% vs 6% in the primary group). CONCLUSIONS: Age and medical history of cervical spinal disc herniation are associated with an increased risk of revision surgery. More importantly, BMI, smoking, alcohol consumption, and other comorbidities are not associated with increased risk of revision surgery within our sample. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Classification Systems of Cleft Lip, Alveolus and Palate: Results of an International Survey.

OBJECTIVE: This study aimed to identify commonly used classification systems by cleft providers around the world, including the perceived indications and limitations of each system. DESIGN: A cross-sectional survey. PARTICIPANTS: A total of 197 registrants from three international cleft/craniofacial meetings. INTERVENTIONS: Participants were sent a web-based questionnaire concerning cleft classification systems. MAIN OUTCOME MEASURES: Frequency of commonly used classification systems, their perceived indications and limitations. RESULTS: A total of 197 respondents from 166 different centers completed the questionnaire. Healthcare professionals from all disciplines responded, with the most frequent respondents being plastic surgeons (38.1%), maxillofacial surgeons (28.4%) and orthodontists (23.9%). Eighteen different classification systems were in use. The most frequently used systems were the International Statistical Classification of Diseases and Related Health Problems (ICD-10) (35.5%), LAHSHAL (34.0%), and Veau (32.5%) classification systems. Most respondents (32.5%) indicated that anatomical and morphological characteristics are essential components of a classification system. However, respondents indicated that their current classification systems lacked sufficient description of cleft extension and severity. CONCLUSIONS: Great variety in the use of classification systems exists among craniofacial specialists internationally. The results recommend the usage of the LAHSHAL classification of OFCs, due to its comprehensiveness, relatively high implementation rate globally, convenience of usage and complementarity with the ICD-10 system. Moreover, it can overcome deficiencies inextricably linked to ICD-10, such as incapacity to describe laterality and clefts of the alveolus. More international exposure to the merits of using the LAHSHAL classification system would be highly recommended.

Decrease in Prevalence of Cleft lip, Alveolus and Palate After Nationwide Introduction of the Second-Trimester Anomaly Scan in the Netherlands.

OBJECTIVE: Some studies have suggested that introducing a second-trimester anomaly scan (SAS) leads to increased rates of termination of pregnancy (TOP) in fetuses with orofacial clefts (OFCs). The aim of this study was to evaluate the impact of a nationwide introduction of SAS on the prevalence of live births with OFCs in the Netherlands. DESIGN: Retrospective cohort study. SETTING: Tertiary setting. POPULATION: Included in the study were all patients diagnosed with OFCs as recorded in the "Dutch Association for Cleft Palate Anomalies" database between 1997 and 2019. INTERVENTIONS: Patients were divided into three categories: cleft lip with or without alveolus (CL/A), cleft lip, alveolus and palate (CLAP) and cleft palate (CP) based on anatomical landmarks at the first consultation. MAIN OUTCOME MEASURES: Prevalence rates of OFCs before and after the nationwide introduction of the SAS on January 1, 2007 were compared. RESULTS: Overall, 1899 patients were diagnosed with CL/A, 2586 with CLAP and 2927 with CP. The prevalence of clefts before and after introduction of the SAS did not differ (P = 0.85). The prevalence of CL/A decreased (P = 0.04), and that of CLAP decreased (P = 0.01) and that of CP increased (P = 0.02). CONCLUSIONS: This study demonstrates a significant decrease in the prevalence of CL/A and CLAP after introduction of the SAS. However, due to an increase in CP, the prevalence of all patients born with OFCs has not changed in the Netherlands between 1997 and 2019.

Excitation Transfer Between Sexual Arousal and Other Emotions in a Community Sample.

Excitation transfer, the transfer of arousal from one emotion to another, might be a mechanism in the development of unusual sexual interests. In this pilot study, we investigated whether we could induce excitation transfer between various emotions and sexual arousal in a laboratory setting with 30 male volunteers. We induced low-level sexual arousal in four different emotional states (aggression/dominance, endearment, fear, disgust) and a neutral state. Sexual arousal was measured using penile plethysmography and self-report. Although there was no mean group effect, possibly due to large interindividual variations, 60% of the subjects showed more sexual arousal in response to sexual stimulation in at least one of the emotional states than in the neutral state. Excitation transfer was most prominent with aggression/dominance and least prominent with disgust. Genital excitation transfer was strongly related to lower penile reactivity and to higher self-reported erotophilia. This pilot study paves the way for further research into excitation transfer as a mechanism to increase the salience of stimuli that otherwise would not have been sexual in nature.

Insights into the role of IL-32 in cancer.

Interleukin 32 (IL-32) is a proinflammatory cytokine involved in the development of several diseases, including cancer. IL-32 is a rather peculiar cytokine because its protein structure does not show resemblance with any of the known cytokines, and an IL-32 receptor to facilitate extracellular signaling has not yet been identified. Thus far, 9 isoforms of IL-32 have been described, all of which show differences in terms of effects and in potency to elicit a specific effect. Since the first report of IL-32 in 2005, there is increasing evidence that IL-32 plays an important role in the pathophysiology of both hematologic malignancies and solid tumors. Some IL-32 isoforms have been linked to disease outcome and were shown to positively influence tumor development and progression in various different malignancies, including gastric, breast and lung cancers. However, there are other reports suggesting a tumor suppressive role for some of IL-32 as well. For example, IL-32γ and IL-32ß expression is associated with increased cancer cell death in colon cancer and melanoma, whereas expression of these isoforms is associated with increased invasion and migration in breast cancer cells. Furthermore, IL-32 isoforms α, ß and γ also play an important role in regulating the anti-tumor immune response, thus also influencing tumor progression. In this review, we provide an overview of the role of IL-32 and its different isoforms in carcinogenesis, invasion and metastasis, angiogenesis and regulation of the anti-tumor immune response.

The Effectiveness of Virtual Reality Exposure-Based Cognitive Behavioral Therapy for Severe Anxiety Disorders, Obsessive-Compulsive Disorder, and Posttraumatic Stress Disorder: Meta-analysis.

BACKGROUND: In recent years, virtual reality exposure-based cognitive behavioral therapy (VRE-CBT) has shown good treatment results in (subclinical) anxiety disorders and seems to be a good alternative to exposure in vivo in regular cognitive behavioral therapy (CBT). However, previous meta-analyses on the efficacy of VRE-CBT on anxiety disorders have included studies on specific phobias and subthreshold anxiety; therefore, these results may not be generalizable to patients with more severe and disabling anxiety disorders. OBJECTIVE: The objective of our study is to determine the efficacy of VRE-CBT on more severe anxiety disorders, excluding specific phobias and subthreshold anxiety disorders. Meta-analyses will be conducted to examine the efficacy of VRE-CBT versus waitlist and regular CBT. Our secondary objectives are to examine whether the efficacy differs according to the type of anxiety disorder, type of recruitment, and type of VRE-CBT (virtual reality exposure either with or without regular CBT). Furthermore, attrition in VRE-CBT and CBT will be compared. METHODS: Studies published until August 20, 2020, were retrieved through systematic literature searches in PubMed, PsycINFO, and Embase. We calculated the effect sizes (Hedges g) for the difference between the conditions and their 95% CIs for posttest and follow-up measurements in a random effects model. A separate meta-analysis was performed to compare attrition between the VRE-CBT and CBT conditions. RESULTS: A total of 16 trials with 817 participants were included. We identified 10 comparisons between VRE-CBT and a waitlist condition and 13 comparisons between VRE-CBT and a CBT condition. With regard to risk of bias, information on random sequence generation, allocation concealment, and risk of bias for selective outcome reporting was often absent or unclear. The mean effect size of VRE-CBT compared with waitlist (nco=10) was medium and significant, favoring VRE-CBT (Hedges g=-0.490, 95% CI -0.82 to -0.16; P=.003). The mean effect size of VRE-CBT compared with CBT (nco=13) was small and nonsignificant, favoring CBT (Hedges g=0.083, 95% CI -0.13 to 0.30; P=.45). The dropout rates between VRE-CBT and CBT (nco=10) showed no significant difference (odds ratio 0.79, 95% CI 0.49-1.27; P=.32). There were no indications of small study effects or publication bias. CONCLUSIONS: The results of our study show that VRE-CBT is more effective than waitlist and as effective as CBT in the treatment of more severe anxiety disorders. Therefore, VRE-CBT may be considered a promising alternative to CBT for patients with more severe anxiety disorders. Higher-quality randomized controlled trials are needed to verify the robustness of these findings.

A three-dimensional analysis of the development of cranial nerves in human embryos.

To increase our understanding of the etiology of specific neurological disorders (e.g., Duane syndrome, glossoptosis in Pierre Robin sequence), proper knowledge of anatomy and embryology of cranial nerves is necessary. We investigated cranial nerve development, studied histological sections of human embryos, and quantitatively analyzed the 3D reconstructions. A total of 28 sectioned and histologically stained human embryos (Carnegie stage [CS] 10 to 23 [21-60 days of development]) were completely digitalized by manual annotation using Amira software. Two specimens per stage were analyzed. Moreover, quantitative volume measurements were performed to assess relative growth of the cranial nerves. A chronologic overview of the morphologic development of each of the 12 cranial nerves, from neural tube to target organ, was provided. Most cranial nerves start developing at CS 12 to 13 (26-32 days of development) and will reach their target organ in stage 17 to 18 (41-46 days). In comparison to the rest of the developing brain, a trend could be identified in which relative growth of the cranial nerves increases at early stages, peaks at CS 17 and slowly decreases afterwards. The development of cranial nerves in human embryos is presented in a comprehensive 3D fashion. An interactive 3D-PDF is provided to illuminate the development of the cranial nerves in human embryos for educational purposes. This is the first time that volume measurements of cranial nerves in the human embryonic period have been presented.

Thyrotrophin and thyroxine support immune homeostasis in humans.

The endocrine and the immune systems interact by sharing receptors for hormones and cytokines, cross-control and feedback mechanisms. To date, no comprehensive study has assessed the impact of thyroid hormones on immune homeostasis. By studying immune phenotype (cell populations, antibody concentrations, circulating cytokines, adipokines and acute-phase proteins, monocyte-platelet interactions and cytokine production capacity) in two large independent cohorts of healthy volunteers of Western European descent from the Human Functional Genomics Project (500FG and 300BCG cohorts), we identified a crucial role of the thyroid hormone thyroxin (T4) and thyroid-stimulating hormone (TSH) on the homeostasis of lymphocyte populations. TSH concentrations were strongly associated with multiple populations of both effector and regulatory T cells, whereas B-cell populations were significantly associated with free T4 (fT4). In contrast, fT4 and TSH had little impact on myeloid cell populations and cytokine production capacity. Mendelian randomization further supported the role of fT4 for lymphocyte homeostasis. Subsequently, using a genomics approach, we identified genetic variants that influence both fT4 and TSH concentrations and immune responses, and gene set enrichment pathway analysis showed enrichment of fT4-affected gene expression in B-cell function pathways, including the CD40 pathway, further supporting the importance of fT4 in the regulation of B-cell function. In conclusion, we show that thyroid function controls the homeostasis of the lymphoid cell compartment. These findings improve our understanding of the immune responses and open the door for exploring and understanding the role of thyroid hormones in the lymphocyte function during disease.

Safety planning-type interventions for suicide prevention: meta-analysis.

BACKGROUND: Safety planning-type interventions (SPTIs) for patients at risk of suicide are often used in clinical practice, but it is unclear whether these interventions are effective. AIMS: This article reports on a meta-analysis of studies that have evaluated the effectiveness of SPTIs in reducing suicidal behaviour and ideation. METHOD: We searched Medline, EMBASE, PsycINFO, Web of Science and Scopus from their inception to 9 December 2019, for studies that compared an SPTI with a control condition and had suicidal behaviour or ideation as outcomes. Two researchers independently extracted the data. To assess suicidal behaviour, we used a random-effects model of relative risk based on a pooled measure of suicidal behaviour. For suicidal ideation, we calculated effect sizes with Hedges' g. The study was registered at PROSPERO (registration number CRD42020129185). RESULTS: Of 1816 unique abstracts screened, 6 studies with 3536 participants were eligible for analysis. The relative risk of suicidal behaviour among patients who received an SPTI compared with control was 0.570 (95% CI 0.408-0.795, P = 0.001; number needed to treat, 16). No significant effect was found for suicidal ideation. CONCLUSIONS: To our knowledge, this is the first study to report a meta-analysis on SPTIs for suicide prevention. Results support the use of SPTIs to help preventing suicidal behaviour and the inclusion of SPTIs in clinical guidelines for suicide prevention. We found no evidence for an effect of SPTIs on suicidal ideation, and other interventions may be needed for this purpose.

A methylation study of long-term depression risk.

Recurrent and chronic major depressive disorder (MDD) accounts for a substantial part of the disease burden because this course is most prevalent and typically requires long-term treatment. We associated blood DNA methylation profiles from 581 MDD patients at baseline with MDD status 6 years later. A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P = 2.0 × 10-16). Top MWAS results were enriched specific pathways, overlapped with genes found in GWAS of MDD disease status, autoimmune disease and inflammation, and co-localized with eQTLS and (genic enhancers of) of transcription sites in brain and blood. Many of these findings remained significant after correction for multiple testing. The major themes emerging were cellular responses to stress and signaling mechanisms linked to immune cell migration and inflammation. This suggests that an immune signature of treatment-resistant depression is already present at baseline. We also created a methylation risk score (MRS) to predict MDD status 6 years later. The AUC of our MRS was 0.724 and higher than risk scores created using a set of five putative MDD biomarkers, genome-wide SNP data, and 27 clinical, demographic and lifestyle variables. Although further studies are needed to examine the generalizability to different patient populations, these results suggest that methylation profiles in blood may present a promising avenue to support clinical decision making by providing empirical information about the likelihood MDD is chronic or will recur in the future.

Poor sleep quality among newly diagnosed head and neck cancer patients: prevalence and associated factors.

BACKGROUND: Head and neck cancer (HNC) patients often suffer from distress attributed to their cancer diagnosis which may disturb their sleep. However, there is lack of research about poor sleep quality among newly diagnosed HNC patients. Therefore, our aim was to investigate the prevalence and the associated factors of poor sleep quality among HNC patients before starting treatment. MATERIALS AND METHODS: A cross-sectional study was conducted using the baseline data from NET-QUBIC study, an ongoing multi-center cohort of HNC patients in the Netherlands. Poor sleep quality was defined as a Pittsburgh Sleep Quality Index (PSQI) total score of > 5. Risk factors examined were sociodemographic factors (age, sex, education level, living situation), clinical characteristics (HNC subsite, tumor stage, comorbidity, performance status), lifestyle factors, coping styles, and HNC symptoms. RESULTS: Among 560 HNC patients, 246 (44%) had poor sleep quality before start of treatment. Several factors were found to be significantly associated with poor sleep: younger age (odds ratio [OR] for each additional year 0.98, 95% CI 0.96-1.00), being female (OR 2.6, 95% CI 1.7-4.1), higher passive coping style (OR 1.18, 95% CI 1.09-1.28), more oral pain (OR 1.10, 95% CI 1.01-1.19), and less sexual interest and enjoyment (OR 1.13, 95% CI 1.06-1.20). CONCLUSION: Poor sleep quality is highly prevalent among HNC patients before start of treatment. Early evaluation and tailored intervention to improve sleep quality are necessary to prepare these patients for HNC treatment and its consequences.

The associations of leptin and adiponectin with the metabolic syndrome in an Indonesian and a Dutch population.

BACKGROUND AND AIMS: At the same BMI, Asian populations develop cardiometabolic complications earlier than Western populations. We hypothesized that a different secretion of the adipocyte-derived hormones leptin and adiponectin plays a role and investigated the associations of the two hormones with the metabolic syndrome (MetS) in an Indonesian and a Dutch population. METHODS AND RESULTS: We performed cross-sectional analyses of the Netherlands Epidemiology of Obesity Study (n = 6602) and the SUGAR Scientific Programme Indonesia-Netherlands Study (n = 1461). We examined sex-stratified associations of leptin and adiponectin with MetS, using multivariate logistic regression including adjustment for total body fat. The mean (SD) leptin (mcg/L) were 4.7 (6.0) in Indonesian men, 18.6 (12.0) in Indonesian women, 9.1 (7.7) in Dutch men, and 23.4 (17.4) in Dutch women. The mean (SD) adiponectin (mg/L) were 5.7 (5.4), 7.5 (7.1), 6.6 (3.3), and 11.3 (4.9), respectively. Within the same BMI category, leptin concentrations were similar in the two populations, whereas adiponectin was lower in the Indonesian population. Per SD of leptin, adjusted prevalence odds ratios (ORs, 95%CI) of MetS were 0.9 (0.6-1.2) in Indonesian men, 1.1 (0.9-1.4) in Indonesian women, 2.2 (1.6-2.8) in Dutch men, and 1.2 (1.0-1.5) in Dutch women. Per SD of adiponectin, the ORs were 0.9 (0.7-1.2), 0.8 (0.7-1.0), 0.6 (0.6-0.8), and 0.4 (0.4-0.5), respectively. CONCLUSIONS: Despite lower adiponectin levels, adiponectin was not related to the MetS in the Indonesian population and can not explain their increased cardiometabolic risk at the same BMI.

The Effect of Glycemic Control on Renal Triglyceride Content Assessed by Proton Spectroscopy in Patients With Type 2 Diabetes Mellitus: A Single-Center Parallel-Group Trial.

OBJECTIVE: Ectopic lipid accumulation in the kidney (fatty kidney) is a potential driver of diabetic kidney disease, and tight glycemic control can reduce risk of diabetic nephropathy. We assessed whether glycemic control influences renal triglyceride content (RTGC). Furthermore, we compared glucagon-like peptide-1 receptor agonist liraglutide versus standard glucose-lowering therapy. DESIGN AND METHODS: In this single-center parallel-group trial, patients with type 2 diabetes mellitus were randomized to liraglutide or placebo added to standard care (metformin/sulfonylurea derivative/insulin). Changes in RTGC after 26 weeks of glycemic control measured by proton spectroscopy and difference in RTGC between treatment groups were analyzed. RESULTS: Fifty patients with type 2 diabetes mellitus were included in the baseline analysis (mean age, 56.5 ± 9.1 years; range, 33-73 years; 46% males). Seventeen patients had baseline and follow-up measurements. Mean glycated hemoglobin was 7.8 ± 0.8%, which changed to 7.3 ± 0.9% after 26 weeks of glycemic control irrespective of treatment group (P = .046). Log-transformed RTGC was -0.68 ± 0.30% and changed to -0.83 ± 0.32% after 26 weeks of glycemic control irrespective of treatment group (P = .049). A 26-week-to-̶baseline RTGC ratio (95% confidence interval) was significantly different between liraglutide (-0.30 [-0.50, -0.09]) and placebo added to standard care (-0.003 [-0.34, 0.34]) (P = .04). CONCLUSION: In this exploratory study, we found that 26 weeks of glycemic control resulted in lower RTGC, in particular for liraglutide; however, larger clinical studies are needed to assess whether these changes reflect a true effect of glycemic control on fatty kidney.

Incidence of Symptomatic Submucous Cleft Palate in the Netherlands: A Retrospective Cohort Study Over a Period of 22 Years.

OBJECTIVE: To analyze the incidence of submucous cleft palate (SMCP) in a large national database and raise awareness among referring providers: pediatricians, speech pathologists, and dentists to minimize delay in diagnosis. DESIGN: Retrospective cohort study. SETTING: Tertiary setting. PATIENTS: Patients were extracted from the "Dutch Association for Cleft and Craniofacial Anomalies" database. A total of 6916 patients were included from 1997 until 2018 and divided into 2 groups (ie, SMCP versus cleft palate [CP]). Patients born before 1997 and adopted patients were excluded. INTERVENTIONS: Clefts were classified as either hard of soft palatal involvement based on anatomical landmarks at first consultation. MAIN OUTCOME MEASURES: Primary outcomes were the patient characteristics in both groups (ie, gender, birth weight, gestational age, and additional anomalies). Secondary outcome was the time of diagnosis among subgroups. RESULTS: In total, 532 patients were diagnosed with SMCP (7.7%). Birth weight, gestational age, and additional anomalies did not differ between subgroups, but there were more males in the SMCP group (P < .001). The median age of diagnosis of the SMCP group was significantly higher than of the CP group (987 vs 27 days; P < .001). Over the course of 22 years, the time of diagnosis for SMCP did not decrease. CONCLUSION: Submucous cleft palate represents <10% of the Dutch cleft population and 19.4% of all CP. Time of diagnosis for SMCP is significantly longer when compared with time of diagnosis of CP, and this has not changed over the study period of 22 years.

Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation.

AIMS/HYPOTHESIS: The aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus. METHODS: This study is a pre-specified subanalysis of the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction In type 2 diAbetes mellitus (MAGNA VICTORIA) study, with primary endpoints being the effects of liraglutide on left ventricular diastolic and systolic function. The MAGNA VICTORIA study was a single-centre, parallel-group trial in 50 individuals with type 2 diabetes mellitus (BMI >25 kg/m2) who were randomly assigned (1:1, stratified for sex and insulin use) to receive liraglutide 1.8 mg once daily or placebo for 26 weeks, added to standard care. Participants, study personnel and outcome assessors were blinded to treatment allocation. The secondary endpoints of visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT) and epicardial fat were measured with MRI. Hepatic triacylglycerol content (HTGC) and myocardial triacylglycerol content (MTGC) were quantified with proton MR spectroscopy. Between-group differences (change from baseline) were tested for significance using ANCOVA. Mean differences with 95% CIs were reported. RESULTS: The trial was completed in 2016. Twenty-four participants were randomised to receive liraglutide and 26 to receive placebo. One patient in the liraglutide group withdrew consent before having received the study drug and was not included in the intention-to-treat analysis. Liraglutide (n = 23) vs placebo (n = 26) significantly reduced body weight (liraglutide 98.4 ± 13.8 kg to 94.3 ± 14.9 kg; placebo 94.5 ± 13.1 kg to 93.9 ± 13.2 kg; estimated treatment effect -4.5 [95% CI -6.4, -2.6] kg). HbA1c declined in both groups without a significant treatment effect of liraglutide vs placebo (liraglutide 66.7 ± 11.5 mmol/mol to 55.0 ± 13.2 mmol/mol [8.4 ± 1.1% to 7.3 ± 1.2%]; placebo 64.7 ± 10.2 mmol/mol to 56.9 ± 6.9 mmol/mol [8.2 ± 1.0% to 7.5 ± 0.7%]; estimated treatment effect -2.9 [95% CI -8.1, 2.3] mmol/mol or -0.3 [95% CI -0.8, 0.2]%). VAT did not change significantly between groups (liraglutide 207 ± 87 cm2 to 203 ± 88 cm2; placebo 204 ± 63 cm2 to 200 ± 55 cm2; estimated treatment effect -7 [95% CI -24, 10] cm2), while SAT was reduced by a significantly greater extent with liraglutide than with placebo (liraglutide 361 ± 142 cm2 to 339 ± 131 cm2; placebo 329 ± 107 cm2 to 333 ± 125 cm2; estimated treatment effect -29 [95% CI -51, -8] cm2). Epicardial fat did not change significantly between groups (liraglutide 8.9 ± 4.3 cm2 to 9.1 ± 4.7 cm2; placebo 9.6 ± 4.1 cm2 to 9.6 ± 4.6 cm2; estimated treatment effect 0.2 [95% CI -1.5, 1.8] cm2). Change in HTGC was not different between groups (liraglutide 18.1 ± 11.2% to 12.0 ± 7.7%; placebo 18.4 ± 9.4% to 14.7 ± 10.0%; estimated treatment effect -2.1 [95% CI -5.3, 1.0]%). MTGC was not different after treatment with liraglutide (1.5 ± 0.6% to 1.2 ± 0.6%) vs placebo (1.3 ± 0.5% to 1.2 ± 0.6%), with an estimated treatment effect of -0.1 (95% CI -0.4, 0.2)%. There were no adjudicated serious adverse events. CONCLUSIONS/INTERPRETATION: Compared with placebo, liraglutide-treated participants lost significantly more body weight. Liraglutide primarily reduced subcutaneous fat but not visceral, hepatic, myocardial or epicardial fat. Future larger studies are needed to confirm the results of this secondary endpoint study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01761318. FUNDING: This study was funded by Novo Nordisk A/S (Bagsvaerd, Denmark).