Digoxin treatment does not reinduce radioiodine uptake in radioiodine refractory non-medullary thyroid carcinoma.

Objective: Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC. Methods: Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies. Results: Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial. Conclusion: Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.

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.

Towards Personalized TSH Reference Ranges: A Genetic and Population-Based Approach in Three Independent Cohorts.

Background: Serum thyroid-stimulating hormone (TSH) measurement is the diagnostic cornerstone for primary thyroid dysfunction. There is high inter-individual but limited intra-individual variation in TSH concentrations, largely due to genetic factors. The currently used wide population-based reference intervals may lead to inappropriate management decisions. Methods: A polygenic score (PGS) including 59 genetic variants was used to calculate genetically determined TSH reference ranges in a thyroid disease-free cohort (n = 6,834). Its effect on reclassification of diagnoses was investigated when compared to using population-based reference ranges. Next, results were validated in a second independent population-based thyroid disease-free cohort (n = 3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease (n = 26,321) as well as individuals on levothyroxine (LT4) treatment (n = 1,132). Results: PGS was a much stronger predictor of individual TSH concentrations than FT4 (total variance in TSH concentrations explained 9.2-11.1% vs. 2.4-2.7%, respectively) or any other nongenetic factor (total variance in TSH concentrations explained 0.2-1.8%). Genetically determined TSH reference ranges differed significantly between PGS quartiles in all cohorts, while the differences in FT4 concentrations were absent or only minor. Up to 24.7-30.1% of individuals, previously classified as having subclinical hypo- and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when genetically determined TSH reference ranges were applied. Individuals in the higher PGS quartiles had a higher probability of being prescribed LT4 treatment compared to individuals from the lower PGS quartiles (3.3% in Q1 vs. 5.2% in Q4, Pfor trend =1.7 × 10-8). Conclusions: Individual genetic profiles have the potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.

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.

Improving patient care by virtual case discussion between plastic surgeons and residents of Uganda and the Netherlands.

INTRODUCTION: Traditional on-site missions of plastic surgeons from "high-income countries" in "low- and middle-income countries" are often limited in time and lack proper follow-up. Regular digital collaboration could lead to a more impactful and durable exchange of knowledge for plastic surgeons and residents in both settings. AIMS: The aim of this study was to evaluate the satisfaction of the first twelve months of weekly digital meetings, explore advantages/disadvantages, and to provide tools for similar initiatives. METHODS: Weekly meetings started from August 2021. An encrypted digital connection allowed residents and plastic surgeons from Uganda and the Netherlands to discuss cases for educational purposes, where treatment options were considered. After twelve months, a survey was sent to participants from both countries to indicate the meetings' strengths, weaknesses, and possible improvements. RESULTS: A total of 18 participants responded to the questionnaire (ten plastic surgeons, six residents, and two researchers). The strengths of the meetings were the accessibility of the meetings, knowledge exchange and practice for residents' final exams. Possible improvements included having a clear format for patient discussion, a session moderator and better internet connectivity. Moreover, a database to assess the impact of the given intervention on the patient cases by evaluating postoperatively (e.g. three months), could further improve clinical care. CONCLUSIONS: Virtual patient discussions subjectively contributed to medical education at both locations. Improved digital infrastructure and a collaborative database could further maximize learning capacity. Furthermore, digital proctoring is a promising way to establish sustainable collaborations between high- and low-resource countries.

Smart surgical glasses for orofacial cleft surgery training in high- and low-income countries: A proof of concept.

INTRODUCTION: The coronavirus 2019 pandemic urged us to find alternatives for education through remote proctoring and international surgical collaborations among high-, middle-, and low-income countries. Smart surgical glasses are promising for remote surgical education and international surgical collaborations. AIMS: This study aimed to assess the usability of smart surgical glasses during cleft surgery and explore their potential in remote surgical education and collaboration. METHODS: Six plastic surgical cases were randomly selected and recorded using the RODS&CONES glasses in 4K (3840 × 2160p). A 23-point questionnaire was sent to one plastic surgeon, one plastic surgery resident, and eight doctors who were not trained to critically appraise the video and audio quality of the smart surgical glasses and their applicability for remote surgical education. RESULTS: The participants indicated that the smart glasses had several significant advantages over conventional on-site education, such as facilitating a better view of the surgical field and providing possibilities for remote interaction. The audio quality was considered excellent. The main limitations were image stabilization issues and loss of video connection due to weak wireless fidelity. CONCLUSIONS: All participants appreciated the use of smart glasses for remote education and considered them a promising tool for enhancing the quality of surgical education. The glasses can enable remote assistance and education of local surgical residents and may facilitate sustainable surgical collaborations among high-, middle-, and low-income countries.

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.

The Relation between Depressive Symptoms and Unsafe Sex among MSM Living with HIV.

In people living with HIV (PLWH), a positive association is often found between depressive symptoms and unsafe sex, which means sex without a condom. However, the results of such studies are inconclusive. The present study compared the numbers of safe and unsafe sexual contacts from men who have sex with men (MSM) (N = 159), living with HIV and attending a mental health clinic, with those of HIV-negative MSM in the general population (N = 198). We determined whether the presence of depressive symptoms was associated with unsafe sex in either of the two study populations. The depressive symptoms were measured with the Inventory of Depressive Symptoms (IDS), (MSM living with HIV) and with the 2012 Sexual Health Monitor (HIV-negative MSM). Finally, we determined whether MSM living with HIV with depressive symptoms, who received psychiatric treatment as usual, engaged in fewer unsafe sexual contacts one year after baseline. The mental-health-treatment-seeking MSM living with HIV engaged in more unsafe sexual contact than the MSM comparison group without HIV. Neither the treatment-seeking MSM living with HIV nor the MSM without HIV in the general population exhibited a relationship between depressive symptoms and unsafe sex. Moreover, the successful treatment of depressive symptoms in the treatment group did not lead to any reduction in the number of unsafe sexual contacts. Further research is needed to develop interventions that might be effective for MSM living with HIV with mental health symptoms to reduce the number of unsafe sexual contacts.

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.

Differentiated thyroid carcinoma: An update.

Differentiated thyroid carcinoma (DTC) is the most common endocrine cancer. Particularly the incidence of small clinically indolent tumors has been increasing significantly during the last decades because of increased diagnostic scrutiny, while the DTC-related mortality remained unchanged. In light of the increased awareness of the significant risk of detecting clinically indolent tumors and the potential harm and burden associated with overly diagnosis and the treatment, the approach towards management of DTC recently underwent a critical appraisal. The focus lays on reducing the unnecessary burden for patients with very low risk DTC and the correct identification of those who require treatment that is more intensive and/or follow-up. Management of DTC includes a range of different modalities, making multidisciplinary collaboration expedient. In this review, we elaborate on the recent developments in diagnosis, staging and management of DTC with specific focus on the more individualized risk assessment-based approach.

Differences in Inflammatory Pathways Between Dutch South Asians vs Dutch Europids With Type 2 Diabetes.

CONTEXT: South Asian individuals are more prone to develop type 2 diabetes (T2D) coinciding with earlier complications than Europids. While inflammation plays a central role in the development and progression of T2D, this factor is still underexplored in South Asians. OBJECTIVE: This work aimed to study whether circulating messenger RNA (mRNA) transcripts of immune genes are different between South Asian compared with Europid patients with T2D. METHODS: A secondary analysis was conducted of 2 randomized controlled trials of Dutch South Asian (n = 45; age: 55 ± 10 years, body mass index [BMI]: 29 ± 4 kg/m2) and Dutch Europid (n = 44; age: 60 ± 7 years, BMI: 32 ± 4 kg/m2) patients with T2D. Main outcome measures included mRNA transcripts of 182 immune genes (microfluidic quantitative polymerase chain reaction; Fluidigm Inc) in fasted whole-blood, ingenuity pathway analyses (Qiagen). RESULTS: South Asians, compared to Europids, had higher mRNA levels of B-cell markers (CD19, CD79A, CD79B, CR2, CXCR5, IGHD, MS4A1, PAX5; all fold change > 1.3, false discovery rate [FDR] < 0.008) and interferon (IFN)-signaling genes (CD274, GBP1, GBP2, GBP5, FCGR1A/B/CP, IFI16, IFIT3, IFITM1, IFITM3, TAP1; all FC > 1.2, FDR < 0.05). In South Asians, the IFN signaling pathway was the top canonical pathway (z score 2.6; P < .001) and this was accompanied by higher plasma IFN-γ levels (FC = 1.5, FDR = 0.01). Notably, the ethnic difference in gene expression was larger for women (20/182 [11%]) than men (2/182 [1%]). CONCLUSION: South Asian patients with T2D show a more activated IFN-signaling pathway compared to Europid patients with T2D, which is more pronounced in women than men. We speculate that a more activated IFN-signaling pathway may contribute to the more rapid progression of T2D in South Asian compared with Europid individuals.

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.

Multikinase Inhibitors for the Treatment of Asymptomatic Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Global Noninterventional Study (RIFTOS MKI).

Background: Sorafenib and lenvatinib are multikinase inhibitors (MKIs) approved for patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC). There is no consensus on when to initiate MKI treatment. The objective of this study was to evaluate time to symptomatic progression (TTSP) in patients with RAI-R DTC for whom the decision to treat with an MKI was made at study entry. Methods: International, prospective, open-label, noninterventional cohort study (NCT02303444). Eligible patients had asymptomatic progressive RAI-R DTC, with ≥1 lesion ≥1 cm in diameter and life expectancy ≥6 months. The decision to treat with an MKI was at the treating physician's discretion. Primary endpoint was TTSP from study entry. Two cohorts were evaluated: patients for whom a decision to initiate an MKI was made at study entry (Cohort 1) and patients for whom there was a decision not to initiate an MKI at study entry (Cohort 2). Cohorts were compared descriptively. Results: The full analysis set (FAS) comprised 647 patients. The median duration of observation was 35.5 months (range <1-59.4). Of 344 MKI-treated patients, 209 received sorafenib, 191 received lenvatinib, and 19 received another MKI at some point. Median TTSP was 55.4 months (interquartile range [IQR] 18.6-not estimable [NE]) overall, 55.4 months (IQR 15.2-NE) in Cohort 1 (n = 169), and 51.4 months (IQR 20.0-NE) in Cohort 2 (n = 478). TTSP ≥36 months was achieved in 64.5% of patients overall, 59.5% of patients in Cohort 1, and 66.4% of patients in Cohort 2. Median overall survival from classification as RAI-R was 167 months and median progression-free survival from start of MKI therapy was 19.2 months and from start of sorafenib therapy 16.7 months. Among sorafenib-treated patients, 70% had dose modifications, 35% had a dose reduction, 89% experienced ≥1 treatment-emergent adverse event (TEAE), and 82% experienced ≥1 drug-related TEAE. Conclusions: This real-world study provides valuable insight into outcomes in patients with asymptomatic, progressive RAI-R DTC under observation or receiving MKI treatment. TTSP in the FAS provides insight into the current prognosis for patients with RAI-R DTC in the era of MKIs. Registration: NCT02303444.

Psychological Problems among Head and Neck Cancer Patients in Relation to Utilization of Healthcare and Informal Care and Costs in the First Two Years after Diagnosis.

BACKGROUND: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients. METHOD: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses. RESULTS: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs. DISCUSSION: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes.

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.

A Data-Driven Clustering Method for Discovering Profiles in the Dynamics of Major Depressive Disorder Using a Smartphone-Based Ecological Momentary Assessment of Mood.

Background: Although major depressive disorder (MDD) is characterized by a pervasive negative mood, research indicates that the mood of depressed patients is rarely entirely stagnant. It is often dynamic, distinguished by highs and lows, and it is highly responsive to external and internal regulatory processes. Mood dynamics can be defined as a combination of mood variability (the magnitude of the mood changes) and emotional inertia (the speed of mood shifts). The purpose of this study is to explore various distinctive profiles in real-time monitored mood dynamics among MDD patients in routine mental healthcare. Methods: Ecological momentary assessment (EMA) data were collected as part of the cross-European E-COMPARED trial, in which approximately half of the patients were randomly assigned to receive the blended Cognitive Behavioral Therapy (bCBT). In this study a subsample of the bCBT group was included (n = 287). As part of bCBT, patients were prompted to rate their current mood (on a 1-10 scale) using a smartphone-based EMA application. During the first week of treatment, the patients were prompted to rate their mood on three separate occasions during the day. Latent profile analyses were subsequently applied to identify distinct profiles based on average mood, mood variability, and emotional inertia across the monitoring period. Results: Overall, four profiles were identified, which we labeled as: (1) "very negative and least variable mood" (n = 14) (2) "negative and moderate variable mood" (n = 204), (3) "positive and moderate variable mood" (n = 41), and (4) "negative and highest variable mood" (n = 28). The degree of emotional inertia was virtually identical across the profiles. Conclusions: The real-time monitoring conducted in the present study provides some preliminary indications of different patterns of both average mood and mood variability among MDD patients in treatment in mental health settings. Such varying patterns were not found for emotional inertia.

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.

The Effects of Common Genetic Variation in 96 Genes Involved in Thyroid Hormone Regulation on TSH and FT4 Concentrations.

OBJECTIVE: While most of the variation in thyroid function is determined by genetic factors, single nucleotide polymorphisms (SNPs) identified via genome-wide association analyses have only explained ~5% to 9% of this variance so far. Most SNPs were in or nearby genes with no known role in thyroid hormone (TH) regulation. Therefore, we performed a large-scale candidate gene study investigating the effect of common genetic variation in established TH regulating genes on serum thyrotropin [thyroid-stimulating hormone (TSH)] and thyroxine (FT4) concentrations. METHODS: SNPs in or within 10 kb of 96 TH regulating genes were included (30 031 TSH SNPs, and 29 962 FT4 SNPs). Associations were studied in 54 288 individuals from the ThyroidOmics Consortium. Linkage disequilibrium-based clumping was used to identify independently associated SNPs. SNP-based explained variances were calculated using SumHer software. RESULTS: We identified 23 novel TSH-associated SNPs in predominantly hypothalamic-pituitary-thyroid axis genes and 25 novel FT4-associated SNPs in mainly peripheral metabolism and transport genes. Genome-wide SNP variation explained ~21% (SD 1.7) of the total variation in both TSH and FT4 concentrations, whereas SNPs in the 96 TH regulating genes explained 1.9% to 2.6% (SD 0.4). CONCLUSION: Here we report the largest candidate gene analysis on thyroid function, resulting in a substantial increase in the number of genetic variants determining TSH and FT4 concentrations. Interestingly, these candidate gene SNPs explain only a minor part of the variation in TSH and FT4 concentrations, which substantiates the need for large genetic studies including common and rare variants to unravel novel, yet unknown, pathways in TH regulation.

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.