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Background Patterns of nodal involvement in adenoid cystic carcinoma (ACC) of the head and neck have not been sufficiently assessed to guide a decision of prophylactic neck dissection (ND). The objective of this study is to analyse the influence of ND on event-free survival (EFS) for patients with cN0 ACC. Patients and methods A multicentre prospective study was conducted between 2009 and 2018. Patients presenting cN0 non-metastatic ACC on any site, and who received surgery on the tumour, were included. EFS was the main judgement criterion. A comparative survival analysis between the groups that received a ND versus those that did not was performed, using a propensity score. Analyses were carried out using the R software. Results Between 2009 and 2018, 322 patients with cN0 ACC were included, out of which 58% were female. The average age was 53 years. Tumours were in minor salivary glands in 58% of cases, and 52% had T3/T4 stages. ND was performed on 46% of patients. Out of them, seven had histological lymph node invasion, out of which six had tumour infiltration in the mucosa of oral cavity. After propensity score, the median EFS for N0 patients with ND was 72 months (95% Confidence Interval (CI) [48–81]), compared to 73 months (95% CI [52–85]) for patients without ND (HR = 1.33; 95% CI [0.82–2.16]; p = 0.2). Conclusion ND of cN0 patients does not provide any benefit on EFS, which suggests that its application on such patients is not necessary.

OBJECTIVES: Tinnitus is a common and burdensome disease, often accompanied by complaints of poor sleep. However, associations of tinnitus with objective estimates of sleep remain unclear, particularly in the general population. We assessed these associations in a population-based cohort of middle-aged and elderly persons.DESIGN: This study included 1456 participants (mean age: 65.0 ± 7.1 years, 52% women) from the population-based Rotterdam Study. Tinnitus was self-reported and in those who reported tinnitus daily, symptom severity was assessed with the Tinnitus Handicap Inventory. We used actigraphy to estimate sleep and 24-hour activity rhythms objectively and sleep diaries to assess self-reported sleep. We estimated the difference in sleep and 24-hour activity rhythms first between those with and those without tinnitus and secondly with tinnitus severity.RESULTS: Tinnitus, reported by 341 (23%) participants, and tinnitus severity, assessed in 194 participants with daily tinnitus, were not associated with actigraphy-estimated sleep or 24-hour activity rhythms, but were associated with a longer self-reported sleep onset latency (adjusted difference tinnitus = 2.36, 95% confidence interval [CI] = 0.95-3.78, adjusted difference tinnitus severity = 0.27, 95% CI = 0.013-0.54). After stratification for hearing loss, tinnitus was associated with longer self-reported sleep onset latency (adjusted difference = 2.26, 95% CI = 0.98-3.53) and less stable 24-hour activity rhythms (adjusted difference = -0.02, 95% CI = -0.04 to -0.00) in those with hearing loss. In those without hearing loss, tinnitus was associated with more stable rhythms (adjusted difference = 0.03, 95% CI = 0.01-0.05).CONCLUSIONS: Having tinnitus is associated with a longer self-reported sleep onset latency, but not with objective estimates of sleep, suggesting that the subjective experience of sleep may be particularly disturbed in those with tinnitus. In addition, hearing loss may modify the association of tinnitus and 24-hour activity rhythms.

International audience; ObjectiveTo assess long-term quality of life (QoL) and psycho-social outcomes, and to determine their predictive factors after oropharyngeal cancer (OPC) surgery and radial forearm free-flap (RFFF) reconstruction.MethodsPatients who had undergone OPC surgery and RFFF reconstruction who were still alive and disease-free at least 1 year after surgery were enrolled in this prospective multicentric study. Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Core (QLQ-C30) and Head and Neck Cancer (QLQ-H&N35) QoL questionnaires, the Voice Handicap Index (VHI-10) questionnaire and the Hospital Anxiety and Depression Scale (HADS). The level of dysphagia was evaluated using the Dysphagia Handicap Index (DHI) and the Dysphagia Outcomes and Severity Scale (DOSS). Predictive factors of these clinical outcomes were determined in univariate and multivariate analysis.ResultsA total of 58 patients were included in this study. Long-term QoL and functioning scales scores were well-preserved (all superior to 70%). Main persistent symptoms were fatigue, reduced sexuality and oral function-related disorders (swallowing, teeth, salivary and mouth-opening problems). HADS anxiety and depression scores were 7.2 and 5.4, respectively. Twenty-one (36%) patients presented an anxiodepressive disorder (HADS global score ≥ 15). Among the 21 patients who were still working before surgery, 11 (52%) had returned to work at the time of our study. The HADS global score (p < 0.001) was the main predictor of QoL, VHI-10 and DOSS scores.ConclusionsPsychological distress is the main determinant of long-term QoL and is therefore of critical importance in the multidisciplinary management of OPC patients.

Introduction: Anastomotic leakage is a severe complication after oesophageal resection with gastric conduit reconstruction. Poor perfusion of the gastric conduit plays an important role in the development of anastomotic leakage. Quantitative near-infrared (NIR) fluorescence angiography with indocyanine green (ICG-FA) is an objective technique that can be used for perfusion assessment. This study aims to assess perfusion patterns of the gastric conduit with quantitative ICG-FA. Methods: In this exploratory study, 20 patients undergoing oesophagectomy with gastric conduit reconstruction were included. A standardized NIR ICG-FA video of the gastric conduit was recorded. Postoperatively, the videos were quantified. Primary outcomes were the time-intensity curves and nine perfusion parameters from contiguous regions of interest on the gastric conduit. A secondary outcome was the inter-observer agreement of subjective interpretation of the ICG-FA videos between six surgeons. The inter-observer agreement was tested with an intraclass correlation coefficient (ICC). Results: In a total of 427 curves, three distinct perfusion patterns were recognized: pattern 1 (steep inflow, steep outflow); pattern 2 (steep inflow, minor outflow); and pattern 3 (slow inflow, no outflow). All perfusion parameters were significantly different between the perfusion patterns. The inter-observer agreement was poor – moderate (ICC:0.345,95%CI:0.164–0.584). Discussion: This was the first study to describe perfusion patterns of the complete gastric conduit after oesophagectomy. Three distinct perfusion patterns were observed. The poor inter-observer agreement of the subjective assessment underlines the need for quantification of ICG-FA of the gastric conduit. Further studies should evaluate the predictive value of perfusion patterns and parameters on anastomotic leakage.

Inferior frontal cortex pars opercularis (IFCop) features a distinct cerebral dominance and vast functional heterogeneity. Left and right IFCop are implicated in developmental stuttering. Weak left IFCop connections and divergent connectivity of hyperactive right IFCop regions have been related to impeded speech. Here, we reanalyzed diffusion magnetic resonance imaging data from 83 children (41 stuttering). We generated connection probability maps of functionally segregated area 44 parcels and calculated hemisphere-wise analyses of variance. Children who stutter showed reduced connectivity of executive, rostral-motor, and caudal-motor corticostriatal projections from the left IFCop. We discuss this finding in the context of tracing studies from the macaque area 44, which leads to the need to reconsider current models of speech motor control. Unlike the left, the right IFCop revealed increased connectivity of the inferior posterior ventral parcel and decreased connectivity of the posterior dorsal parcel with the anterior insula, particularly in stuttering boys. This divergent connectivity pattern in young children adds to the debate on potential core deficits in stuttering and challenges the theory that right hemisphere differences might exclusively indicate compensatory changes that evolve from lifelong exposure. Instead, early right prefrontal connectivity differences may reflect additional brain signatures of aberrant cognition–emotion–action influencing speech motor control.

OBJECTIVE: Patient-reported voice quality is an important outcome during counseling in early-stage glottic cancer. However, there is a paucity of adequate longitudinal studies concerning voice outcomes. This study aimed to investigate longitudinal trajectories for patient-reported voice quality and associated risk factors for treatment modalities such as transoral CO2 laser microsurgery, single vocal cord irradiation, and local radiotherapy.STUDY DESIGN: A longitudinal observational cohort study.SETTING: Tertiary cancer center.METHODS: Patients treated for Tcis-T1b, N0M0 glottic cancer were included in this study (N = 294). The Voice Handicap Index was obtained at baseline and during follow-up (N = 1944). Mixed-effects models were used for investigating the different trajectories for patient-reported voice quality.RESULTS: The mean follow-up duration was 43.4 (SD 21.5) months. Patients received transoral CO2 laser microsurgery (57.8%), single vocal cord irradiation (24.5%), or local radiotherapy (17.5%). A steeper improvement during the first year after treatment for single vocal cord irradiation (-15.7) and local radiotherapy (-12.4) was seen, compared with a more stable trajectory for laser surgery (-6.1). All treatment modalities showed equivalent outcomes during long-term follow-up. Associated risk factors for different longitudinal trajectories were age, tumor stage, and comorbidity.CONCLUSION: Longitudinal patient-reported voice quality after treatment for early-stage glottic cancer is heterogeneous and nonlinear. Most improvement is seen during the first year of follow-up and differs between treatment modalities. No clinically significant differences in long-term trajectories were found. Insight into longitudinal trajectories can enhance individual patient counseling and provide the foundation for an individualized dynamic prediction model.

Objective: To identify risk factors of hearing decline between 9 and 13 years of age. The risk factors examined included sociodemographic, health, and lifestyle-related factors. Methods: This study was embedded within a population-based prospective cohort study from fetal life onwards in the Netherlands. Pure-tone audiometry and tympanometry were performed at the age of 9 and 13 years. The hearing decline was defined as an increase in low-frequency or high-frequency pure-tone average of at least 5 dB in one of both ears. Multivariable logistic regression was performed to examine the association of possible risk factors with hearing decline. The study was conducted from April 2012 to October 2015, and from April 2016 to September 2019. Results: Of the 3,508 participants included, 7.8% demonstrated a hearing decline in the low frequencies, and 11.3% in the high frequencies. Participants who reported alcohol consumption were more likely to have a hearing decline in the low frequencies (OR 1.5, 95% CI 1.1; 2.0). Moreover, a lower educational level was associated with an increased odds of having a hearing decline in the high frequencies (OR 1.4, 95% CI 1.0; 1.8). Age, sex, household income, personal music player use, and body mass index were not associated with hearing decline. Conclusion: Educational level and risky behavior were significantly associated with hearing decline from childhood to early adolescence. The findings of the present study can help in the design of public health interventions to prevent hearing loss at a young age. Level of Evidence: 2 (prospective cohort study) Laryngoscope, 133:389–395, 2023.

Esophageal adenocarcinoma causes 6% of cancer-related deaths worldwide. Near-infrared fluorescence molecular endoscopy (NIR-FME) uses a tracer that targets overexpressed proteins. In this study, we aimed to investigate the feasibility of an epidermal growth factor receptor (EGFR)-targeted tracer, cetuximab-800CW, to improve detection of early-stage esophageal adenocarcinoma. Methods: We validated EGFR expression in 73 esophageal tissue sections. Subsequently, we topically administered cetuximab-800CW and performed high-definition white-light endoscopy (HD-WLE), narrow-band imaging, and NIR-FME in 15 patients with Barrett esophagus (BE). Intrinsic fluorescence values were quantified using multidiameter single-fiber reflectance and single-fiber fluorescence spectroscopy. Back-table imaging, histopathologic examination, and EGFR immunohistochemistry on biopsy samples collected during NIR-FME procedures were performed and compared with in vivo imaging results. Results: Immunohistochemical preanalysis showed high EGFR expression in 67% of dysplastic tissue sections. NIR-FME visualized all 12 HD-WLE-visible lesions and 5 HD-WLE-invisible dysplastic lesions, with increased fluorescence signal in visible dysplastic BE lesions compared with nondysplastic BE as shown by multidiameter single-fiber reflectance/single-fiber fluorescence, reflecting a target-to-background ratio of 1.5. Invisible dysplastic lesions also showed increased fluorescence, with a target-to-background ratio of 1.67. Immunohistochemistry analysis showed EGFR overexpression in 16 of 17 (94%) dysplastic BE lesions, which all showed fluorescence signal. Conclusion: This study has shown that NIR-FME using cetuximab-800CW can improve detection of dysplastic lesions missed by HD-WLE and narrow-band imaging.

Background/purpose: Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients’ quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC. Material and methods: We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT. Results: All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions. Conclusion: The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

OBJECTIVES: To study the effectivity of a transformed NAL non-linear version 2 (NAL-NL2) gain prescription for percutaneous bone conduction devices (BCDs) and to investigate how to take into account output constraints for the lower frequencies. DESIGN: The NAL-NL2 prescription was converted to a bone conduction prescription rule. Adaptations were needed, as this converted rule prescribes more output at low frequencies than the device delivers. Three adaptations with different audibility and compression were compared. Setting 1 (S1, "optimal audibility") had most audibility due to adapted frequency-dependent compression, setting 2 (S2, "moderate audibility") had moderate output reduction below 1 kHz, and setting 3 (S3, "reduced audibility, least distortion") had most output reduction. Eighteen experienced BCD users rated their relative sound quality in paired comparisons for different sounds (own voice, mixed voices, traffic noise, and music). In addition speech intelligibility in quiet and noise were assessed. RESULTS: The relative sound quality rating for the adapted prescriptions varied between the stimuli: more low-frequency sound was preferred for music (S1 over S3), and less low-frequency sound was preferred for the own voice (S2 and S3 over S1). No differences in quality rating were found for mixed voices or traffic noise. Speech intelligibility in quiet scores at 45 dB SPL was significantly lower for S3 than for S1. Speech intelligibility in noise was significantly reduced in all settings and S3 yielded significantly better speech intelligibility in noise than S1. CONCLUSIONS: With a moderate gain reduction for low frequencies to comply with device constraints the transformed NAL-NL2 prescription was found suitable for fitting BCDs. Perceived sound quality depended on the gain settings, but also on the sound spectra and how the sound was appreciated. A moderate gain reduction below 1 kHz seems to be the optimal adaptation as it has a neutral or positive relative sound quality for all stimuli without negative effects on Speech intelligibility. The NAL-NL2-BC prescribed a sufficient amount of gain, as indicated by the speech tests.

Psychoneurological symptoms are commonly reported by newly diagnosed head and neck cancer (HNC) patients, yet there is limited research on the associations of these symptoms with biomarkers of stress and inflammation. In this article, pre-treatment data of a multi-center cohort of HNC patients were analyzed using a network analysis to examine connections between symptoms (poor sleep quality, anxiety, depression, fatigue, and oral pain), biomarkers of stress (diurnal cortisol slope), inflammation markers (c-reactive protein [CRP], interleukin [IL]-6, IL-10, and tumor necrosis factor alpha [TNF-α]), and covariates (age and body mass index [BMI]). Three centrality indices were calculated: degree (number of connections), closeness (proximity of a variable to other variables), and betweenness (based on the number of times a variable is located on the shortest path between any pair of other variables). In a sample of 264 patients, poor sleep quality and fatigue had the highest degree index; fatigue and CRP had the highest closeness index; and IL-6 had the highest betweenness index. The model yielded two clusters: a symptoms—cortisol slope—CRP cluster and a IL-6—IL-10—TNF-α—age—BMI cluster. Both clusters were connected most prominently via IL-6. Our findings provide evidence that poor sleep quality, fatigue, CRP, and IL-6 play an important role in the interconnections between psychoneurological symptoms and biomarkers of stress and inflammation in newly diagnosed HNC patients.

Background and study aims Retrospectively, minimally 5% of patients with esophageal squamous cell carcinoma (ESCC) and 11 % with head and neck squamous cell carcinoma (HNSCC) in Western countries developed a second primary tumor (SPT). SPT screening in ESCC and HNSCC patients is not implemented routinely in daily practice in many Western countries. This study aimed to assess medical specialist knowledge and opinions regarding screening for head and neck SPTs (HNSPTs) in ESCC patients and vice versa in the Netherlands. Methods A nationwide survey among gastroenterologists and head and neck (HN) surgeons was conducted between December 2020 and March 2021. The survey consisted of 27 questions and focused on knowledge of medical specialists of the prevalence and opinions toward implementing screening for HNSPTs in ESCC patients and vice versa. Results One hundred twenty-eight gastroenterologists (20.5 %) and 31 HN surgeons (50.0 %) completed the survey. The expected median prevalence of HNSPTs in ESCC was 7.0 % (interquartile range [IQR]: 5.0–15.0) among gastroenterologists and 5.0 % (IQR:3.0–8.0) among HN surgeons. For ESPTs in HNSCC, the expected median prevalence was 9.5 % (IQR: 5.0–12.0) among gastroenterologists and 4.0 % (IQR: 2.0–5.0) among HN surgeons. Screening for HNSPTs and ESPTs was considered promising by 35.2 % and 39.6 %, respectively, which increased to 54.7 % of the specialists after providing incidence data on SPTs. Of the HN surgeons, 41.3 % felt they were as capable as gastroenterologists of performing esophageal screening. Conclusions This Dutch nationwide survey revealed a lack of knowledge and different perspectives among specialists about screening to detect SPTs in ESCC and HNSCC patients. Adequate education seems essential to increase awareness among specialists and improve SPT detection, independent of the need for implementation of screening for SPTs in ESCC and HNSCC patients.

Injury : international journal of the care of the injured 53(8), 2774-2782 (2022). doi:10.1016/j.injury.2022.05.009, Published by Elsevier Science, Amsterdam [u.a.]

Patients with mandibular hypoplasia and upper airway obstruction are at an increased risk of feeding and swallowing difficulties. Little has been described regarding these outcomes following mandibular distraction. The aim of this study was to evaluate the effect of mandibular distraction on feeding and swallowing function. A retrospective study was performed on 22 patients with non-isolated mandibular hypoplasia and severe upper airway obstruction treated with mandibular distraction. Median age at first mandibular distraction was 3.1 years (interquartile range 2.3–6.0 years) and the median follow-up time was 3.5 years (interquartile range 2.0–9.4 years). Prior to mandibular distraction, feeding difficulties were present in 18 patients. Swallowing difficulties were present in 20 patients, all of whom had problems in the oral phase of swallowing, while 11 patients had additional problems in the pharyngeal phase. Following mandibular distraction, at the time of follow-up, feeding difficulties persisted in 13 patients. Swallowing difficulties in the oral phase remained present in all 20 patients, while pharyngeal phase problems persisted in seven patients. In conclusion, feeding and swallowing difficulties are highly prevalent in non-isolated patients and often persist following mandibular distraction. Moreover, these can be the reason that decannulation cannot be accomplished. Hence, awareness and close follow-up by a specialized speech therapist is of paramount importance.

Objective Informal caregivers of head and neck cancer (HNC) patients have a high caregiver burden and often face complex practical caregiving tasks. This may result in unmet supportive care needs, which can impact their quality of life (QoL) and cause psychological distress. In this study, we identify caregivers’ unmet needs during long-term follow-up and identify caregivers prone to unmet supportive care needs. Methods Data were used from the multicenter prospective cohort study NETherlands QUality of life and Biomedical cohort studies In Cancer (NET-QUBIC). The unmet supportive care needs, psychological distress, caregiver burden, and QoL were measured for 234 informal caregivers and their related patients at baseline, 3, 6, 12, and 24 months after. Mixed effect models for repeated measurements were used. Results At baseline, most caregivers (70.3%) reported at least one unmet supportive care need, with most of the identified needs in the “healthcare & illness” domain. During the follow-up period, caregivers’ unmet needs decreased significantly in all domains. Nevertheless, 2 years after treatment, 28.3% were still reporting at least one unmet need. Financial problems were increasingly associated with unmet needs over time. Furthermore, caring for a patient who themselves had many unmet needs, an advanced tumor stage, or severe comorbidity was associated with significantly more unmet needs in caregivers. Conclusions The current study shows the strong likelihood of caregivers of HNC patients facing unmet supportive care needs and the interaction between the needs of patients and caregivers. It is important to optimally support informal caregivers by involving them from the start when counseling patients, by providing them with relevant and understandable information, and by referring vulnerable caregivers for (psychosocial) support.

Purpose Despite major improvements in rehabilitation possibilities, children with sensorineural hearing loss are at risk for psychosocial difficulties. These difficulties can impact their educational and career achievements and may be two to three times more common in children with hearing loss compared to those with normal hearing. Early identification of psychosocial difficulties can be facilitated using the Strengths and Difficulties Questionnaire (SDQ) and may improve outcomes and quality of life. We implemented the SDQ into the clinical follow-up of children with hearing loss in a tertiary referral hospital. With this, prevalence and severity of difficulties in specific psychosocial domains and several predictors were investigated. Methods A retrospective, cross-sectional investigation was performed of the following factors in association with the SDQ results: type of hearing device, type and degree of hearing loss, speech perception in quiet and in noise, and type of schooling. Results Between June 2020 and January 2022, parents of 312 children (age 4–18) completed the SDQ. An additional 113 child-reports were completed. The response rate of the parents was 69%. Problems with peer relationships and prosocial behavior were the most affected areas with clinically elevated scores in 22% of the children. Psychosocial difficulties were distributed similarly across types of hearing device, nature and degrees of hearing loss, and educational settings. Better speech perception in quiet was significantly associated with fewer parent-reported conduct problems. Conclusion The results of the present study suggest that children with hearing loss may be at risk of experiencing challenges with social interactions and attachment in social contexts. Using the SDQ in clinical follow-up may improve the chances for early psychological assessment and intervention. In addition, the study found that children’s mental health may be impacted by their communication abilities.

Near-infrared (NIR) fluorescence imaging using exogenous fluorescent agents provides whole-field images in real-time to assist the surgeon in the excision of a tumor. Although the method has high sensitivity, the specificity can sometimes be lower than expected. Raman spectroscopy can detect tumors with high specificity. Therefore, a combination of both techniques can be advantageous. A complication that must be addressed is that the NIR spectral region is favored by both techniques for (in vivo) tissue analysis. When fluorescence and Raman emissions spectrally overlap, it becomes challenging or impossible to detect the Raman signal. In this paper, by avoiding this overlap, we describe a Raman spectroscopy setup capable of recording high-quality Raman spectra from tissue containing NIR exogenous fluorescent agents. We identify an optimal wavelength interval (900-915 nm) for Raman excitation, which avoids both excitation of fluorescent dyes and Raman signal self-absorption by the tissue. In this way, Raman spectroscopy can be combined with the currently most-used NIR fluorescent dyes. This combined novel setup could pave the way for clinical trials benefiting from both fluorescence imaging and Raman spectroscopy to avoid positive margins in cancer surgery.

Research examining the development of behavior, emotions and language, and their intertwining is limited as only few studies had a longitudinal design, mostly with a short follow-up period. Moreover, most studies did not evaluate whether internalizing symptoms and externalizing symptoms are independently associated with language ability. This study examines bidirectional associations between internalizing symptoms, externalizing symptoms and language ability in childhood in a large, population-based cohort. Longitudinal data from the Millennium Cohort Study, a cohort of children in the United Kingdom followed from birth to 11 years (n = 10,878; 50.7% boys), were analyzed. Internalizing and externalizing symptoms were based on parent reports. Language ability (higher scores reflecting poorer ability) was assessed by trained interviewers at ages 3, 5, 7 and 11 years. Structural Equation Models (SEM) were performed, including random-intercept cross-lagged panel models (RI-CLPM) and cross-lagged panel models (CLPM). Internalizing symptoms, externalizing symptoms and language ability were stable over time and co-occur with each other from early life onwards. Over time, externalizing symptoms in early childhood were associated with less growth in language skills and with increases in internalizing symptoms. In late childhood, language ability was negatively associated with later internalizing and externalizing symptoms. The early start, co-occurrence and persistent nature of internalizing symptoms, externalizing symptoms and (poorer) language ability highlights the importance of comprehensive assessments in young children who present problems in one of these domains. Specifically, among children in the early grades of elementary school, those with language difficulties may benefit from careful monitoring as they are more likely to develop difficulties in behavior and emotions.

Stuttering is a neurodevelopmental disorder affecting 5–8 % of preschool-age children, continuing into adulthood in 1 % of the population. The neural mechanisms underlying persistence and recovery from stuttering remain unclear and little information exists on neurodevelopmental anomalies in children who stutter (CWS) during preschool age, when stuttering symptoms typically first emerge. Here we present findings from the largest longitudinal study of childhood stuttering to date, comparing children with persistent stuttering (pCWS) and those who later recovered from stuttering (rCWS) with age-matched fluent peers, to examine the developmental trajectories of both gray matter volume (GMV) and white matter volume (WMV) using voxel-based morphometry. A total of 470 MRI scans were analyzed from 95 CWS (72 pCWS and 23 rCWS) and 95 fluent peers between 3 and 12 years of age. We examined overall group and group by age interactions in GMV and WMV in preschool age (3–5 years old) and school age (6–12 years old) CWS and controls, controlling for sex, IQ, intracranial volume, and socioeconomic status. The results provide broad support for a possible basal ganglia-thalamocortical (BGTC) network deficit starting in the earliest phases of the disorder and point to normalization or compensation of earlier occurring structural changes associated with stuttering recovery.

ObjectiveTo describe the association between midlife carotid atherosclerosis and late-life hearing loss among participants in the Atherosclerosis Risk in Communities (ARIC) study.Design, Setting, and ParticipantsFor this cross-sectional study and temporal analysis of a cohort within the ongoing ARIC prospective cohort study, participants were recruited from 4 communities in the US. The analysis evaluated information on mean carotid intima-media thickness (cIMT), from visit 1 (1987-1989) to visit 4 (1994-1996), carotid plaque presence at visit 4, and audiometric data from visit 6 (2016-2017). The cIMT measures were calculated from ultrasonography recordings by trained readers at the ARIC Ultrasound Reading Center. At each visit, cIMT was computed as the average of 3 segments: the distal common carotid, the carotid artery bifurcation, and the proximal internal carotid arteries. Presence of carotid plaque was determined based on an abnormal wall thickness, shape, or wall texture. Audiometric 4-frequency pure tone average (PTA) was measured and calculated for the better-hearing ear and modeled as a continuous variable. Linear regression estimated the association between cIMT and carotid plaque with hearing, adjusting for age, sex, race and study center, education level, body mass index (calculated as weight in kilograms divided by height in meters squared), smoking status, hypertension, cholesterol levels, diabetes, and exposure to occupational noise. Missing data (exposure and covariates) were imputed with multiple imputation by chained equations. Data analyses were performed from April 6 to July 13, 2022.Main Outcomes and MeasuresHearing loss assessed using 4-frequency (0.5, 1.0, 2.0, and 4.0 kilohertz) PTA for both ears and carotid plaque at visit 4 and mean cIMT from visit 1 to visit 4.ResultsAmong a total of 3594 participants (mean [SD] age at visit 4, 59.4 [4.6] years; 2146 [59.7%] female; 819 [22.8%] Black and 2775 [77.2%] White individuals), fully adjusted models indicated that an additional 0.1 mm higher mean cIMT was associated with 0.59 dB (95% CI, 0.17 to 1.02 dB) higher PTA. Compared with participants without carotid plaque, plaque presence was associated with 0.63 dB (95% CI, −0.57 to 1.84 dB) higher PTA.Conclusion and RelevanceThe findings of this cross-sectional study with temporal analyses of a cohort with the ongoing ARIC study found that subclinical atherosclerosis in midlife was associated with worse hearing in older adulthood. Prevention and control of carotid atherosclerosis during middle age may positively affect the hearing health of older adults.

Introduction Care for head and neck cancers is complex in particular for the rare ones. Knowledge is limited and histological heterogeneity adds complexity to the rarity. There is a wide consensus that to support clinical research on rare cancer, clinical registries should be developed within networks specializing in rare cancers. In the EU, a unique opportunity is provided by the European Reference Networks (ERN). The ERN EURACAN is dedicated to rare adults solid cancers, here we present the protocol of the EURACAN registry on rare head and neck cancers (ClinicalTrials.gov Identifier: NCT05483374). Study design Registry-based cohort study including only people with rare head and neck cancers. Objectives to help describe the natural history of rare head and neck cancers; to evaluate factors that influence prognosis; to assess treatment effectiveness; to measure indicators of quality of care. Methods Settings and participants It is an hospital based registry established in hospitals with expertise in head and neck cancers. Only adult patients with epithelial tumours of nasopharynx; nasal cavity and paranasal sinuses; salivary gland cancer in large and small salivary glands; and middle ear will be included in the registry. This registry won’t select a sample of patients. Each patient in the facility who meets the above mentioned inclusion criteria will be followed prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for the patient follow-up. Variables Data will be collected on patient characteristics (eg. patient demographics, lifestyle, medical history, health status); exposure data (eg. disease, procedures, treatments of interest) and outcomes (e.g. survival, progression, progression-free survival, etc.). In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will be also collected. Statistical methods The data analyses will include descriptive statistics showing patterns of patients’ and cancers’ variables and indicators describing the quality of care. Multivariable Cox’s proportional hazards model and Hazard ratios (HR) for all-cause or cause specific mortality will be used to determine independent predictors of overall survival, recurrence etc. Variables to include in the multivariable regression model will be selected based on the results of univariable analysis. The role of confounding or effect modifiers will be evaluated using stratified analysis or sensitivity analysis. To assess treatment effectiveness, multivariable models with propensity score adjustment and progression-free survival will be performed. Adequate statistical (eg. marginal structural model) methods will be used if time-varying treatments/confounders and confounding by indication (selective prescribing) will be present. Results The registry initiated recruiting in May 2022. The estimated completion date is December 2030 upon agreement on the achievement of all the registry objectives. As of October 2022, the registry is recruiting. There will be a risk of limited representativeness due to the hospital-based nature of the registry and to the fact that hospital contributing to the registry are expert centres for these rare cancers. Clinical Follow-up could also be an issue but active search of the life status of the patients will be guaranteed.

Silver oxide (AgO) thin films were prepared by using a cylindrical direct current reactive magnetron sputtering system at 10−5 torr initial pressure on BK7 glass substrate. Samples deposited for 3, 5 and 7 minutes. Surface characterization of AgO thin films in the nanometer scale can be accurately determined using the atomic force microscopy (AFM) and X-ray diffraction (XRD). The average roughness (Ravg), maximum peak to valley height (Rt) and root mean square (Rrms) roughness are used to analyze the surface morphology of AgO films. The linear optical absorption data were measured in the visible-near infrared spectral regions and the nonlinear refractive index (n2) of thin films is evaluated by the moiré deflectometery technique. The investigation indicates that, increase in AgO thickness leads to reduction in nonlinear refractive index.

BackgroundLooking older for one’s chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which facial ageing reflects systemic ageing of the human body.ObjectivesTo investigate the association between ΔPA and age-related morbidities of different organ systems, where ΔPA represents the difference between perceived age (PA) and chronological age.MethodsWe performed a cross-sectional analysis on data from the Rotterdam Study, a population-based cohort study in the Netherlands. High-resolution facial photographs of 2679 men and women aged 51.5–87.8 years of European descent were used to assess PA. PA was estimated and scored in 5-year categories using these photographs by a panel of men and women who were blinded for chronological age and medical history. A linear mixed model was used to generate the mean PAs. The difference between the mean PA and chronological age was calculated (ΔPA), where a higher (positive) ΔPA means that the person looks younger for their age and a lower (negative) ΔPA that the person looks older. ΔPA was tested as a continuous variable for association with ageing-related morbidities including cardiovascular, pulmonary, ophthalmological, neurocognitive, renal, skeletal and auditory morbidities in separate regression analyses, adjusted for age and sex (model 1) and additionally for body mass index, smoking and sun exposure (model 2).ResultsWe observed 5-year higher ΔPA (i.e. looking younger by 5 years for one’s age) to be associated with less osteoporosis [odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62–0.93], less chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77–0.95), less age-related hearing loss (model 2; B = −0.76, 95% CI −1.35 to −0.17) and fewer cataracts (OR 0.84, 95% CI 0.73–0.97), but with better global cognitive functioning (g-factor; model 2; B = 0.07, 95% CI 0.04–0.10).ConclusionsPA is associated with multiple morbidities and better cognitive function, suggesting that systemic ageing and cognitive ageing are, to an extent, externally visible in the human face.

Contains fulltext : 273921.pdf (Publisher’s version ) (Open Access) BACKGROUND: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti. METHODS: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated. RESULTS: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass. CONCLUSION: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC.

This scoping review addresses the challenges of neuroanesthesiologic research: the population, the methods/treatment/exposure, and the outcome/results. These challenges are put into the context of a future research agenda for peri-/intraoperative anesthetic management, neurocritical care, and applied neurosciences. Finally, the opportunities of adaptive trial design in neuroanesthesiologic research are discussed.

Purpose The purpose of this study was to assess whether the vascularisation of the meniscus could be visualised intra-operatively using near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) in patients undergoing total knee arthroplasty (TKA). Methods The anterior horn (i.e., Cooper classification: zones C and D) of the meniscus that was least affected (i.e., least degenerative) was removed during TKA surgery in ten patients to obtain a cross section of the inside of the meniscus. Thereafter, 10 mg of ICG was injected intravenously, and vascularisation of the cross section of the meniscus was assessed using the Quest spectrum NIRF camera system. We calculated the percentage of patients in whom vascularisation was observed intra-operatively using NIRF imaging compared to immunohistochemistry. Results Meniscal vascularisation using NIRF imaging was observed in six out of eight (75%) patients in whom vascularisation was demonstrated with immunohistochemistry. The median extent of vascularisation was 13% (interquartile range (IQR) 3–28%) using NIRF imaging and 15% (IQR 11–23%) using immunohistochemistry. Conclusion This study shows the potential of NIRF imaging to visualise vascularisation of the meniscus, as vascularisation was observed in six out of eight patients with histologically proven meniscal vascularisation. Level of evidence IV.

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.

Purpose: Very preterm (VPT) children are at risk for speech and language problems throughout school age. However, little is known about early speech sound production in these children. This study aims to present a detailed description of early speech sound production and its trajectories in VPT children from 2 to 4 years of age. In addition, this study aimed to determine if early speech sound production is associated with speech production and expressive language function at 4 years of age. Method: In 63 VPT children (< 32 weeks of gestation, 41 boys, mean gestational age = 28.8 weeks, mean birth weight = 1,135 g), speech sound production was assessed by naturalistic speech analysis at 2 years of corrected age and speech and language function by standardized tests at 4 years of age. Results: Speech sound production was found to be abnormal in 49% of the VPT children at 2 years of age and in 19% at 4 years of age. Four different speech production trajectories from 2 to 4 years of age could be identified: a normal trajectory, an abnormal trajectory, a catch-up trajectory, and a growing-into-deficit trajectory. Early speech production, defined by the number of acquired consonants at 2 years of age, significantly predicted the word production score at 4 years of age and the sentence production score at 4 years of age. Conclusions: Compared to the general population, an alarmingly high proportion of VPT children showed speech production problems at 2 years of age. About half of these children showed persistent speech problems at 4 years of age. Moreover, these problems were associated with expressive language problems at the age of 4 years. Supplemental Material: https://doi.org/10.23641/asha.19310822

Contains fulltext : 246727.pdf (Publisher’s version ) (Open Access) Background: This study assessed the course of fear of cancer recurrence (FCR) in patients newly diagnosed with head and neck cancer (HNC), identified FCR trajectories and factors associated with FCR trajectories. Methods: Six hundred and seventeen HNC patients from the NET-QUBIC cohort study completed the Cancer Worry Scale-6 at diagnosis, 3 and 6 months post-treatment. FCR trajectories were identified using Latent Class Growth Analysis. Associations were explored between FCR trajectories and baseline demographic and medical variables, coping and self-efficacy. Results: Overall, FCR decreased slightly between baseline and 3 months post-treatment and remained stable up to 6 months. Two FCR trajectories were identified: "high stable" (n = 125) and "low declining" (n = 492). Patients with high stable FCR were younger, reported more negative adjustment, passive coping, and reassuring thoughts, and less avoidance. Conclusions: The majority of HNC patients have low declining FCR after diagnosis, but one in five patients experience persistent high FCR up to 6 months post-treatment. 12 p.

Objectives: To examine whether adolescents exceed recommended noise exposure limits when using personal listening devices (PLDs) and to investigate the relationship between objectively measured PLD use and hearing thresholds Study Design: Cross-sectional study. Setting: This study was embedded within an ongoing prospective birth cohort study in Rotterdam, the Netherlands. Data were collected from May 2017 to September 2019. Methods: A smartphone application was developed to measure daily noise exposure from PLDs. Listening habits were monitored among 314 adolescents with a mean age of 13 years 7 months (SD, 5 months), of whom 51.6% were male. Hearing acuity was measured by pure tone audiometry, and tympanometry was performed in both ears. Results: Within the study group, 2.2% adolescents exceeded the recommended daily noise dose (85 dBA as an 8-hour time-weighted average) among all days when the application was active and 9.9% when among only the listening days. No significant correlation was found between the daily noise dose from PLDs and pure tone thresholds. Conclusions: The majority of adolescents exhibited listening habits that could be considered safe. As noise-induced hearing loss develops slowly over time, it could be that the effects of PLD use on hearing are not evident yet in this young population with a relatively short duration of PLD use.

OBJECTIVES: Antibiotics may contribute to the development of functional gastrointestinal disorders (FGIDs). This study aimed to determine whether antibiotics during the first week of life, infantile colic in the first year of life, gut-associated immune markers at 1 year of age, and allergies at 4-6 years of age in term-born children were associated with a higher prevalence of FGIDs at 4-6 years of age. METHODS: A prospective observational cohort of 436 term-born infants was followed up at the age of 4-6 years; 151 received broad-spectrum antibiotics (AB+), and 285 healthy controls (AB-). Validated Questionnaire On Pediatric Gastrointestinal Symptoms-Rome III and International Study of Asthma and Allergy in Childhood questionnaires were sent to parents of 418 available children. The independent t-test, chi-squared test or non-parametric test and logistic multivariate regression analyses were used. RESULTS: In total, 340 of 418 (81%) questionnaires were completed. Only the presence of functional abdominal pain was significantly higher in AB+ than AB- (4% vs 0.4%, respectively, P = 0.045). Children with food allergy fulfilled significantly more often the criteria for irritable bowel syndrome (IBS) and abdominal migraine (26% vs 9%, P = 0.002 and 7% vs 1%, P = 0.043, respectively) compared to non-allergic children. No differences in FGIDs existed at the age of 4-6 years between children with and without a history of infantile colic. There were significant differences in gut-associated immune markers between children with and without FGIDs. CONCLUSION: Antibiotics during the first week of life resulted in a higher risk for functional abdominal pain at 4-6 years. Furthermore, food allergy was associated with IBS and abdominal migraine at 4-6years.

Objective: To date, no hearing-specific self-report tool is available in Dutch to give insight into how deficits in auditory skills are experienced by a child in daily life or to examine the impact of hearing loss on children’s quality of life. Therefore, we aimed to translate and validate the Speech, Spatial, and Qualities of Hearing Scale (SSQ) and the Hearing Environments and Reflection on Quality of Life (HEAR-QL) Questionnaire for children and adolescents into Dutch. Design: Translation of the questionnaires into Dutch was conducted by means of the forward-backward procedure. Participants were invited to complete the questionnaires digitally. We examined discriminant validity, internal consistency, and test-retest reliability. Study sample: A total of 121 subjects between 7 and 18 years old were included, of which 54 normal hearing and 67 bilaterally hearing-impaired subjects. Hearing-impaired subjects were fitted with hearing aids, bone conductive devices and/or cochlear implants. Results: All questionnaires were shown to significantly discriminate between the normal hearing and the hearing-impaired group. Satisfying internal consistency and good test-retest reliability were found. Conclusions: The Dutch SSQ and HEAR-QL questionnaires for children and adolescents appear to be valid and reliable self-report tools for management and follow-up of those with hearing loss.

Purpose: This study aimed to evaluate the effect of speech recognition performance, working memory capacity (WMC), and a noise reduction algorithm (NRA) on listening effort as measured with pupillometry in cochlear implant (CI) users while listening to speech in noise. Method: Speech recognition and pupil responses (peak dilation, peak latency, and release of dilation) were measured during a speech recognition task at three speech-to-noise ratios (SNRs) with an NRA in both on and off conditions. WMC was measured with a reading span task. Twenty experienced CI users participated in this study. Results: With increasing SNR and speech recognition performance, (a) the peak pupil dilation decreased by only a small amount, (b) the peak latency decreased, and (c) the release of dilation after the sentences increased. The NRA had no effect on speech recognition in noise or on the peak or latency values of the pupil response but caused less release of dilation after the end of the sentences. A lower reading span score was associated with higher peak pupil dilation but was not associated with peak latency, release of dilation, or speech recognition in noise. Conclusions: In CI users, speech perception is effortful, even at higher speech recognition scores and high SNRs, indicating that CI users are in a chronic state of increased effort in communication situations. The application of a clinically used NRA did not improve speech perception, nor did it reduce listening effort. Participants with a relatively low WMC exerted relatively more listening effort but did not have better speech reception thresholds in noise.

Despite promising clinical results in osteochondral defect repair, a recently developed bi-layered collagen/collagen-magnesium-hydroxyapatite scaffold has demonstrated less optimal subchondral bone repair. This study aimed to improve the bone repair potential of this scaffold by adsorbing bone morphogenetic protein 2 (BMP-2) and/or platelet-derived growth factor-BB (PDGF-BB) onto said scaffold. The in vitro release kinetics of BMP-2/PDGF-BB demonstrated that PDGF-BB was burst released from the collagen-only layer, whereas BMP-2 was largely retained in both layers. Cell ingrowth was enhanced by BMP-2/PDFG-BB in a bovine osteochondral defect ex vivo model. In an in vivo semi-orthotopic athymic mouse model, adding BMP-2 or PDGF-BB increased tissue repair after four weeks. After eight weeks, most defects were filled with bone tissue. To further investigate the promising effect of BMP-2, a caprine bilateral stifle osteochondral defect model was used where defects were created in weight-bearing femoral condyle and non-weight-bearing trochlear groove locations. After six months, the adsorption of BMP-2 resulted in significantly less bone repair compared with scaffold-only in the femoral condyle defects and a trend to more bone repair in the trochlear groove. Overall, the adsorption of BMP-2 onto a Col/Col-Mg-HAp scaffold reduced bone formation in weight-bearing osteochondral defects, but not in non-weight-bearing osteochondral defects.

Objectives A previously developed decision model to prioritize surgical procedures in times of scarce surgical capacity used quality of life (QoL) primarily derived from experts in one center. These estimates are key input of the model, and might be more context-dependent than the other input parameters (age, survival). The aim of this study was to validate our model by replicating these QoL estimates. Methods The original study estimated QoL of patients in need of commonly performed procedures in live expert-panel meetings. This study replicated this procedure using a web-based Delphi approach in a different hospital. The new QoL scores were compared with the original scores using mixed effects linear regression. The ranking of surgical procedures based on combined QoL values from the validation and original study was compared to the ranking based solely on the original QoL values. Results The overall mean difference in QoL estimates between the validation study and the original study was − 0.11 (95% CI: -0.12 - -0.10). The model output (DALY/month delay) based on QoL data from both studies was similar to the model output based on the original data only: The Spearman’s correlation coefficient between the ranking of all procedures before and after including the new QoL estimates was 0.988. Discussion Even though the new QoL estimates were systematically lower than the values from the original study, the ranking for urgency based on health loss per unit of time delay of procedures was consistent. This underscores the robustness and generalizability of the decision model for prioritization of surgical procedures.

Simple Summary The treatment outcomes in patients with head and neck cancer vary greatly, and serious side effects are often observed. Being able to predict therapy effects is therefore crucial for choosing the best treatment option for each patient. In this study, we developed an assay to evaluate how head and neck tumor cells respond to radiation and chemotherapy. Treatment of thin patient-derived cancer tissue slices in the laboratory (in vitro) resulted in large differences in individual tumor's reactions to treatment. In the sensitive tumors, cancer cells repaired the DNA damage inflicted by therapy only partially, stopped multiplying, and showed increased levels of cell death. On the other hand, resistant tumors were able to recover from the damage caused by the treatment. The next crucial step is to investigate whether the differences we observed in vitro can indeed predict the treatment outcomes; this is currently being tested in an ongoing clinical trial. Background: Head and neck squamous cell carcinoma (HNSCC) displays a large heterogeneity in treatment response, and consequently in patient prognosis. Despite extensive efforts, no clinically validated model is available to predict tumor response. Here we describe a functional test for predicting tumor response to radiation and chemotherapy on the level of the individual patient. Methods: Resection material of 17 primary HNSCC patients was cultured ex vivo, irradiated or cisplatin-treated, after which the effect on tumor cell vitality was analyzed several days after treatment. Results: Ionizing radiation (IR) affected tumor cell growth and viability with a clear dose-response relationship, and marked heterogeneity between tumors was observed. After a single dose of 5Gy, proliferation in IR-sensitive tumors dropped below 30% of the untreated level, while IR-resistant tumors maintained at least 60% of proliferation. IR-sensitive tumors showed on average a twofold increase in apoptosis, as well as an increased number and size of DNA damage foci after treatment. No differences in the homologous recombination (HR) proficiency between IR-sensitive and -resistant tumors were detected. Cisplatin caused a decrease in proliferation, as well as induction of apoptosis, again with marked variation between the samples. Conclusions: Our functional ex vivo assay discriminated between IR-sensitive and IR-resistant HNSCC tumors, and may also be suitable for predicting response to cisplatin. Its predictive value is currently under investigation in a prospective clinical study.

Objective In order to understand how informal caregivers of head and neck cancer (HNC) patients deal with the consequences of the disease, we investigated their self-efficacy and coping style in relation to symptoms of anxiety and depression (distress) and quality of life (QoL) over time. In addition, factors associated with self-efficacy and coping style were investigated. Methods A total of 222 informal caregivers and their related HNC patients were prospectively followed as part from the multicenter cohort NETherlands QUality of life and Biomedical cohort studies In Cancer (NET-QUBIC). Self-efficacy and coping style were measured at baseline, and distress and QoL at baseline and 3, 6, 12, and 24 months after treatment. Results Informal caregivers had a high level of self-efficacy comparable with patients. Caregivers used “seeking social support,” “passive reacting,” and “expression of emotions” more often than patients. Factors associated with self-efficacy and coping were higher age and lower education. Higher self-efficacy was related with better QoL and “active tackling” was associated with less depression symptoms. “Passive reacting” and “expression of emotions” were associated with higher psychological distress and reduced QoL. Conclusion Among informal caregivers of HNC patients, higher self-efficacy and “active tackling” were associated with better functioning over time, while “passive reacting” and “expression of negative emotions” were associated with worse functioning. Awareness of the differences in self-efficacy skills and coping and their relationship with QoL and psychological distress will help clinicians to identify caregivers that may benefit from additional support that improve self-efficacy and “active tackling” and reduce negative coping styles.

Objective: To investigate the oncological safety and potential cost savings of selective histopathological examination after appendectomy. Background: The necessity of routine histopathological examination after appendectomy has been questioned, but prospective studies investigating the safety of a selective policy are lacking. Methods: In this multicenter, prospective, cross-sectional study, inspection and palpation of the (meso)appendix was performed by the surgeon in patients with suspected appendicitis. The surgeon's opinion on additional value of histopathological examination was reported before sending all specimens to the pathologist. Main outcomes were the number of hypothetically missed appendiceal neoplasms with clinical consequences benefiting the patient (upper limit two-sided 95% confidence interval below 3:1000 considered oncologically safe) and potential cost savings after selective histopathological examination. Results: Seven thousand three hundred thirty-nine patients were included. After a selective policy, 4966/7339 (67.7%) specimens would have been refrained from histopathological examination. Appendiceal neoplasms with clinical consequences would have been missed in 22/4966 patients. In 5/22, residual disease was completely resected during additional surgery. Hence, an appendiceal neoplasm with clinical consequences benefiting the patient would have been missed in 1.01:1000 patients (upper limit 95% confidence interval 1.61:1000). In contrast, twice as many patients (10/22) would not have been exposed to potential harm due to re-resections without clear benefit, whereas consequences were neither beneficial nor harmful in the remaining seven. Estimated cost savings established by replacing routine for selective histopathological examination were 725,400 per 10,000 patients. Conclusions: Selective histopathological examination after appendectomy for suspected appendicitis is oncologically safe and will likely result in a reduction of pathologists' workload, less costs, and fewer re-resections without clear benefit.

Tissue engineering bone via endochondral ossification requires the generation of a cartilage template which undergoes vascularisation and remodelling. While this is a promising route for bone repair, achieving effective cartilage vascularisation remains a challenge. Here, we investigated how mineralisation of tissue-engineered cartilage affects its pro-angiogenic potential. To generate in vitro mineralised cartilage, human mesenchymal stromal cell (hMSC)-derived chondrogenic pellets were treated with β-glycerophosphate (BGP). After optimising this approach, we characterised the changes in matrix components and pro-angiogenic factors by gene expression analysis, histology and ELISA. Human umbilical vein endothelial cells (HUVECs) were exposed to pellet-derived conditioned media, and migration, proliferation and tube formation were assessed. We established a reliable strategy to induce in vitro cartilage mineralisation, whereby hMSC pellets are chondrogenically primed with TGF-β for 2 weeks and BGP is added from week 2 of culture. Cartilage mineralisation determines loss of glycosaminoglycans, reduced expression but not protein abundance of collagen II and X, and decreased VEGFA production. Finally, the conditioned medium from mineralised pellets showed a reduced ability to stimulate endothelial cell migration, proliferation and tube formation. The pro-angiogenic potential of transient cartilage is thus stage-dependent, and this aspect must be carefully considered in the design of bone tissue engineering strategies.

Contains fulltext : 292662.pdf (Publisher’s version ) (Open Access) Background & aims: The aim of this study was to investigate the effect of a behavioral intervention on sleep problems, which are significant and an unmet clinical need in children with Angelman Syndrome (AS). Methods & procedures: Children (2-18 years) with AS and sleep problems were randomized to a behavioral intervention program or a control group. Intervention consisted of a standardized program including home visits, psycho-education, feedback based on direct observation of bedtime routine and video footage of the night and behavioral treatment techniques by a behavioral therapist. Change in sleep duration (primary) and parental sleep, nighttime visits, sleep hygiene, daytime behavior, parental stress and quality of life (secondary) were assessed post-intervention and at follow-up using questionnaires, diary, actigraphy and videosomnography. Outcomes & results: The groups, 9 children in each, did not differ at baseline. We found a significant effect of intervention on wake after sleep onset with classical statistical analysis (videosomnography). With single case analysis we found a positive effect on total sleep time (diary and actigraphy) and wake after sleep onset (diary) with a persistent effect on total sleep time (actigraphy) and wake after sleep onset (diary). On secondary outcome there was a significant and persistent effect on sleep hygiene and several quality of life domains. Conclusions & implications: Behavioral intervention has a positive and persistent effect on sleep problems in children with AS. We advise psycho-education for all parents and use of videosomnography for both evaluation of and feedback on sleep behavior patterns, individual behavioral advice and specific behavioral techniques for children with sleep problems. 15 p.

Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1; also known as deleted in oral cancer or DOC1) is a tumor suppressor gene known to play functional roles in both cell cycle regulation and in the epigenetic control of embryonic stem cell differentiation, the latter as a core subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex. In the vast majority of oral squamous cell carcinomas (OSCC), expression of the CDK2AP1 protein is reduced or lost. Notwithstanding the latter (and the DOC1 acronym), mutations or deletions in its coding sequence are extremely rare. Accordingly, CDK2AP1 protein-deficient oral cancer cell lines express as much CDK2AP1 mRNA as proficient cell lines. Here, by combining in silico and in vitro approaches, and by taking advantage of patient-derived data and tumor material in the analysis of loss of CDK2AP1 expression, we identified a set of microRNAs, namely miR-21-5p, miR-23b-3p, miR-26b-5p, miR-93-5p, and miR-155-5p, which inhibit its translation in both cell lines and patient-derived OSCCs. Of note, no synergistic effects were observed of the different miRs on the CDK2AP1–3-UTR common target. We also developed a novel approach to the combined ISH/IF tissue microarray analysis to study the expression patterns of miRs and their target genes in the context of tumor architecture. Last, we show that CDK2AP1 loss, as the result of miRNA expression, correlates with overall survival, thus highlighting the clinical relevance of these processes for carcinomas of the oral cavity.

Background: Patients with end-stage heart failure refractory to medication can be treated with a heart transplant (HTx). These patients are subjected to a preoperative screening procedure according to International Society for Heart and Lung Transplantation guidelines. Additionally, in our hospital, a routine ear, nose, and throat (ENT) screening is performed, directed toward the identification of asymptomatic infections and head and neck neoplasms. There are no studies demonstrating that this screening has additional value in these patients. Methods: To investigate the yield of protocolled ENT screening in candidates for HTx, we retrospectively reviewed the medical records of patients who were subjected to the screening procedure between 2012 and 2020. Results: The study population consisted of 251 patients of whom 177 (70.5%) were male with a median age of 52 years (IQR, 45-59 years). Ten patients (4.0%) were diagnosed with an infection (sinus) or a neoplasm, resulting in a number needed to screen of 25. In all cases, ENT consultation or sinus radiography did not influence the decision to list patients for HTx. Furthermore, no major ENT infections or occurrence of de novo head and neck malignant neoplasm were observed during follow-up after HTx. Conclusions: The clinically relevant yield of protocolled ENT screening in candidates for HTx is low. Based on these findings, we believe that only patients with abnormal findings on a routine sinus computed tomography scan and/or specific ENT complaints should be referred to an otorhinolaryngologist.

Introduction Upper airway stimulation (UAS) with electric activation of the hypoglossal nerve has emerged as a promising treatment for patients with moderate-to-severe obstructive sleep apnea. Objective To retrospectively analyze objective and subjective outcome measures after long-term follow-up in obstructive sleep apnea patients receiving upper airway stimulation. Methods An observational retrospective single-center cohort study including a consecutive series of patients diagnosed with obstructive sleep apnea receiving upper airway stimulation. Results Twenty-five patients were included. The total median apnea-hypopnea index (AHI) significantly decreased from 37.4 to 8.7 events per hour at the 12-month follow-up (p Conclusion Upper airway stimulation is an effective and safe treatment for obstructive sleep apnea in patients with continuous positive airway pressure (CPAP) failure or intolerance. However, it is possible that the existing in and exclusion criteria for UAS therapy in the Netherlands have positively influenced our results.

Contains fulltext : 290931.pdf (Publisher’s version ) (Open Access) This study aimed at investigating the change in social eating problems from diagnosis to 24 months after primary (chemo)radiotherapy and its associations with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. Adult patients from the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) treated with curative intent with primary (chemo)radiotherapy for newly-diagnosed HNC and who provided baseline social eating data were included. Social eating problems were measured at baseline and at 3-, 6-, 12-, and 24-month follow-up, with hypothesized associated variables at baseline and at 6 months. Associations were analyzed through linear mixed models. Included patients were 361 (male: 281 (77.8%), age: mean = 63.3, SD = 8.6). Social eating problems increased at the 3-month follow-up and decreased up to 24 months (F = 33.134, p < 0.001). The baseline-to-24 month change in social eating problems was associated with baseline swallowing-related quality of life (F = 9.906, p < 0.001) and symptoms (F = 4.173, p = 0.002), nutritional status (F = 4.692, p = 0.001), tumor site (F = 2.724, p = 0.001), age (F = 3.627, p = 0.006), and depressive symptoms (F = 5.914, p < 0.001). The 6-24-month change in social eating problems was associated with a 6-month nutritional status (F = 6.089, p = 0.002), age (F = 5.727, p = 0.004), muscle strength (F = 5.218, p = 0.006), and hearing problems (F = 5.155, p = 0.006). Results suggest monitoring social eating problems until 12-month follow-up and basing interventions on patients' features.

Background: Indocyanine green near-infrared fluorescence bowel perfusion assessment has shown its potential benefit in preventing anastomotic leakage. However, the surgeon's subjective visual interpretation of the fluorescence signal limits the validity and reproducibility of the technique. Therefore, this study aimed to identify objective quantified bowel perfusion patterns in patients undergoing colorectal surgery using a standardized imaging protocol. Method: A standardized fluorescence video was recorded. Postoperatively, the fluorescence videos were quantified by drawing contiguous region of interests (ROIs) on the bowel. For each ROI, a time-intensity curve was plotted from which perfusion parameters (n = 10) were derived and analyzed. Furthermore, the inter-observer agreement of the surgeon’s subjective interpretation of the fluorescence signal was assessed. Results: Twenty patients who underwent colorectal surgery were included in the study. Based on the quantified time-intensity curves, three different perfusion patterns were identified. Similar for both the ileum and colon, perfusion pattern 1 had a steep inflow that reached its peak fluorescence intensity rapidly, followed by a steep outflow. Perfusion pattern 2 had a relatively flat outflow slope immediately followed by its plateau phase. Perfusion pattern 3 only reached its peak fluorescence intensity after 3 min with a slow inflow gradient preceding it. The inter-observer agreement was poor-moderate (Intraclass Correlation Coefficient (ICC): 0.378, 95% CI 0.210–0.579). Conclusion: This study showed that quantification of bowel perfusion is a feasible method to differentiate between different perfusion patterns. In addition, the poor-moderate inter-observer agreement of the subjective interpretation of the fluorescence signal between surgeons emphasizes the need for objective quantification.