Population-based study of environmental heavy metal exposure and hearing loss: A systematic review and meta-analysis.

Background and Objectives: Previous studies have shown an association between environmental exposure to heavy metals and hearing loss. However, the findings regarding the relationship between exposure to different metals and hearing loss development are inconsistent. To address this, we conducted a meta-analysis to explore the link between common heavy metal exposures and hearing loss. This study examined the effects of lead (Pb), cadmium (Cd), and mercury (Hg) pollution on hearing loss at various levels, and systematically reviewed the literature on manganese (Mn), barium (Ba), arsenic (As), and hearing loss. Methods: We conducted systematic searches in five major databases, including PubMed, Web of Science, Embase, Cochrane Library, and Scopus. In addition, we searched three Chinese digital libraries: CNKI, Wanfang Data, and Wipu. From an initial pool of 649 articles, we carefully screened and selected 15 articles for further analysis. The effect sizes from these selected studies were synthesized through a meta-analysis to calculate the overall effect size. Results: Our findings showed that: (1) There was a significant association between Pb and Cd exposure and hearing loss; (2) There is a proportional relationship between the increase of metal index detected in blood and hearing loss; (3) In the PTA measurement of hearing loss at different frequencies, the 4 kHz high frequency range had a stronger correlation with hearing loss than the low frequency, with OR 1.44 (1.22, 1.71); and (4) There was a more significant correlation between Barium (Ba) levels in nails and hair than in urine. Conclusions: The study presented evidence of a significant association between human hearing loss and exposure to lead (Pb) and cadmium (Cd). It not only revealed a positive correlation between blood heavy metal concentrations and the incidence of hearing loss but also highlighted that long-term exposure indicators of heavy metals were more indicative of the correlation with hearing loss. Lastly, the study recommends utilizing high frequency 4 kHz for the effective assessment and diagnosis of hearing loss caused by exposure to heavy metals.

Head and neck cancer of unknown primary: unveiling primary tumor sites through machine learning on DNA methylation profiles.

BACKGROUND: The unknown tissue of origin in head and neck cancer of unknown primary (hnCUP) leads to invasive diagnostic procedures and unspecific and potentially inefficient treatment options for patients. The most common histologic subtype, squamous cell carcinoma, can stem from various tumor primary sites, including the oral cavity, oropharynx, larynx, head and neck skin, lungs, and esophagus. DNA methylation profiles are highly tissue-specific and have been successfully used to classify tissue origin. We therefore developed a support vector machine (SVM) classifier trained with publicly available DNA methylation profiles of commonly cervically metastasizing squamous cell carcinomas (n = 1103) in order to identify the primary tissue of origin of our own cohort of squamous cell hnCUP patient's samples (n = 28). Methylation analysis was performed with Infinium MethylationEPIC v1.0 BeadChip by Illumina. RESULTS: The SVM algorithm achieved the highest overall accuracy of tested classifiers, with 87%. Squamous cell hnCUP samples on DNA methylation level resembled squamous cell carcinomas commonly metastasizing into cervical lymph nodes. The most frequently predicted cancer localization was the oral cavity in 11 cases (39%), followed by the oropharynx and larynx (both 7, 25%), skin (2, 7%), and esophagus (1, 4%). These frequencies concord with the expected distribution of lymph node metastases in epidemiological studies. CONCLUSIONS: On DNA methylation level, hnCUP is comparable to primary tumor tissue cancer types that commonly metastasize to cervical lymph nodes. Our SVM-based classifier can accurately predict these cancers' tissues of origin and could significantly reduce the invasiveness of hnCUP diagnostics and enable a more precise therapy after clinical validation.

Essential Palatal Myoclonus and Clicking Tinnitus in a Nine-Year-Old Boy-A Case Report.

The work describes a case of palatal myoclonus with distressing tinnitus in a 9-year-old boy and its successful treatment with injections of botulinum toxin. This case report discusses common questions about myoclonic-induced clicking tinnitus and provides answers. Laryngoscope, 134:397-399, 2024.

[Structured ABEV Exercises for the Treatment of vestibular dysfunction]. / Strukturierte ABEV-Übungen zur Behandlung vestibulärer Funktionsstörungen.

INTRODUCTION: In addition to medication, the standard clinical treatment for vestibular vertigo primarily includes physical therapy in the form of regular exercises. Vertidisan is a future digital health application (DiGA) for structured dizziness therapy. Its content is multimodal and consists of Adaptive Balance and Eye Movements and Visual Stimulation (ABEV) exercises, which are expected to have an anti-vertigo effect through neural learning. METHODS: A cohort study with 104 patients with intra-individual control was conducted to examine the clinical efficacy of solely 16 ABEV exercises for the treatment of peripheral vestibulopathies which are also used digitally in the future DiGA Vertidisan. Using the short version vertigo symptom scale short form1 vertigo and related symptoms (VSS-sf1-VER) of the vertigo-specific and validated VSS rating scale (Vertigo Symptom Scale) as the primary outcome variable, the vertigo scores before therapy (time T0) were compared with the corresponding data at the end of a period of 12-16 weeks (time T1). RESULTS: Complete datasets on T0 and T1 were available for N=104 patients. The mean VSS-sf1-V score decreased from 3.80 (median 4, SD 0.47) to 0.92 (median 1, SD 1.19) from T0 to T1 (weeks 12-16). The result is statistically significant (p=0.001) and shows a high clinical effect size. CONCLUSION: In summary, the analysis of the dizziness score shows a statistically and clinically significant reduction in dizziness through the use of the 16 ABEV exercises.

Novel Discovery of the Somatostatin Receptor (SSTR2) in Pleomorphic Adenomas via Immunohistochemical Analysis of Tumors of the Salivary Glands.

Reliable preoperative diagnosis between salivary gland tumor entities is difficult. In this monocentric retrospective study, we examined the somatostatin receptor 2 (SSTR2) status of salivary gland tumors after salivary gland tumor resection via immunohistochemistry (IHC), and stains were compared in analogy to the HER2 mamma scale. A total of 42.3% of all pleomorphic adenoma (PA) tumors (42 of 99, 95% confidence interval 32.5-52.8%) demonstrated ≥20% of cells displaying the SSTR2 as compared to just 1% of all other tumors (1/160, 95% CI 0.02-3.4%). The other tumor was a neuroendocrine carcinoma. PA had a higher intensity of SSTR2 staining, with 90.9% staining ≥ an intensity of 2 (moderate). Tumors with an intensity of SSTR2 expression equal to or greater than 2 had an 89.9% likelihood of being a PA (95% CI: 82.2-95.0%, AUC: 0.928). Only one Warthin tumor demonstrated a 'strong' SSTR2 staining intensity. No Warthin tumor showed a percentage of cells staining for SSTR2 above ≥20%. This result demonstrates consistent and strong expression of SSTR2 in PAs as compared to Warthin tumors, which may allow physicians to utilize radioligand-somatostatin analog PET CT/MR imaging to diagnose the PA. SSTR2 positivity, if shown to be clinically relevant, may allow peptide receptor radionuclide therapy in the future.

A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity.

Type 1 conventional dendritic cells (cDC1) can support T cell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8+ T cell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1+ stem-like CD8+ T cells. We identify a distinct population of immunostimulatory CCR7neg cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8+ T cell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7neg cDC1 interact with CD8+ T cells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer T cell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy.

Antibiotics Significantly Decrease the Survival of Head and Neck Carcinoma Patients with Immunotherapy: A Real-World Analysis of More Than 3000 Cases.

OBJECTIVE: The human gut microbiome is strongly influenced by the administration of drugs, namely antibiotics. We hypothesized that the effectiveness of immunotherapy with pembrolizumab in oral squamous cell carcinoma patients is decreased by the administration of antibiotics three months before and after immunotherapy. METHODS: We retrieved data from patients diagnosed with head and neck squamous cell carcinoma (HNSCC) (International Classification of Diseases [ICD]-10 codes C00-C14) and receiving immunotherapy with pembrolizumab from the TriNetX network. Two cohorts were built: patients in cohort I did not receive any antibiotics within three months before or up to three months after immunotherapy, while patients in cohort II were administered antibiotics at least once within three months before or after immunotherapy. To exclude confounders, we matched cohorts 1:1 for age, sex, secondary lymph node metastases, nicotine dependence, the insertion of feeding devices, body mass index (BMI) and severe sepsis. After defining the primary outcome as "death", a Kaplan-Meier analysis was performed, and the risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were calculated. RESULTS: A total of 3651 patients were enrolled, and after matching, each cohort consisted of 1362 patients. Among cohorts I and II, 346 and 511 patients were deceased within one year (risk of death = 25.5 and 38.3%, respectively), whereby the risk difference was significant (p = 0.000; log-rank test). The RR was 0.68 (95% confidence interval: 0.60-0.76), OR was 0.57 (0.48-0.67) and HR was 0.58 (0.51-0.67). CONCLUSIONS: Our hypothesis was confirmed: administering antibiotics significantly decreases the drug effectiveness of immunotherapy. We hypothesize that this finding is associated with antibiotic-related changes in the gut microbiome. Prospective clinical studies on the gut microbiome in cancer patients are necessary to understand the complex ecosystem of microbiota during immunotherapy. TRIAL REGISTRATION: Due to the retrospective nature of the study, no registration was necessary.

[Laryngeal-preservation surgery in laryngeal cancer]. / Kehlkopferhaltende Operationen bei Larynxkarzinomen.

After oral cavity and pharyngeal cancer, laryngeal cancer is the third most common malignant tumor in the head and neck region. According to the current German S3 guideline on the diagnosis, treatment, and follow-up of laryngeal cancer, larynx-preserving surgical interventions are part of the standard treatment of this disease, even in advanced tumor stages. However, in order to achieve the desired function-preserving effect, an exact indication is of crucial importance. In this article, the most important larynx-preserving interventions and their indications but also the respective contraindications are presented, with the aim of illuminating the surgical treatment options up to just before total laryngectomy.

Efficacy of human C1 esterase inhibitor concentrate for treatment of ACE-inhibitor induced angioedema.

BACKGROUND: ACE inhibitor (ACEi) induced angioedema predominantly affects the upper aerodigestive tract. As ACEi induced angioedema is mediated by bradykinin, therapeutic response to antihistamines and glucocorticoids remains unsatisfactory. In bradykinin mediated hereditary angioedema, C1-esterase inhibitor (C1INH) is an effective and approved treatment since many years. Our aim was to evaluate the therapeutic effect of C1INH in ACEi induced angioedema. METHODS: We performed a double-blind, parallel-group, multicentre randomised placebo-controlled trial between December 2013 and September 2018. Eligible were adults with ACEi induced angioedema with airway obstruction. Participants were randomised 1:1 to single doses of either C1INH (20 IU/kg) or placebo (0.9% NaCl) i.v in addition to standard care (i.v. 500 mg prednisolone and 2.68 mg clemastine) i.v. Composite symptom scores were assessed at baseline and up to 48 h, at discharge and 1 week after discharge. Physician assessed time to complete oedema resolution (TCER) and time to onset of relief (TOR). RESULTS: 30 patients (16 C1INH, 14 placebo) were randomised and dosed. 25 (9 C1INH, 12 placebo) completed the study. TCER was 29.63 h ± 15.56 h in the C1INH and 17.29 h ± 10.40 h in the placebo arm (p = 0.0457). TORs were 4.13 h ± 3.38 h and 2.86 h ± 1.29 h for C1INH and placebo, respectively (p = 0.4443). There were no adverse events related to study medication. CONCLUSIONS: In the context of baseline application of steroids and antihistamines C1INH was inferior in the treatment of ACEi induced angioedema when compared to placebo with respect to time to complete resolution of symptoms. Eudra-CT Number: 2012-001670-28.

Comparison of PD-L1 expression in squamous cell cancer of unknown primary and oropharyngeal squamous cell carcinoma.

PURPOSE: The tumorigenesis of squamous cell cancer of unknown primary (SCCUP) in the head and neck area has not been decoded so far, while poor survival rates and limited therapeutic options pose a serious challenge. The aim of this project was to investigate immunological characteristics of SCCUPs and compare them to oropharyngeal squamous cell carcinoma (OPSCC). METHODS: PD-L1 expression (TC) was examined by immunohistochemistry in 50 lymph node metastases of SCCUP and 47 primaries of OPSCC. CD3 + and CD8 + lymphocytic infiltration was measured in 5 high power fields. Expression of p16 and HPV ISH were assessed. RESULTS: SCCUP demonstrated a significantly higher expression of PD-L1 than OPSCC. In p16-negative SCCUPs PD-L1 proved to be an independent prognostic factor to prioritize high-risk patients. CONCLUSIONS: Immunologic differences between SCCUP and OPSCC were detected. A higher PD-L1 expression in SCCUP could potentially facilitate further evaluation of checkpoint inhibitor therapy.

Comparing TIMP-1 and Hsp70 in Blood and Saliva as Potential Prognostic Markers in HNSCC.

(1) Background: Currently, there is no clinically used liquid biomarker in head and neck squamous cell carcinoma (HNSCC) patients. One reason could be the limited shedding of tumor material in early disease stages. Molecular diagnostics assessing both blood and especially saliva could potentially improve the accuracy of biomarkers. In this prospective study, two markers, tissue inhibitor of metalloprotease-1 (TIMP-1) and heat shock protein 70 (Hsp70), were analyzed in HNSCC patients. The purpose of the study was to evaluate differences between saliva and serum as sample material. Further, their prognostic and predictive value and usefulness for early detection was assessed. (2) Methods: A total of 73 HNSCC patients were prospectively monitored by collecting blood and saliva before, during, and after therapy, as well as in the follow-up period between 2018 and 2021. In total, 212 serum and 194 saliva samples were collected. A control group consisting of 40 subjects (15 patients with local infections in the head and neck area and 25 without infections) were examined as well. The collected samples were evaluated for the two proteins by using an enzyme-linked immunosorbent assay (ELISA). (3) RESULTS: The TIMP-1 concentration correlated significantly in blood and saliva, whereas the Hsp70 concentration did not. Saliva TIMP-1 was significantly higher in tumor patients compared to the control group (p = 0.013). High pretreatment TIMP-1 saliva levels were associated with significantly poorer disease-free survival (DFS) (p = 0.02). A high saliva TIMP-1/Hsp70 ratio was significantly associated with poorer DFS (HR: 1.4; 95% CI: 1.04-1.88; p = 0.026) and a high TIMP-1 serum concentration was significantly associated with poorer PFS (HR: 1.9; 95% CI: 1.2, 2.8; p = 0.003) and poorer overall survival (OS) (HR: 2.9; 95% CI: 1.4, 5.9; p = 0.003) in the Cox proportional hazards model. The saliva TIMP-1 to Hsp70 ratio was significantly higher at the time of recurrence (p = 0.015). Conclusion: TIMP-1 in serum is a promising prognostic marker for HNSCC. Saliva TIMP-1 and the saliva TIMP-1 to Hsp70 ratio provides additional information on the disease-free survival.

Stereopsis Only: Validation of a Monocular Depth Cues Reduced Gamified Virtual Reality with Reaction Time Measurement.

The visual depth perception is composed of monocular and binocular depth cues. Studies show that in absence of binocular depth cues the performance of visuomotor tasks like pointing to or grasping objects is limited. Thus, binocular depth cues are of great importance for motor control required in everyday life. However, binocular depth cues like retinal disparity (basis for stereopsis) might be influenced due to developmental disorders of the visual system. For example, amblyopia in which one eye's visual input is not processed leads to loss of stereopsis. The primary amblyopia treatment is occlusion of the healthy eye to force the amblyopic eye to train. However, improvements in stereopsis are poor. Therefore, binocular treatments arose that equilibrate both eyes' visual input to enable binocular vision. However, most approaches rely on divided stimuli which do not account for loss of stereopsis. We created a Virtual Reality (VR) with reduced monocular depth cues in which a stereoscopic task is shown to both eyes simultaneously, consisting of two balls jumping towards the user. One ball appears closer to the user which must be identified. To evaluate the task performance the reaction time is measured. We validated our approach with 18 participants with stereopsis under three contrast settings including one leading to monocular vision. The number of correct responses reduces from 90% under binocular vision to 52% under monocular vision corresponding to random guessing. Our results indicate that it is possible to disable monocular depth cues and create a dynamic stereoscopic task inside a VR.

NOTCH1 Intracellular Domain and the Tumor Microenvironment as Prognostic Markers in HNSCC.

(1) Background: NOTCH1 is the second most common mutated gene in whole-exome sequencing of HNSCC. The aim of this project was to gain further insight into the relevance of NOTCH1 in HNSCC, potentially establishing NOTCH1 as a prognostic marker or therapeutic target; (2) Methods: NOTCH1 was silenced via RNA interference in six HNSCC cell lines and the impact was evaluated in migration and proliferation assays. Subsequently, the protein expression of NOTCH1 intracellular domain (NICD) and NOTCH1 mRNA expression were examined in 70 oropharyngeal squamous cell cancer tissue samples. Lastly, the NICD expression was compared with the local infiltration of lymphocytes, measured with the immunoscore; (3) Results: Knockdown of NOTCH1 decreased migration and proliferation. A high NICD expression was associated with lower OS. A high immunoscore resulted in significantly better OS. NICD expression was independent of the immunoscore and as a whole differentiated three distinct prognostic groups; (4) Conclusions: These data suggest that NOTCH1 is involved in migration and proliferation of HNSCC cell lines. In vivo, NICD expression was associated with overall survival and could, therefore, be used as a prognostic marker. NICD expression differs from NOTCH1 mRNA levels, potentially explaining the previously suggested bimodal role as an oncogene and tumor suppressor in HNSCC.

Obstruction level associated with outcome in hypoglossal nerve stimulation.

PURPOSE: Selective hypoglossal nerve stimulation (sHNS) constitutes an effective surgical alternative for patients with obstructive sleep apnea (OSA). sHNS results in tongue protrusion and consecutive alleviation of obstructions at the tongue base level (lower obstructions). Furthermore, obstructions at the soft palate level (upper obstructions) may be prevented through palatoglossal coupling as seen on sleep endoscopy. However, it has not been studied if the distribution of obstruction level during a whole night measurement is a relevant factor for the treatment outcome. METHODS: Obstruction levels were measured with a manometry system during a whole night of sleep in 26 patients with OSA (f = 1, m = 25; age 59.4 ± 11.3; BMI = 29.6 ± 3.6) either before (n = 9) or after sHNS implantation (n = 12). Five patients received a measurement before and after implantation. Obstructions were categorized into velar (soft palate and above), infravelar (below soft palate), and multilevel obstructions. An association between obstruction level and treatment outcome was calculated. RESULTS: The mean distribution of preoperative obstruction level could be divided into the following: 38% velar, 46% multilevel, and 16% infravelar obstructions. Patients with a good treatment response (defined as AHI < 15/h and AHI reduction of 50%) had fewer preoperative velar obstructions compared to non-responder (17% vs. 54%, p-value = 0.006). In patients measured after sHNS implantation, a significantly higher rate of multilevel obstructions per hour was measured in non-responders (p-value = 0.012). CONCLUSIONS: Selective hypoglossal nerve stimulation was more effective in patients with fewer obstructions at the soft palate level. Manometry may be a complementary diagnostic procedure for the selection of patients for HNS.

MEK1/2 regulates APOBEC3B and polymerase iota-induced mutagenesis in head and neck cancer cells.

Resistance to chemotherapy provides a major challenge in treatment of metastatic cancer. Prolonged exposure to almost any drug regimen leads to the formation of resistant subclones in almost all advanced solid tumors. Tumor heterogeneity because of intrinsic genetic instability is seen as one of the major contributing factors. In this work, we present evidence that genetic instability measured by mutation frequency is induced by treatment with the EGFR inhibitor afatinib or cisplatin in head and neck squamous cancer cells. We find that APOBEC3B and polymerase iota are upregulated, and inhibition of MEK1/2 by U0126 leads to downregulation on the protein level. Costimulation of afatnib and cisplatin with U0126 leads to a significantly lower mutation frequency. These findings may represent a molecular mechanism for dynamically controlling genetic instability during chemotherapy in head and neck squamous cell carcinoma (HNSCC) cancer cells.

Hess Screen Revised: How Eye Tracking and Virtual Reality change Strabismus Assessment.

Strabismus is a visual disorder characterized by eye misalignment. The extent of ocular misalignment is denoted as the deviation angle. With the advent of Virtual Reality (VR) Head-Mounted-Displays (HMD) and eye tracking technology, new possibilities measuring strabismus arise. Major research addresses the novel field of VR strabismus assessment by replicating prism cover tests while there is a paucity of research on screen tests. In this work the Hess Screen Test was implemented in VR using a HMD with eye tracking for an objective measurement of the deviation angle. In a study, the functionality was tested and compared with a 2D monitor-based test. The results showed significant differences in the measured deviation angle between the methods. This can be attributed to the type of dissociation of the eyes.

Liposomal Inhalation after Tracheostomy-A Randomized Controlled Trial.

BACKGROUND: Tracheostomy is a common procedure in critical care. The aim of this study was to evaluate the application of a liposomal inhalation compared to standard physiologic saline (SPS) inhalation on basis of objective and subjective parameters of airway inflammation. METHODS: We evaluated in this two-armed, double-blinded and randomized control group study the effect of liposomal compared with SPS inhalation in newly tracheotomized patients. The primary endpoint was defined as trend of tracheobronchial IL-6 secretion at day 1 compared to day 10. Further objective and subjective parameter were evaluated. RESULTS: Fifty patients were randomized in each arm. Tracheal IL-6 levels decreased significantly only after liposomal inhalation. Both inhalative agents seem to have an effect on the respiratory impairment after tracheostomy. Subjective patient impairment was reduced significantly from day 1 to day 10 after tracheostomy with liposomal inhalation. CONCLUSIONS: Liposomal inhalation demonstrated an advantage over SPS inhalation in newly tracheotomized patients.

Assessing Visual Exploratory Activity of Athletes in Virtual Reality Using Head Motion Characteristics.

Maximizing performance success in sports is about continuous learning and adaptation processes. Aside from physiological, technical and emotional performance factors, previous research focused on perceptual skills, revealing their importance for decision-making. This includes deriving relevant environmental information as a result of eye, head and body movement interaction. However, to evaluate visual exploratory activity (VEA), generally utilized laboratory settings have restrictions that disregard the representativeness of assessment environments and/or decouple coherent cognitive and motor tasks. In vivo studies, however, are costly and hard to reproduce. Furthermore, the application of elaborate methods like eye tracking are cumbersome to implement and necessitate expert knowledge to interpret results correctly. In this paper, we introduce a virtual reality-based reproducible assessment method allowing the evaluation of VEA. To give insights into perceptual-cognitive processes, an easily interpretable head movement-based metric, quantifying VEA of athletes, is investigated. Our results align with comparable in vivo experiments and consequently extend them by showing the validity of the implemented approach as well as the use of virtual reality to determine characteristics among different skill levels. The findings imply that the developed method could provide accurate assessments while improving the control, validity and interpretability, which in turn informs future research and developments.

Long-term changes of stimulation intensities in hypoglossal nerve stimulation.

STUDY OBJECTIVES: Hypoglossal nerve stimulation (HNS) is a novel therapy in the treatment of obstructive sleep apnea. Previous studies have focused on the effectiveness of HNS, but there are no studies specifically investigating the long-term changes of the stimulation intensities in HNS. Increasing stimulation intensity requirements have been reported in the past in other peripheral nerve stimulation therapies. The aim of this study was to investigate the development of stimulation intensities over the observation period of 4 years. METHODS: All patients who were implanted with an HNS system since December 2013 and maintained a bipolar configuration over the observation period were included. Sensation threshold (ST), functional threshold, the titrated stimulation intensity (SI), and the apnea-hypopnea index (AHI) were recorded. RESULTS: A total of 82 patients were enrolled (sex: 69 men, 13 women, age: 60 ± 11 years, body mass index: 29. 8 ± 4.0 kg/m²). Two months after surgery, the median ST was 0.8 ± 0.5 V. During the observation period of 48 months, no significant change of ST was observed. The median ST was 1.0 ± 0.4 V (P = 0.93) at 48 months. Similar results were found for functional threshold and the titrated stimulation intensity. There was a significant reduction of the baseline median AHI when compared with the median AHI at 1, 12, 24, 36 and 48 months after surgery (P < 0.05). CONCLUSIONS: The stimulation intensities in HNS show no significant changes over 4 years. Despite the constant stimulation intensity, AHI was significantly reduced. This indicates that the stimulation threshold of the hypoglossal nerve does not change over time with this therapy.