[Acceptance of digital apps in the follow-up of patients with head and neck tumors]. / Akzeptanz digitaler Apps in der Nachsorge von Patient*innen mit Kopf-Hals-Tumoren.

BACKGROUND: Patient-reported outcome (PRO) measures lead to improved quality of life in cancer patients and possibly to earlier detection of tumor recurrence. OBJECTIVE: Patient interest in complementing tumor follow-up care with apps for recording PROs was assessed using a questionnaire. MATERIALS AND METHODS: An independently created questionnaire to record the interest of tumor patients in a digitalized form of tumor follow-up care was evaluated (n = 110). RESULTS: In the study, the majority of tumor patients were interested in using an app for tumor disease. Taking age into account, the number increased even further for patients < 60 years of age, as expected. In line with this, human papillomavirus (HPV)-positive patients showed significantly greater interest (p = 0.021). CONCLUSION: The introduction of an app is supported by the majority of tumor patients. In addition to recording PROs, other applications (appointment reminders, patient files, sports/nutrition programs) could also be integrated.

Only One of Three Bcs1 Homologs in Aspergillus fumigatus Confers Respiratory Growth.

The mitochondrial translocase Bcs1 is required for the correct assembly of complex III of the mitochondrial respiratory chain. Because of its importance, Bcs1 was recently proposed as a target for antifungal agents. The function of this AAA (ATPase Associated with diverse cellular Activities) protein has been extensively characterized in Saccharomyces cerevisiae. This yeast as well as previously studied mammals each encode only one homolog. In contrast, the pathogenic mold Aspergillus fumigatus encodes three putative Bcs1 homologs, none of which have been characterized to date. To study the role of these three homologs in A. fumigatus, conditional and deletion mutants of the respective genes AFUA_3G13000 (bcs1A), AFUA_4G01260 (bcs1B), and AFUA_2G14760 (bcs1C) were generated. A deletion or downregulation of bcs1A resulted in drastically reduced growth and sporulation rates and in a significantly altered susceptibility to azole antifungals. In contrast, mutants lacking Bcs1B or Bcs1C did not show any phenotypes differing from the wild type. Salicylhydroxamic acid-an inhibitor of the alternative oxidase that allows the respiratory chain to bypass complex III in some species-caused a complete growth arrest of the bcs1A deletion mutant. In a Galleria mellonella infection model, the deletion of bcs1A resulted in significantly decreased virulence. Only Bcs1A was able to partially complement a deletion of BCS1 in S. cerevisiae. The subcellular localization of Bcs1B and Bcs1C outside of mitochondria suggests that these Bcs1 homologs exert cellular functions different from that of Bcs1. Our data demonstrate that Bcs1A is the sole Bcs1 ortholog in A. fumigatus.

[Digital health applications in otorhinolaryngology]. / Digitale Gesundheitsanwendungen in der Hals­, Nasen- und Ohrenheilkunde.

BACKGROUND: With the passing of the "Digital Care Act" by the German Bundestag at the end of 2019, it was made possible, among other things, for digital health applications to be reimbursed by statutory health insurance companies under certain conditions. The aim of this work is to identify digital health applications related to ear, nose, and throat medicine and to describe the underlying evidence. MATERIALS AND METHODS: The digital health applications register was analyzed to identify digital health applications with an indication area relating to an otorhinolaryngologic disease. Digital health applications were included that were either permanently or provisionally included, or currently deleted if further information was available. The underlying evidence was assessed according to the recommendations of the Oxford Center for Evidence-Based Medicine for therapeutic studies. RESULTS: A total of six digital health applications with a direct or indirect connection to otorhinolaryngology were identified, three of which were permanently and two provisionally included in the directory. One digital health application has currently been withdrawn by the manufacturer. The permanently recorded digital health applications are based on evidence level 1b. CONCLUSION: The introduction of digital health applications is sometimes also discussed critically, but they represent an innovative approach and various digital health applications with a high level of underlying evidence are already available, especially for the ear, nose, and throat area.

Point Shear Wave Elastography in Diagnosis and Follow-Up of Salivary Gland Affection after Head and Neck Cancer Treatment.

Therapies of head and neck squamous cell carcinoma (HNSCC), particularly irradiation and chemotherapy (C/RT), can affect salivary glands to some extent. Recent studies suggest that point shear wave elastography (pSWE) is well suited for the diagnosis and rating of homogenous damage to parenchymatous organs. The purpose of this study was to assess the value of this sonographic modality as a tool for the evaluation both of salivary gland affection after HNSCC therapy and the effect of a salivary replacement therapy based on liposomes. A total of 69 HNSCC patients were included in this study. All patients had finished cancer treatment and attended regular follow-up. pSWE values of ipsi- and contralateral parotid (PG) and submandibular glands (SMG) were obtained in a standardized manner and compared to those of a healthy control (HC) group. After a two months treatment with a liposomal saliva replacement therapy pSWE quantification was performed again. Ipsi- and contralateral salivary glands suffer under standard HNSCC tumor therapy. Here, the ipsilateral parotid gland (PG) is primarily affected. Therefore, a sequence of manifestation (surgery < surgery plus adjuvant C/RT < primary C/RT) is comprehensible, evaluated by pSWE measurements. The examination of all glands and statistical analysis of the values compared to controls resulted in an pSWE cutoff value for affected glandular tissue of >2 m/s. Using a liposomal saliva replacement therapy, pSWE values of the ipsilateral PG can be improved, although the level of HC could not be restored.

Biaxial tensile test and meso damage numerical simulation of HTPB propellant.

Aiming at the shortcomings of the current research on the mechanical properties of solid propellants under complex stress conditions, an effective cross-shaped test piece configuration and variable-scale biaxial tensile test method are designed in this paper, and the meso-simulation model of propellant is constructed by Micro-CT test and random filling algorithm. Then, based on the Hook-Jeeves method and the cohesive force model, the mechanical performance parameters of each mesoscopic component were obtained, and finally the damage evolution process of the propellant was numerically simulated. The results show that the stress-strain curve of the propellant under biaxial loading is similar to that of uniaxial stretching, and has obvious rate dependence and stress state dependence. The mechanical properties of the propellant under biaxial tensile loading are significantly lower than those in uniaxial stretching, and the maximum elongation is only 45-85% of that in uniaxial stretching. The fracture process of propellant can be divided into initial linear stage, damage evolution stage and fracture stage. The dewetting phenomenon generally occurs at the interface between the large-sized AP particles and the matrix. With the loading of the load, the pores formed by the dewetting and matrix tearing continue to converge into cracks and expand in the direction perpendicular to the resultant force, and finally fracture. The propellant dehumidifies more easily under high strain rate loading, but the degree of dewetting is lower when the same strain is reached.

Persisting sicca complaints in sarcoidosis.

Background: Sarcoidosis is a systemic inflammatory disease that is characterized by non-caseating granulomas. Besides the lung as classical site of involvement, extrapulmonary manifestations are common, for example cervical lymph nodes or the salivary glands. The aim of this investigation is the analysis of the long-term course of glandular symptoms with a focus on persisting sicca symptoms. Materials and methods: All patients with the diagnosis of sarcoidosis over a period of 20 years in the departments of otorhinolaryngology, nephrology and pneumology were identified. In addition to clinical examinations and functional evaluation of the salivary glands, a sonographic examination of the salivary glands was carried out. Results: A total of 76 patients were included in the study (age 35.1 ± 21.6 years). At baseline, 32 out of 76 patients were suffering from xerostomia, 36 from dry eyes. While other salivary gland symptoms, such as gland enlargement, pain or facial nerve impairment, dissolved during the further course of the disease, xerostomia was still present in 29 and dry eyes in 35 out of 76 patients at the time of follow-up (which took place on average after 88.2 months). Conclusion: Sicca symptoms persist in patients with the diagnosis of sarcoidosis, while other salivary gland symptoms completely dissolve during the further course of the disease. This development appears to be independent of the type of therapy and should be considered during the follow-up of these patients, since sicca symptoms can cause further ocular, oral and dental damage.

Multimodal Evaluation of Long-Term Salivary Gland Alterations in Sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic inflammatory disease characterized by non-caseating granulomas. In addition to the lungs as classical site of affection, extrapulmonary manifestations are common, for example in the cervical lymph nodes or the salivary glands. The aim of this investigation is the analysis of the long-term course of glandular symptoms and the sonographic evaluation of long-term salivary gland changes. MATERIAL AND METHODS: All patients with a diagnosis of sarcoidosis over a period of 20 years in the departments of otorhinolaryngology, rheumatology, and pneumology were identified. In addition to clinical examinations and functional evaluation of the salivary glands, a sonographic examination of the salivary glands was carried out. The changes in the area of the salivary glands were assessed using B-mode sonography and different elastographic methods with appropriate scoring systems. RESULTS: A total of 76 patients were included in the study (age 35.1 ± 21.6 years). Overall, 17 patients presented with salivary gland manifestation at the time of the initial diagnosis. Of these patients, 15 received steroid therapy, 6 were also treated with another drug, and 2 patients were not treated with drugs. The time span between initial diagnosis and follow-up was 88.2 months (±83.0). At the time of the initial diagnosis, 17/17 complained of swelling of the salivary glands, 9/17 of xerostomia, and 8/17 of pain in the area of the salivary glands. At the time of follow-up, 5/17 reported swelling of the salivary glands, 6/17 reported xerostomia, and 1/17 reported pain in the salivary gland area. Sonography showed sonomorphological abnormalities of the salivary glands only in individual cases, with only mild alterations on average. CONCLUSION: In summary, it can be observed that patients with initial symptoms in the area of the salivary glands, such as swelling or pain, also suffer more frequently from dry mouth and eyes. In all patients, however, these symptoms regressed over time. A previous diagnosis of sarcoidosis with involvement of the salivary glands only leads to permanent abnormalities in the area of the salivary glands in individual cases.

Inhalative Treatment of Laryngitis Sicca in Patients with Sjögren's Syndrome-A Pilot Study.

Xerostomia and keratoconjunctivitis sicca are the main symptoms of Sjögren's syndrome. Often patients also suffer from laryngeal complaints, but there is a lack of specific treatment options. The aim of this study was to evaluate the effect of a liposomal inhalation therapy. Patients with Sjögren's syndrome were included and received a two-month period of liposomal inhalation therapy. The effect was evaluated by standardized questionnaires (patient-reported indices) and measurement of unstimulated whole salivary flow and glandular stiffness. Forty-five patients were included in this study. A comparison of baseline and therapeutic values demonstrated a significant improvement of the EULAR Sjögren's syndrome patient reported index (ESSPRI) with a baseline of 5.0 ± 2.1 and a therapeutic value of 4.1 ± 2.4 (p = 0.012). This improvement was mainly based on the item on dryness within this score. Overall, the therapy was well tolerated. In conclusion, an inhalative application of liposomes had a beneficial effect on the reported dryness in patients with Sjögren's syndrome. A first insight into the effect of inhalation therapy on laryngeal symptoms could thus be obtained and at the same time the basis was created on which case calculations can be carried out in the future.

Etiology and predictors of cluster attacks of hereditary angioedema that recur despite pharmaceutical treatment.

Introduction: Hereditary angioedema (HAE) is a disease that leads to recurrent swelling of the skin and mucous membranes, including the upper airway tract. Apart from being deadly, these attacks can be debilitating, which leads to a poor quality of life in patients. Clinicians are occasionally confronted with patients who have recurrent attacks despite treatment with C1 esterase inhibitor concentrate or ß2-receptor antagonists. The goal of this study was to investigate repeated attacks that occur 48 hours to 7 days ("cluster attacks") after treatment, to determine why they occur and the factors that may be associated with them, and thus to prevent their occurrence. Methods: We conducted a multicenter mixed retrospective-prospective study with data acquired from all documented attacks in our patients with collective (n = 132) between 2015 and 2018. Results: Eighty-five percent (n = 132) of our total patient collective (N = 156) agreed to participate in the study. Nine percent of these patients (n = 12) had cluster attacks, with a total of 48 cluster attacks. The data procured from the patients were mixed retrospective-prospective. Approximately 72% of all the cluster attacks were caused by exogenous stimuli (41% due to psychological stress, 29% due to physical stimuli, and 2% due to menstruation). Cluster attacks occurred in 7% of the patients who received prophylactic therapy in comparison with 12.5% of patients who received on-demand therapy. Cluster attacks comprised 48.4% of all the attacks that patients with cluster-attacks (n= 9) experienced. In addition, the patients who were underdosing their C1 esterase inhibitor treatment had cluster attacks more often. A lower "time to repeated attack" was seen in the patients who received on-demand therapy compared with those who received prophylactic therapy. Discussion: The percentage of the patients who had attacks as a result of exogenous triggers was higher in the cluster-attack group (70.5%) compared with the general HAE population (30-42%). Repeated attacks, therefore, were strongly associated with external triggers. The patients who received prophylactic treatment and who experienced cluster attacks were highly likely to have been underdosing, which may explain the repeated attacks despite treatment. In the patients prone to cluster attacks, prophylaxis should be considered.

[GERD and adjuvant radio-chemotherapy predespose to recurrent voice prosthesis leakage]. / GERD und adjuvante Radiochemotherapie prädisponieren für rezidivierende Stimmprotheseninsuffizienz.

After total laryngectomy, regaining ability to speech is a keystone in regards of life quality. Voice prostheses have been shown to be a sufficient tool for satisfying communication, although frequent replacements of prostheses are burdening certain patients. Therefore, a more accurate understanding of mechanisms of prosthetic leakage is urgently needed. METHODS: We performed a retrospective analysis of 58 Patients after laryngectomy. Additionally, we analyzed pre- and post-therapeutic CT-scans of 22 Patients regarding pharyngeal stenosis. RESULTS: In 40 Patients, at least one replacement of voice prosthesis was documented during observation period, median device life was 235 days. Patients treated with adjuvant radiotherapy (RT) showed a significantly longer device life than patients with adjuvant radio-chemotherapy (RCT, p = 0.002). Furthermore, patients suffering of gastroesophageal reflux disease (GERD) showed a significantly shortened device life (p = 0.04).17 patients (42.5 %) suffered of clinically relevant stenosis of the neopharynx, which was treated with dilatation in 14 patients (82 %) and did not affect prosthesis device life. CONCLUSION: GERD is a risk factor for shortened voice prosthesis' device life and therefore should be treated effectively after laryngectomy. Also, adjuvant RCT predisposes a shortened device life.Stenosis is observed frequently after laryngectomy but does not affect device life when effectively treated.

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.

Abnormal dynamic functional connectivity and brain states in Alzheimer's diseases: functional near-infrared spectroscopy study.

Communication within the brain is highly dynamic. Alzheimer's disease (AD) exhibits dynamic progression corresponding to a decline in memory and cognition. However, little is known of whether brain dynamics are disrupted in AD and its prodromal stage, mild cognitive impairment (MCI). For our study, we acquired high sampling rate functional near-infrared spectroscopy imaging data at rest from the entire cortex of 23 patients with AD dementia, 25 patients with amnestic mild cognitive impairment (aMCI), and 30 age-matched healthy controls (HCs). Sliding-window correlation and k-means clustering analyses were used to construct dynamic functional connectivity (FC) maps for each participant. We discovered that the brain's dynamic FC variability strength ( Q ) significantly increased in both aMCI and AD group as compared to HCs. Using the Q value as a measurement, the classification performance exhibited a good power in differentiating aMCI [area under the curve ( AUC = 82.5 % )] or AD ( AUC = 86.4 % ) from HCs. Furthermore, we identified two abnormal brain FC states in the AD group, of which the occurrence frequency ( F ) exhibited a significant decrease for the first-level FC state (state 1) and a significant increase for the second-level FC state (state 2). We also found that the abnormal F in these two states significantly correlated with the cognitive impairment in patients. These findings provide the first evidence to demonstrate the disruptions of dynamic brain connectivity in aMCI and AD and extend the traditional static (i.e., time-averaged) FC findings in the disease (i.e., disconnection syndrome) and thus provide insights into understanding the pathophysiological mechanisms occurring in aMCI and AD.

Azole-induced cell wall carbohydrate patches kill Aspergillus fumigatus.

Azole antifungals inhibit the fungal ergosterol biosynthesis pathway, resulting in either growth inhibition or killing of the pathogen, depending on the species. Here we report that azoles have an initial growth-inhibitory (fungistatic) activity against the pathogen Aspergillus fumigatus that can be separated from the succeeding fungicidal effects. At a later stage, the cell wall salvage system is induced. This correlates with successive cell integrity loss and death of hyphal compartments. Time-lapse fluorescence microscopy reveals excessive synthesis of cell wall carbohydrates at defined spots along the hyphae, leading to formation of membrane invaginations and eventually rupture of the plasma membrane. Inhibition of ß-1,3-glucan synthesis reduces the formation of cell wall carbohydrate patches and delays cell integrity failure and fungal death. We propose that azole antifungals exert their fungicidal activity by triggering synthesis of cell wall carbohydrate patches that penetrate the plasma membrane, thereby killing the fungus. The elucidated mechanism may be potentially exploited as a novel approach for azole susceptibility testing.

Selective upper airway stimulation in older patients.

OBJECTIVE: Selective stimulation of the hypoglossal nerve has proven to be an effective therapy for patients with obstructive sleep apnea (OSA). The aim of the study is to investigate the efficacy of selective upper airway stimulation (sUAS) in older adults. METHODS: All consecutive patients older than 64 years and who received an implant for sUAS were enrolled. As a control group, an equal number of patients younger than 65 years with matched apnea hypopnea index (AHI) and body-mass-index (BMI) were selected. Treatment outcome data were collected including daytime sleepiness as well as demographics with co-morbidities, BMI, adverse events and adherence to therapy. RESULTS: 62 patients were included. Both the control and study group did not differ significantly for AHI, BMI, and Epworth Sleepiness Scale (ESS) (28.7-28.4/h; 30.1 to 28.4 kg/m2; 14.6 to 12.0 points); but co-morbidities were significantly higher in the study group. Our data showed no significant difference between the outcomes of study and control group for AHI, Oxygen desaturation index (ODI) and ESS (6.0-6.0/h; 7.9 to 5.5/h; 5.0 to 7.0 points). Serious adverse events did not occur in both groups and surgical implantation time did not differ. CONCLUSION: sUAS leads to significant reductions of AHI, ODI and ESS in older patients. Despite higher age and more co-morbidities, surgical implantation time was not affected. Older patients showed higher usage of sUAS. Advanced age seems not to be a limiting factor for treatment outcomes of sUAS, thus indication for this treatment can also be applied to older people.

Decreased resting-state brain signal complexity in patients with mild cognitive impairment and Alzheimer's disease: a multiscale entropy analysis.

Multiscale entropy (MSE) analysis is a novel entropy-based analysis method for quantifying the complexity of dynamic neural signals and physiological systems across multiple temporal scales. This approach may assist in elucidating the pathophysiologic mechanisms of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Using resting-state fNIRS imaging, we recorded spontaneous brain activity from 31 healthy controls (HC), 27 patients with aMCI, and 24 patients with AD. The quantitative analysis of MSE revealed that reduced brain signal complexity in AD patients in several networks, namely, the default, frontoparietal, ventral and dorsal attention networks. For the default and ventral attention networks, the MSE values also showed significant positive correlations with cognitive performances. These findings demonstrated that the MSE-based analysis method could serve as a novel tool for fNIRS study in characterizing and understanding the complexity of abnormal cortical signals in AD cohorts.

Improving surgical results in complex nerve anatomy during implantation of selective upper airway stimulation.

The following report presents a case of two late embedded hypoglossus branches during implantation of an upper airway stimulation device that caused a mixed activation of the tongue when included in the stimulation cuff. In the end, correct cuff placement could be achieved by careful examination of the hypoglossal nerve anatomy, precise nerve dissection, tongue motion analysis and intraoperative nerve monitoring.

Mitochondrial dynamics in the pathogenic mold Aspergillus fumigatus: therapeutic and evolutionary implications.

Mitochondria within eukaryotic cells continuously fuse and divide. This phenomenon is called mitochondrial dynamics and crucial for mitochondrial function and integrity. We performed a comprehensive analysis of mitochondrial dynamics in the pathogenic mold Aspergillus fumigatus. Phenotypic characterization of respective mutants revealed the general essentiality of mitochondrial fusion for mitochondrial genome maintenance and the mold's viability. Surprisingly, it turned out that the mitochondrial rhomboid protease Pcp1 and its processing product, s-Mgm,1 which are crucial for fusion in yeast, are dispensable for fusion, mtDNA maintenance and viability in A. fumigatus. In contrast, mitochondrial fission mutants show drastically reduced growth and sporulation rates and increased heat susceptibility. However, reliable inheritance of mitochondria to newly formed conidia is ensured. Strikingly, mitochondrial fission mutants show a significant and growth condition-dependent increase in azole resistance. Parallel disruption of fusion in a fission mutant partially rescues growth and sporulation defects and further increases the azole resistance phenotype. Taken together, our results indicate an emerging dispensability of the mitochondrial rhomboid protease function in mitochondrial fusion, the suitability of mitochondrial fusion machinery as antifungal target and the involvement of mitochondrial dynamics in azole susceptibility.

Aspergillus fumigatus devoid of cell wall ß-1,3-glucan is viable, massively sheds galactomannan and is killed by septum formation inhibitors.

Echinocandins inhibit ß-1,3-glucan synthesis and are one of the few antimycotic drug classes effective against Aspergillus spp. In this study, we characterized the ß-1,3-glucan synthase Fks1 of Aspergillus fumigatus, the putative target of echinocandins. Data obtained with a conditional mutant suggest that fks1 is not essential. In agreement, we successfully constructed a viable Δfks1 deletion mutant. Lack of Fks1 results in characteristic growth phenotypes similar to wild type treated with echinocandins and an increased susceptibility to calcofluor white and sodium dodecyl sulfate. In agreement with Fks1 being the only ß-1,3-glucan synthase in A. fumigatus, the cell wall is devoid of ß-1,3-glucan. This is accompanied by a compensatory increase of chitin and galactosaminogalactan and a significant decrease in cell wall galactomannan due to a massively enhanced galactomannan shedding. Our data furthermore suggest that inhibition of hyphal septation can overcome the limitations of echinocandin therapy. Compounds inhibiting septum formation boosted the antifungal activity of caspofungin. Thus, development of clinically applicable inhibitors of septum formation is a promising strategy to improve existing antifungal therapy.