This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.

We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 affecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma.

Amid the COVID-19 pandemic, digital health literacy (DHL) has become a significant public health concern. This research aims to assess information seeking behavior, as well as the ability to find relevant information and deal with DHL among university students in Pakistan. An online-based cross-sectional survey, using a web-based interviewing technique, was conducted to collect data on DHL. Simple bivariate and multivariate linear regression was performed to assess the association of key characteristics with DHL. The results show a high DHL related to COVID-19 in 54.3% of students. Most of the Pakistani students demonstrated similar to 50% DHL in all dimensions, except for reliability. Multivariate findings showed that gender, sense of coherence and importance of information were found to be significantly associated with DHL. However, a negative association was observed with students ' satisfaction with information. This led to the conclusion that critical operational and navigations skills are essential to achieve COVID-19 DHL and cope with stress, particularly to promote both personal and community health. Focused interventions and strategies should be designed to enhance DHL amongst university students to combat the pandemic.

Objectives: We aimed to assess the impact of image context information on the accuracy of deep learning models for tooth classification on panoramic dental radiographs. Methods: Our dataset contained 5008 panoramic radiographs with a mean number of 25.2 teeth per image. Teeth were segmented bounding-box-wise and classified by one expert; this was validated by another expert. Tooth segments were cropped allowing for different context; the baseline size was 100% of each box and was scaled up to capture 150%, 200%, 250% and 300% to increase context. On each of the five generated datasets, ResNet-34 classification models were trained using the Adam optimizer with a learning rate of 0.001 over 25 epochs with a batch size of 16. A total of 20% of the data was used for testing; in subgroup analyses, models were tested only on specific tooth types. Feature visualization using gradient-weighted class activation mapping (Grad-CAM) was employed to visualize salient areas. Results: F1-scores increased monotonically from 0.77 in the base-case (100%) to 0.93 on the largest segments (300%; p = 0.0083; Mann-Kendall-test). Gains in accuracy were limited between 200% and 300%. This behavior was found for all tooth types except canines, where accuracy was much higher even for smaller segments and increasing context yielded only minimal gains. With increasing context salient areas were more widely distributed over each segment; at maximum segment size, the models assessed minimum 3-4 teeth as well as the interdental or inter-arch space to come to a classification. Conclusions: Context matters; classification accuracy increased significantly with increasing context.

The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem cells (CSCs) and resistance to chemoradiotherapy. We investigated whether the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF) can enhance the sensitivity of therapy. Cell viability was assessed by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and apoptosis assays, and the cell cycle and reactive oxygen species (ROS) levels were evaluated by fluorescence-activated cell sorting (FACS). The radio-sensitizing effect was measured by a colony formation assay. The synergistic effects were calculated by combination index (CI) analyses. The DSF and DSF/Cu2+ inhibited the cell proliferation (inhibitory concentration 50 (IC50) of DSF and DSF/Cu2+ were 13.96 μM and 0.24 μM). DSF and cisplatin displayed a synergistic effect (CI values were <1). DSF or DSF/Cu2+ abolished the cisplatin-induced G2/M arrest (from 52.9% to 40.7% and 41.1%), and combining irradiation (IR) with DSF or DSF/Cu2+ reduced the colony formation and attenuated the G2/M arrest (from 53.6% to 40.2% and 41.9%). The combination of cisplatin, DSF or DSF/Cu2+, and IR enhanced the radio-chemo sensitivity by inducing apoptosis (42.04% and 32.21%) and ROS activity (46.3% and 37.4%). DSF and DSF/Cu2+ enhanced the sensitivity of HNSCC to cisplatin and IR. Confirming the initial data from patient-derived tumor xenograft (PDX) supported a strong rationale to repurpose DSF as a radio-chemosensitizer and to assess its therapeutic potential in a clinical setting.

Background: Stress and depression are known to contribute to coronary artery disease (CAD) with catecholamines (CA), altering the balance to a pro- and anti-inflammatory stetting and potentially playing a key role in the underlying pathophysiology. This study aimed to elucidate the impact of social stress on the CA system and inflammation markers in patients suffering from CAD and depression. Methods: 93 subjects were exposed to the Trier Social Stress Test (TSST). Based on the results of the depression subscale of the Hospital Anxiety and Depression Scale (HADS, German Version) and the presence/absence of CAD, they were divided into four groups. A total of 21 patients suffered from CAD and depression (+D+CAD), 26 suffered from CAD alone (-D+CAD), and 23 suffered from depression only (+D-CAD); another 23 subjects served as healthy controls (-D-CAD). Subjects were registered at 09:00 AM at the laboratory. A peripheral venous catheter was inserted, and after a 60-min-resting period, the TSST was applied. Prior to and 5, 15, 30, and 60 min after the stress test, plasma epinephrine, norepinephrine, and dopamine concentrations (High Performance Liquid Chromatography (HPLC)) were measured together with the inflammation markers interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). High-sensitive C-reactive protein (hs-CRP, Enzyme-linked Immunosorbent Assay (ELISA)) was measured prior to TSST. Results: (+D-CAD) and (+D+CAD) patients showed significantly lower epinephrine and dopamine levels compared to the (-D+CAD) and (-D-CAD) participants at baseline (prior to TSST). Over the whole measurement period after the TSST, no inter-group difference was detected. Partial correlation (controlling for age, gender and Body Mass Index (BMI)) revealed a significant direct relation between MCP-1 and norepinephrine (r = 0.47, p = 0.03) and MCP-1 and epinephrine (r = 0.46, p = 0.04) in patients with -D+CAD at rest. Conclusions: The stress response of the CA system was not affected by depression or CAD, whereas at baseline we detected a depression-related reduction of epinephrine and dopamine release independent of CAD comorbidity. Reduced norepinephrine and dopamine secretion in the central nervous system in depression, known as 'CA-deficit hypothesis', are targets of antidepressant drugs. Our results point towards a CA-deficit in the peripheral nervous system in line with CA-deficit of the central nervous system and CA exhaustion in depression. This might explain somatic symptoms such as constipation, stomach pain, diarrhoea, sweating, tremor, and the influence of depression on the outcome of somatic illness such as CAD.

Background: periacetabular osteotomy (PAO) is known as the gold standard surgical treatment in young adults with symptomatic hip dysplasia. With the aim of reducing soft tissue trauma, we developed a new rectus and sartorius sparing (RASS) approach. We hypothesized that this new PAO technique was equal regarding acetabular reorientation, complication rate, and short-term clinical outcome parameters, compared to our conventional, rectus sparing (RS) approach. Patients and Methods: we retrospectively assessed all PAO procedures performed by a single surgeon between 2016 and 2019 (n = 239 hips in 217 patients). The cases in which the new RASS technique were used (n = 48) were compared to the RS cases for acetabular orientation parameters, surgical time, perioperative reduction of hemoglobin level, and length of hospital stay (LOHS). Inclusion criteria were a lateral center-edge angle (LCEA) <25 degrees and osteoarthritis Tonnis grade ≤1. Patients with acetabular retroversion or additional femoral osteotomy were excluded. Results: the mean patient age at the time of surgery was 29 years (14 to 50, SD ± 8.5). Females accounted for 79.5% in this series. The mean preoperative LCEA were 16 degrees (7 to 24 degrees, SD ± 4.4) and 15 degrees (0 to 23 degrees, SD ± 6) in the RASS and the RS group, respectively (p = 0.96). The mean preoperative acetabular index (AI) angles were 14 degrees (2 to 25 degrees, SD ± 4) and 14 degrees (7 to 29 degrees, SD ± 4.3), respectively (p = 0.67). The mean postoperative LCEA were significantly improved to 31 degrees (25 to 37 degrees, SD ± 3.5, p < 0.001) and 30.2 degrees (20 to 38 degrees, SD ± 4, p < 0.001), respectively. The mean postoperative AI angles improved to 2.8 degrees (-3 to 13 degrees, SD ± 3.3, p < 0.001) and 3 degrees (-2 to 15 degrees, SD ± 3.3, p < 0.001), respectively. There were no significant differences between the RASS and the RS group for surgical time, perioperative reduction in hemoglobin level, and LOHS. No blood transfusions were necessary perioperatively in either group. No major perioperative complication occurred in either group. We observed one surgical site infection (SSI) requiring superficial debridement in the RS group. Conclusion: the RASS approach for PAO showed to be a safe procedure with equivalent acetabular reorientation and equivalent clinical outcome parameters compared to the RS approach. Additionally, patients have fewer postoperative restrictions in mobilization with the RASS approach.

Diaphragmatic hernia (DH) after a liver resection (LR) is an uncommon but potentially severe complication. In this retrospective study, we aim to share our experience with DH in our hepatic surgery center. We retrospectively analyzed 3107 patients who underwent a liver resection between January 2012 and September 2019. The diagnosis of DH was based on clinical examination and radiological imaging and confirmed by intraoperative findings during surgical repair. Five out of 3107 (0.16%) patients after LR developed DH. Especially, all five DH patients had a major right-sided LR before (n = 716, 0.7%). The mean time interval between initial LR and occurrence of DH was 30 months (range 15 to 44 months). DH exclusively occurred after a right or extended right hepatectomy. Two patients underwent emergency surgery, three were asymptomatic, and DH was diagnosed in follow-up imaging. Three of these five treated patients (60%) developed DH recurrence: two of three (67%) patients after suture repair alone and the only patient after suture repair in combination with an absorbable mesh. The patient who was treated with a composite mesh implant did not show any signs of DH recurrence after 52 months of follow-up. In patients who develop DH after liver surgery, a mesh augmentation with nonresorbable material is generally recommended. In order to diagnose these patients in an early state, we recommend that special attention be paid and a prompt and targeted diagnostic examination of patients with abdominal complaints after right-sided liver resections take place.

Background and Objectives: The programs of enhanced recovery after surgery are the new revolution in surgical departments; however, features of this concept have not been systematically explored. Therefore, the purpose of this study was to explore Enhanced recovery after surgery (ERAS)-related research using bibliometric analysis. Materials and Methods: The search strategy of ERAS programs was conducted in the Web of Science database. Bibliometric analysis was further performed by Excel and Bibliometrix software. The relationship between citation counts and Mendeley readers was assessed by linear regression analysis. Results: 8539 studies from 1994-2019 were included in the present research, with reporting studies originating from 91 countries using 18 languages. The United States (US) published the greatest number of articles. International cooperation was discovered in 82 countries, with the most cooperative country being the United Kingdom. Henrik Kehlet was found to have published the highest number of studies. The journal Anesthesia and Analgesia had the largest number of articles. Linear regression analysis presented a strong positive correlation between citations and Mendeley readers. Most research was related to gastrointestinal surgery in this field. Conclusion: This bibliometric analysis shows the current status of ERAS programs from multiple perspectives, and it provides reference and guidance to scholars for further research.

Adequate tissue engineered models are required to further understand the (patho)physiological mechanism involved in the destructive processes of cartilage and subchondral bone during rheumatoid arthritis (RA). Therefore, we developed a human in vitro 3D osteochondral tissue model (OTM), mimicking cytokine-induced cellular and matrix-related changes leading to cartilage degradation and bone destruction in order to ultimately provide a preclinical drug screening tool. To this end, the OTM was engineered by co-cultivation of mesenchymal stromal cell (MSC)-derived bone and cartilage components in a 3D environment. It was comprehensively characterized on cell, protein, and mRNA level. Stimulating the OTM with pro-inflammatory cytokines, relevant in RA (tumor necrosis factor α, interleukin-6, macrophage migration inhibitory factor), caused cell- and matrix-related changes, resulting in a significantly induced gene expression of lactate dehydrogenase A, interleukin-8 and tumor necrosis factor α in both, cartilage and bone, while the matrix metalloproteases 1 and 3 were only induced in cartilage. Finally, application of target-specific drugs prevented the induction of inflammation and matrix-degradation. Thus, we here provide evidence that our human in vitro 3D OTM mimics cytokine-induced cell- and matrix-related changes-key features of RA-and may serve as a preclinical tool for the evaluation of both new targets and potential drugs in a more translational setup.

Functional spinopelvic parameters are crucial for describing spinal alignment (SA), but this is susceptible to variation. Anatomically fixed pelvic shape is defined by the parameters pelvic radius (PR), pelvic incidence (PI), and sacral table angle (STA). In patients with lumbosacral transitional vertebrae (LSTV), the spinopelvic alignment may be altered by changes of these parameters and influences of SA. There have been no reports studying the relation between LSTV, four (4 LV) and six (6 LV) lumbar vertebrae, and fixed anatomical spinopelvic parameters. A retrospective analysis of 819 abdomen-pelvis CT scans was performed, identifying 53 patients with LSTV. In a matched-pair analysis, we analyzed the influence of LSTV and the subgroups 4 LV (n = 9) and 6 LV (n = 11) on PR, PI, and STA. LSTV were classified according to Castellvi classification. In patients with 6 LV, measurement points at the superior endplates of S1 and S2 were compared. The prevalence of LSTV was 6.5% (53/819), 6 LV was 1.3% (11/819), and 4 LV was 1.1% (9/819) in our study population. PI significantly increased (p < 0.001), STA significantly decreased (p < 0.001), and PR (p = 0.051) did not differ significantly in the LSTV group (n = 53). Similar findings were observed in the 4 LV subgroup, with an increase in PI (p < 0.021), decrease in STA (p < 0.011), and no significant difference in PR (p < 0.678). The same results were obtained in the 6 LV subgroup at measuring point S2 (true S1) PI (p = 0.010), STA (p = 0.004), and PR (p = 0.859), but not at measuring point S1 (true L6). Patients with LSTV, 4 LV, and 6 LV showed significant differences in PI and STA compared to the matched control group. PR showed no significant differences. The altered spinopelvic anatomy in LSTV patients need to be reflected in preoperative planning rebalancing the sagittal SA.

For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies.

Simple Summary: Several efforts like dose-escalated salvage radiation therapy and the use of androgen deprivation therapy aimed to improve the postoperative treatment in patients with biochemical recurrence of prostate cancer after prostatectomy. However, the oncological outcome is still not satisfactory. Hyperthermia is well-known to improve the efficacy of radiation therapy, whereas only limited data for postoperative therapy in prostate cancer are available. Thus, we conducted a prospective multicenter non-randomized Phase-II-Trial (HTProstate) investigating the implementation of combined salvage radiation therapy and regional hyperthermia in case of biochemical recurrence after prostatectomy with the aim to evaluate the safety, feasibility, and oncological outcome of this approach. The results of our planned interim analysis (n = 50) met the criteria of safety (only one patient with acute grade 3 hyperthermia-specific toxicity), showed feasibility of planned radiation and hyperthermia therapy, no significant changes in quality of life and promising short-term prostate-specific antigen response. Late toxicity and robust oncological outcome data will be reported after completion of the trial.

Abstract: Efforts to improve the outcome of prostate cancer (PC) patients after radical prostatectomy (RP) include adjuvant or salvage radiation therapy (SRT), but still up to 50% of patients develop a disease progression after radiotherapy (RT). Regional hyperthermia (HT) is well-known to improve tumor sensitivity to RT in several entities. Here we report on a planned interim analysis of tolerability and feasibility after recruitment of the first 50 patients of a trial combining SRT and HT. We conducted a prospective multicenter non-randomized Phase-II-Trial (HTProstate-NCT04159051) investigating the implementation of combined moderate-dose escalated SRT (70 Gy in 35 fractions) and locoregional deep HT (7-10 HT sessions). The primary endpoints were the rate of acute genitourinary (GU), gastrointestinal (GI), and HT-related toxicities, completed HT sessions (≥7), and SRT applications per protocol (≥95% of patients). The two-step design included a planned interim analysis for acute GU-, GI- and HT-specific toxicities to ensure patients' safety. Between November 2016 and December 2019, 52 patients entered into the trial. After 50 patients completed therapy and three months of follow-up, we performed the planned interim analysis. 10% of patients developed acute grade 2 GU and 4% grade 2 GI toxicities. No grade ≥3 GU or GI toxicities occurred. HT-specific symptoms grade 2 and 3 were observed in 4% and 2% of all patients. Thus, the pre-specified criteria for safety and continuation of recruitment were met. Moreover, ≥7 HT treatments were applicable, indicating the combination of SRT + HT to be feasible. Evaluation of early QoL showed no significant changes. With its observed low rate of GU and GI toxicities, moderate and manageable rates of HT-specific symptoms, and good feasibility, the combined SRT + HT seems to be a promising treatment approach for biochemical recurrence after RP in PC patients.

Nuck's hydroceles, which develop in a protruding part of the parietal peritoneum into the female inguinal canal, are rare abnormalities and a cause of inguinal swelling, mostly resulting in pain. They appear when this evagination of the parietal peritoneum into the inguinal canal fails to obliterate. Our review of the literature on this topic included several case reports and two case series that presented cases of Nuck hydroceles which underwent surgical therapy. We present six consecutive cases of symptomatic hydroceles of Nuck's canal from September 2016 to January 2020 at the Department of Surgery of Charite Berlin. Several of these patients had a long history of pain and consecutive consultations to outpatient clinics without diagnosis. These patients underwent laparoscopic or conventional excision and if needed simultaneous hernioplasty in our institution. Ultrasonography and/or Magnetic Resonance Imaging were used to display the cystic lesion in the inguinal area, providing the diagnosis of Nuck's hydrocele. This finding was confirmed intraoperatively and by histopathological review. Ultrasound and magnetic resonance imaging (MRI) captures, intraoperative pictures and video of minimal invasive treatment are provided. Nuck's hydroceles should be included in the differential diagnosis of an inguinal swelling. We recommend an open approach to external Type 1 Nuck ' s hydroceles and a laparoscopic approach to intra-abdominal Type 2 Nuck hydroceles. Complex hydroceles like Type 3 have to be evaluated individually, as they are challenging and the surgical outcome is dependent on the surgeon's skills. If inguinal channel has been widened by the presence of a Nuck's hydrocele, a mesh plasty, as performed in hernia surgery, should be considered.

Heart failure (HF) is a severe clinical syndrome accompanied by a number of comorbidities. Ischemic stroke occurs frequently in patients with HF as a complication of the disease. In the present review, we aimed to summarize the current state of research on the role of cardio-cerebral interactions in the prevalence, etiology, and prognosis of both diseases. The main pathophysiological mechanisms underlying the development of stroke in HF and vice versa are discussed. In addition, we reviewed the results of recent clinical trials investigating the prevalence and prevention of stroke in patients with HF.

Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common type of chronic liver disease in developed nations, affecting around 25% of the population. Elucidating the factors causing NAFLD in individual patients to progress in different rates and to different degrees of severity, is a matter of active medical research. Here, we aim to provide evidence that the intra-hepatic heterogeneity of rheological, metabolic and tissue-regenerating capacities plays a central role in disease progression. We developed a generic mathematical model that constitutes the liver as ensemble of small liver units differing in their capacities to metabolize potentially cytotoxic free fatty acids (FFAs) and to repair FFA-induced cell damage. Transition from simple steatosis to more severe forms of NAFLD is described as self-amplifying process of cascading liver failure, which, to stop, depends essentially on the distribution of functional capacities across the liver. Model simulations provided the following insights: (1) A persistently high plasma level of FFAs is sufficient to drive the liver through different stages of NAFLD; (2) Presence of NAFLD amplifies the deleterious impact of additional tissue-damaging hits; and (3) Coexistence of non-steatotic and highly steatotic regions is indicative for the later occurrence of severe NAFLD stages.

Due to the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, a large number of elective knee replacement procedures had to be postponed in both early and late 2020 in most western countries including Germany and the UK. It is unknown how public interest and demand for total knee arthroplasties was affected. Public interest in knee pain, knee osteoarthritis and knee arthroplasty in Germany and the UK was investigated using Google Trend Analysis. In addition, we monitored for changes in patient composition in our outpatient department. As of early March in Germany and of late March in the UK, until the lockdown measures, a 50 to 60% decrease in relative search frequency was observed in all categories investigated compared to the beginning of the year. While public interest for knee pain rapidly recovered, decreased interest for knee osteoarthritis and replacement lasted until the easing of measures. Shortly prior to and during the first lockdown mean search frequency for knee replacement was significantly decreased from 39.7% and 36.6 to 26.9% in Germany and from 47.7% and 50.9 to 23.7% in the UK (Germany: p = 0.022 prior to lockdown, p < 0.001 during lockdown; UK: p < 0.0001 prior to and during lockdown). In contrast, mean search frequencies did not differ significantly from each other for any of the investigated time frames during the second half of 2020 in both countries. Similarly, during the first lockdown, the proportion of patients presenting themselves to receive primary knee arthroplasty compared to patients that had already undergone knee replacement declined markedly from 64.7% to 46.9%. In contrast, patient composition changed only marginally during the lockdown measures in late 2020 in both Germany and the UK. We observed a high level of public interest in knee arthroplasty despite the ongoing pandemic. The absence of a lasting decline in interest in primary knee arthroplasty suggests that sufficient symptom reduction cannot be achieved without surgical care for a substantial number of patients.

Objectives: The present study aimed to train deep convolutional neural networks (CNNs) to detect caries lesions on Near-Infrared Light Transillumination (NILT) imagery obtained either in vitro or in vivo and to assess the models' generalizability. Methods: In vitro, 226 extracted posterior permanent human teeth were mounted in a diagnostic model in a dummy head. Then, NILT images were generated (DIAGNOcam, KaVo, Biberach), and images were segmented tooth-wise. In vivo, 1319 teeth from 56 patients were obtained and segmented similarly. Proximal caries lesions were annotated pixel-wise by three experienced dentists, reviewed by a fourth dentist, and then transformed into binary labels. We trained ResNet classification models on both in vivo and in vitro datasets and used 10-fold cross-validation for estimating the performance and generalizability of the models. We used GradCAM to increase explainability. Results: The tooth-level prevalence of caries lesions was 41% in vitro and 49% in vivo, respectively. Models trained and tested on in vivo data performed significantly better (mean ± SD accuracy: 0.78 ± 0.04) than those trained and tested on in vitro data (accuracy: 0.64 ± 0.15; p < 0.05). When tested in vitro, the models trained in vivo showed significantly lower accuracy (0.70 ± 0.01; p < 0.01). Similarly, when tested in vivo, models trained in vitro showed significantly lower accuracy (0.61 ± 0.04; p < 0.05). In both cases, this was due to decreases in sensitivity (by -27% for models trained in vivo and -10% for models trained in vitro). Conclusions: Using in vitro setups for generating NILT imagery and training CNNs comes with low accuracy and generalizability. Clinical significance: Studies employing in vitro imagery for developing deep learning models should be critically appraised for their generalizability. Applicable deep learning models for assessing NILT imagery should be trained on in vivo data.

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.