Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation.

Chaperone-mediated autophagy (CMA) targets soluble proteins for lysosomal degradation. Here we found that CMA was activated in T cells in response to engagement of the T cell antigen receptor (TCR), which induced expression of the CMA-related lysosomal receptor LAMP-2A. In activated T cells, CMA targeted the ubiquitin ligase Itch and the calcineurin inhibitor RCAN1 for degradation to maintain activation-induced responses. Consequently, deletion of the gene encoding LAMP-2A in T cells caused deficient in vivo responses to immunization or infection with Listeria monocytogenes. Impaired CMA activity also occurred in T cells with age, which negatively affected their function. Restoration of LAMP-2A in T cells from old mice resulted in enhancement of activation-induced responses. Our findings define a role for CMA in regulating T cell activation through the targeted degradation of negative regulators of T cell activation.

Catalytic antibodies in arrhythmogenic cardiomyopathy patients cleave desmoglein 2 and N-cadherin and impair cardiomyocyte cohesion.

AIMS: Arrhythmogenic cardiomyopathy (AC) is a severe heart disease predisposing to ventricular arrhythmias and sudden cardiac death caused by mutations affecting intercalated disc (ICD) proteins and aggravated by physical exercise. Recently, autoantibodies targeting ICD proteins, including the desmosomal cadherin desmoglein 2 (DSG2), were reported in AC patients and were considered relevant for disease development and progression, particularly in patients without underlying pathogenic mutations. However, it is unclear at present whether these autoantibodies are pathogenic and by which mechanisms show specificity for DSG2 and thus can be used as a diagnostic tool. METHODS AND RESULTS: IgG fractions were purified from 15 AC patients and 4 healthy controls. Immunostainings dissociation assays, atomic force microscopy (AFM), Western blot analysis and Triton X-100 assays were performed utilizing human heart left ventricle tissue, HL-1 cells and murine cardiac slices. Immunostainings revealed that autoantibodies against ICD proteins are prevalent in AC and most autoantibody fractions have catalytic properties and cleave the ICD adhesion molecules DSG2 and N-cadherin, thereby reducing cadherin interactions as revealed by AFM. Furthermore, most of the AC-IgG fractions causing loss of cardiomyocyte cohesion activated p38MAPK, which is known to contribute to a loss of desmosomal adhesion in different cell types, including cardiomyocytes. In addition, p38MAPK inhibition rescued the loss of cardiomyocyte cohesion induced by AC-IgGs. CONCLUSION: Our study demonstrates that catalytic autoantibodies play a pathogenic role by cleaving ICD cadherins and thereby reducing cardiomyocyte cohesion by a mechanism involving p38MAPK activation. Finally, we conclude that DSG2 cleavage by autoantibodies could be used as a diagnostic tool for AC.

Accuracy of a portable lower-limb muscle strength measuring device with a training function.

[Purpose] Quadriceps muscle strength is essential for daily living activities. Therefore, we developed a compact and simple lower limb muscle strength measuring device (LocomoScan [LCS]). This study aimed to compare LCS with other instruments to analyze its simplicity, reproducibility, and accuracy. [Participants and Methods] One hundred and four healthy university students (56 males and 48 females) were included in the study. The knee extension force was measured using LCS, and the knee extension torque was measured using other devices (Cybex). In addition, lower leg muscle mass was measured using a body composition meter. The reproducibility of LCS and the correlation between the knee extension torque and lower leg muscle mass were evaluated. [Results] The measurement reproducibility of LCS was significantly higher. The knee extension force confirmed the proportional relative reliability of Cybex with knee extension torque. A relationship between knee extension force and lower limb muscle mass was also observed, indicating that muscle mass cannot be estimated as muscle strength. [Conclusion] The high reproducibility of the knee extension force measurement using LCS demonstrates its potential as a portable alternative instrument for muscle strength measurement in clinical practice. Therefore, LCS device is a simple and effective tool for assessing muscle strength.

Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy.

Chaperone-mediated autophagy (CMA), a selective form of degradation of cytosolic proteins in lysosomes, contributes to maintenance of proteostasis and to the cellular adaptation to stress. CMA substrates are delivered by a cytosolic chaperone to the lysosomal surface, where, upon unfolding, they are internalized through a membrane translocation complex. The molecular components that participate in CMA substrate targeting and translocation are well characterized, but those involved in CMA regulation remain mostly unknown. In this study, we have identified that CMA is under the positive control of the phosphatase PHLPP1 that associates with the lysosomal membrane and counteracts the inhibitory effect of mTORC2 on CMA. Lysosomal Akt, a target of the mTORC2/PHLPP1 kinase-phosphatase pair, modulates CMA activity by controlling the dynamics of assembly and disassembly of the CMA translocation complex at the lysosomal membrane. The lysosomal mTORC2/PHLPP1/Akt axis could become a target to restore CMA dysfunction in aging and disease.

The Matsudai Knee Osteoarthritis Survey showed the longitudinal changes of knee phenotypes in alignment and structure during 23-28 years.

PURPOSE: The longitudinal changes in alignment and structure, including the joint line and cortical bone thickness (CBT) of the femur and tibia, and knee phenotype in patients with knee osteoarthritis (OA) remain unknown. The aim of this retrospective study was to clarify the longitudinal changes in matched healthy subjects. METHODS: The follow-up Matsudai Knee Osteoarthritis Survey was administered between 23 and 28 years. This study included 285 healthy knees from 235 females with an average age of 53 ± 6 years at baseline. The non-OA individuals, with an average age of 79 ± 4 years, were divided into three groups at baseline according to their follow-up radiographic results [the non-OA (n = 52), early OA (n = 131), and advanced OA groups (n = 102)]. Changes in alignment, joint line, CBT, and knee phenotype were assessed at baseline and at follow-up using standing anteroposterior radiographs. RESULTS: This study showed significant varus changes in the alignment (p < 0.001) and tibial and femoral joint line parameters (p < 0.05) in the OA group. Decreased CBT and increased mediolateral CBT ratios were observed in all groups (p < 0.001). The knee phenotypes in the OA groups were changed to varus angles, especially in the alignment and tibial joint line. CONCLUSIONS: The longitudinal changes of knee phenotypes in alignment and structure (CBT and joint line) from baseline to follow-up were shown in the OA groups. In addition, alignment and tibial structural factors at baseline are useful in predicting the incidence of knee OA in daily practice. LEVELS OF EVIDENCE: III.

[Refractory esophageal stricture of esophageal mucous membrane pemphigoid after allogeneic hematopoietic stem cell transplantation].

Haploidentical allogeneic hematopoietic stem cell transplantation from her brother was performed on a 41-year-old lady with no prior history of pemphigoid to treat recurrent AML. On day 59 following transplantation, she experienced esophageal stenosis. During immunosuppressive therapy for graft vs. host disease, this condition was controlled with periodic esophageal dilatation (GVHD). Her esophageal stricture, which required periodic dilatation, grew worse after she stopped immunosuppressive therapy because of recurrent AML. The esophageal mucosa was easily hemorrhagic and desquamative. Histologic analysis revealed that the squamous cell layers had been divided. Indirect immunofluorescence was negative for IgG and positive for IgA on the epidermal layers, while direct immunofluorescence showed a linear deposition of IgG on the basement membrane zone. It was determined through immunoblotting utilizing recombinant protein of BP180 C-terminal domain that both IgG and IgA antibodies were present, supporting the diagnosis of mucous membrane pemphigoid with anti-BP180. After allogeneic transplantation, basal epidermal cell destruction by GVHD may result in autoimmune blistering disorders, which expose basement membrane proteins and antigen presentation. A similar mechanism could apply to our situation. For rare GVHD cases, a thorough histological diagnosis is required.

A phase I study of the safety and efficacy of talimogene laherparepvec in Japanese patients with advanced melanoma.

Talimogene laherparepvec (T-VEC) is approved for the treatment of unresectable melanoma in the USA, Europe, and Australia. This phase I, multicenter, open-label, dose de-escalation study evaluated the safety and efficacy of T-VEC in Japanese patients with unresectable stage IIIB-IV melanoma. Eligible adult patients had histologically confirmed stage IIIB-IVM1c cutaneous melanoma, may have received prior systemic anticancer therapy, must have had ≥1 injectable lesion, serum lactate dehydrogenase ≤1.5x upper limit of normal, ECOG performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. T-VEC was injected intralesionally (first dose, ≤4.0 ml of 106  PFU/ml; after 3 weeks and then every 2 weeks thereafter, ≤4.0 ml of 108  PFU/ml). Primary endpoints were dose-limiting toxicities (DLTs) and durable response rate (DRR). Of 18 enrolled patients (72.2% female), 16 had received ≥1 prior line of therapy. Ten patients discontinued T-VEC due to disease progression. Median (range) follow-up was 20.0 (4-37) months. No DLTs were observed; 17 (94.4%) patients had treatment-emergent adverse events (AEs). Fourteen (77.8%) patients had treatment-related AEs; the most frequent were pyrexia (44.4%), malaise (16.7%), chills, decreased appetite, pruritus, and skin ulcer (11.1% each). The primary efficacy endpoint was met: 2 (11.1%) patients had a durable partial response ≥6 months. The DRR was consistent with that observed in a phase III trial of T-VEC in non-Asian patients. The safety profile was consistent with the patients' underlying disease and the known safety profile of T-VEC.

Risk factors for acute encephalitis and early seizure recurrence in complex febrile seizures.

The purpose of this study is to elucidate risk factors for central nervous system infection and early seizure recurrence in children with febrile seizures (FSs) and thus facilitate outpatient management of complex FS. This single-center, retrospective cohort study investigated 688 children (6-60 months old) with FSs in Japan during 2011-2021. We investigated the incidence and clinical manifestations of children with acute encephalitis or bacterial meningitis. Logistic regression modeling was used to examine risk factors for seizure recurrence within 24 h. Among children with recurrent FSs, the distribution of intervals between first and second FS was assessed. Among 145 children with complex FSs, 2 patients (1.4%) had acute viral encephalitis and none had bacterial meningitis. Acute encephalitis was found in 2 of 8 patients (25%) with FSs prolonged ≥30 min and 2 of 3 patients (67%) requiring ≥2 intravenous anticonvulsants to stop seizures. Seizure recurrence within 24 h was observed in 16% of participants and was independently associated with preceding use of diazepam and family history of FS. In 82% of patients with FS recurrence within 24 h, early recurrences occurred within 8 h of the first seizure.      Conclusion: Patients with prolonged or refractory FSs are still indicated for hospital admission due to the risk of acute encephalitis. FS patients with a family history of FS may be managed safely by 8-h observation or single-dose rectal diazepam as prophylaxis against early recurrent seizure. What is Known: • Hospitalization has been recommended for children with complex febrile seizures due to the increased risk of central nervous infections. • Recent studies showed low incidences of bacterial meningitis (<1%) in children with complex febrile seizures in the presence of routine immunization. What is New: • Acute encephalitis was identified in 1.4% of children with complex febrile seizures, characterized by prolonged seizures ≥30 min and refractory seizures. • Early recurrent seizures may be safely managed by prophylactic diazepam or 8-h expectant observation.

The coronal inclination of the medial tibial plateau affects coronal gait kinematics for varus osteoarthritic knees.

PURPOSE: This study aims to (1) measure the kinematics of lower extremity alignment and the bony position relative to the ground during walking, focusing on the coronal plane, and (2) determine the correlation between the kinematics and coronal inclination of the medial tibial plateau (coronal inclination) for healthy and varus knee osteoarthritis (OA). METHODS: In this study, 43 women (non-OA, 9 knees; early OA, 13 knees; advanced OA, 21 knees; mean age 58 ± 17 years) were examined. The knee phenotypes in varus knee OA were varied. Three-dimensional (3D) knee kinematics were calculated in gait analysis by combining the motion capture system and the 3D lower extremity alignment assessment system via biplanar long-leg X-rays, applying the 3D-2D registration technique. The main parameters were the kinematics of the bony axes relative to the ground in the coronal plane during the stance phase of the gait. The differences in overall kinematics were assessed using repeated measures ANOVA with Tukey's post hoc test. The association between kinematic parameters and coronal inclination was evaluated by multiple linear regression after univariate analysis. RESULTS: The tibia tilted laterally during the loading response, and a plateau area subsequently appeared until the terminal stance phase, whereas the femur slowly tilted laterally until the terminal stance phase. The dynamic alignment showed a relatively large varus angular change during the loading response in all groups. The trend of motion was similar among all groups (p = n.s.), although to varying degrees. The coronal inclination was the more dominant factor than the Kellgren-Lawrence (K-L) grades (ß = - 0.423, p = 0.005) when the change in dynamic alignment was determined. CONCLUSIONS: The TAA plateau area after the loading response implies that the tibial articular surface may become horizontal. The femur slowly tilted laterally until the terminal stance phase in response to the tibial motion. Consequently, the dynamic alignment showed a varus angular change, in which coronal MCT was more involved than K-L grades.

The medial inclination of the proximal tibia is associated with the external knee adduction moment in advanced varus knee osteoarthritis.

PURPOSE: Whether the inclined articular surface on the medial proximal tibia and the external knee adduction moment (KAM) correlate remains unclear. The hypothesis was that a steeper inclined articular surface correlated with a larger KAM in advanced knee osteoarthritis (OA). METHODS: A total of 44 females (non-OA, 9 knees; early OA, 14 knees; advanced OA, 21 knees; mean age, 58 ± 16 years) were examined. Three-dimensional (3D) assessment was used on biplanar long-leg radiographs and 3D bone models using a 3D to 2D image registration technique. The approximation plane in the proximal tibia was determined using the least-square method. The joint moments were mathematically calculated in a gait analysis, applying a motion capture system and force plates. The main evaluation parameters were the femorotibial angle (FTA), the coronal inclination of the approximation plane in the medial proximal tibia (coronal inclination), and internal knee joint moments. The KAM means the external moments balanced with the internal knee abduction moments. RESULTS: The advanced OA showed a larger internal abduction moment (p = 0.017) at the loading response than the other groups. The larger FTA and steeper coronal inclination correlated with the larger internal abduction moment (FTA, p < 0.001; coronal inclination, p = 0.003) at the loading response. CONCLUSIONS: As the clinical relevance, the association among the coronal inclination of the medial proximal tibia, lower extremity alignment, and KAM is one of the key factors to help better understand the etiology of knee OA. LEVEL OF EVIDENCE: III.

Correlation of Coronary Artery Abnormalities with Fever Pattern in Patients with Kawasaki Disease.

OBJECTIVE: To investigate the incidence of coronary artery abnormalities (CAAs) by fever pattern after intravenous immunoglobulin (IVIG) therapy in patients with Kawasaki disease. STUDY DESIGN: This retrospective cohort study included 172 patients with Kawasaki disease aged ≤12 years who underwent IVIG therapy and had no CAAs before treatment. Resistance to initial IVIG was defined as persistent fever ≥37.5 °C for ≥24 hours after therapy or the recurrence of Kawasaki disease after initial defervescence. The patients were divided into 3 groups: IVIG responders, nonresponders with persistent fever, and nonresponders with recurrent fever. CAAs were evaluated 2 or 4 weeks and 12 months after onset and were defined by a coronary artery z-score ≥2.5. RESULTS: The incidence of CAAs within 12 months after onset was significantly higher in nonresponders with persistent fever (27%) compared with the other 2 groups. On multivariate logistic regression analysis, being a nonresponder with persistent fever was an independent risk factor for having CAAs within 12 months after the onset of Kawasaki disease (OR, 6.48; P = .007). CONCLUSIONS: In patients with Kawasaki disease resistant to IVIG therapy, persistent fever, but not recurrent fever, was found to be a risk factor for the incidence of CAAs. Aggressive additional therapy may be beneficial to prevent CAA formation in patients with Kawasaki disease with persistent fever.

Impact of clinical practice guidelines for vacuum-assisted delivery on maternal and neonatal outcomes in Japan: A single-center observational study.

AIM: Practice guidelines for vacuum-assisted delivery in Japan were revised in 2014 to improve clinical safety. We aimed to determine the success rates of vacuum delivery before and after the release of the revised guidelines. METHODS: This retrospective observational study included singleton deliveries at term gestation. Success rate of vacuum delivery, duration of extraction, number of tractions and maternal and neonatal injuries were compared between 2011-2014 and 2015-2019. RESULTS: Vacuum extraction was attempted in 249 (15%) of 1657 deliveries. Duration of extraction was shorter in 2015-2019 (median, 3.0 min; interquartile range [IQR], 1.0-5.8 min) than in 2011-2014 (median, 4.0 min; IQR, 2.0-6.5 min; P = 0.0045). No significant differences were seen in success of vacuum extraction (98%), prolonged (>20 min) duration of extraction (1.5%) and repeated (>5 pulls) tractions (3.1%) in vacuum deliveries during 2011-2014, compared to success of vacuum extraction (94%), prolonged duration of extraction (1.6%) and repeated tractions (1.1%) in those during 2015-2019. Likewise, no significant differences were identified in maternal or neonatal injuries. CONCLUSION: Successful vacuum-assisted deliveries and shortened duration of extraction were still confirmed after guideline revision. However, because of consistent safe practice with vacuum delivery from before the revision, improvements in maternal and neonatal injuries were not observed.

Hepatitis C virus infection increases autophagosome stability by suppressing lysosomal fusion through an Arl8b-dependent mechanism.

Autophagy is a conserved cellular process involving intracellular membrane trafficking and degradation. Pathogens, including hepatitis C virus (HCV), often exploit this process to promote their own survival. The aim of this study was to determine the mechanism by which HCV increases steady-state autophagosome numbers while simultaneously inhibiting flux through the autophagic pathway. Using the lysosomal inhibitor bafilomycin A1, we showed that HCV-induced alterations in autophagy result from a blockage of autophagosome degradation rather than an increase in autophagosome generation. In HCV-infected cells, lysosome function was normal, but a tandem RFP-GFP-LC3 failed to reach the lysosome even under conditions that activate autophagy. Autophagosomes and lysosomes isolated from HCV-infected cells were able to fuse with each other normally in vitro, suggesting that the cellular fusion defect resulted from trafficking rather than an inability of vesicles to fuse. Arl8b is an Arf-like GTPase that specifically localizes to lysosomes and plays a role in autophagic flux through its effect on lysosomal positioning. At basal levels, Arl8b was primarily found in a perinuclear localization and co-localized with LC3-positive autophagosomes. HCV infection increased the level of Arl8b 3-fold and redistributed Arl8b to a more diffuse, peripheral pattern that failed to co-localize with LC3. Knockdown of Arl8b in HCV-infected cells restored autophagosome-lysosome fusion and autophagic flux to levels seen in control cells. Thus, HCV suppresses autophagic flux and increases the steady-state levels of autophagosomes by increasing the expression of Arl8b, which repositions lysosomes and prevents their fusion with autophagosomes.

Age- and sex-related characteristics in cortical thickness of femoral diaphysis for young and elderly subjects.

INTRODUCTION: Cortical thickness of the femoral diaphysis is assumed to be a preferred parameter in the assessment of the structural adaptation by mechanical use and biological factors. This study aimed to investigate the age- and sex-specific characteristics in cortical thickness of the femoral diaphysis between young and elderly non-obese people. MATERIALS AND METHODS: This study investigated 34 young subjects (21 men and 13 women; mean age: 27 ± 8 years) and 52 elderly subjects (29 men and 23 women; mean age: 70 ± 6 years). Three-dimensional (3D) cortical thickness of the femoral diaphysis was automatically calculated for 5000-8000 measurement points using the high-resolution cortical thickness measurement from clinical CT data. In 12 assessment regions created by combining three heights (proximal, central, and distal diaphysis) and four areas of the axial plane at 90° (medial, anterior, lateral, and posterior areas) in the femoral coordinate system, the standardized thickness was assessed using the femoral length. RESULTS: As per the trends, (1) there were no differences in medial and lateral thicknesses, while the posterior thickness was greater than the anterior thickness, (2) the thickness in men was higher than that in women, and (3) the thickness in young subjects was higher than that in elderly subjects. CONCLUSIONS: The results of this study are of clinical relevance as reference points to clarify the causes of various pathological conditions for diseases of the lower extremities.

The weather condition and epidemics as triggers for febrile seizure: A single-center retrospective observational study.

OBJECTIVE: The objective of this study was to investigate the association between the weather and epidemic condition and risk of febrile seizures (FSs) in Japan. STUDY DESIGN: This single-center, retrospective study included 560 children (age, 6-60 months) with FSs who were transported to our center by ambulance from January 2011 through December 2018. The weather (temperature, atmospheric pressure, relative air humidity, amount of rainfall, sunshine duration, and air concentration of nitrogen dioxide [NO2] and sulfur dioxide [SO2]) and epidemic (influenza virus infection, infectious gastroenteritis, and exanthem subitum) conditions in this region were compared between the periods (days or weeks) with the transportation of children with FS to our hospital and those without such transportation. RESULTS: In the univariate analyses, neither daily or weekly weather condition nor weekly epidemic condition was correlated to FS transportation. Furthermore, the multiple logistic regression analysis suggested that epidemic influenza virus infection (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.08-1.73) and infectious gastroenteritis (OR, 1.64; 95% CI, 1.09-2.54) were the independent risk factors for FS occurrence and weather condition was not associated with FS risk. CONCLUSIONS: Febrile seizure incidence may be increased by epidemic febrile infections but not by weather condition.

Comparison of initial and final diagnoses in children with acute febrile illness: A retrospective, descriptive study: Initial and final diagnoses in children with acute fever.

BACKGROUND: This study aimed to elucidate the etiologies and diagnostic errors of early-phase pediatric fever without an obvious cause. METHODS: This single-center, retrospective, descriptive study included 1334 febrile children hospitalized at Beppu Medical Center in Japan between 2014 and 2018. Eligibility criteria were age ≤12 years, axillary temperature ≥38.0°C, and fever duration ≤7 days at admission. Initial diagnoses on the day of admission and final diagnoses at defervescence were divided into initial fever with identified source (FIS) and initial fever without source (FWS) and final FIS and final FWS, respectively. The etiology of initial FWS and diagnostic discordance between initial FIS and final FIS were investigated. RESULTS: Of the 1334 participants, 94 (7.0%) were diagnosed with initial FWS. Among patients with initial FWS, final diagnoses were confirmed in 40 (43%), including Kawasaki disease in 17, urinary tract infection in 5, bacteremia in 4, exanthem subitum in 3, and the others in 11. Among the 1275 patients diagnosed with final FIS, diagnostic discordances between initial and final diagnoses were observed in 131 patients (10%). The multiple logistic regression analysis identified increased serum C-reactive protein value at admission (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.06-1.13), exanthem subitum (OR: 409; 95% CI: 119-1399), and Kawasaki disease (OR: 14.3; 95% CI: 8.7-23.3) as independent risk factors for diagnostic discordance. CONCLUSION: Exanthem subitum and Kawasaki disease may be undiagnosed or misdiagnosed in febrile children with fever duration ≤7 days.

Automatic diagnosis of melanoma using hyperspectral data and GoogLeNet.

BACKGROUND: Melanoma is a type of superficial tumor. As advanced melanoma has a poor prognosis, early detection and therapy are essential to reduce melanoma-related deaths. To that end, there is a need to develop a quantitative method for diagnosing melanoma. This paper reports the development of such a diagnostic system using hyperspectral data (HSD) and a convolutional neural network, which is a type of machine learning. MATERIALS AND METHODS: HSD were acquired using a hyperspectral imager, which is a type of spectrometer that can simultaneously capture information about wavelength and position. GoogLeNet pre-trained with Imagenet was used to model the convolutional neural network. As many CNNs (including GoogLeNet) have three input channels, the HSD (involving 84 channels) could not be input directly. For that reason, a "Mini Network" layer was added to reduce the number of channels from 84 to 3 just before the GoogLeNet input layer. In total, 619 lesions (including 278 melanoma lesions and 341 non-melanoma lesions) were used for training and evaluation of the network. RESULTS AND CONCLUSION: The system was evaluated by 5-fold cross-validation, and the results indicate sensitivity, specificity, and accuracy of 69.1%, 75.7%, and 72.7% without data augmentation, 72.3%, 81.2%, and 77.2% with data augmentation, respectively. In future work, it is intended to improve the Mini Network and to increase the number of lesions.

Articular surface of the medial proximal tibia is aligned parallel to the ground in three-dimensional space under weight-bearing conditions in healthy and varus osteoarthritic knees.

PURPOSE: To test the hypothesis that an inclined articular surface on the medial proximal tibia is aligned more parallel to the ground in three-dimensional (3D) space under weight-bearing (WB) conditions (parallel phenomenon) than under non-WB (NWB) conditions in healthy and varus osteoarthritic knees. METHODS: We examined 55 healthy knees (26 women, 29 men; mean age, 70 ± 6 years) and 108 varus osteoarthritic knees (66 women, 16 men; mean age, 74 ± 7 years). For the evaluation under WB conditions, a 3D assessment system was used on biplanar long-leg radiographs and 3D bone models using a 3D-to-2D image registration technique. In addition, the least square method was used to determine the approximation plane. The angles between the normal vector for the approximation plane of an articular surface on the medial proximal tibia and each axis of the tibial or world coordinate system were calculated. RESULTS: Morphologically, the inclination of the approximation plane was steeper in osteoarthritic knees than in healthy knees (p < 0.0001). The approximation plane was aligned more parallel to the ground under WB conditions than under NWB conditions in healthy (p < 0.0001) and osteoarthritic knees (p < 0.0001). CONCLUSIONS: The parallel phenomenon in the medial proximal tibia was confirmed for healthy and varus osteoarthritic knees. The medial proximal tibia plays an important role in the parallel phenomenon, assumingly associated with varus alignment and varus thrust. The inclination of the medial proximal tibia may become a new parameter for imaging investigations. LEVEL OF EVIDENCE: III.

Man against machine: diagnostic performance of a deep learning convolutional neural network for dermoscopic melanoma recognition in comparison to 58 dermatologists.

Background: Deep learning convolutional neural networks (CNN) may facilitate melanoma detection, but data comparing a CNN's diagnostic performance to larger groups of dermatologists are lacking. Methods: Google's Inception v4 CNN architecture was trained and validated using dermoscopic images and corresponding diagnoses. In a comparative cross-sectional reader study a 100-image test-set was used (level-I: dermoscopy only; level-II: dermoscopy plus clinical information and images). Main outcome measures were sensitivity, specificity and area under the curve (AUC) of receiver operating characteristics (ROC) for diagnostic classification (dichotomous) of lesions by the CNN versus an international group of 58 dermatologists during level-I or -II of the reader study. Secondary end points included the dermatologists' diagnostic performance in their management decisions and differences in the diagnostic performance of dermatologists during level-I and -II of the reader study. Additionally, the CNN's performance was compared with the top-five algorithms of the 2016 International Symposium on Biomedical Imaging (ISBI) challenge. Results: In level-I dermatologists achieved a mean (±standard deviation) sensitivity and specificity for lesion classification of 86.6% (±9.3%) and 71.3% (±11.2%), respectively. More clinical information (level-II) improved the sensitivity to 88.9% (±9.6%, P = 0.19) and specificity to 75.7% (±11.7%, P < 0.05). The CNN ROC curve revealed a higher specificity of 82.5% when compared with dermatologists in level-I (71.3%, P < 0.01) and level-II (75.7%, P < 0.01) at their sensitivities of 86.6% and 88.9%, respectively. The CNN ROC AUC was greater than the mean ROC area of dermatologists (0.86 versus 0.79, P < 0.01). The CNN scored results close to the top three algorithms of the ISBI 2016 challenge. Conclusions: For the first time we compared a CNN's diagnostic performance with a large international group of 58 dermatologists, including 30 experts. Most dermatologists were outperformed by the CNN. Irrespective of any physicians' experience, they may benefit from assistance by a CNN's image classification. Clinical trial number: This study was registered at the German Clinical Trial Register (DRKS-Study-ID: DRKS00013570; https://www.drks.de/drks_web/).