Background: The effects of lipopolysaccharide (LPS) on cell proliferation and osteogenic potential (OP) of MSCs have been frequently studied. Objective: to compare the effects of LPS on periodontal-ligament-derived mesenchymal stem cells (PDLSCs) in monolayer and 3D culture. Methods: The PDLSCs were colorimetrically assessed for proliferation and osteogenic potential (OP) after LPS treatment. The 3D cells were manually prepared by scratching and allowing them to clump up. The clumps (C-MSCs) were treated with LPS and assessed for Adenosine triphosphate (ATP) and OP. Raman spectroscopy was used to analyze calcium salts, DNA, and proline/hydroxyproline. Multiplexed ELISA was performed to assess LPS induced local inflammation. Results: The proliferation of PDLSCs decreased with LPS. On Day 28, LPS-treated cells showed a reduction in their OP. C-MSCs with LPS did not show a decrease in ATP production. Principal bands identified in Raman analysis were the P–O bond at 960 cm⁻¹ of the mineral component, 785 cm⁻¹, and 855 cm⁻¹ showing qualitative changes in OP, proliferation, and proline/hydroxyproline content, respectively. ELISA confirmed increased levels of IL-6 and IL-8 but with the absence of TNF-α and IL-1β secretion. Conclusions: These observations demonstrate that C-MSCs are more resistant to the effects of LPS than cells in monolayer cell culture. Though LPS stimulation of C-MSCs creates an early pro-inflammatory milieu by secreting IL-6 and IL-8, PDLSCs possess inactivated TNF promoter and an ineffective caspase-1 activating process. Full article

Tumor regrowth and heterogeneity are important clinical parameters during radiotherapy, and the probability of treatment benefit critically depends on the tumor progression pattern in the interval between the fractional irradiation treatments. We propose an analytic, easy-to-use method to take into account clonal subpopulations with different specific growth rates and radiation resistances. The different strain regrowth effects, as described by Gompertz law, require a dose-boost to reproduce the survival probability of the corresponding homogeneous system and for uniform irradiation. However, the estimate of the survival fraction for a tumor with a hypoxic subpopulation is more reliable when there is a slow specific regrowth rate and when the dependence on the oxygen enhancement ratio of radiotherapy is consistently taken into account. The approach is discussed for non-linear two-population dynamics for breast cancer and can be easily generalized to a larger number of components and different tumor phenotypes. Full article

Hereditary dentin defects can be categorized as a syndromic form predominantly related to osteogenesis imperfecta (OI) or isolated forms without other non-oral phenotypes. Mutations in the gene encoding dentin sialophosphoprotein (DSPP) have been identified to cause dentinogenesis imperfecta (DGI) Types II and III and dentin dysplasia (DD) Type II. While DGI Type I is an OI-related syndromic phenotype caused mostly by monoallelic mutations in the genes encoding collagen type I alpha 1 chain (COL1A1) and collagen type I alpha 2 chain (COL1A2). In this study, we recruited families with non-syndromic dentin defects and performed candidate gene sequencing for DSPP exons and exon/intron boundaries. Three unrelated Korean families were further analyzed by whole-exome sequencing due to the lack of the DSPP mutation, and heterozygous COL1A2 mutations were identified: c.3233G>A, p.(Gly1078Asp) in Family 1 and c.1171G>A, p.(Gly391Ser) in Family 2 and 3. Haplotype analysis revealed different disease alleles in Families 2 and 3, suggesting a mutational hotspot. We suggest expanding the molecular genetic etiology to include COL1A2 for isolated dentin defects in addition to DSPP. Full article

(1) Background: Subcutaneous apomorphine infusion (SCAI) is one of the three main treatment options for motor fluctuations in advanced Parkinson’s disease (PD). The adherence to SCAI is generally considered to be low due to adverse events and because it is perceived as a treatment option to be used for a limited period only. We evaluated the reasons for discontinuation of SCAI in relation to when patients stopped treatment. (2) Methods: We reviewed the medical records of PD patients treated with SCAI at a single center, capturing patient demographics and the reasons for cessation of SCAI. (3) Results: 101 patients were included in the analysis, with a median time on treatment of 6.34 years. The main reasons for stopping SCAI were adverse events, death, and dissatisfaction with treatment. In the first 6 years of treatment, the predominant side effects leading to discontinuation were somnolence and hallucinations. (4) Conclusions: We suggest that SCAI can be an effective long-term treatment option for advanced PD, but it requires careful patient selection, a high level of communication with the patient and carer, and rigorous monitoring of the effects of treatment and for any adverse events so they can be promptly managed. Full article

Background: To evaluate the performance of a machine-learning (ML) algorithm to detect and classify choroidal neovascularization (CNV), secondary to age-related macular degeneration (AMD) on spectral-domain optical coherence tomography (SD-OCT) images. Methods: Baseline fluorescein angiography (FA) and SD-OCT images from 1037 treatment-naive study eyes and 531 fellow eyes, without advanced AMD from the phase 3 HARBOR trial (NCT00891735), were used to develop, train, and cross-validate an ML pipeline combining deep-learning–based segmentation of SD-OCT B-scans and CNV classification, based on features derived from the segmentations, in a five-fold setting. FA classification of the CNV phenotypes from HARBOR was used for generating the ground truth for model development. SD-OCT scans from the phase 2 AVENUE trial (NCT02484690) were used to externally validate the ML model. Results: The ML algorithm discriminated CNV absence from CNV presence, with a very high accuracy (area under the receiver operating characteristic [AUROC] = 0.99), and classified occult versus predominantly classic CNV types, per FA assessment, with a high accuracy (AUROC = 0.91) on HARBOR SD-OCT images. Minimally classic CNV was discriminated with significantly lower performance. Occult and predominantly classic CNV types could be discriminated with AUROC = 0.88 on baseline SD-OCT images of 165 study eyes, with CNV from AVENUE. Conclusions: Our ML model was able to detect CNV presence and CNV subtypes on SD-OCT images with high accuracy in patients with neovascular AMD. Full article

Background: Psoriasis is a chronic inflammatory disease characterized by an excessive hyperproliferation of keratinocytes and a combination of genetic, epigenetic, and environmental influences. The pathogenesis of psoriasis is complex and the exact mechanism remains elusive. Objectives: The study of the prevalence of psoriasis will allow the estimation of the number of people suffering from this condition at the national level, as well as the development and validation of a questionnaire to estimate the prevalence and the risk factors associated with the disease. Methods: A quantitative research was conducted at a national level among the target population in order to validate the questionnaire and estimate the national prevalence. Results: Declaratively, the prevalence of psoriasis in the studied group (N = 1500) is 4%, the first symptoms appearing around the age of 50, with a certified diagnosis being made on average at 55 years. The prevalence of psoriasis vulgaris was 4.99%. Conclusions: The results obtained will be useful in guiding future initiatives and communication campaigns related to this condition, and the methodological approach used will provide the opportunity to make recommendations for improving similar initiatives in the future. Full article

Automated detection of the region of interest (ROI) is a critical step in the two-step classification system in several medical image applications. However, key information such as model parameter selection, image annotation rules, and ROI confidence score are essential but usually not reported. In this study, we proposed a practical framework of ROI detection by analyzing hip joints seen on 7399 anteroposterior pelvic radiographs (PXR) from three diverse sources. We presented a deep learning-based ROI detection framework utilizing a single-shot multi-box detector with a customized head structure based on the characteristics of the obtained datasets. Our method achieved average intersection over union (IoU) = 0.8115, average confidence = 0.9812, and average precision with threshold IoU = 0.5 (AP50) = 0.9901 in the independent testing set, suggesting that the detected hip regions appropriately covered the main features of the hip joints. The proposed approach featured flexible loose-fitting labeling, customized model design, and heterogeneous data testing. We demonstrated the feasibility of training a robust hip region detector for PXRs. This practical framework has a promising potential for a wide range of medical image applications. Full article

Objective. To evaluate the incidence of post-embolization syndrome (PES) and the effect of venoactive therapy on its development, severity, and duration after endovascular embolization of gonadal veins (EEGV) with coils in patients with pelvic congestion syndrome (PCS). Materials and Methods. We analyzed the outcomes of EEGV with coils in 70 female patients who received (n = 38; group 1) or did not receive (n = 32; group 2) treatment with a venoactive drug (VAD) before and after the procedure. Assessments of the EEGV efficacy and for possible signs of PES were done on days 1, 5, 10, 15, 20, and 30 after the intervention. All patients underwent transvaginal and transabdominal duplex ultrasound scanning (DUS) after EEGV. In addition, patients with PES were examined using the computed tomography of the pelvic veins in the postprocedural period. Results. Technical success of EEGV was achieved in 100% of patients. Pelvic venous pain (PVP) reduction after EEGV was observed in 77.1% of patients. The PES was diagnosed in 18.6% of cases (10.5% in group 1 vs. 28.1% in group 2, p > 0.05). In three patients of group 1, the protrusion of coils was suspected and eventually verified during the resection of the left gonadal vein with coils. The group 1 patients had less severe post-embolization pain (6.2 ± 0.4 vs. 7.8 ± 0.3 scores in group 2; p = 0.009) and three times shorter duration of PES (5.0 ± 1.2 vs. 16.2 ± 2.7 days; p = 0.003). No significant differences in the diameters of gonadal veins, side of embolization, and number of coils were revealed between patients with and without PES. The rate of parametrium vein thrombosis was found to be significantly higher in patients with PES than in those without PES (30.7% vs. 18.5%, respectively; p < 0.05). Conclusion. The PES is a frequent complication of EEGV with coils and occurs in 18.6% of patients. Venoactive treatment does not effect the incidence of this complication but reduces the PES severity and duration. Full article

HLA-B*27 is an important marker for spondyloarthritis (SpA), however, many SpA patients are HLA-B*27 negative. Thus, the aim of this study was to investigate the influence of IL17, TNF and VDR gene polymorphisms in SpA patients who were HLA-B*27 negative. This case-control study was conducted in 158 patients [102 patients with ankylosing spondylitis (AS) and 56 with psoriatic arthritis (PsA)] and 184 controls. HLA-B*27 genotyping was performed using PCR-SSP and IL17A (rs2275913), IL17F (rs763780), TNF-308 (rs1800629), TNF-238 (rs361525), FokI C>T (rs2228570), TaqI C>T (rs731236), ApaI A>C (rs7975232), and BsmI C>T (rs1544410) using PCR-RFLP. Statistical analyses were performed by Chi-square and logistic regression using OpenEpi and SNPStats software. The IL17F C allele frequency was higher in patients with SpA, AS and PsA compared to controls. The IL17F T/C genotype frequency was higher in SpA patients in an overdominant inheritance model and when men and women were separately analyzed. IL17A_IL17F AC haplotype was significantly associated to the risk for SpA patients. As for VDR, the ApaI a/a was a potential risk factor for SpA in men. In conclusion, IL17F C variant contributed to the risk of SpA in Brazilian patients who were HLA-B*27 negative and could be a potential marker for SpA. Full article

Management of Parkinson’s disease traditionally relies solely on clinical assessment. The PKG objectively measures affected persons’ movements in daily life. The present study evaluated how often PKG data changed treatment decisions in routine clinical care and to what extent the clinical assessment and the PKG interpretation differed. PKG recordings were performed before routine visits. The neurologist first made a clinical assessment without reviewing the PKG. Signs and symptoms were recorded, and a treatment plan was documented. Afterward, the PKG was evaluated. Then, the neurologist decided whether to change the initial treatment plan or not. PKG review resulted in a change in the initial treatment plan in 21 of 66 participants (31.8%). The clinical assessment and the PKG review differed frequently, mainly regarding individual overall presence of motor problems (67%), profile of bradykinesia/wearing off (79%), dyskinesia (35%) and sleep (55%). PKG improved the dialogue with the participant in 88% of cases. PKG and clinical variables were stable when they were repeated after 3–6 months. In conclusion, PKG information changes treatment decisions in nearly a third of people with Parkinson’s disease in routine care. Standard clinical assessment and PKG evaluation are often non-identical. Objective measurements in people living with Parkinson’s disease can add therapeutically relevant information. Full article

Precision medicine is essential for the modern care of a patient with cancer. Comprehensive molecular profiling of the tumor itself is necessary to determine the presence or absence of certain targetable abnormalities or biomarkers. In particular, lung cancer is a disease for which targetable genomic alterations will soon guide therapy in the majority of cases. In this comprehensive review of solid tumor-based biomarkers, we describe the genomic alterations for which targeted agents have been approved by the United States Food and Drug Administration (FDA). While focusing on alterations leading to approvals in a tumor-agnostic fashion (MSI-h, TMB-h, NTRK) and on those alterations with approvals in multiple malignancies (BRAF, ERBB2, RET, BRCA, PD-L1), we also describe several biomarkers or indications that are likely to lead to an approved drug in the near future (e.g., KRAS G12C, PD-L1 amplification, HER2 overexpression in colon cancer, HER2 mutations in lung cancer). Finally, we detail the current landscape of additional actionable alterations (EGFR, ALK, ROS1, MET) in lung cancer, a biomarker-rich malignancy that has greatly benefitted from the precision oncology revolution. Full article

The combination of 3D printing and navigation promises improvements in surgical procedures and outcomes for complex bone tumor resection of the trunk, but its features have rarely been described in the literature. Five patients with trunk tumors were surgically treated in our institution using a combination of 3D printing and navigation. The main process includes segmentation, virtual modeling and build preparation, as well as quality assessment. Tumor resection was performed with navigated instruments. Preoperative planning supported clear margin multiplanar resections with intraoperatively adaptable real-time visualization of navigated instruments. The follow-up ranged from 2–15 months with a good functional result. The present results and the review of the current literature reflect the trend and the diverse applications of 3D printing in the medical field. 3D printing at hospital sites is often not standardized, but regulatory aspects may serve as disincentives. However, 3D printing has an increasing impact on precision medicine, and we are convinced that our process represents a valuable contribution in the context of patient-centered individual care. Full article

Introduction: The calipered kinematically-aligned (KA) total knee arthroplasty (TKA) strives to restore the patient’s individual pre-arthritic (i.e., native) posterior tibial slope when retaining the posterior cruciate ligament (PCL). Deviations from the patient’s individual pre-arthritic posterior slope tighten and slacken the PCL in flexion that drives tibial rotation, and such a change might compromise passive internal tibial rotation and coupled patellofemoral kinematics. Methods: Twenty-one patients were treated with a calipered KA TKA and a PCL retaining implant with a medial ball-in-socket and a lateral flat articular insert conformity that mimics the native (i.e., healthy) knee. The slope of the tibial resection was set parallel to the medial joint line by adjusting the plane of an angel wing inserted in the tibial guide. Three trial inserts that matched and deviated 2°> and 2°< from the patient’s pre-arthritic slope were 3D printed with goniometric markings. The goniometer measured the orientation of the tibia (i.e., trial insert) relative to the femoral component. Results: There was no difference between the radiographic preoperative and postoperative tibial slope (0.7 ± 3.2°, NS). From extension to 90° flexion, the mean passive internal tibial rotation with the pre-arthritic slope insert of 19° was greater than the 15° for the 2°> slope (p < 0.000), and 15° for the 2°< slope (p < 0.000). Discussion: When performing a calipered KA TKA with PCL retention, the correct target for setting the tibial component is the patient’s individual pre-arthritic slope within a tolerance of ±2°, as this target resulted in a 15–19° range of internal tibial rotation that is comparable to the 15–18° range reported for the native knee from extension to 90° flexion. Full article

Accurate nuclear segmentation in histopathology images plays a key role in digital pathology. It is considered a prerequisite for the determination of cell phenotype, nuclear morphometrics, cell classification, and the grading and prognosis of cancer. However, it is a very challenging task because of the different types of nuclei, large intraclass variations, and diverse cell morphologies. Consequently, the manual inspection of such images under high-resolution microscopes is tedious and time-consuming. Alternatively, artificial intelligence (AI)-based automated techniques, which are fast and robust, and require less human effort, can be used. Recently, several AI-based nuclear segmentation techniques have been proposed. They have shown a significant performance improvement for this task, but there is room for further improvement. Thus, we propose an AI-based nuclear segmentation technique in which we adopt a new nuclear segmentation network empowered by residual skip connections to address this issue. Experiments were performed on two publicly available datasets: (1) The Cancer Genome Atlas (TCGA), and (2) Triple-Negative Breast Cancer (TNBC). The results show that our proposed technique achieves an aggregated Jaccard index (AJI) of 0.6794, Dice coefficient of 0.8084, and F1-measure of 0.8547 on TCGA dataset, and an AJI of 0.7332, Dice coefficient of 0.8441, precision of 0.8352, recall of 0.8306, and F1-measure of 0.8329 on the TNBC dataset. These values are higher than those of the state-of-the-art methods. Full article

The rationale of an Advanced Integrative Model and an Advanced Integrative Approach is presented. In the context of Allopathic Medicine, this model introduces the evaluation, clinical exploration, diagnosis, and treatment of concomitant medical problems to the diagnosis of Autism Spectrum Disorder. These may be outside or inside the brain. The concepts of static or chronic, dynamic encephalopathy and condition for Autism Spectrum Disorder are defined in this model, which looks at the response to the treatments of concomitant medical problemsto the diagnosis of Autism Spectrum Disorder. (1) Background: Antecedents and rationale of an Advanced Integrative Model and of an Advanced Integrative Approach are presented; (2) Methods: Concomitant medical problems to the diagnosis of Autism Spectrum Disorder and a discussion of the known responses of their treatments are presented; (3) Results: Groups in Autism are defined and explained, related to the responses of the treatments of the concomitant medical problems to ASD and (4) Conclusions: The analysis in the framework of an Advanced Integrative Model of three groups including the concepts of static encephalopathy; chronic, dynamic encephalopathy and condition for Autism Spectrum Disorder explains findings in the field, previously not understood. Full article