Learning from crowds for automated histopathological image segmentation.

Automated semantic segmentation of histopathological images is an essential task in Computational Pathology (CPATH). The main limitation of Deep Learning (DL) to address this task is the scarcity of expert annotations. Crowdsourcing (CR) has emerged as a promising solution to reduce the individual (expert) annotation cost by distributing the labeling effort among a group of (non-expert) annotators. Extracting knowledge in this scenario is challenging, as it involves noisy annotations. Jointly learning the underlying (expert) segmentation and the annotators' expertise is currently a commonly used approach. Unfortunately, this approach is frequently carried out by learning a different neural network for each annotator, which scales poorly when the number of annotators grows. For this reason, this strategy cannot be easily applied to real-world CPATH segmentation. This paper proposes a new family of methods for CR segmentation of histopathological images. Our approach consists of two coupled networks: a segmentation network (for learning the expert segmentation) and an annotator network (for learning the annotators' expertise). We propose to estimate the annotators' behavior with only one network that receives the annotator ID as input, achieving scalability on the number of annotators. Our family is composed of three different models for the annotator network. Within this family, we propose a novel modeling of the annotator network in the CR segmentation literature, which considers the global features of the image. We validate our methods on a real-world dataset of Triple Negative Breast Cancer images labeled by several medical students. Our new CR modeling achieves a Dice coefficient of 0.7827, outperforming the well-known STAPLE (0.7039) and being competitive with the supervised method with expert labels (0.7723). The code is available at https://github.com/wizmik12/CRowd_Seg.

Advances in Technology Promote Patient-Centered Care in Cardiac Rehabilitation.

Patient-centered health care (PCC) is a framework of clinical care focused on the patient's individual health care needs. In particular, it emphasizes the development of a partnership between the patient, physician, and healthcare workers to actively involve and empower the patient in their health care decisions. Additionally, PCC goals include ensuring access to care, emotional support, engaging patient support systems, physical comfort, and continuity of care. Technology also provides a platform to engage patients and their families in their care and can be a useful tool to gauge their level of interest, knowledge, and motivations to adequately educate them on the many factors that contribute to their disease, including diet, exercise, medication adherence, psychological support, and early symptom detection. In this article, we summarize the importance of technology in promoting PCC in cardiac rehabilitation and the impact technology may have on the different aspects of patient and physician relationships. Modern technological devices including smartphones, tablets, wearables, and other internet-enabled devices have been shown to help patient-staff communication, cater to patients' individual needs, increase access to health care, and implement aspects of PCC domains.

Loss of dystrophin is common in uterine leiomyosarcoma: a potential biomarker for clinical application.

Uterine leiomyosarcoma (LMS) is a deadly disease with high rates of recurrence and a poor prognosis. Its tumorigenesis remains largely unknown, and no specific biomarkers can be used for the differential diagnosis of LMS from other mimics. Recent whole-genome studies revealed a loss of dystrophin is common in LMS, especially in uterine LMS. To investigate the expression pattern of dystrophin expression across different types of uterine smooth muscle tumors, immunohistochemistry was performed, including usual-type leiomyoma, fumarate hydratase-deficient leiomyoma, leiomyoma with bizarre nuclei, conventional LMS, and normal myometrium for this study. To further evaluate the genomic change in dystrophin gene region, whole-genome sequencing in 10 LMS cases were analyzed. Dystrophin expression was detected in 94% (45/48) of myometrium, 97% (34/35) of usual-type leiomyoma, 84% (26/31) of fumarate hydratase-deficient leiomyoma, 60% (12/20) of leiomyoma with bizarre nuclei, and 18% (6/34) of LMS. Loss of dystrophin expression was significantly different between benign and malignant tumors (LMS cases counted as malignant only) (p < 0.01). Of note, copy number loss in the dystrophin genomic region was found in all 10 cases of LMS. Additionally, patients with dystrophin-positive LMS tend to have a better overall survival than patients with dystrophin-negative LMS.

Potential Role of Insulin-Like Growth Factors in Myofascial Pain Syndrome: A Narrative Review.

ABSTRACT: Insulin-like growth factors have diverse functions in skeletal muscles by acting through multiple signaling pathways, including growth regulation and differentiation, anti-inflammation, and antioxidation. Insulin-like growth factors have anti-inflammatory effects and also play roles in nociceptive pathways, determining pain sensitivity, in addition to their protective role against ischemic injury in both the nervous system and skeletal muscle. In skeletal muscle, insulin-like growth factors maintain homeostasis, playing key roles in maintenance, accelerating muscle regeneration, and repair processes. As part of their maintenance role, increased levels of insulin-like growth factors may be required for the repair mechanisms after exercise. Although the role of insulin-like growth factors in myofascial pain syndrome is not completely understood, there is evidence from a recent study that insulin-like growth factor 2 levels in patients with myofascial pain syndrome are lower than those of healthy individuals and are associated with increased levels of inflammatory biomarkers. Importantly, higher insulin-like growth factor 2 levels are associated with increased pain severity in myofascial pain syndrome patients. This may suggest that too low or high insulin-like growth factor levels may contribute to musculoskeletal disorder process, whereas a midrange levels may optimize healing without contributing to pain hypersensitivity. Future studies are required to address the mechanisms of insulin-like growth factor 2 in myofascial pain syndrome and the optimal level as a therapeutic agent.

Uterine Leiomyosarcoma Associated With Leiomyoma With Bizarre Nuclei: Histology and Genomic Analysis of 2 Cases.

Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with overall benign clinical course. It has histologic features showing focal or diffuse nuclear atypia surrounded by usual type leiomyoma. Uterine leiomyosarcomas (LMS) are a group of rare and aggressive malignancies with limited treatment options available. The potential association between LM-BN with LMS is largely unknown. In this study, we report 2 cases of uterine smooth muscle tumor with typical histologic and molecular evidence of LM-BN, which are associated with its progression to the malignant counterpart of LMS. We summarize the detailed histologic, morphologic, and genomic characteristics of these 2 sets of cases. Our findings suggest that LMS progressing from preexisting LM-BN can be one of the tumor pathogenesis pathways in uterine leiomyosarcomas.

Sodium-glucose cotransporter-2-induced euglycemic diabetic ketoacidosis unmasks latent autoimmune diabetes in a patient misdiagnosed with type 2 diabetes mellitus: a case report.

BACKGROUND: Euglycemic diabetic ketoacidosis is an uncommon but life-threatening complication associated with the use of sodium-glucose cotransporter 2 inhibitors that causes lower than expected blood glucose levels typically seen in diabetic ketoacidosis. CASE PRESENTATION: We present a case of 64-year-old Caucasian male patient previously diagnosed with type 2 diabetes treated with a sodium-glucose cotransporter 2 inhibitor who developed severe ketoacidosis. Serum glucose levels on initial presentation were slightly above normal baseline level. The patient was revealed to have latent autoimmune diabetes in adults. CONCLUSION: This case highlights the importance of prescribing sodium-glucose cotransporter 2 inhibitors to the correct patient population and the significance of accurately differentiating between various types of diabetes.

Exercise rehabilitation in cardiac resynchronization: systematic review and a meta-analysis.

The benefit of exercise training in cardiac resynchronization therapy (CRT) recipients is not well established. We conducted a systematic review and meta-analysis to determine the effect of exercise training on clinical outcomes in CRT recipients.A comprehensive search until 2019 was conducted of MEDLINE, Epub, Embase, CINAHL and Cochrane databases as well as a bibliographic hand search to identify additional studies. We included all studies that compared aerobic exercise interventions in adults treated with CRT devices with adults treated with usual CRT care. These studies evaluated patient clinical characteristics, exercise testing measures, hemodynamic measures, echocardiography parameters, biomarkers and adverse events. Independent reviewers evaluated study eligibility, abstracted data and assessed risk of bias in duplicate. We used random-effect meta-analysis methods to estimate mean differences and odds ratios. Grades of Recommendation, Assessment, Development and Evaluation system were used to quantify absolute effects and quality of evidence. I2 was used to evaluate heterogeneity.We identified seven studies, six randomized control trials and one observational study, totaling 332 CRT patients in the exercise intervention and 534 patients receiving usual care. Peak VO2 was 2.4 ml/kg/min higher in the exercise group in comparison with the control group (pooled mean difference 2.26, 95% CI 1.38-3.13, I2 = 53%, high quality). AT-VO2 improved with exercise rehabilitation, and heterogeneity was considered low (pooled mean difference 3.96, 95% CI 2.68-5.24, I2 = 0.0%, moderate quality).Peak VO2 and AT-VO2 are increased with aerobic exercise in CRT recipients, demonstrating a significant improvement in functional capacity.

The Levels of Insulin-Like Growth Factor in Patients with Myofascial Pain Syndrome and in Healthy Controls.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) plays an important role in muscle maintenance and repair. The role of IGF-2 in the muscle is less clear. OBJECTIVE: To compare the levels of IGF-1 and IGF-2 in participants with acute myofascial pain syndrome (MPS) versus healthy controls and to determine whether age, gender, body mass index (BMI), region of pain, and pain intensity are associated with IGF levels. DESIGN: A case-control study design included a total of 74 participants. SETTING: Hospital emergency department. PARTICIPANTS: Participants presenting with acute MPS (n = 43) and non-MPS controls (n  =  31). MAIN OUTCOME MEASURES: Serum IGF-1 and IGF-2 (pg/mL) were measured in participants with MPS within 24 hours of symptom onset, and in non-MPS controls. Group and gender differences in serum IGF-1 and IGF-2 were assessed, with group and gender as factors, while controlling for age and BMI. RESULTS: The mean IGF-1 levels were not significantly different between MPS and controls (88 554.1, confidence interval [CI], 79 724.4-97 383.7 vs. 97 911.2, CI, 85 322.8-110 493.6). Significant differences were also not observed in IGF-1 levels between men and women with MPS nor between men and women in the control group. Mean levels of IGF-2 were significantly lower in patients with MPS than in controls (226 608.9, CI, 180 057.3-273 160.5 versus 460 343.9, CI, 387 809.4-532 878.2, P < .001). There were no significant gender differences in the levels of IGF-2 in patients with MPS. Mean IGF-2 levels (pg/mL) of men and women with MPS were lower (253 343.0, CI, 179 891.0-326 795.0, and 204 524.2, CI, 141 176.4-267 872.0, respectively) than those of healthy men and women (428 177.2, CI, 368 345.7-488 008.6, and 511 274.4, 355 178.6-687 370.1, respectively). Lower BMI and younger age were associated with higher levels of IGF-2. Pain intensity was associated with IGF-2 but not with IGF-1, whereas region of pain was not associated with either IGF-1 or IGF-2 levels. CONCLUSIONS: IGF-2 levels were lower in patients with acute MPS versus healthy controls with no gender differences, and IGF-1 levels were not different among the groups. Future studies should investigate the role of IGF-2 in muscle maintenance and repair in MPS.

Feasibility, Safety, and Effectiveness of a Mobile Application in Cardiac Rehabilitation.

BACKGROUND: Cardiac rehabilitation (CR) is underutilized globally despite evidence of clinical benefit. Major obstacles for wider adoption include distance from the rehabilitation center, travel time, and interference with daily routine. Tele-cardiac rehabilitation (tele-CR) can potentially address some of these limitations, enabling patients to exercise in their home environment or community. OBJECTIVES: To evaluate the clinical and physiological outcomes as well as adherence to tele-CR in patients with low cardiovascular risk and to assess exercise capacity, determined by an exercise stress test, using a treadmill before and following the 6-month intervention. METHODS: A total of 22 patients with established coronary artery disease participated in a 6-month tele-CR program. Datos Health (Ramat Gan, Israel), a digital health application and care-team dashboard, was used for remote monitoring, communication, and management of the patients. RESULTS: Following the 6-month tele-CR intervention, there was significant improvement in exercise capacity, assessed by estimated metabolic equivalents with an increase from 10.6 ± 0.5 to 12.3 ± 0.5 (P = 0.002). High-density lipoproteins levels significantly improved, whereas low-density lipoproteins, triglyceride, glycosylated hemoglobin, and systolic and diastolic blood pressure levels were not significantly changed. Exercise adherence was consistent among patients, with more than 63% of patients participating in a moderate intensity exercise program for 150 minutes per week. CONCLUSIONS: Patients who participated in tele-CR adhered to the exercise program and attained clinically significant functional improvement. Tele-CR is a viable option for populations that cannot, or elect not to, participate in center-based CR programs.

Improving characterization and diagnosis quality of myofascial pain syndrome: a systematic review of the clinical and biomarker overlap with delayed onset muscle soreness.

INTRODUCTION: Myofascial pain syndrome (MPS) is one of the most common conditions of chronic musculoskeletal pain, yet its mechanisms are still poorly understood. Delayed Onset Muscle Soreness (DOMS) is also a regional pain syndrome that has clinical similarities to MPS, but has been better investigated. Emerging research suggests that DOMS may be a valid experimental model for studying MPS; however, a comparison of the similarities and differences of these two conditions has previously not been performed. Herein, we aimed to identify the similarities and differences in the clinical features and biomarkers between DOMS and MPS in order to better define MPS and identify future areas of (DOMS-informed) MPS research. EVIDENCE ACQUISITION: In order to identify similarities and differences in the clinical manifestation and biomarkers of DOMS and MPS, scoping literature searches were performed using Medline (1965-2019), Embase (1966-2019) and Central (1966-2019) databases. Fifty-three full-text articles were reviewed out of the 2836 articles retrieved in the search. EVIDENCE SYNTHESIS: A scoping review of the literature demonstrated that DOMS and MPS similarly present as conditions of musculoskeletal pain that are associated with decreased strength and limited range of motion. However, while taut bands and discrete tender spots were described in DOMS, none of the studies reviewed have characterized whether these tender points represent the classic myofascial trigger point phenomenon observed in MPS. Certain systemic circulation biomarkers, including inflammatory cytokines and growth factors, were commonly elevated in MPS and DOMS; further research is needed to determine if other biomarkers that are currently characterized in DOMS are useful to enhance the clinical evaluation of MPS. CONCLUSIONS: DOMS and MPS share clinical and biomarker similarities suggesting that DOMS may be a useful model for studying MPS.

Atypical dysphagia with end-stage oesophageal disease 30 years post Angelchik device placement in a 72-year-old man.

Here we describe an atypical presentation of progressive dysphagia in a 72-year-old man leading to frequent regurgitations over the course of 30 years. Investigations revealed a foreign body ring surrounding the proximal stomach and dilation of the oesophagus proximal to the gastro-oesophageal junction. An Angelchik device was extracted; however, the patient's rapid deterioration prior to surgery, in addition to his severely dysfunctional oesophagus, required placement of a jejunostomy feeding tube. Device removal was complicated by prior abdominal surgery, necessitating a thoracic approach. This case offers guidance on the management of patients with Angelchik prostheses who develop similar complications, while drawing attention to the importance and difficulties of early, definitive diagnosis in oesophageal pathology such as achalasia and gastro-oesophageal reflux disease.

Ultrasound-Guided Interventional Procedures: Myofascial Trigger Points With Structured Literature Review.

Ultrasound-guided injections in pain medicine are a common intervention. They have been used to manage myofascial trigger points (MTrPs) in different muscles of the body. The main objectives of this article were to review ultrasound-guided injection techniques used for treating MTrPs. We also summarize the anatomy and sonoanatomy of MTrPs using the upper trapezius muscle as an example.

Fetal and neonatal alloimmune thrombocytopenia.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is an alloimmune disorder resulting from platelet opsonization by maternal antibodies that destroy fetal platelets. The major risk of FNAIT is severe bleeding, particularly intracranial hemorrhage. Miscarriage has also been reported but the incidence requires further study. Analogous to adult autoimmune thrombocytopenia (ITP), the major target antigen in FNAIT is the platelet membrane glycoprotein (GP)IIbIIIa. FNAIT caused by antibodies against platelet GPIbα or other antigens has also been reported, but the reported incidence of the anti-GPIbα-mediated FNAIT is far lower than in ITP. To date, the maternal immune response to fetal platelet antigens is still not well understood and it is unclear why bleeding is more severe in FNAIT than in ITP. In this review, we introduce the pathogenesis of FNAIT, particularly those new discoveries from animal models, and discuss possible improvements for the diagnosis, therapy, and prevention of this devastating disease.

Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc-FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell-Morell receptors, which is fundamentally different from the classical Fc-FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP.

Maternal anti-platelet ß3 integrins impair angiogenesis and cause intracranial hemorrhage.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against ß3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIbα, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-ß3 integrin-mediated, but not anti-GPIbα-mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti-ß3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signaling, and increased endothelial cell apoptosis, all of which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis were further reproduced in neonates by injection of anti-ß3 integrin, but not anti-GPIbα antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and AKT phosphorylation were inhibited only by murine anti-ß3 integrin antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest that fetal hemostasis is distinct and that impairment of angiogenesis rather than thrombocytopenia likely causes FNAIT-associated ICH. Additionally, our results indicate that maternal IVIG therapy can effectively prevent this devastating disorder.

Platelets and platelet alloantigens: Lessons from human patients and animal models of fetal and neonatal alloimmune thrombocytopenia.

Platelets play critical roles in hemostasis and thrombosis. Emerging evidence indicates that they are versatile cells and also involved in many other physiological processes and disease states. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life threatening bleeding disorder caused by fetal platelet destruction by maternal alloantibodies developed during pregnancy. Gene polymorphisms cause platelet surface protein incompatibilities between mother and fetus, and ultimately lead to maternal alloimmunization. FNAIT is the most common cause of intracranial hemorrhage in full-term infants and can also lead to intrauterine growth retardation and miscarriage. Proper diagnosis, prevention and treatment of FNAIT is challenging due to insufficient knowledge of the disease and a lack of routine screening as well as its frequent occurrence in first pregnancies. Given the ethical difficulties in performing basic research on human fetuses and neonates, animal models are essential to improve our understanding of the pathogenesis and treatment of FNAIT. The aim of this review is to provide an overview on platelets, hemostasis and thrombocytopenia with a focus on the advancements made in FNAIT by utilizing animal models.

Remote Ischemic Conditioning Prevents Lung and Liver Injury After Hemorrhagic Shock/Resuscitation: Potential Role of a Humoral Plasma Factor.

OBJECTIVE: To evaluate the efficacy of remote ischemic conditioning (RIC) on organ protection after hemorrhagic shock/resuscitation (S/R) in a murine model. BACKGROUND: Ischemia/reperfusion resulting from S/R contributes to multiple organ dysfunction in trauma patients. We hypothesized that RIC before shock (remote ischemic preconditioning), during shock (remote ischemic "PER"conditioning), or during resuscitation (remote ischemic "POST"conditioning) could confer organ protection. We also tested the effect of ischemic conditioned plasma on neutrophil migration in vivo using transgenic zebrafish models. METHODS: C57Bl/6 mice were subjected to S/R with or without hindlimb RIC. Serum levels of alanine aminotransferase and tumor necrosis factor-alpha, and liver tumor necrosis factor-alpha and interleukin 1ß mRNA were evaluated. In some experiments, lung protein leakage, cytokines, and myeloperoxidase activity were investigated. Plasma from mice subjected to RIC was microinjected into zebrafish, and neutrophil migration was assessed after tailfin transection or copper sulfate treatment. RESULTS: In mice subjected to S/R, remote ischemic preconditioning, remote ischemic "PER"conditioning, and remote ischemic "POST"conditioning each significantly reduced serum alanine aminotransferase and liver mRNA expression of tumor necrosis factor-alpha and interleukin 1ß and improved liver histology compared with control S/R mice. Lung injury and inflammation were also significantly reduced in mice treated with remote ischemic preconditioning. Zebrafish injected with plasma or dialyzed plasma (fraction >14 kDa) from ischemic conditioned mice had reduced neutrophil migration toward sites of injury compared with zebrafish injected with control plasma. CONCLUSIONS: RIC protects against S/R-induced organ injury, in part, through a humoral factor(s), which alters neutrophil function. The beneficial effects of RIC, performed during the S/R phase of care, suggest a role for its application early in the posttrauma period.

Co-stimulation with LPS or Poly I:C markedly enhances the anti-platelet immune response and severity of fetal and neonatal alloimmune thrombocytopenia.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies against fetal/neonatal platelets. FNAIT is also linked with miscarriages, although the incidence and mechanisms of fetal death have not been well studied. IntegrinαIIbß3 (GPIIbIIIa) and the GPIbα complex are major glycoproteins expressed on platelets and are also major antigens targeted in autoimmune thrombocytopenia (ITP), but reported cases of anti-GPIb-mediated FNAIT are rare. Bacterial and viral infections have been causally linked with the pathogenesis of immune-mediated thrombocytopenia (ITP); however, it is unknown whether these infections contribute to the severity of FNAIT. Here, immune responses against platelet antigens were examined by transfusing wild-type (WT) mouse platelets into ß3-/- or GPIbα-/- mice. To mimic bacterial or viral infections, lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly I:C) were injected intraperitoneally following platelet transfusions. The FNAIT model was established by breeding the immunised female mice with WT male mice. We demonstrated for the first time that the platelet GPIbα has lower immunogenicity compared to ß3 integrin. Interestingly, co-stimulation with LPS or Poly I:C markedly enhanced the immune response against platelet GPIbα and caused severe pathology of FNAIT (i.e. miscarriages). LPS or Poly I:C also enhanced the immune response against platelet ß3 integrin. Our data suggest that bacterial and viral infections facilitate the anti-platelet GPIbα response, which may lead to a severe non-classical FNAIT (i.e. miscarriage but not neonatal bleeding) that has not been adequately reported in humans.