Immune thrombocytopenia: Pathophysiology and impacts of Romiplostim treatment.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disease caused by immune-mediated platelet destruction and decreased platelet production. ITP is characterized by an isolated thrombocytopenia (<100 × 109/L) and increased risk of bleeding. The disease has a complex pathophysiology wherein immune tolerance breakdown leads to platelet and megakaryocyte destruction. Therapeutics such as corticosteroids, intravenous immunoglobulins (IVIg), rituximab, and thrombopoietin receptor agonists (TPO-RAs) aim to increase platelet counts to prevent hemorrhage and increase quality of life. TPO-RAs act via stimulation of TPO receptors on megakaryocytes to directly stimulate platelet production. Romiplostim is a TPO-RA that has become a mainstay in the treatment of ITP. Treatment significantly increases megakaryocyte maturation and growth leading to improved platelet production and it has recently been shown to have additional immunomodulatory effects in treated patients. This review will highlight the complex pathophysiology of ITP and discuss the usage of Romiplostim in ITP and its ability to potentially immunomodulate autoimmunity.

Desialylated Platelet Clearance in the Liver is a Novel Mechanism of Systemic Immunosuppression.

Platelets are small, versatile blood cells that are critical for hemostasis/thrombosis. Local platelet accumulation is a known contributor to proinflammation in various disease states. However, the anti-inflammatory/immunosuppressive potential of platelets has been poorly explored. Here, we uncovered, unexpectedly, desialylated platelets (dPLTs) down-regulated immune responses against both platelet-associated and -independent antigen challenges. Utilizing multispectral photoacoustic tomography, we tracked dPLT trafficking to gut vasculature and an exclusive Kupffer cell-mediated dPLT clearance in the liver, a process that we identified to be synergistically dependent on platelet glycoprotein Ibα and hepatic Ashwell-Morell receptor. Mechanistically, Kupffer cell clearance of dPLT potentiated a systemic immunosuppressive state with increased anti-inflammatory cytokines and circulating CD4+ regulatory T cells, abolishable by Kupffer cell depletion. Last, in a clinically relevant model of hemophilia A, presensitization with dPLT attenuated anti-factor VIII antibody production after factor VIII ( infusion. As platelet desialylation commonly occurs in daily-aged and activated platelets, these findings open new avenues toward understanding immune homeostasis and potentiate the therapeutic potential of dPLT and engineered dPLT transfusions in controlling autoimmune and alloimmune diseases.

The role of T cells and myeloid-derived suppressor cells in refractory immune thrombocytopenia.

Immune thrombocytopenia (ITP) is characterized by a dysregulated immune response against platelets, affecting both their destruction and production. A role for an abnormal T-cell compartment has been established in ITP pathogenesis and treatments that increase platelet counts in patients with ITP have shown improvements in T-cell profiles. On the other hand, patients who were refractory to treatment appear to retain the T-cell abnormalities as before. Myeloid-derived suppressive cells (MDSCs) are also emerging as key contributors to the immune pathology of ITP and response to treatment. In this review, we will discuss how various treatments affect the T-cell and MDSC compartments in ITP. The review will focus on studies that have examined the underlying mechanisms and/or genetic basis responsible for refractoriness to a given treatment and highlight remaining challenges in identifying factors and mechanisms to predict response to treatment.

An Overview to the Index to Chromosome Numbers in Asteraceae Database: Revisiting Base Chromosome Numbers, Polyploidy, Descending Dysploidy, and Hybridization.

A brief overview to the Index to Chromosome Numbers in Asteraceae database is provided. The database contains karyological information on Asteraceae and has been repeatedly improved and updated and is now hosted at the National Bioscience Database center. Also, we take the opportunity to revisit the evolution of base chromosome numbers in Asteraceae, emphasizing the phenomena of polyploidy, descending dysploidy, and hybridization, common in the family. Chromosome numbers for species included in one of the most recent phylogenetic treatments of the Asteraceae were obtained from the Index to Chromosome Numbers in Asteraceae database were mapped on to the modified phylogeny diagram, and base chromosome numbers were determined for each branch of the phylogeny. Results for tribal base numbers were the same as those hypothesized in our previous work with additional base numbers added for tribes not previously recognized but supported by newer phylogenetic methods. The Asteraceae show an ancestral base chromosome number of x = 9 and originated in the Antarctica (Gondowanaland) in Cretaceous (80 Mys ago). The x = 9 number has been retained through successive South American lineages of the Barnadesieeae, Gochnatieae, Stiffieae, Wunderlichieae, Astereae, and Senecioneae following northward migration. Northward migration to Africa was accompanied with x = 10 becoming the dominant base chromosome number as the family evolved multiple additional tribes. Northward migration to Australasia with x = 9 was in Astereae and the families Goodeneaseae, Menyanthaceae, and Stylydiaceae. The evolution of the North American Heliantheae alliance began with the appearance of x2 = 19 which persisted in multiple additional new tribes. Frequent dysploidy decreases, polyploidy and hybridization occurred throughout the history of the family.

Breast Reconstruction Use and Impact on Surgical and Oncologic Outcomes Amongst Inflammatory Breast Cancer Patients-A Systematic Review.

Breast reconstruction is generally discouraged in women with inflammatory breast cancer (IBC) due to concerns with recurrence and poor long-term survival. We aim to determine contemporary trends and predictors of breast reconstruction and its impact on oncologic outcomes among women with IBC. A systematic literature review for all studies published up to 15 September 2022 was conducted via MEDLINE, Embase, and the Cochrane Library. Studies comparing women diagnosed with IBC undergoing a mastectomy with or without breast reconstruction were evaluated. The initial search yielded 225 studies, of which nine retrospective cohort studies, reporting 2781 cases of breast reconstruction in 29,058 women with IBC, were included. In the past two decades, immediate reconstruction rates have doubled. Younger age, higher income (>USD 25,000), private insurance, metropolitan residence, and bilateral mastectomy were associated with immediate reconstruction. No significant difference was found in overall survival, breast cancer-specific survival or recurrence rates between women undergoing versus not undergoing (immediate or delayed) reconstruction. There is a paucity of data on delayed breast reconstruction following IBC. Immediate breast reconstruction may be a consideration for select patients with IBC, although prospective data is needed to clarify its safety.

Patient Outcomes after Fat Grafting to the Radiated Chest Wall before Delayed Two-stage Alloplastic Breast Reconstruction.

Two-stage alloplastic breast reconstruction in patients having received mastectomy and radiation is associated with a high rate of complications. Fat grafting has been shown to mitigate the effects of radiation on the chest wall to allow for alloplastic reconstruction. In this study, we assess the outcomes (after a mean follow-up of 28 months), including complications and revisional procedures, of women who had fat grafting to the radiated chest wall before two-stage implant-based breast reconstruction. Methods: A retrospective chart review was performed on consecutive patients seeking delayed implant-based reconstruction after simple mastectomy and postmastectomy radiation therapy between 2011 and 2015. All patients underwent two sessions of fat grafting to the radiated chest wall before inserting a tissue expander and subsequent exchange to a silicone implant. Results: Twenty patients were included in the study. No reconstructive failures were recorded. The short-term complication rate was 5%, with one hematoma leading to a revisional procedure. The mean follow-up after reconstruction was 28 months. During follow-up, two patients (10%) developed capsular contracture grade IV with implant malposition, leading to capsular revision and implant exchange. Four patients (20%) underwent additional fat grafting for contour deformities. Conclusions: Fat grafting before two-stage alloplastic breast reconstruction in patients treated with mastectomy and postmastectomy radiation therapy may provide an alternate method of alloplastic reconstruction in a select group of patients who are not suitable for autogenous reconstruction. Follow-up data show that additional surgery may be required for correction of implant malposition and capsular contracture.

A Safe and Efficient Technique for Pedicled TRAM Flap Breast Reconstruction.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the indications for a unilateral pedicled transverse rectus abdominis (TRAM) flap-based breast reconstruction. 2. Understand the different types and designs of pedicled TRAM flap used in both immediate and delayed breast reconstruction. 3. Understand the essential landmarks and relevant anatomy of the pedicled TRAM flap. 4. Understand the steps of raising the pedicled TRAM flap, the subcutaneous transfer, and the insetting of the flap on the chest wall. 5. Understand the nature of donor-site management and closure of the defect. 6. Develop a postoperative plan for continuing care and pain management. SUMMARY: This article focuses primarily on the unilateral, ipsilateral pedicled TRAM flap. Although the bilateral pedicled TRAM flap may be a reasonable option in some cases, they have been shown to have a significant impact on abdominal wall strength and integrity. Other types of autogenous flaps using the same lower abdominal tissue, such as a free muscle-sparing TRAM or a deep inferior epigastric flap, can be performed as a bilateral procedure with less impact on the abdominal wall. Breast reconstruction with a pedicled transverse rectus abdominis flap has persisted for decades as a reliable and safe form of autologous breast reconstruction leading to a natural and stable breast shape.

Phenotypic Characterization of Acoustically Enriched Extracellular Vesicles from Pathogen-Activated Platelets.

Extracellular vesicles (EVs) are derived from the membrane of platelets and released into the circulation upon activation or injury. Analogous to the parent cell, platelet-derived EVs play an important role in hemostasis and immune responses by transfer of bioactive cargo from the parent cells. Platelet activation and release of EVs increase in several pathological inflammatory diseases, such as sepsis. We have previously reported that the M1 protein released from the bacterial pathogen Streptococcus pyogenes directly mediates platelet activation. In this study, EVs were isolated from these pathogen-activated platelets using acoustic trapping, and their inflammation phenotype was characterized using quantitative mass spectrometry-based proteomics and cell-based models of inflammation. We determined that M1 protein mediated release of platelet-derived EVs that contained the M1 protein. The isolated EVs derived from pathogen-activated platelets contained a similar protein cargo to those from physiologically activated platelets (thrombin) and included platelet membrane proteins, granule proteins, cytoskeletal proteins, coagulation factors, and immune mediators. Immunomodulatory cargo, complement proteins, and IgG3 were significantly enriched in EVs isolated from M1 protein-stimulated platelets. Acoustically enriched EVs were functionally intact and exhibited pro-inflammatory effects on addition to blood, including platelet-neutrophil complex formation, neutrophil activation, and cytokine release. Collectively, our findings reveal novel aspects of pathogen-mediated platelet activation during invasive streptococcal infection.

Goldenrod herbariomics: Hybrid-sequence capture reveals the phylogeny of Solidago.

PREMISE: The phylogenetic relationships among the ca. 138 species of goldenrods (Solidago; Asteraceae) have been difficult to infer due to species richness, and shallow interspecific genetic divergences. This study aims to overcome these obstacles by combining extensive sampling of goldenrod herbarium specimens with the use of a custom Solidago hybrid-sequence capture probe set. METHODS: A set of tissues from herbarium samples comprising ca. 90% of Solidago species was assembled and DNA was extracted. A custom hybrid-sequence capture probe set was designed, and data from 854 nuclear regions were obtained and analyzed from 209 specimens. Maximum likelihood and coalescent approaches were used to estimate the genus phylogeny for 157 diploid samples. RESULTS: Although DNAs from older specimens were both more fragmented and produced fewer sequencing reads, there was no relationship between specimen age and our ability to obtain sufficient data at the target loci. The Solidago phylogeny was generally well-supported, with 88/155 (57%) nodes receiving ≥95% bootstrap support. Solidago was supported as monophyletic, with Chrysoma pauciflosculosa identified as sister. A clade comprising Solidago ericameriodes, Solidago odora, and Solidago chapmanii was identified as the earliest diverging Solidago lineage. The previously segregated genera Brintonia and Oligoneuron were identified as placed well within Solidago. These and other phylogenetic results were used to establish four subgenera and fifteen sections within the genus. CONCLUSIONS: The combination of expansive herbarium sampling and hybrid-sequence capture data allowed us to quickly and rigorously establish the evolutionary relationships within this difficult, species-rich group.

Health state utility values in patients undergoing chest masculinization surgery.

BACKGROUND: Chest masculinization surgery is the most common gender-affirming procedure performed in transgender and gender-diverse individuals. While evidence on the health-related quality of life (HRQL) impact of chest masculinization is starting to emerge, data on health state utility values (HSUVs) associated with the surgery is largely missing. The objectives of this study were to estimate the HSUVs using EQ-5D for patients seeking chest masculinization surgery and assess the determinants of EQ-5D score at 6 months postoperatively. METHODS: Patients seeking chest masculinization at a single community plastic surgery clinic by 2 surgeons completed 3 patient-reported outcome measures - EQ-5D-3L, Patient Health Questionnaire (PHQ)-9, and BODY-Q Chest module - preoperatively and postoperatively at 6 weeks and 6-months. Friedman test was used to assess the differences in PROM scores at the 3 timepoints. Simple and backward stepwise regression analyses of 6-month postoperative EQ-5D scores were performed. RESULTS: A total of 113 patients (mean [SD] age, 25.7 [6.9] years) were included. The mean [SD] EQ-5D scores at preoperative, postoperative 6 weeks and 6 months were 0.81 [0.15], 0.84 [0.15] and 0.87 [0.12], respectively. Postoperatively, problems were most frequently reported in the dimensions "pain/discomfort" and "anxiety/depression". Preoperative PHQ-9 score was a predictor of 6-month postoperative EQ-5D scores following simple (p < 0.01) and backward stepwise linear regression analysis (p < 0.01). CONCLUSION: Chest masculinization was associated with an improvement in overall HRL at 6 months postoperatively; however, this did not achieve statistical significance. Preoperative depression severity was a significant determinant of postoperative HRL. Consequently, additional support must be offered to patients who have a higher level of preoperative depression.

Binge-reading on immune thrombocytopenia: Everything you ever wanted to know.

Immune thrombocytopenia (ITP) is a complex clinical and pathophysiological autoimmune disorder and in the past decade, thousands of papers have been published on this topic. To shed light on the global scientific output, Ou et al. performed a comprehensive bibliometric analysis of the ITP literature to clarify the major hotspots and future research directions. Commentary on: Ou et al. A bibliometric analysis of primary immune thrombocytopenia from 2011 to 2021. Br J Haematol 2023;201:954-970.

Contemporary Trends in Breast Reconstruction Use and Impact on Survival Among Women with Inflammatory Breast Cancer.

BACKGROUND: Breast reconstruction is generally discouraged in women with inflammatory breast cancer (IBC). Nevertheless, reconstruction rates are increasing in this population. OBJECTIVE: We aimed to determine contemporary trends and predictors of breast reconstruction use and its impact on mortality among IBC patients. METHODS: Demographic, clinicopathologic, and follow-up data for women with non-metastatic IBC having mastectomy between 2004 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Rates and predictors of immediate breast reconstruction, along with survival outcomes between the breast reconstruction and no reconstruction groups were calculated. To account for selection bias, a propensity score analysis matching one reconstruction patient to three no reconstruction patients was performed. RESULTS: A total of 4076 women with non-metastatic IBC who underwent mastectomy (388 [9.5%] with breast reconstruction and 3688 [90.5%] without) were included. The proportion of women undergoing breast reconstruction and contralateral prophylactic mastectomy increased from 6.2 to 15.3% and 12.9 to 29.6%, respectively, between 2004 and 2015. Younger age, higher annual income, metropolitan residence, and bilateral mastectomy predicted breast reconstruction use. The 10-year breast cancer-specific survival was 62.9% for women having breast reconstruction and 47.6% for women not having breast reconstruction. After propensity-matched analysis, 10-year cancer-specific survival was similar between the reconstruction (56.6%) and no reconstruction (62.2%) groups (adjusted hazard ratio 0.96, 95% confidence interval 0.79-1.16; p = 0.65). CONCLUSIONS: Breast reconstruction rates continue to rise among IBC patients, particularly young women and women with access to reconstruction. Breast reconstruction is not associated with inferior breast cancer-specific survival and can be an option for select patients.

Enrichment of Complement, Immunoglobulins, and Autoantibody Targets in the Proteome of Platelets from Patients with Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex disease characterized by autoimmunity toward apoptotic cells, excessive amounts of circulating immune complexes, and complement activation. A decreased platelet size has been observed in SLE and their nonhemostatic functions may play an active role in the disease. The main objective of this study was to find clues that could explain their decreased size and functional role, analyzing the entire platelet proteome. METHODS: Platelets were isolated from 23 patients with SLE. The five individuals with the highest and lowest average platelet forward scatter were selected for further analysis. Platelet protein content was analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS) and compared with platelets from five healthy controls. Data are available via ProteomeXchange with identifier PXD031202. RESULTS: Out of 2,572 proteins identified, 396 had significantly different levels (ANOVA q-value ≤ 0.01). Forty proteins, including immunoglobulin-, complement- and phosphatidylserine-binding proteins had higher abundance in platelets from SLE patients, largely independent of size (fold difference of ≥1.5 and a t-test p-value of ≤0.05 as cut-off). Functional characterization revealed increased degranulation and skewed hemostatic balance in platelets from SLE patients. In the SLE proteome, immunoglobulin proteins were negatively correlated to serum complement C3 and C4 and the highest relative levels were detected in platelets of normal size. CONCLUSION: Platelets from SLE patients shared a specific protein profile, including immunoglobulins, complement proteins, and autoantigens, largely independent of the platelet size and in agreement with an integrated role for platelets in SLE.

Canadian Expert Opinion on Breast Reconstruction Access: Strategies to Optimize Care during COVID-19.

BACKGROUND: Breast reconstructive services are medically necessary, time-sensitive procedures with meaningful health-related quality of life benefits for breast cancer survivors. The COVID-19 global pandemic has resulted in unprecedented restrictions in surgical access, including access to breast reconstructive services. A national approach is needed to guide the strategic use of resources during times of fluctuating restrictions on surgical access due to COVID-19 demands on hospital capacity. METHODS: A national team of experts were convened for critical review of healthcare needs and development of recommendations and strategies for patients seeking breast reconstruction during the pandemic. Following critical review of literature, expert discussion by teleconference meetings, and evidenced-based consensus, best practice recommendations were developed to guide national provision of breast reconstructive services. RESULTS: Recommendations include strategic use of multidisciplinary teams for patient selection and triage with centralized coordinated use of alternate treatment plans during times of resource restrictions. With shared decision-making, patient-centered shifting and consolidation of resources facilitate efficient allocation. Targeted application of perioperative management strategies and surgical treatment plans maximize the provision of breast reconstructive services. CONCLUSIONS: A unified national approach to strategically reorganize healthcare delivery is feasible to uphold standards of patient-centered care for patients interested in breast reconstruction.

Dissecting platelet proteomics to understand the pathophysiology of immune thrombocytopenia: studies in mouse models.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by enhanced platelet clearance and defective platelet production. Diagnosis by exclusion and trial-and-error treatment strategies is common practice, and despite the advancement in treatment options, many patients remain refractory. Although the existence of different pathophysiological entities is acknowledged, we are still far from stratifying and understanding ITP. To investigate, we sought to dissect the platelet proteome dynamics in so-called passive and active preclinical ITP mouse models, with which we propose to phenocopy respectively acute/newly diagnosed and persistent/chronic stages of ITP in humans. We obtained the platelet proteome at the thrombocytopenic stage and after platelet count recovery (reached naturally or by IVIg-treatment, depending on the model). Although most of the proteomic alterations were common to both ITP models, there were model-specific protein dynamics that accompanied and explained alterations in platelet aggregation responses, as measured in the passive ITP model. The expression dynamics observed in Syk may explain, extrapolated to humans and pending validation, the increased bleeding tendency of patients with ITP when treated with fostamatinib as third or later- as opposed to second line of treatment. We propose that the platelet proteome may give diagnostic and prognostic insights into ITP and that such studies should be pursued in humans.