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T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell malignancy characterized by marked lymphocytosis, B symptoms, lymphadenopathy, and hepatosplenomegaly. There is no standard treatment approach, and in the absence of an allogeneic transplant, the prognosis remains poor. The disease-defining cytogenetic abnormality in T-PLL is the juxtaposition of the TCL1-family oncogene to the TCR gene enhancer locus primarily due to an inversion of chromosome 14, that is, inv(14). The application of next-generation sequencing technologies led to the discovery of highly recurrent gain-of-function mutations in JAK1/3 and STAT5B in over 70% of T-PLL providing opportunities for therapeutic intervention using small molecule inhibitors. Additional genetic mechanisms that may contribute to the pathogenesis of T-PLL remain unknown. Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T-PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient's disease course over a 25-month post-treatment duration using ruxolitinib and duvelisib.
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Janus Quinase 2 , Leucemia Prolinfocítica de Células T , Humanos , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/patologia , Janus Quinase 2/genética , Proteínas de Fusão Oncogênica/genética , Masculino , Translocação Genética , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Cromossomos Humanos Par 9/genéticaRESUMO
Nonhematopoietic lymph node stromal cells (LNSCs) regulate lymphocyte trafficking, survival, and function for key roles in host defense, autoimmunity, alloimmunity, and lymphoproliferative disorders. However, the study of LNSCs in human diseases is complicated by a dependence on viable lymphoid tissues, which are most often excised prior to establishment of a specific diagnosis. Here, we demonstrate that cryopreservation can be used to bank lymphoid tissue for the study of LNSCs in human disease. Using human tonsils and lymph nodes (LN), lymphoid tissue fragments were cryopreserved for subsequent enzymatic digestion and recovery of viable nonhematopoietic cells. Flow cytometry and single-cell transcriptomics identified comparable proportions of LN stromal cell types in fresh and cryopreserved tissue. Moreover, cryopreservation had little effect on transcriptional profiles, which showed significant overlap between tonsils and LN. The presence and spatial distribution of transcriptionally defined cell types were confirmed by in situ analyses. Our broadly applicable approach promises to greatly enable research into the roles of LNSCs in human disease.
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Bancos de Espécimes Biológicos , Criopreservação , Humanos , Linfócitos , Linfonodos/patologia , Células EstromaisRESUMO
Embryo quality is an important determinant of successful implantation and a resultant live birth. Current clinical approaches for evaluating embryo quality rely on subjective morphology assessments or an invasive biopsy for genetic testing. However, both approaches can be inherently inaccurate and crucially, fail to improve the live birth rate following the transfer of in vitro produced embryos. Optical imaging offers a potential non-invasive and accurate avenue for assessing embryo viability. Recent advances in various label-free optical imaging approaches have garnered increased interest in the field of reproductive biology due to their ability to rapidly capture images at high resolution, delivering both morphological and molecular information. This burgeoning field holds immense potential for further development, with profound implications for clinical translation. Here, our review aims to: (1) describe the principles of various imaging systems, distinguishing between approaches that capture morphological and molecular information, (2) highlight the recent application of these technologies in the field of reproductive biology, and (3) assess their respective merits and limitations concerning the capacity to evaluate embryo quality. Additionally, the review summarizes challenges in the translation of optical imaging systems into routine clinical practice, providing recommendations for their future development. Finally, we identify suitable imaging approaches for interrogating the mechanisms underpinning successful embryo development.
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Imagem Óptica , Humanos , Imagem Óptica/métodos , Animais , Desenvolvimento Embrionário/fisiologia , Embrião de Mamíferos/diagnóstico por imagem , Embrião de Mamíferos/fisiologia , Feminino , GravidezRESUMO
Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. There are vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others having milder/more moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of patients with Castleman disease, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face a significant hospitalization burden, requiring more time in the hospital than iMCDNOS patients during the year surrounding diagnosis (median [interquartile range]: 36 [18-61] days vs. 0 [0-4] days; P<0.001). In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO. iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004). Lastly, we observed severe iMCD-related morbidities, such as acute renal failure, sepsis and pneumonia, among others, arising after iMCD diagnosis, impairing the patients' quality of life. These data demonstrate a substantial disease burden experienced by iMCD patients and emphasize the importance of ongoing research into iMCD to aid disease control.
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Hiperplasia do Linfonodo Gigante , Humanos , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Longitudinais , Idoso , Efeitos Psicossociais da Doença , Hospitalização , Sistema de RegistrosRESUMO
Glioma is one of the most common central nervous system (CNS) cancers that can be found within the brain and the spinal cord. One of the pressing issues plaguing the development of therapeutics for glioma originates from the selective and semipermeable CNS membranes: the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). It is difficult to bypass these membranes and target the desired cancerous tissue because the purpose of the BBB and BSCB is to filter toxins and foreign material from invading CNS spaces. There are currently four varieties of Food and Drug Administration (FDA)-approved drug treatment for glioma; yet these therapies have limitations including, but not limited to, relatively low transmission through the BBB/BSCB, despite pharmacokinetic characteristics that allow them to cross the barriers. Steps must be taken to improve the development of novel and repurposed glioma treatments through the consideration of pharmacological profiles and innovative drug delivery techniques. This review addresses current FDA-approved glioma treatment's gaps, shortcomings, and challenges. We then outline how incorporating computational BBB/BSCB models and innovative drug delivery mechanisms will help motivate clinical advancements in glioma drug delivery. Ultimately, considering these attributes will improve the process of novel and repurposed drug development in glioma and the efficacy of glioma treatment.
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The World Health Organization and the International Consensus Classification have both addressed and categorized T-cell lymphomas and histiocytic and dendritic tumours. Differences in the classification systems has generated considerable debate. Falini and colleagues now provide some clarity for the readership, with a framework for navigating the current classifications. They highlight the importance of finding a common path to formulate a single classification scheme in the near future. Commentary on: Falini et al. A comparison of the International Consensus and 5th WHO classifications of T-cell lymphomas and histiocytic/dendritic cell tumours. Br J Haematol 2023;203:369-383.
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High-grade B-cell lymphomas with 11q aberrations (HGBL-11q) represent a World Health Organization-defined group of lymphomas that harbor recurrent chromosome 11q aberrations involving proximal gains and telomeric losses. Although a limited number of HGBL-11q cases evaluated thus far appear to show a similar course and prognosis as Burkitt lymphoma (BL), many molecular differences have been appreciated, most notably the absence of MYC rearrangement. Despite biological differences between BL and HGBL-11q, histomorphologic and immunophenotypic distinction remains challenging. Here, we provide a comparative whole proteomic profile of BL- and HGBL-11q-derived cell lines, identifying numerous shared and differentially expressed proteins. Transcriptome profiling performed on paraffin-embedded tissue samples from primary BL and HGBL-11q lymphomas was additionally performed to provide further molecular characterization. Overlap of proteomic and transcriptomic data sets identified several potential novel biomarkers of HGBL-11q, including diminished lymphoid enhancer-binding factor 1 expression, which was validated by immunohistochemistry staining in a cohort of 23 cases. Altogether, these findings provide a comprehensive multimodal and comparative molecular profiling of BL and HGBL-11q and suggest the use of enhancer-binding factor 1 as an immunohistochemistry target to distinguish between these aggressive lymphomas.
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Linfoma de Burkitt , Linfoma de Células B , Linfoma Difuso de Grandes Células B , Proteogenômica , Humanos , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Fator 1 de Ligação ao Facilitador Linfoide , Proteômica , Linfoma de Células B/genética , Linfoma de Células B/patologia , Aberrações Cromossômicas , Biomarcadores , Linfoma Difuso de Grandes Células B/patologiaRESUMO
Approximately 30% of pediatric patients with anaplastic large cell lymphoma (ALCL) relapse. Although brentuximab vedotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group (COG) trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed nonlocalized anaplastic large cell lymphoma kinase (ALK)+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin. All patients received 5-day prophase, followed by 6 cycles of chemotherapy. Brentuximab vedotin was given on day 1 of each of the 6 cycles. Of the 67 patients eligible for toxicity evaluation, 66 completed all 6 cycles of chemotherapy, resulting in 399 evaluable cycles. There were no toxic deaths, no case of progressive multifocal leukoencephalopathy syndrome, and no case of grade 3 or 4 neuropathy. The 2-year event-free survival (EFS) was 79.1% (95% confidence interval [CI], 67.2-87.1). The 2-year overall survival (OS) was 97.0% (95% CI, 88.1-99.2). Fourteen patients relapsed. Eleven of 14 (79%) relapses occurred within 10 months of diagnosis; only 1 patient (1.5%) relapsed during therapy. Quantitative reverse transcription polymerase chain reaction for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value for EFS (P = .0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity or alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy, and the OS and EFS estimates compare favorably with results obtained using conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01979536.
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Quinase do Linfoma Anaplásico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Brentuximab Vedotin/administração & dosagem , Linfoma Anaplásico de Células Grandes , Proteínas de Neoplasias , Adolescente , Adulto , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/mortalidade , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Taxa de SobrevidaRESUMO
Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.
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Linfoma Folicular , Linfoma Difuso de Grandes Células B , Linfoma de Célula do Manto , Humanos , Adulto , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Imunoterapia Adotiva , Linfócitos TRESUMO
BACKGROUND: Reusable menstrual products have expanded the choices available for menstrual care and can offer long-term cost and environmental benefits. Yet, in high-income settings, efforts to support period product access focus on disposable products. There is limited research to understand young people's product use and preferences in Australia. METHODS: Quantitative and open-text qualitative data were collected through an annual cross-sectional survey of young people (aged 15-29) in Victoria, Australia. The convenience sample was recruited through targeted social media advertisements. Young people who reported menstruating in the past 6 months (n = 596) were asked questions about their menstrual product use, use of reusable materials, product priorities and preferences. RESULTS: Among participants, 37% had used a reusable product during their last menstrual period (24% period underwear, 17% menstrual cup, 5% reusable pads), and a further 11% had tried using a reusable product in the past. Reusable product use was associated with older age (age 25-29 PR = 3.35 95%CI = 2.09-5.37), being born in Australia (PR = 1.74 95%CI = 1.05-2.87), and having greater discretionary income (PR = 1.53 95%CI = 1.01-2.32). Participants nominated comfort, protection from leakage and environmental sustainability as the most important features of menstrual products, followed by cost. Overall, 37% of participants reported not having enough information about reusable products. Having enough information was less common among younger participants (age 25-29 PR = 1.42 95%CI = 1.20-1.68) and high school students (PR = 0.68 95%CI = 0.52-0.88). Respondents highlighted the need for earlier and better information, challenges navigating the upfront cost and availability of reusables, positive experiences with reusables, and challenges for use, including cleaning reusables and changing them outside the home. CONCLUSIONS: Many young people are using reusable products, with environmental impacts an important motivator. Educators should incorporate better menstrual care information in puberty education and advocates should raise awareness of how bathroom facilities may support product choice.
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Produtos de Higiene Menstrual , Puberdade , Humanos , Adolescente , Vitória , Estudos Transversais , Escolaridade , Menstruação , Conhecimentos, Atitudes e Prática em SaúdeRESUMO
BACKGROUND: Perceived stigma is a complex societal phenomenon that is harboured especially by female sex workers because of the interplay of a myriad of factors. As such, a precise measure of the contribution of different social practices and characteristics is necessary for both understanding and intervening in matters related to perceived stigma. We developed a Perceived Stigma Index that measures the factors that greatly contribute to the stigma among sex workers in Kenya, and thereby inform a framework for future interventions. METHODS: Social Practice Theory was adopted in the development of the Perceived Stigma Index in which three social domains were extracted from data collected in the WHISPER or SHOUT study conducted among female sex workers (FSW), aged 16-35 years in Mombasa, Kenya. The three domains included: Social demographics, Relationship Control and Sexual and Gender-based Violence, and Society awareness of sexual and reproductive history. The factor assessment entailed Exploratory Factor Analysis (EFA), Confirmatory Factor Analysis (CFA), and the internal consistency of the index was measured using Cronbach's alpha coefficient. RESULTS: We developed a perceived stigma index to measure perceived stigma among 882 FSWs with a median age of 26 years. A Cronbach's alpha coefficient of 0.86 (95% confidence interval (CI) 0.85-0.88) was obtained as a measure of the internal consistency of our index using the Social Practice Theory. In regression analysis, we identified three major factors that contribute to the perceived stigma and consists of : (i) income and family support (ß = 1.69; 95% CI); (ii) society's awareness of the sex workers' sexual and reproductive history (ß = 3.54; 95% CI); and (iii) different forms of relationship control e.g. physical abuse (ß = 1.48; 95%CI that propagate the perceived stigma among the FSWs. CONCLUSION: Social practice theory has solid properties that support and capture the multi-dimensional nature of perceived stigma. The findings support the fact that social practices contribute or provoke this fear of being discriminated against. Thus, in offering interventions to curb perceived stigma, focus should fall on the education of the society on the importance of acceptance and integration of the FSWs as part of the society and the eradication of sexual and gender based violence meted out on them. TRIAL REGISTRATION: The trial was registered in the Australian New Zealand Clinical Trials Registry, ACTRN12616000852459.
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Infecções por HIV , Profissionais do Sexo , Humanos , Feminino , Adulto , Quênia , Austrália , Comportamento Sexual , Estigma SocialRESUMO
BACKGROUND: Formative experiences in adolescence lay the foundation for healthy and pleasurable romantic and sexual relationships. Exposure to pornography may affect these experiences. OBJECTIVE: We aimed to synthesize evidence published in the past decade on the relationship between exposure to pornography and sexual behavior (earlier age of first sex [<16 years], condomless sex, past-year multiple partners [>1], lifetime multiple partners [>1], group sex, sexual aggression including forced sex, paid sex, teenage pregnancy, and history of sexually transmitted infection) in adolescents aged between 10 and 19 years. METHODS: We identified 19 eligible studies by searching MEDLINE, PsycINFO, Cochrane, CINAHL, Embase, and Web of Science databases from January 2010 to November 2022. RESULTS: Out of 8 studies that assessed earlier age of first sex, 5 studies, including 1 longitudinal study, found a statistically significant association with exposure to pornography. Given that most studies were cross-sectional or had substantial limitations, causal inference could not be made. Also, exposure to pornography was not measured consistently. The evidence was conflicting or insufficient to draw any conclusions regarding other outcomes. CONCLUSIONS: More quantitative research is needed to elucidate the association between pornography exposure and sexual behavior, and sex education should adopt evidence-based approaches to minimize the potential harms from pornography. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42021227390; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=227390.
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Literatura Erótica , Comportamento Sexual , Adolescente , Adulto , Criança , Feminino , Humanos , Gravidez , Adulto Jovem , Estudos Longitudinais , Educação SexualRESUMO
BACKGROUND: Sexually transmissible infections (STI) are prevalent and increasing among young Australians. This study examined trends in STI testing, sexual health knowledge/behaviours, and pornography use in young people aged 15- 29years in Victoria, Australia between 2015 and 2021. METHODS: Seven online cross-sectional surveys were conducted in a convenience sample of young people, recruiting a total of 7014 participants (67% female). Logistic regression analyses determined trends over time in binary outcomes. RESULTS: There was a decrease in reports of lifetime vaginal sex over time, while lifetime anal sex remained stable. Among those who had ever had vaginal sex, results showed an increase in the use of long-acting reversible contraceptives on the last occasion of vaginal sex. There was no change in STI testing or condom use with all partner types. Knowledge of STIs and sexual health changed over time: the proportion knowing that chlamydia can make women infertile decreased over time, while knowledge that taking the pill does not reduce fertility increased. There was no change in pornography use after adjusting for demographic variables. CONCLUSIONS: Although uptake of long-acting contraceptives increased, STI knowledge and testing, as well as consistent condom use, remained low. Public health interventions should continue to address these critical components of STI prevention.
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Saúde Sexual , Infecções Sexualmente Transmissíveis , Feminino , Humanos , Adolescente , Masculino , Vitória/epidemiologia , Estudos Transversais , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Literatura Erótica , Assunção de Riscos , Comportamento Sexual , AnticoncepcionaisRESUMO
Castleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched-control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non-fatal outcomes, and provide preliminary suggestions for parameters to evaluate further.
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Hiperplasia do Linfonodo Gigante , Trombocitopenia , Hiperplasia do Linfonodo Gigante/diagnóstico , Progressão da Doença , Febre , Humanos , Sistema de Registros , Trombocitopenia/diagnósticoRESUMO
Castleman disease (CD) represents a group of rare, heterogeneous and poorly understood disorders that share characteristic histopathological features. Unicentric CD (UCD) typically involves a single enlarged lymph node whereas multicentric CD (MCD) involves multiple lymph node stations. To understand the cellular basis of CD, we undertook a multi-platform analysis using targeted RNA sequencing, RNA in-situ hybridization (ISH), and adaptive immune receptor rearrangements (AIRR) profiling of archived tissue from 26 UCD, 14 MCD, and 31 non-CD reactive controls. UCD showed differential expression and upregulation of follicular dendritic cell markers (CXCL13, clusterin), angiogenesis factors (LPL, DLL4), extracellular matrix remodeling factors (TGFß, SKIL, LOXL1, IL-1ß, ADAM33, CLEC4A), complement components (C3, CR2) and germinal center activation markers (ZDHHC2 and BLK) compared to controls. MCD showed upregulation of IL-6 (IL-6ST, OSMR and LIFR), IL-2, plasma cell differentiation (XBP1), FDC marker (CXCL13, clusterin), fibroblastic reticular cell cytokine (CCL21), angiogenesis factor (VEGF), and mTORC1 pathway genes compared to UCD and controls. ISH studies demonstrated that VEGF was increased in the follicular dendritic cell-predominant atretic follicles and the interfollicular macrophages of MCD compared to UCD and controls. IL-6 expression was higher along interfollicular vasculature-associated cells of MCD. Immune repertoire analysis revealed oligoclonal expansions of T-cell populations in MCD cases (2/6) and UCD cases (1/9) that are consistent with antigen-driven T cell activation. The findings highlight the unique genes, pathways and cell types involved in UCD and MCD. We identify potential novel targets in CD that may be harnessed for therapeutics.
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Hiperplasia do Linfonodo Gigante , Proteínas ADAM , Hiperplasia do Linfonodo Gigante/genética , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/terapia , Clusterina , Citocinas , Humanos , Interleucina-6 , Transcriptoma , Fator A de Crescimento do Endotélio VascularRESUMO
Idiopathic multicentric Castleman disease (iMCD) is a polyclonal lymphoproliferative disorder characterized by constitutional symptoms, generalized lymphadenopathy, cytopenias, and multi-organ dysfunction due to excessive cytokines, notably Interleukin-6. Idiopathic multicentric Castleman disease is often sub-classified into iMCD-TAFRO, which is associated with thrombocytopenia (T), anasarca (A), fever/elevated C-reactive protein (F), renal dysfunction (R), and organomegaly (O), and iMCD not otherwise specified (iMCD-NOS), which is typically associated with thrombocytosis and hypergammaglobulinemia. The diagnosis of iMCD is challenging as consensus clinico-pathological diagnostic criteria were only recently established and include several non-specific lymph node histopathological features. Identification of further clinico-pathological features commonly found in iMCD could contribute to more accurate and timely diagnoses. We set out to characterize bone marrow (BM) histopathological features in iMCD, assess differences between iMCD-TAFRO and iMCD-NOS, and determine if these findings are specific to iMCD. Examination of BM specimens from 24 iMCD patients revealed a high proportion with hypercellularity, megakaryocytic atypia, reticulin fibrosis, and plasmacytosis across patients with both iMCD-NOS and iMCD-TAFRO with significantly more megakaryocytic hyperplasia (p = 0.001) in the iMCD-TAFRO cases. These findings were also consistent with BM findings from 185 published cases of iMCD-NOS and iMCD-TAFRO. However, these findings are relatively nonspecific as they can be seen in various other infectious, malignant, and autoimmune diseases.
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Hiperplasia do Linfonodo Gigante , Trombocitopenia , Medula Óssea/patologia , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/patologia , Febre/diagnóstico , Febre/patologia , Humanos , Linfonodos/patologiaRESUMO
Quantum mechanical (QM) descriptors of small molecules have wide applicability in understanding organic reactivity and molecular properties, but the substantial compute cost required for ab initio QM calculations limits their broad usage. Here, we investigate the use of deep learning for predicting QM descriptors, with the goal of enabling usage of near-QM accuracy electronic properties on large molecular data sets such as those seen in drug discovery. Several deep learning approaches have previously been benchmarked on a published data set called QM9, where 12 ground-state properties have been calculated for molecules with up to nine heavy atoms, limited to C, H, N, O, and F elements. To advance the work beyond the QM9 chemical space and enable application to molecules encountered in drug discovery, we extend the QM9 data set by creating a QM9-extended data set covering an additional â¼20,000 molecules containing S and Cl atoms. Using this extended set, we generate new deep learning models as well as leverage ANI-2x models to provide predictions on larger, more diverse molecules common in drug discovery, and we find the models estimate 11 of 12 ground-state properties reasonably. We use the predicted QM descriptors to augment graph convolutional neural network (GCNN) models for selected ADME end points (rat microsomal clearance, hepatic clearance, total clearance, and P-glycoprotein efflux) and found varying degrees of performance improvement compared to nonaugmented GCNN models, including pronounced improvement in P-glycoprotein efflux prediction.
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Aprendizado Profundo , Animais , Ratos , Redes Neurais de Computação , Descoberta de Drogas , Transporte BiológicoRESUMO
BACKGROUND: Squamoid eccrine ductal carcinoma (SEDC) represents a subtype of eccrine carcinomas that are diagnostically challenging for both clinicians and dermatopathologists. OBJECTIVE: To provide an updated review of SEDC and examine patient outcomes with different treatment modalities. METHODS: A review of Ovid MEDLINE was performed to review the English language medical literature of SEDC. RESULTS: A comprehensive review of clinical presentation, histologic findings, rates of lymphovascular and metastatic disease, treatment modalities and recurrence rates are reviewed. LIMITATIONS: There is a limitation on available data because of the rare incidence. CONCLUSIONS: SEDC is a rare adnexal neoplasm with a relatively high rate of local recurrence, lymphovascular invasion, perineural invasion, and metastases. Clinicians should be aware of this entity as close follow-up is essential to detect recurrence and metastatic disease. Mohs micrographic surgery seems to result in superior patient outcomes.
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Carcinoma Ductal/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Glândulas Écrinas , Neoplasias das Glândulas Sudoríparas/diagnóstico , Idoso , Carcinoma Ductal/patologia , Carcinoma Ductal/cirurgia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Bochecha , Diagnóstico Diferencial , Humanos , Masculino , Cirurgia de Mohs , Neoplasias das Glândulas Sudoríparas/patologia , Neoplasias das Glândulas Sudoríparas/cirurgiaRESUMO
BACKGROUND: Social media-delivered health promotion has demonstrated limited uptake and effectiveness among young adults. Understanding how young adults interact with existing social media platforms for health might provide insight for future health promotion interventions. OBJECTIVE: The aim of this study is to describe how young adults interact with different social media platforms for health and health information. METHODS: We used a web-based conversation methodology to collect data from 165 young adults aged 18 to 24 years. Participants participated in an extended conversation with moderators and other participants about health and social media. They were prompted to discuss how they find health information, how they use different social media platforms, and how they evaluate the trustworthiness of information. A thematic qualitative analysis was applied to the data. RESULTS: Young adults spent a lot of time scrolling through Facebook newsfeeds, which often resulted in seeing health-related content either from their friends, news sources, or advertisements. Some actively sought out information about specific health areas by joining groups or following relevant pages. YouTube was considered a useful source for learning about everything and was often the go-to when searching for information or advice (after Google). Young adults found the video format easy to learn from. They stated that they could identify accurate YouTube health content by cross-checking multiple videos, by feeling that the presenter was real and relatable, or just through instinctively judging a video's credibility. Instagram was a source of inspiration for health and wellness from those whose lives were dedicated to healthy lifestyles and fitness. Twitter, Tumblr, and Snapchat were rarely used for health information. CONCLUSIONS: Most young adults obtain health information from social media, both actively and through passive exposure. Participants indicated looking to social media influencers for health and lifestyle inspiration and judged the credibility of sources by appearance and instinct. Health experts should try to use the channels in the way that young adults already use them; use relatable role models on Instagram and YouTube, eye-catching headlines and support groups on Facebook, and easy to follow instruction videos via YouTube. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1111/1747-0080.12448.
Assuntos
Mídias Sociais , Comunicação , Promoção da Saúde , Humanos , Estilo de Vida , Adulto JovemRESUMO
BACKGROUND: Globally, suboptimal dietary choices are a leading cause of noncommunicable diseases. Evidence for effective interventions to address these behaviors, particularly in young adults, is limited. Given the substantial time young adults spend in using social media, there is interest in understanding the current and potential role of these platforms in shaping dietary behavior. OBJECTIVE: This study aims to explore the influence of social media on young adults' dietary behaviors. METHODS: We recruited 234 young adults aged 18-24 years and living in Australia, using market and social research panels. We applied a digital ethnography approach to collect data from web-based conversations in a series of forums, where participants responded to different health-themed questions related to health behavior change and persuasion on social media. We conducted a qualitative thematic analysis. RESULTS: Participants described how social media influenced their decisions to change their health behaviors. Access to social support and health information through web-based communities was juxtaposed with exposure to highly persuasive fast-food advertisements. Some participants expressed that exposure to web-based health-focused content induced feelings of guilt about their behavior, which was more prominent among women. Fast-food advertisements were discussed as a contributor to poor health behaviors and indicated as a major barrier to change. CONCLUSIONS: Young adults reported that social media is highly persuasive toward dietary behavior through different pathways of social influence. This suggests that social norms on the web are an important aspect of changing young adults' health behaviors. The commercialization of social media also encourages poor health behaviors, largely through fast-food advertisements. Future social media-delivered dietary interventions should acknowledge the social and environmental factors that challenge the ability of young adults to make individual health behavior improvements. Care should also be taken to ensure that future interventions do not further elicit guilt in a way that contributes to poor mental health within this community.