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Trade-offs resulting from the high demand of offspring production are a central focus of many subdisciplines within the field of biology. Yet, despite the historical and current interest on this topic, large gaps in our understanding of whole-organism trade-offs that occur in reproducing individuals remain, particularly as it relates to the nuances associated with female reproduction. This volume of Integrative and Comparative Biology (ICB) contains a series of papers that focus on reviewing trade-offs from the female-centered perspective of biology (i.e., a perspective that places female reproductive biology at the center of the topic being investigated or discussed). These papers represent some of the work showcased during our symposium held at the 2024 meeting of the Society for Integrative and Comparative Biology (SICB) in Seattle, Washington. In this roundtable discussion, we use a question-and-answer format to capture the diverse perspectives and voices involved in our symposium. We hope that the dialogue featured in this discussion will be used to motivate researchers interested in understanding trade-offs in reproducing females and provide guidance on future research endeavors.
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ABSTRACT: Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare autosomal recessive, life-threatening disorder caused by a severe deficiency of the plasma enzyme, ADAMTS13. The current estimated prevalence of hTTP in different regions of the world, 0.5 to 2.0 patients per million, is determined by the frequency of diagnosed patients. To evaluate more accurately the worldwide prevalence of hTTP, and also the prevalence within distinct ethnic groups, we used data available in exome and genome sequencing of 807 162 (730 947 exomes, 76 215 genomes) subjects reported recently by the Genome Aggregation Database (gnomAD-v4.1). Among 1 614 324 analyzed alleles in the gnomAD population we identified 6321 distinct ADAMTS13 variants. Of these, 758 were defined as pathogenic; 140 (18%) variants had been previously reported and 618 (82%) were novel (predicted as pathogenic). In total 10 154 alleles (0.6%) were carrying the reported or predicted pathogenic variants; 7759 (77%) with previously reported variants. Considering all 758 pathogenic variants and also only the 140 previously reported variants, we estimated a global hTTP prevalence of 40 and 23 cases per 106, respectively. Considering only the 140 previously reported variants, the highest estimated prevalence was in East Asians (42 per 106). The estimated prevalences of other populations were: Finnish, 32 per 106; non-Finnish Europeans, 28 per 106; Admixed Americans, 19 per 106; Africans/African Americans, 6 per 106; and South Asians, 4 per 106. The lowest prevalences were Middle Eastern, 1 per 106 and Ashkenazi Jews, 0.7 per 106. This population-based genetic epidemiology study reports that hTTP prevalence is substantially higher than the currently estimated prevalence based on diagnosed patients. Many patients with hTTP may not be diagnosed or may have died during the neonatal period.
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Púrpura Trombocitopênica Trombótica , Humanos , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/epidemiologia , Prevalência , Testes Genéticos , Proteína ADAMTS13/genética , Alelos , Saúde Global , Feminino , Mutação , Predisposição Genética para DoençaRESUMO
Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation. Here, we demonstrate that p300/CBP are determinant cofactors of the active AR enhanceosome in prostate cancer. Histone H2B N-terminus multisite lysine acetylation (H2BNTac), which is exclusively reliant on p300/CBP catalytic function, marked active enhancers and was notably elevated in prostate cancer lesions relative to the adjacent benign epithelia. Degradation of p300/CBP rapidly depleted acetylation marks associated with the active AR enhanceosome, which was only partially phenocopied by inhibition of their reader bromodomains. Notably, H2BNTac was effectively abrogated only upon p300/CBP degradation, which led to a stronger suppression of p300/CBP-dependent oncogenic gene programs relative to bromodomain inhibition or the inhibition of its catalytic domain. In vivo experiments using an orally active p300/CBP proteolysis targeting chimera (PROTAC) degrader (CBPD-409) showed that p300/CBP degradation potently inhibited tumor growth in preclinical models of castration-resistant prostate cancer and synergized with AR antagonists. While mouse p300/CBP orthologs were effectively degraded in host tissues, prolonged treatment with the PROTAC degrader was well tolerated with no significant signs of toxicity. Taken together, our study highlights the pivotal role of p300/CBP in maintaining the active AR enhanceosome and demonstrates how target degradation may have functionally distinct effects relative to target inhibition, thus supporting the development of p300/CBP degraders for the treatment of advanced prostate cancer.
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Uterine natural killer cells (uNKs) are a tissue resident lymphocyte population that are critical for pregnancy success. Although mouse models have demonstrated that NK deficiency results in abnormal placentation and poor pregnancy outcomes, the generalizability of this knowledge to humans remains unclear. Here we identify uterus transplant (UTx) recipients as a human population with reduced endometrial NK cells and altered pregnancy phenotypes. We further show that the NK reduction in UTx is due to impaired transcriptional programming of NK tissue residency due to blockade of the transcription factor nuclear factor of activated T cells (NFAT). NFAT-dependent genes played a role in multiple molecular circuits governing tissue residency in uNKs, including early residency programs involving AP-1 transcription factors as well as TGFß-mediated upregulation of surface integrins. Collectively, our data identify a previously undescribed role for NFAT in uterine NK tissue residency and provide novel mechanistic insights into the biologic basis of pregnancy complications due to alteration of tissue resident NK subsets in humans. One Sentence Summary: Role of NFAT in uterine NK cell tissue residency.
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While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these imaging subtypes, highlighting downregulation in interferon alpha and gamma pathways in the high-risk subtype. In summary, our study demonstrates that these habitat imaging subtypes effectively stratify NSCLC patients based on their risk levels for disease recurrence after initial curative surgery or radiotherapy, providing valuable insights for personalized treatment approaches.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fluordesoxiglucose F18 , Compostos Radiofarmacêuticos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Estudos RetrospectivosRESUMO
Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.
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Edição de Genes , Rim , Animais , Suínos , Humanos , Animais Geneticamente Modificados , Xenoenxertos , Transplante Heterólogo , Rejeição de Enxerto/genéticaRESUMO
Introduction: There has been debate regarding the advantages of cruciate-retaining over posterior stabilized (PS) knee arthroplasty and vice versa. Many authors consider any coronal plane deformity > 15° as a contraindication for cruciate-retaining total knee arthroplasty. We aimed to compare whether functional outcome, deformity correction, and survivorship of cruciate retaining knee arthroplasty (CR) for severe varus deformity are equivalent to that ofposterior cruciate ligament substituting (PS) for 6 years. Materials and Methods: We conducted a retrospective comparative study among patients who underwent Total Knee Replacement in the Orthopedics Department of a tertiary care hospital between 2016 and 2018 August who had a varus deformity of more than 15°. The first author exclusively performed CR operation (Group A) for all complex knees. In contrast, the second author performed PS surgery (Group B) for any coronal plane deformity over 15°. Clinical evaluation included completing a Knee Society Score (KSS) Evaluation Form. Pre-operative scoring was collected from the hospital database. All clinical examinations and radiographs at the final follow-up were done by the third author, who was unbiased and not involved with the initial patient care. Results: here were 39 patients in Group A (CR) and 28 patients in Group B (PS). In Group A, the mean pre-operative varus was 22.05 ± 2.72° and the pre-operative KSS was 32.94 ± 6.79. Postoperatively, the deformity corrected to a mean valgus of 5.48 ± 1.8° and mean KSS of 89.17 ± 5.79. In Group B, the mean pre-operative varus was 22.14±3.82° and pre-operative KSS was 32.82 ± 5.98. Postoperatively, the deformity corrected to a mean valgus of 4.85 ± 2.1° and mean KSS of 90.17 ± 5.13. The mean insert thickness was 11.76 ± 1.75 mm and 11.42 ± 1.75mm among the CRand PS groups, respectively. Concerning deformity correction (P = 0.19) and functional outcome (P = 0.46), both groups showed equal improvement with a 100% survival rate for 6 years. Conclusion: We concluded that CRknee replacements are possible with excellent functional and radiological outcomes in severe varus arthritic knees with a 100 % survival rate.
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Resident memory T cells (TRMs), which are memory T cells that are retained locally within tissues, have recently been described as antigen-specific frontline defenders against pathogens in barrier and nonbarrier epithelial tissues. They have also been noted for perpetuating chronic inflammation. The conditions responsible for TRM differentiation are still poorly understood, and their contributions, if any, to sterile models of chronic kidney disease (CKD) remain a mystery. In this study, we subjected male C57BL/6J mice and OT-1 transgenic mice to five consecutive days of 2 mg/kg aristolochic acid (AA) injections intraperitoneally to induce CKD or saline injections as a control. We evaluated their kidney immune profiles at 2 wk, 6 wk, and 6 mo after treatment. We identified a substantial population of TRMs in the kidneys of mice with AA-induced CKD. Flow cytometry of injured kidneys showed T cells bearing TRM surface markers and single-cell (sc) RNA sequencing revealed these cells as expressing well-known TRM transcription factors and receptors responsible for TRM differentiation and maintenance. Although kidney TRMs expressed Cd44, a marker of antigen experience and T cell activation, their derivation was independent of cognate antigen-T cell receptor interactions, as the kidneys of transgenic OT-1 mice still harbored considerable proportions of TRMs after injury. Our results suggest a nonantigen-specific or antigen-independent mechanism capable of generating TRMs in the kidney and highlight the need to better understand TRMs and their involvement in CKD.NEW & NOTEWORTHY Resident memory T cells (TRMs) differentiate and are retained within the kidneys of mice with aristolochic acid (AA)-induced chronic kidney disease (CKD). Here, we characterized this kidney TRM population and demonstrated TRM derivation in the kidneys of OT-1 transgenic mice with AA-induced CKD. A better understanding of TRMs and the processes by which they can differentiate independent of antigen may help our understanding of the interactions between the immune system and kidneys.
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Ácidos Aristolóquicos , Diferenciação Celular , Rim , Células T de Memória , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica , Animais , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Masculino , Ácidos Aristolóquicos/toxicidade , Rim/imunologia , Rim/metabolismo , Rim/patologia , Células T de Memória/imunologia , Células T de Memória/metabolismo , Camundongos Transgênicos , Memória Imunológica , Modelos Animais de Doenças , CamundongosRESUMO
The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood. Here, we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase. NSD2 expression is abnormally gained in prostate cancer cells and its functional inhibition impairs AR trans-activation potential through partial off-loading from over 40,000 genomic sites, which is greater than 65% of the AR tumor cistrome. The NSD2-dependent AR sites distinctly harbor a chimeric AR-half motif juxtaposed to a FOXA1 element. Similar chimeric motifs of AR are absent at the NSD2-independent AR enhancers and instead contain the canonical palindromic motifs. Meta-analyses of AR cistromes from patient tumors uncovered chimeric AR motifs to exclusively participate in tumor-specific enhancer circuitries, with a minimal role in the physiological activity of AR. Accordingly, NSD2 inactivation attenuated hallmark cancer phenotypes that were fully reinstated upon exogenous NSD2 re-expression. Inactivation of NSD2 also engendered increased dependency on its paralog NSD1, which independently maintained AR and MYC hyper-transcriptional programs in cancer cells. Concordantly, a dual NSD1/2 PROTAC degrader, called LLC0150, was preferentially cytotoxic in AR-dependent prostate cancer as well as NSD2-altered hematologic malignancies. Altogether, we identify NSD2 as a novel subunit of the AR neo-enhanceosome that wires prostate cancer gene expression programs, positioning NSD1/2 as viable paralog co-targets in advanced prostate cancer.
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The water-soluble chitosan derivative (WSCD) was made by mixing chitosan with sodium hydroxide, treating the mixture with chloroacetic acid, and then forming a Schiff base with vanillin in an acidic medium. In this study, we examined the corrosion-inhibiting ability of a WSCD on mild steel surfaces in acidic environments. Weight loss, EIS, PDP, LPS, and OCP measurements were used to study the corrosion resistance on mild steel surfaces in 1 M HCl solutions with known concentrations of WSCD. The results show that WSCD functions effectively as a mixed-type anodic and cathodic inhibitor, providing 87 % corrosion inhibition efficiency at 75 ppm. Using SEM to investigate the morphology of corroded mild steel with and without varying amounts of WSCD, impedance measurements show the development of a thin film of inhibitor on the metal surface, the extent of which increases as the inhibitor concentration rises. The WSCD molecule first adsorbs on mild steel and follows Langmuir adsorption isotherm. It is found that the (∆Gads0)adsorption's free energy is -17.473 kJ/mol. The contact angle measurements confirm that the hydrophobicity of the metal surface has increased as a result of the inhibitor's thin film development.
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Benzaldeídos , Quitosana , Aço , Corrosão , Água , Propriedades de Superfície , ÁcidosRESUMO
Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. We used a nontargeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model. Here we identified an upregulation of metabolic pathways such as fatty acid oxidation, fatty acid biosynthesis, and peroxisome proliferator-activated receptor (PPAR)-α signaling in proximal tubule epithelial cell and endothelial cell clusters. We also revealed highly upregulated genes such as Zbtb16, Cyp4a14, and Pdk4, which are involved in metabolism and metabolic switching and may serve as future therapeutic targets. The ability of arsenicals to inhibit enzymes such as pyruvate dehydrogenase has been previously described in vitro. This, along with our own data, led us to conclude that arsenical-induced acute kidney injury may be due to a metabolic impairment in proximal tubule and endothelial cells and that ameliorating these metabolic effects may lead to the development of life-saving therapies. SIGNIFICANCE STATEMENT: In this study, we demonstrate that cutaneous arsenical exposure leads to a transcriptional shift enhancing fatty acid metabolism in kidney cells, indicating that metabolic alterations might mechanistically link topical arsenical exposure to acute kidney injury. Targeting metabolic pathways may generate promising novel therapeutic approaches in combating arsenical-induced acute kidney injury.
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Injúria Renal Aguda , Arsenicais , Camundongos , Humanos , Animais , Células Endoteliais/metabolismo , Rim/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Células Epiteliais/metabolismo , Ácidos Graxos/metabolismo , Arsenicais/efeitos adversos , Arsenicais/metabolismoRESUMO
Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies.
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Transplante de Células-Tronco Hematopoéticas , Hipertensão , Transplante de Órgãos , Microangiopatias Trombóticas , Adulto , Humanos , Criança , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/terapia , Microangiopatias Trombóticas/diagnóstico , Hipertensão/complicações , Insuficiência de Múltiplos Órgãos/terapia , Insuficiência de Múltiplos Órgãos/complicações , Transplante de Órgãos/efeitos adversos , Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Building a competitive research program within a department of surgery requires a significant commitment by the department and the institution to provide the necessary resources for faculty recruitment, retention of current faculty, and physical space/infrastructure to support research activities. We expanded the academic footprint of our department as demonstrated by the expansion of the department of surgery research funding by 13-fold over a period of 7 years, resulting in an increase in national ranking from 55th place to 10th place in the National Institutes of Health extramural funding. This required attention to multiple factors that affect the ability of faculty to establish and maintain competitive research programs. We executed a plan that established a leadership structure that coordinates resources and provides mentorship to faculty. The department invested heavily in the recruitment of new faculty, especially junior faculty, but also some mid-career and senior investigators to develop a critical mass in specific areas for competitive large grant and program project applications. The pipeline of new trainees interested in research was augmented by successful training grant applications that created a mechanism by which residents and fellows can pursue research for periods ranging from a few weeks to 2 years. Administrative infrastructure was created to assist faculty in grant submissions as well as post-award management. Finally, in partnership with institutional leadership, the department acquired the physical space necessary to support both dry-lab and wet-lab research activities. To achieve true excellence, an academic surgery department must maintain excellence in both the clinical and research areas, which, in the context of an academic medical center, are not separate goals.
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Pesquisa Biomédica , Mentores , Estados Unidos , Humanos , Docentes , National Institutes of Health (U.S.) , Centros Médicos Acadêmicos , LiderançaRESUMO
ABSTRACT: Although it is caused by a single-nucleotide mutation in the ß-globin gene, sickle cell anemia (SCA) is a systemic disease with complex, incompletely elucidated pathologies. The mononuclear phagocyte system plays critical roles in SCA pathophysiology. However, how heterogeneous populations of hepatic macrophages contribute to SCA remains unclear. Using a combination of single-cell RNA sequencing and spatial transcriptomics via multiplexed error-robust fluorescence in situ hybridization, we identified distinct macrophage populations with diversified origins and biological functions in SCA mouse liver. We previously found that administering the von Willebrand factor (VWF)-cleaving protease ADAMTS13 alleviated vaso-occlusive episode in mice with SCA. Here, we discovered that the ADAMTS13-cleaved VWF was cleared from the circulation by a Clec4f+Marcohigh macrophage subset in a desialylation-dependent manner in the liver. In addition, sickle erythrocytes were phagocytized predominantly by Clec4f+Marcohigh macrophages. Depletion of macrophages not only abolished the protective effect of ADAMTS13 but exacerbated vaso-occlusive episode in mice with SCA. Furthermore, promoting macrophage-mediated VWF clearance reduced vaso-occlusion in SCA mice. Our study demonstrates that hepatic macrophages are important in the pathogenesis of SCA, and efficient clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in SCA mice.
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Anemia Falciforme , Doenças Vasculares , Camundongos , Animais , Fator de von Willebrand/genética , Hibridização in Situ Fluorescente , Anemia Falciforme/patologia , Macrófagos/patologia , Proteína ADAMTS13/genéticaRESUMO
OBJECTIVES: The purpose of this study was to describe the emergency department (ED) visit chief complaints and discharge diagnoses of patients with an opioid use disorder (OUD) empaneled to a primary care clinic. DESIGN: ED visits were retrospectively reviewed through electronic health records. Patients with a history of using multiple substances and medical or psychiatric conditions were compared to those without these conditions. SETTING: This study was conducted at Harbor-UCLA ED, a safety-net level one trauma center. PATIENTS AND PARTICIPANTS: Eligible participants were empaneled to the Harbor-UCLA Family Health Center with a diagnosis of OUD between January 1, 2018, and December 31, 2020. MAIN OUTCOME MEASURES: The primary outcome measures included number of ED visits, hospital admissions, chief complaints, and discharge diagnoses. RESULTS: The total number of patients was 59. The most common chief complaints were musculoskeletal (34 percent), gastrointestinal (18 percent), general (13 percent), and skin (8.6 percent). The most common discharge diagnoses were musculoskeletal (27 percent), gastrointestinal (20 percent), infectious (11 percent), substance use disorder related (11 percent), psychiatric (7 percent), and cardiovascular (7 percent). Co-occurring alcohol use was associated with a higher number of visits, 3.18 versus 1.15 (p = 0.021), and a higher percentage of patients with frequent visits, 46 percent versus 8 percent (p = 0.008). Patients with diabetes had more frequent visits, 40 percent versus 10 percent (p = 0.036), and were more likely to be admitted, 43 percent versus 15 percent (p = 0.010). CONCLUSIONS: This study highlights the importance of screening and the management of alcohol use and diabetes among patients with OUD.
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Diabetes Mellitus , Transtornos Relacionados ao Uso de Opioides , Humanos , Estudos Retrospectivos , Provedores de Redes de Segurança , Analgésicos Opioides , Serviço Hospitalar de Emergência , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/terapiaRESUMO
Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw-Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. The result is circulating ultra-large multimers of VWF that can cause microthrombi, intravascular occlusion and organ damage, especially at times of turbulent circulation. Patients with hTTP may have many overt or clinically silent manifestations, and a high index of suspicion is required for diagnosis. For the treatment of hTTP, the goal is simply replacement of ADAMTS13. The primary treatment is prophylaxis with plasma infusions or plasma-derived factor VIII products, providing sufficient ADAMTS13 to prevent acute episodes. When acute episodes occur, prophylaxis is intensified. Recombinant ADAMTS13, which is near to approval, will immediately be the most effective and also the most convenient treatment. In this review, we discuss the possible clinical manifestations of this rare disease and the relevant differential diagnoses in different age groups. An extensive discussion on prophylaxis and treatment strategies is also presented. Unique real patient cases have been added to highlight critical aspects of hTTP manifestations, diagnosis and treatment.
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Púrpura Trombocitopênica Trombótica , Humanos , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/terapia , Fator de von Willebrand/genética , Proteínas ADAM/genética , Mutação , Diagnóstico DiferencialRESUMO
BACKGROUND: Current ADAMTS13 activity assays are important for diagnosing thrombotic thrombocytopenic purpura (TTP) but are unreliable to assay ADAMTS13 activity in animal models. The Cattle-FRETS71 assay is capable of detecting ADAMTS13 activity in plasma from multiple animal species, making it a potentially useful reagent at all stages of clinical research. The performance of Cattle-FRETS71 in TTP diagnosis is not yet known. OBJECTIVES: We evaluated the performance of the Cattle-FRETS71 substrate against the human FRETS-rVWF71 and the FRETS-VWF73 commercial substrates in human plasma and serum samples to validate its utility in diagnosing TTP in patients. METHODS: Internal validation was performed using heparinized plasma samples (n = 81). External validation was a blinded study using serum samples from the Oklahoma TTP Registry (n = 118, collected 2004-2014) that had been initially assayed by FRETS-VWF73 within 1 year of collection. Additional validation was performed with citrated plasma samples with variable ADAMTS13 activities (n = 32) that were analyzed by FRETS-VWF73. RESULTS: There was an excellent correlation (r = 0.94) between Cattle-FRETS71 and FRETS-rVWF71 for assayed heparinized plasma samples (n = 81). Assay results between Cattle-FRETS71 and FRETS-VWF73 of Oklahoma TTP Registry serum samples (n = 118) and citrated plasma samples (n = 32) were comparably good (r = 0.81 and r = 0.85, respectively). CONCLUSION: The Cattle-FRETS71 assay is comparable with other assays in quantifying ADAMTS13 activity in human plasma collected from patients with documented or suspected TTP. The versatility of Cattle-FRETS71, combined with its specificity and sensitivity, makes it a useful tool for the standardization of ADAMTS13 activity across basic and clinical research paradigms.
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Púrpura Trombocitopênica Trombótica , Humanos , Bovinos , Animais , Púrpura Trombocitopênica Trombótica/diagnóstico , Corantes Fluorescentes/química , Proteínas ADAM/metabolismo , Proteína ADAMTS13 , Transferência Ressonante de Energia de Fluorescência/métodos , Fator de von Willebrand/química , Ácido CítricoRESUMO
Objective: Pericardial fluid biomarkers reflect the physiologic state of the myocardium. Previously, we showed a sustained increase in pericardial fluid biomarkers compared with blood in the 48 hours after cardiac surgery. We assess the feasibility of analyzing 9 common cardiac biomarkers from pericardial fluid collected during cardiac surgery and test a preliminary hypothesis of association between the most common biomarkers, troponin and brain natriuretic peptide, and length of stay after surgery. Methods: We prospectively enrolled 30 patients aged 18 years or more undergoing coronary artery or valvular surgery. Patients with ventricular assist devices, atrial fibrillation surgery, thoracic aorta surgery, redo surgery, concomitant noncardiac surgery, and preoperative inotropic support were excluded. Before pericardial excision during surgery, a 1-cm pericardial incision was made to insert an 18-gauge catheter and collect 10 mL of pericardial fluid. Concentrations of 9 established biomarkers of cardiac injury or inflammation including brain natriuretic peptide and troponin were measured. Zero truncated Poisson regression adjusted for Society of Thoracic Surgery Preoperative Risk of Mortality tested for a preliminary association between pericardial fluid biomarkers and length of stay. Results: Pericardial fluid was collected and pericardial fluid biomarkers resulted for all patients. Adjusted for Society of Thoracic Surgery risk, brain natriuretic peptide, and troponin were associated with increased intensive care unit and overall hospital length of stay. Conclusions: In 30 patients, pericardial fluid was obtained and analyzed for cardiac biomarkers. Adjusting for Society of Thoracic Surgery risk, pericardial fluid troponin and brain natriuretic peptide were preliminarily associated with increased length of stay. Further investigation is needed to validate this finding and to investigate the potential clinical utility of pericardial fluid biomarkers.