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The continued evolution of SARS-CoV-2 underscores the need to understand qualitative aspects of the humoral immune response elicited by spike immunization. Here, we combine monoclonal antibody (mAb) isolation with deep B cell receptor (BCR) repertoire sequencing of rhesus macaques immunized with prefusion-stabilized spike glycoprotein. Longitudinal tracing of spike-sorted B cell lineages in multiple immune compartments demonstrates increasing somatic hypermutation and broad dissemination of vaccine-elicited B cells in draining and non-draining lymphoid compartments, including the bone marrow, spleen and, most notably, periaortic lymph nodes. Phylogenetic analysis of spike-specific monoclonal antibody lineages identified through deep repertoire sequencing delineates extensive intra-clonal diversification that shaped neutralizing activity. Structural analysis of the spike in complex with a broadly neutralizing mAb provides a molecular basis for the observed differences in neutralization breadth between clonally related antibodies. Our findings highlight that immunization leads to extensive intra-clonal B cell evolution where members of the same lineage can both retain the original epitope specificity and evolve to recognize additional spike variants not previously encountered.
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Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Linfocitos B , Macaca mulatta , Filogenia , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Anticuerpos Neutralizantes/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Linfocitos B/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos Monoclonales/inmunología , Epítopos/inmunología , COVID-19/inmunología , COVID-19/virología , Humanos , Vacunas contra la COVID-19/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/genética , Hipermutación Somática de Inmunoglobulina , InmunizaciónRESUMEN
Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.
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Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/inmunología , Humanos , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/química , Reacciones Cruzadas/inmunología , Microscopía por Crioelectrón , Pruebas de NeutralizaciónRESUMEN
Potential synergism between Bruton's tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142).
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Benzamidas , Linfoma de Células B Grandes Difuso , Pirazinas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Lenalidomida/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Rituximab/uso terapéutico , Resultado del TratamientoRESUMEN
The present study describes an unusual case of bilateral sudden hearing loss associated with iron deficiency anemia. Although hematologic disorders such as anemia or leukemia have been reported to be associated with sudden hearing loss, bilateral sudden hearing loss, which was presented as the first manifestation of iron deficiency anemia, has not been reported. A 74-year-old man presented with simultaneous bilateral sudden hearing loss without vertigo. A complete blood count test revealed a hemoglobin level of 6.4 g/dL and a ferritin level of 14.5 mg/mL, indicating iron deficiency anemia. Postcontrast 3D FLAIR MRI showed enhancement of the bilateral cochlea, vestibules, and lateral semicircular and posterior semicircular canals. After treatment, the patient's hearing loss partially improved.
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BACKGROUND: Previous studies have suggested that patients with polycythemia vera (PV) who exhibit hydroxyurea-resistance (HU-R) and -intolerance (HU-I) may have distinct characteristics and clinical outcomes. However, to date, no studies have reported a comparison between these two groups or assessed prognostic factors in these patients. METHODS: The objective of this study was to evaluate clinical outcomes and identify prognostic factors among PV patients with HU-R or HU-I. We conducted a review of PV patients who received frontline treatment with HU from nine centers and identified 90 patients with HU-R or HU-I. RESULTS: The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio, 6.27, 95% confidence interval, 1.83-21.47, P = 0.003). Additionally, higher lactate dehydrogenase levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. CONCLUSION: These findings suggest that patients with HU-R face a higher risk of hematological transformation, but have a comparable risk of thrombosis to patients with HU intolerance. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.
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Hidroxiurea , Policitemia Vera , Humanos , Progresión de la Enfermedad , Factores de Riesgo de Enfermedad Cardiaca , Hidroxiurea/farmacología , Policitemia Vera/tratamiento farmacológico , Trombosis/epidemiología , Estudios RetrospectivosRESUMEN
Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells. The malignant clones produce cytokines that drive self-perpetuating inflammatory responses and tend to transform into more aggressive clones, leading to disease progression. The progression of MPNs follows a biological sequence from the early phases of malignancy, polycythemia vera, and essential thrombocythemia, to advanced myelofibrosis and leukemic transformation. To date, the treatment of MPNs has focused on preventing thrombosis by decreasing blood cell counts and relieving disease-related symptoms. However, interferon (IFN) has been used to treat MPNs because of its ability to attack cancer cells directly and modulate the immune system. IFN also has the potential to modulate diseases by inhibiting JAK2 mutations, and recent studies have demonstrated clinical and molecular improvements. Long-acting IFN is administered less frequently and has fewer adverse effects than conventional IFN. The current state of research on long-acting IFN in patients with MPNs is discussed, along with future directions.
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Trastornos Mieloproliferativos , Neoplasias , Policitemia Vera , Mielofibrosis Primaria , Humanos , Interferones/genética , Interferones/uso terapéutico , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Policitemia Vera/diagnóstico , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Neoplasias/complicaciones , Mutación , Janus Quinasa 2/genéticaRESUMEN
The use of digital manufacturing, particularly additive manufacturing using three-dimensional (3D) printing, is expanding in the field of dentistry. 3D-printed resin appliances must undergo an essential process, post-washing, to remove residual monomers; however, the effect of the washing solution temperature on the biocompatibility and mechanical properties remains unclear. Therefore, we processed 3D-printed resin samples under different post-washing temperatures (without temperature control (N/T), 30 °C, 40 °C, and 50 °C) for different durations (5, 10, 15, 30, and 60 min) and evaluated the degree of conversion rate, cell viability, flexural strength, and Vickers hardness. Increasing the washing solution temperature significantly improved the degree of conversion rate and cell viability. Conversely, increasing the solution temperature and time decreased the flexural strength and microhardness. This study confirmed that the washing temperature and time influence the mechanical and biological properties of the 3D-printed resin. Washing 3D-printed resin at 30 °C for 30 min was most efficient to maintain optimal biocompatibility and minimize changes of mechanical properties.
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Impresión Tridimensional , Resinas Sintéticas , Ensayo de Materiales , Temperatura , Propiedades de SuperficieRESUMEN
The antibody response to SARS-CoV-2 shows biased immunoglobulin heavy chain variable (IGHV) gene usage, allowing definition of genetic signatures for some classes of neutralizing antibodies. We investigated IGHV gene usage frequencies by sorting spike-specific single memory B cells from individuals infected with SARS-CoV-2 early in the pandemic. From two study participants and 703 spikespecific B cells, the most used genes were IGHV1-69, IGHV3-30-3, and IGHV3-30. Here, we focused on the IGHV3-30 group of genes and an IGHV3-30-3-using ultrapotent neutralizing monoclonal antibody, CAB-F52, which displayed broad neutralizing activity also in its germline-reverted form. IGHV3-30-3 is encoded by a region of the IGH locus that is highly variable at both the allelic and structural levels. Using personalized IG genotyping, we found that 4 of 14 study participants lacked the IGHV3-30-3 gene on both chromosomes, raising the question if other, highly similar IGHV genes could substitute for IGHV3-30-3 in persons lacking this gene. In the context of CAB-F52, we found that none of the tested IGHV3-33 alleles, but several IGHV3-30 alleles could substitute for IGHV3-30-3, suggesting functional redundancy between the highly homologous IGHV3-30 and IGHV3-30-3 genes for this antibody.
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Purpose: We investigated the prognostic value of maximum tumor dissemination (Dmax), the distance between malignant lesions that were farthest apart, as assessed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), and other clinical factors in patients with diffuse large B-cell lymphoma (DLBCL).We investigated the prognostic value of maximum tumor dissemination (Dmax), the distance between malignant lesions that were farthest apart, as assessed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), and other clinical factors in patients with diffuse large B-cell lymphoma (DLBCL). Methods: Patients who underwent FDG PET/CT for initial staging and treatment response evaluation of DLBCL were reviewed retrospectively. Baseline Dmax, maximum standardized uptake value, total summation of all metabolic tumor volumes (tMTV), and total summation of all total lesion glycolysis (tTLG) were measured. The treatment response was evaluated at the interim and end of first-line treatment (EOT) using the Deauville score (DS). FDG PET/CT parameters and other clinical factors including sex, age, serum lactate dehydrogenase (LDH) level, stage, performance status, and the International Prognostic Index (IPI) were analyzed to identify factors prognostic of the time to progression (TTP) and disease-specific survival (DSS). Results: A total of 63 patients were included. Univariate survival analysis identified Dmax (> 275 mm), tMTV (> 180 mL), tTLG (> 1300), interim DS (≥ 4), and EOT DS (≥ 4) as significant predictors of poor TTP. Serum LDH level (> 640 IU/L), IPI (≥ 4), tMTV (> 180 mL), tTLG (> 1300), interim DS (≥ 4), and EOT DS (≥ 4) were significant predictors of DSS. After multivariate survival analysis, Dmax (P = 0.008) and EOT DS (P = 0.005) were independent predictors of TTP. EOT DS was an independent predictor of DSS (P = 0.029). Conclusions: Dmax at the time of diagnosis and the EOT response assessed by FDG PET/CT provide useful prognostic information additive to the IPI in patients with DLBCL.
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The human immunoglobulin heavy-chain (IGH) locus is exceptionally polymorphic, with high levels of allelic and structural variation. Thus, germline IGH genotypes are personal, which may influence responses to infection and vaccination. For an improved understanding of inter-individual differences in antibody responses, we isolated SARS-CoV-2 spike-specific monoclonal antibodies from convalescent health care workers, focusing on the IGHV1-69 gene, which has the highest level of allelic variation of all IGHV genes. The IGHV1-69∗20-using CAB-I47 antibody and two similar antibodies isolated from an independent donor were critically dependent on allele usage. Neutralization was retained when reverting the V region to the germline IGHV1-69∗20 allele but lost when reverting to other IGHV1-69 alleles. Structural data confirmed that two germline-encoded polymorphisms, R50 and F55, in the IGHV1-69 gene were required for high-affinity receptor-binding domain interaction. These results demonstrate that polymorphisms in IGH genes can influence the function of SARS-CoV-2 neutralizing antibodies.
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COVID-19 , SARS-CoV-2 , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , COVID-19/genética , Anticuerpos Antivirales , Polimorfismo Genético , Anticuerpos Neutralizantes , Células GerminativasRESUMEN
An economic system is an exemplar of a complex system in which all agents interact simultaneously. Interactions between countries have generally been studied using the flow of resources across diverse trade networks, in which the degree of dependence between two countries is typically measured based on the trade volume. However, indirect influences may not be immediately apparent. Herein, we compared a direct trade network to a trade network constructed using the personalized PageRank (PPR) encompassing indirect influences. By analyzing the correlation of the gross domestic product (GDP) between countries, we discovered that the PPR trade network has greater explanatory power on the propagation of economic events than direct trade by analyzing the GDP correlation between countries. To further validate our observations, an agent-based model of the spreading economic crisis was implemented for the Russia-Ukraine war of 2022. The model also demonstrates that the PPR explains the actual impact more effectively than the direct trade network. Our research highlights the significance of indirect and long-range relationships, which have often been overlooked.
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In this multicenter phase II study, we evaluated the safety and efficacy of imatinib in patients with steroid-resistant chronic graft-versus-host disease (cGVHD) and evaluated the quality of life (QOL) of the enrolled patients using the Short Form 36 (SF-36) health survey questionnaire. Thirty-six patients who were diagnosed with steroid-refractory cGVHD and treated with imatinib between March 2013 and February 2019 received 100 mg/day of imatinib for 2 weeks. Depending on the patient's condition and investigator's decision, the imatinib dose was allowed to be increased by 100 mg every 2 weeks up to 400 mg/day. Patients who achieved stable disease (SD), partial remission (PR), and complete remission (CR) at 3-month response evaluations continued imatinib for up to 6 months. The majority of the patients had multi-organ cGVHD, with skin (63.9%), lungs (44.4%), mouth (38.9%), and eyes (38.9%) as the most common sites. The overall response rate was 58.3%, including 3 and 18 patients with CR and PR, respectively, and an overall decline in National Institutes of Health (NIH) severity scores was observed at study completion in the absence of significant adverse effects. The overall response rates were 70.5%, 66.7%, 34.8%, and 25% in patients with gastrointestinal, liver, skin, and lung cGVHD, respectively. Factors representing emotional well-being were significantly improved based on the patient-reported QOL evaluation using SF-36. The effect of imatinib on steroid tapering, which was notable in responders, was also present in 50% of those who achieved SD without worsening cGVHD. Imatinib exhibited therapeutic efficacy in steroid-refractory and steroid-dependent cGVHD with tolerable toxicity.Clinical Trial Registration: KCT0006785.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Crónica , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Mesilato de Imatinib/uso terapéutico , Calidad de Vida , Esteroides/uso terapéuticoRESUMEN
INTRODUCTION/BACKGROUND: Ruxolitinib is an established treatment for myelofibrosis (MF) that has demonstrated clinical benefit by reducing spleen size and debilitating MF-related symptoms. However, despite the efficacy of ruxolitinib, anemia remains a major adverse event that causes dose modification or discontinuation in real-world practice. Additionally, dependence on red blood cell (RBC) transfusion (TF) is common during treatment; therefore, we explored the outcome of ruxolitinib therapy with a primary focus on RBC TF. PATIENTS/METHODS: We retrospectively reviewed the medical records of 123 MF patients treated with ruxolitinib between January 2012 and April 2020 at eight academic centers in Korea. RESULTS: At ruxolitinib initiation, 38 patients (30.9%) underwent ≥ 2 units of RBC TF over 8 weeks. The most common reason for permanent discontinuation was intolerant anemia (10/63, 15.9%). The most common reasons for temporary interruption were nonhematologic toxicity (26/55, 21.1%), anemia (23/55, 18.7%) and thrombocytopenia (13/55, 10.6%). Among the 123 patients in the study, 57 (46.3%), 42 (34.1%), and 40 patients (32.5%) who were receiving or stopped ruxolitinib therapy had a status of RBC TF dependence, long-term RBC TF dependence, or severe RBC TF dependence, respectively. The presence of ≥ 2 units of RBC transfusion over 8 weeks at ruxolitinib initiation was an independent risk factor for persistent RBC TF dependence. CONCLUSION: The requirement for RBC TF is commonly encountered during treatment of MF with ruxolitinib, particularly among those with pre-existing ≥ 2 units of RBC TF over 8 weeks. For those patients, overcoming the barrier of maintenance TF is demanding.
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Anemia , Hematología , Mielofibrosis Primaria , Anemia/etiología , Transfusión de Eritrocitos , Humanos , Nitrilos , Mielofibrosis Primaria/diagnóstico , Pirazoles , Pirimidinas , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Prior research suggests a link between obstructive sleep apnea (OSA) and the likelihood of developing a variety of solid tumors; however, there are no studies assessing OSA and leukemia. This study is the first to identify a potential association between OSA and leukemia using data from the Korea National Health Insurance Service database. METHODS: A total of 162,646 patients (≥20 years of age and without any cancer history) newly diagnosed with OSA between 2011 and 2017 were included. A control group of 813,230 subjects was selected using propensity score matching based on age and sex. The mean follow-up time was 4.4 ± 2.0 years. The primary endpoint was newly diagnosed leukemia of any type. The leukemia hazard ratio (95% confidence interval [CI]) was calculated for patients with OSA and compared with that of patients in the control group. RESULTS: The incidence of leukemia among patients with OSA was significantly higher than that in the controls (1.35 [1.05-1.74]). The hazard ratio was the highest, 1.74 in those under 40 years, and gradually decreased with age, to 1.38 in those aged 40-65 years and 0.96 in those over 65. In particular, the incidence of lymphoid leukemia (2.06 [1.18-3.60]) was higher than that of myeloid (1.34 [1.00-1.81]) or unspecified leukemia (0.60 [0.20-1.58]). CONCLUSION: OSA is associated with an increased incidence of leukemia, particularly in patients younger than 40 years of age.
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Seguro , Leucemia , Apnea Obstructiva del Sueño , Adulto , Humanos , Incidencia , Lactante , Leucemia/epidemiología , República de Corea/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Apnea Obstructiva del Sueño/epidemiología , Taiwán/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Approximately 50% of limited-stage ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) patients with adverse prognostic factors relapse after radiotherapy. Chemoimmunotherapy has been proposed as an alternative frontline therapy. However, only a few studies have reported its long-term treatment outcome. METHODS: In 2011, we commenced a phase 2 trial to investigate the efficacy of rituximab, cyclophosphamide, doxorubicin, and prednisolone (R-CVP) in bilateral and non-conjunctival limited-stage OAML patients. Results of the clinical trial showed a response rate of 100% and a 4-year progression-free survival of 90.3% without significant toxicity. We extended the study period to December 2020 to determine the long-term efficacy of R-CVP chemoimmunotherapy. RESULTS: At a median observation period of 66.0 months, eight of 33 study patients had relapsed. The cumulative incidence of relapse was 18.9% at 5 years and 44.7% at 8 years. The majority of relapses developed more than 4 years after treatment. Local relapse was more prevalent than distant relapse. The relapse risk of orbital and lacrimal diseases was likely to be higher than that of conjunctival and eyelid diseases (HR: 2.5, 95% CI: 0.498-12.500, p = 0.25). CONCLUSION: Although the response rate was remarkable for chemoimmunotherapy, the risk of late relapse was considerable. Based on our findings, clinical trials for limited-stage OAML patients should have a long-term observation period. To minimize radiation toxicity and reduce the risk of delayed relapse (local relapse and distant relapse), a future study with sequential or combination treatment of local low-dose radiation and systemic chemoimmunotherapy can be considered.
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Neoplasias del Ojo , Linfoma de Células B de la Zona Marginal , Neoplasias del Ojo/tratamiento farmacológico , Estudios de Seguimiento , Humanos , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Recurrencia Local de Neoplasia , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is one of the most fatal complications of hematopoietic cell transplantation (HCT), and defibrotide is the only curative drug. We conducted this study to confirm the survival rate of VOD/SOS patients diagnosed in Korea and assess the efficacy of defibrotide. METHODS: Patients diagnosed with VOD/SOS after allogenic HCT between 2003 and 2020 were enrolled. We investigated day +100 survival rates and associated risk factors in patients who satisfied the modified Seattle criteria within 50 days of HCT. RESULTS: A total of 110 patients satisfied the modified Seattle criteria, of which 65.5% satisfied the Baltimore criteria. Thirty-seven patients were treated with defibrotide. The day +100 survival rate of the 110 patients was 65.3%. The survival rates in patients who did not meet the Baltimore criteria and in those who did were 86.8% and 53.7%, respectively (p = 0.001). The day +100 survival rate of patients treated with defibrotide was 50.5%. Among the patients receiving defibrotide, those whose creatinine levels were more than 1.2 times the baseline had a significantly lower survival rate at 26.7% (p = 0.014). On multivariate regression analysis, the hazard ratio of satisfaction of the Baltimore criteria was 4.54 (95% confidence interval [CI], 1.69 to 12.21; p = 0.003). In patients treated with defibrotide, the hazard ratio was 8.70 (95% CI, 2.26 to 33.45; p = 0.002), when creatinine was more than 1.2 times the baseline on administration. CONCLUSION: The day +100 survival rate was significantly lower when the Baltimore criteria were satisfied, and when there was an increase in creatinine at the time of defibrotide administration.
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Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Creatinina , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Polidesoxirribonucleótidos/efectos adversosRESUMEN
Minoxidil was originally introduced as a potent vasodilator, but is now widely used as a topical treatment for human alopecia. A 4-year-old neutered male Norwegian Forest cat presented with a 2-day history of anorexia, lethargy, and dyspnoea. A physical examination revealed hypothermia, tachypnoea, hypotension, and bilateral pulmonary crackles. The radiographs revealed pulmonary oedema and pleural effusions. The hypotension and pleural effusions exacerbated despite the supportive therapy, and the underlying cause remained undetermined. A further medical inquiry revealed the cat had been exposed to a topical minoxidil solution 3 days before admission. Accordingly, minoxidil toxicosis was managed using both i.v. fluids and vasopressors. Dopamine and norepinephrine were infused for 3 days to normalise the patient's blood pressure and related clinical signs. The cat recovered fully and was discharged 6 days after the minoxidil exposure. This is the first report on the successful management of minoxidil toxicosis in a cat. To broaden our knowledge of minoxidil toxicosis in cats, we have also described the serial changes in the clinical findings of this cat over the treatment period. Furthermore, on the basis of the experience gained from this case, we suggest an optimised management plan for future cases of feline minoxidil toxicosis.
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The development of a 3D-Printed Load Cell (PLC) was studied using a nanocarbon composite strain sensor (NCSS) and a 3D printing process. The miniature load cell was fabricated using a low-cost LCD-based 3D printer with UV resin. The NCSS composed of 0.5 wt% MWCNT/epoxy was used to create the flexure of PLC. PLC performance was evaluated under a rated load range; its output was equal to the common value of 2 mV/V. The performance was also evaluated after a calibration in terms of non-linearity, repeatability, and hysteresis, with final results of 2.12%, 1.60%, and 4.42%, respectively. Creep and creep recovery were found to be 1.68 (%FS) and 4.16 (%FS). The relative inferiorities of PLC seem to originate from the inherent hyper-elastic characteristics of polymer sensors. The 3D PLC developed may be a promising solution for the OEM/design-in load cell market and may also result in the development of a novel 3D-printed sensor.
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Fracture of a dental implant (DI) is a rare mechanical complication that is a critical cause of DI failure and explantation. The purpose of this study was to evaluate the reliability and validity of a three different deep convolutional neural network (DCNN) architectures (VGGNet-19, GoogLeNet Inception-v3, and automated DCNN) for the detection and classification of fractured DI using panoramic and periapical radiographic images. A total of 21,398 DIs were reviewed at two dental hospitals, and 251 intact and 194 fractured DI radiographic images were identified and included as the dataset in this study. All three DCNN architectures achieved a fractured DI detection and classification accuracy of over 0.80 AUC. In particular, automated DCNN architecture using periapical images showed the highest and most reliable detection (AUC = 0.984, 95% CI = 0.900-1.000) and classification (AUC = 0.869, 95% CI = 0.778-0.929) accuracy performance compared to fine-tuned and pre-trained VGGNet-19 and GoogLeNet Inception-v3 architectures. The three DCNN architectures showed acceptable accuracy in the detection and classification of fractured DIs, with the best accuracy performance achieved by the automated DCNN architecture using only periapical images.