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Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers could inform immunotherapy mediators. We identified a treatment-naive patient who has metastatic uterine leiomyosarcoma and has experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2 and showed sparse PD-L1 staining. PD-1+ cell infiltration significantly decreased in the resistant tumor (p = 0.039). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.
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Resistencia a Antineoplásicos/genética , Leiomiosarcoma/patología , Fosfohidrolasa PTEN/genética , Neoplasias Uterinas/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Análisis Mutacional de ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/genética , Persona de Mediana Edad , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Transcriptoma , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genéticaRESUMEN
Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.
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Línea Celular Tumoral , Neoplasias/genética , Neoplasias/patología , Antineoplásicos/farmacología , Biomarcadores de Tumor , Metilación de ADN , Resistencia a Antineoplásicos , Etnicidad/genética , Edición Génica , Histonas/metabolismo , Humanos , MicroARNs/genética , Terapia Molecular Dirigida , Neoplasias/metabolismo , Análisis por Matrices de Proteínas , Empalme del ARNRESUMEN
BACKGROUND: There is unclear added benefit of intravenous thrombolysis (IVT) with endovascular thrombectomy (EVT). We performed a cost-effectiveness analysis to assess the cost-effectiveness of comparing EVT with IVT versus EVT alone. METHODS: We used a decision tree to examine the short-term costs and outcomes at 90 days after the occurrence of index stroke to compare the cost-effectiveness of EVT alone with EVT plus IVT for patients with stroke. Subsequently, we developed a Markov state transition model to assess the costs and outcomes over 1-year, 5-year, and 20-year time horizons. We estimated total and incremental cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio. RESULTS: The average costs per patient were estimated to be $47,304, $49,510, $59,770, and $76,561 for EVT-only strategy and $55,482, $57,751, $68,314, and $85,611 for EVT with IVT over 90 days, 1 year, 5 years, and 20 years, respectively. The cost saving of EVT-only strategy was driven by the avoided medication costs of IVT (ranging from $8,178 to $9,050). The additional IVT led to a slight decrease in QALY estimate during the 90-day time horizon (loss of 0.002 QALY), but a small gain over 1-year and 5-year time horizons (0.011 and 0.0636 QALY). At a willingness-to-pay threshold of $50,000 per QALY gained, the probabilities of EVT only being cost-effective were 100%, 100%, and 99.3% over 90-day, 1-year, and 5-year time horizons. CONCLUSION: Our cost-effectiveness model suggested that EVT only may be cost-effective for patients with acute ischemic stroke secondary to large vessel occlusion.
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Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/cirugía , Terapia Trombolítica , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/cirugía , Análisis de Costo-Efectividad , Trombectomía , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/cirugía , Resultado del Tratamiento , Análisis Costo-BeneficioRESUMEN
Chronic obstructive pulmonary disease (COPD) carries a high burden of morbidity and mortality to patient and a high cost to health care systems. Lung transplantation is a last resort available for end-stage COPD patients interested in pursuing it and meeting the strict transplant requirements. It requires commitment from patients and their loved ones to support them through this tough process. This review will cover history of transplant, indications, candidate selection, evaluation testing, transplant listing, type of transplant (single versus bilateral), posttransplant complications, immunosuppression, and rejection. It is tailored to the COPD patient when applicable; however, many aspects of lung transplantation are shared amongst all lung diseases eligible for transplant.
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Clinical prediction models serve as valuable instruments for assessing the risk of crucial outcomes and facilitating decision-making in clinical settings. Constructing these models requires nuanced analytical decisions and expertise informed by the current statistical literature. Access and thorough understanding of such literature may be limited for neurocritical care physicians, which may hinder the interpretation of existing predictive models. The present emphasis is on narrowing this knowledge gap by providing neurocritical care specialists with methodological guidance for interpreting predictive models in neurocritical care. Presented are the statistical learning principles integral to constructing a model predicting hospital mortality (nonsurvival during hospitalization) in patients with moderate and severe blunt traumatic brain injury using components of the IMPACT-Core model. Discussion encompasses critical elements such as model flexibility, hyperparameter selection, data imbalance, cross-validation, model assessment (discrimination and calibration), prediction instability, and probability thresholds. The intricate interplay among these components, the data set, and the clincal context of neurocritical care is elaborated. Leveraging this comprehensive exploration of statistical learning can enhance comprehension of articles encompassing model generation, tailored clinical care, and, ultimately, better interpretation and clinical applicability of predictive models.
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The progression of the Internet of Things (IoT) has brought about a complete transformation in the way we interact with the physical world. However, this transformation has brought with it a slew of challenges. The advent of intelligent machines that can not only gather data for analysis and decision-making, but also learn and make independent decisions has been a breakthrough. However, the low-cost requirement of IoT devices requires the use of limited resources in processing and storage, which typically leads to a lack of security measures. Consequently, most IoT devices are susceptible to security breaches, turning them into "Bots" that are used in Distributed Denial of Service (DDoS) attacks. In this paper, we propose a new strategy labeled "Temporary Dynamic IP" (TDIP), which offers effective protection against DDoS attacks. The TDIP solution rotates Internet Protocol (IP) addresses frequently, creating a significant deterrent to potential attackers. By maintaining an "IP lease-time" that is short enough to prevent unauthorized access, TDIP enhances overall system security. Our testing, conducted via OMNET++, demonstrated that TDIP was highly effective in preventing DDoS attacks and, at the same time, improving network efficiency and IoT network protection.
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A checklist of 113 monogenean species parasitizing marine fishes (60 species) from different localities in Egypt is provided. The list is supplemented by eight newly collected monogenean species from Red Sea fishes, off Safaga and El-Quseir. Five of these species are new Egyptian records: Calydiscoides euzeti Justine, 2007, Calydiscoides rohdei Oliver, 1984, Lethrinitrema austrosinense (Li & Chen, 2005) Sun, Li & Yang, 2014, Pseudohaliotrema sphincteroporus Yamaguti, 1953, and Pentatres sphyraenae Euzet & Razarihelisoa, 1959. Furthermore, Lutjanus ehrenbergii (Peters), Lethrinus nebulosus (Forsskål), Lethrinus mahsena (Forsskål), Siganus stellatus (Forsskål), and Sphyraena flavicauda Rüppell represent new host records. The current study also lists nine monogenean species from the Gulf of Aqaba for which the coordinates of the sampling localities were not clearly defined, but which could also belong to the Egyptian fauna as the gulf is part of the Red Sea basin. Dactylogyrus aegyptiacus Ramadan, 1983 is transferred to Ecnomotrema Kritsky, 2023 as E. aegyptiacum (Ramadan, 1983) n. comb. Entobdella aegyptiacus Amer, 1990, Polylabroides aegyptiacus Mahmoud & Shaheed 1998, Gotocotyla sigani Abdel Aal, Ghattas & Badawy, 2001, Neohexostoma epinepheli Abdel Aal, Ghattas & Badawy, 2001, Neothoracocotyle commersoni Abdel Aal, Ghattas & Badawy, 2001, Acleotrema maculatum Morsy, El Fayoumi & Fahmy, 2014, Diplectanum harid Morsy, El Fayoumi, Al Shahawy & Fahmy, 2014, and Pseudorhabdosynochus chlorostigma Morsy, El Fayoumi, Al Shahawy & Fahmy, 2014, are considered species inquirendae. Paranaella diplodae Bayoumy, Abd El-Hady & Hassanain, 2007 is considered incertae sedis. Allencotyla lutini El-Dien, 1995 and Lamellodiscus diplodicus Bayoumy, 2003 are regarded as nomina nuda.
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Lista de Verificación , Peces , Animales , Humanos , Egipto , Especificidad de la EspecieRESUMEN
OBJECTIVE: The aim of this review was to review the ethical and multidisciplinary clinical challenges facing trauma surgeons when resuscitating patients presenting with penetrating brain injury (PBI) and multicavitary trauma. BACKGROUND: While there is a significant gap in the literature on managing PBI in patients presenting with multisystem trauma, recent data demonstrate that resuscitation and prognostic features for such patients remains poorly described, with trauma guidelines out of date in this field. METHODS: We reviewed a combination of recent multidisciplinary evidence-informed guidelines for PBI and coupled this with expert opinion from trauma, neurosurgery, neurocritical care, pediatric and transplant surgery, surgical ethics and importantly our community partners. RESULTS: Traditional prognostic signs utilized in traumatic brain injury may not be applicable to PBI with a multidisciplinary team approach suggested on a case-by-case basis. Even with no role for neurosurgical intervention, neurocritical care, and neurointerventional support may be warranted, in parallel to multicavitary operative intervention. Special considerations should be afforded for pediatric PBI. Ethical considerations center on providing the patient with the best chance of survival. Consideration of organ donation should be considered as part of the continuum of patient, proxy and family-centric support and care. Community input is crucial in guiding decision making or protocol establishment on an institutional level. CONCLUSIONS: Support of the patient after multicavitary PBI can be complex and is best addressed in a multidisciplinary fashion with extensive community involvement.
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Lesiones Traumáticas del Encéfalo , Traumatismos Penetrantes de la Cabeza , Obtención de Tejidos y Órganos , Humanos , Niño , Resucitación/métodos , Procedimientos NeuroquirúrgicosRESUMEN
This review describes the gold-catalyzed reactions of specially activated alkynes, allenes, and alkenes. Such species are characterized by the presence of either electron-donating or electron-withdrawing groups as substituents of the carbon π-system. They are intrinsically polarized, and when compared to their nonspecially activated counterparts can therefore be involved in gold-catalyzed transformations featuring increased regio-, stereo-, and chemoselectivities. The chemistry of specially activated carbon π-systems under homogeneous gold catalysis is extremely rich and varied. The reactivity observed with nonspecially activated unsaturated systems can often be transposed to specially activated ones without loss of efficiency. However, specially activated carbon π-systems also exhibit specific reactivities that cannot be attained with regular substrates. In this family of carbon π-systems, ynamides and their analogs, along with alkynyl carbonyl derivatives, are the classes of substrates that have retained the most attention. This review provides an overview of the chemistry developed with all classes of specially activated carbon π-systems by discussing their general and specific reactivities, presenting and commenting on their gold-catalyzed transformations as well as their applications.
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INTRODUCTION: Survival following lung transplant is low. With limited donor lung availability, predicting post-transplant survival is key. We investigated the predictive value of pre-transplant CT biomarkers on survival. METHODS: In this single-center retrospective cohort study of adults in a diverse, underserved, urban lung transplant program (11/8/2017-5/20/2022), chest CTs were analyzed using TeraRecon to assess musculature, fat, and bone. Erector spinae and pectoralis muscle area and attenuation were analyzed. Sarcopenia thresholds were 34.3 (women) and 38.5 (men) Hounsfield Units (HU). Visceral and subcutaneous fat area and HU, and vertebral body HU were measured. Demographics and pre-transplant metrics were recorded. Survival analyses included Kaplan-Meier and Cox proportional hazard. RESULTS: The study cohort comprised 131 patients, 50 women, mean age 60.82 (SD 10.15) years, and mean follow-up 1.78 (SD 1.23) years. Twenty-nine percent were White. Mortality was 32.1%. Kaplan-Meier curves did not follow the proportional hazard assumption for sex, so analysis was stratified. Pre-transplant EMR metrics did not predict survival. Women without sarcopenia at erector spinae or pectoralis had 100% survival (p = 0.007). Sarcopenia did not predict survival in men and muscle area did not predict survival in either sex. Men with higher visceral fat area and HU had decreased survival (p = 0.02). Higher vertebral body density predicted improved survival in men (p = 0.026) and women (p = 0.045). CONCLUSION: Pre-transplantation CT biomarkers had predictive value in lung transplant survival and varied by sex. The absence of sarcopenia in women, lower visceral fat attenuation and area in men, and higher vertebral body density in both sexes predicted survival in our diverse, urban population.
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Trasplante de Pulmón , Sarcopenia , Masculino , Adulto , Humanos , Femenino , Persona de Mediana Edad , Sarcopenia/diagnóstico por imagen , Estudios Retrospectivos , Población Urbana , Biomarcadores , Trasplante de Pulmón/efectos adversos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Intracranial pressure (ICP) can be continuously and reliably measured using invasive monitoring through an external ventricular catheter or an intraparenchymal probe. We explore electroencephalography (EEG) to identify a reliable real-time noninvasive ICP correlate. METHODS: Using a previously described porcine model of intracranial hypertension, we examined the cross correlation between ICP time series and the slope of the EEG power spectral density as described by Ï. We calculated Ï as tan-1 (slope of power spectral density) and normalized it by π, where slope is that of the power-law fit (log frequency vs. log power) to the power spectral density of the EEG signal. Additionally, we explored the relationship between the Ï time series and cerebral perfusion pressure. A total of 11 intracranial hypertension episodes across three different animals were studied. RESULTS: The mean correlation between Ï angle and ICP was - 0.85 (0.15); the mean correlation with cerebral perfusion pressure was 0.92 (0.02). Significant correlation occurred at zero lag. In the absence of intracranial hypertension, the absolute value of the Ï angle was greater than 0.9 (mean 0.936 radians). However, during extreme intracranial hypertension causing cerebral circulatory arrest, the Ï angle is on average below 0.9 radians (mean 0.855 radians). CONCLUSIONS: EEG Ï angle is a promising real-time noninvasive measure of ICP/cerebral perfusion using surface electroencephalography.
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We design and evaluate two experimental systems for a single and simultaneous electro-optical semiconductor optical amplifier Mach-Zehnder interferometer (SOA-MZI) mixing system based on the differential modulation mode. These systems and the optimization of their optical and electrical performance largely depend on characteristics of an optical pulse source (OPS), operating at a frequency of f= 39 GHz and a pulse width of 1 ps. The passive power stability of the electro-optical mixing output over one hour is better than 0.3% RMS (root mean square), which is excellent. Additionally, we generate up to 22 dBm of the total average output power with an optical conversion gain of 32 dB, while achieving a record output optical signal to noise ratio (OSNR) up to 77 dB. On the other hand, at the SOA-MZI output, the 128 quadratic amplitude modulation (128-QAM) signal at an intermediate frequency (IF), f1, is up-mixed to higher output frequencies nf ± f1. The advantages of the resulting 128-QAM mixed signal during electrical conversion gains (ECGs) and error vector magnitudes (EVMs) are also evaluated. The performed empirical SOA-MZI mixing can operate up to 118.5 GHz in its high-frequency range. The positive and almost constant conversion gains are achieved. Indeed, the obtained conversion gain values are very close across the entire range of output frequencies. The largest frequency range achieved during experimental work is 118.5 GHz, where the EVM achieves 6% at a symbol rate of 10 GSymb/s. Moreover, the peak data rate of the 128-QAM up mixed signal can reach 70 GBit/s. Finally, the study of the simultaneous electro-optical mixing system is accepted with unmatched performance improvement.
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Telecommunication has shaped our civilization and fueled economic growth significantly throughout human history [...].
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BACKGROUND: Data on large vessel occlusion (LVO) management due to intracranial atherosclerotic disease (ICAD) are scarce. OBJECTIVE: To compare clinical outcomes between patients with ICAD and those without ICAD following mechanical thrombectomy (MT). METHODS: We performed a retrospective analysis of consecutive patients who underwent MT for LVO in a large academic comprehensive stroke center, and compared in-hospital mortality, 90-day mortality, favorable functional outcome at 90 days, and symptomatic intracranial hemorrhage (ICH) using chi-squared tests and multivariate logistic regression analyses. We defined ICAD as observable plaque at occlusion site post-thrombectomy. RESULTS: Among 215 patients (mean age 67.1 ± 16.0 years; 60.5% female; 83.6% Black, median NIHSS score 16), ICAD was present in 38 patients (17.7%). Diabetes and dyslipidemia were more common in those with ICAD (57.9% vs. 38.4%, p = 0.027 and 29.0% vs. 14.7%, p = 0.035, respectively). Substantial reperfusion (TICI ≥2b) was achieved less often (84.2% vs. 94.4%, p = 0.031) but symptomatic ICH was also less common in ICAD patients (0% vs. 9.0%, p = 0.081). In-hospital and 90-day mortality were more common (36.8% vs. 15.8%, p = 0.003 and 52.6% vs. 26.6%, p = 0.002, respectively) and favorable functional outcome (mRS 0-2) at 90 days was less common (7.9% vs. 33.9%, p = 0.001) in ICAD patients. After adjusting for prognostic variables, ICAD was independently associated with in-hospital mortality (OR=4.1, 95% CI 1.7-9.7), 90-day mortality (OR=3.7, 95% CI 1.6-8.6), and poor functional outcome at 90 days (OR=5.5, 95% CI 1.6-19.4). CONCLUSION: Symptomatic ICAD in a predominantly African American cohort is associated with increased odds of mortality and poor functional outcome at 90 days in patients with LVO undergoing MT.
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Isquemia Encefálica , Arteriosclerosis Intracraneal , Accidente Cerebrovascular , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Trombectomía/efectos adversos , Hemorragias Intracraneales/diagnóstico por imagen , Hemorragias Intracraneales/etiología , Arteriosclerosis Intracraneal/complicaciones , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/terapiaRESUMEN
The occurrence of postoperative pancreatic fistula following laparoscopic pancreaticoduodenectomy (LPD) is a significant concern, yet there is currently a lack of consensus on reliable predictive methods for this complication. Therefore, the aim of this study was to assess the clinical significance of C-reactive protein (CRP) and procalcitonin (PCT) values and their reliability in early predicting the development of clinically relevant pancreatic fistula (CRPF) following LPD.A retrospective analysis was conducted using data from 120 patients who had LPD between September 2019 and December 2021. Preoperative assessment data, standard patients' demographic and clinicopathological characteristics, intra- and postoperative evaluation, as well as postoperative laboratory values on postoperative days (PODs) 1, 3, and 7, including white blood cells (WBCs), CRP, and PCT, were prospectively recorded on a dedicated database. Two clinicians separately collected and cross-checked all of the data.Among 120 patients [77 men (64%), 43 women (36%], CRPF occurred in 15 patients (11 grade B and 4 grade C fistulas). The incidence rate of CRPF was 12.3%. A comparison of the median values of WBCs, PCT, and CRP across the two groups revealed that the CRPF group had higher values on most PODs than the non-CRPF group. Receiver operating characteristic (ROC) analysis was used to calculate the area under the curve (AUC) and cutoff values. It was discovered that POD 3 has the most accurate and significant values for WBCs, CRP, and PCT. According to the ROC plots, the AUC for WBCs was 0.842, whereas the AUC for PCT was 0.909. As for CRP, the AUC was 0.941 (95% CI 0.899-0.983, p < 0.01) with a cutoff value of 203.45, indicating a sensitivity of 93.3% and specificity of 91.4%.Both CRP and PCT can be used to predict the early onset of CRPF following LPD, with CRP being slightly superior on POD 3.
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Proteína C-Reactiva , Laparoscopía , Masculino , Humanos , Femenino , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Pancreaticoduodenectomía/efectos adversos , Estudios Retrospectivos , Polipéptido alfa Relacionado con Calcitonina , Fístula Pancreática/diagnóstico , Fístula Pancreática/etiología , Reproducibilidad de los Resultados , Curva ROC , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Laparoscopía/efectos adversosRESUMEN
Direct C-H bond functionalization is a useful strategy for the straightforward formation of C-C and C-Heteroatom bonds. In the present work, a unique approach for the challenging electrophilic Au-catalyzed α-C-H bond functionalization of tertiary amines is presented. Electronic, steric and conformational synergistic effects exerted by the use of a malonate unit in the substrate were key to the success of this transformation. This new reactivity was applied to the synthesis of tetrahydro-γ-carboline products which, under oxidative conditions, could be converted into valuable structural motifs found in bioactive alkaloid natural products.
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Aminas , Oro , Estructura Molecular , Catálisis , Conformación Molecular , Aminas/químicaRESUMEN
INTRODUCTION: Identifying which patients can receive immediate intramedullary nailing (IMN) after bilateral femoral shaft fracture may improve health-related quality of life outcomes and decrease healthcare costs. This retrospective study evaluated the perioperative factors that guided emergency department transfer of patients to the operating room (OR) where IMN or temporizing external fixation (TEF) was performed, to the intensive care unit (ICU), or to the orthopedic ward. The hypothesis was that patients referred initially to the OR or to the ICU had more serious co-morbidities, complications, or orthopedic polytrauma, increasing the likelihood that they would benefit from "damage control orthopedics" and TEF use. METHODS: A Level I Trauma Center database (2010-2020) review identified the records of 23 patients that met study inclusion and exclusion criteria. Most sustained their injury in a motor vehicle accident (87%) and were not wearing a seatbelt. RESULTS: Patients transferred to the operating room had a greater body mass index and shorter times between admission and surgery. Those transferred to the OR or ICU had higher injury severity scores (ISS), higher arterial blood O2 partial pressure (paO2) values on the first post-surgical day, and had more red blood cell unit (RBCU) transfusions during hospitalization. Patients transferred to the ICU more often underwent TEF and had shorter initial surgical procedure duration. Those with pneumothorax, rib fractures, or with other orthopedic comorbidities were more often transferred to the OR or ICU and those with acute complications requiring exploratory laparotomy were transferred to the OR. CONCLUSIONS: Patients with higher BMI, ISS, greater RBCU transfusion needs, with pneumothorax, rib fractures, or acute complications requiring exploratory laparotomy were more likely to be initially transferred to the OR or ICU. Patients transferred to the orthopedic ward represented a more heterogenous group with greater possibility for benefitting from earlier definitive IMN.
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Fracturas del Fémur , Fijación Intramedular de Fracturas , Neumotórax , Fracturas de las Costillas , Humanos , Estudios Retrospectivos , Fijación Intramedular de Fracturas/efectos adversos , Fijación Intramedular de Fracturas/métodos , Calidad de Vida , Fracturas del Fémur/cirugía , Fracturas del Fémur/complicaciones , Fémur , Resultado del TratamientoRESUMEN
Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1) in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.
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Resistencia a Antineoplásicos , Genoma Humano/genética , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/genética , Apoptosis , Progresión de la Enfermedad , Evolución Molecular , Exoma/genética , Genómica , Humanos , Pérdida de Heterocigocidad , Masculino , Mitocondrias/metabolismo , Mutación , Proteína Homeótica Nanog/deficiencia , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Factor 3 de Transcripción de Unión a Octámeros/deficiencia , Filogenia , Proteínas Proto-Oncogénicas p21(ras)/genética , Teratoma/genética , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patología , Transcriptoma/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Zerovalent Iron Nanoparticles (MC-ZVI NPs) were synthesized from Musa coocinea peel extract as reducing and stabilizing agent using a novel synthesis technique. The synthesis of MC-ZVI NPs was confirmed using UV-vis spectroscopy showing a sharp absorption peak at 341 nm. Further the chemical and structural characterization of MC-ZVI NPs were performed using Fourier Transform Infrared spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and Dynamic Light Scattering technique (DLS). FTIR analysis revealed the presence of phytochemical molecules associated with the MC-ZVI NPs. SEM analysis revealed the synthesized MC-ZVI NPs were in spherical shaped, while DLS analysis confirmed the synthesis of poly dispersed and non-homogenous MC-ZVI NPs. The antimicrobial efficacy of MC-ZVI NPs synthesized using Musa coccinea peel extract was tested against bacterial (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Bacillus subtilis) and fungal (Aspergillus niger) pathogens. But MC-ZVI NPs exhibited maximum of 19 mm zone of inhibition against B. subtilis and A. niger. Further the free radical scavenging activity MC-ZVI NPs was confirmed using DPPH, hydroxyl radical, hydrogen peroxide, FRAP assay showing displayed effective antioxidant activity. Thus, the present idea will give a fast and cost effective approach to synthesize MC-ZVI NPs with antimicrobial property for application in biomedical purposes.
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Antiinfecciosos , Nanopartículas del Metal , Musa , Antibacterianos/química , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Antioxidantes/farmacología , Bacillus subtilis , Hierro/química , Nanopartículas del Metal/química , Pruebas de Sensibilidad Microbiana , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
BACKGROUND: Unplanned readmission to the neurological intensive care unit (ICU) is an underinvestigated topic in patients admitted after spontaneous intracerebral hemorrhage (ICH). The purpose of this study is to investigate the frequency, clinical risk factors, and outcome of bounce back to the neurological ICU in a cohort of patients admitted after ICH. METHODS: This is a retrospective observational study inspecting bounce back to the neurological ICU in patients admitted with spontaneous ICH over an 8-year period. For each patient, demographics, medical history, clinical presentation, length of ICU stay, unplanned readmission to neurological ICU, cause of readmission, and mortality were reviewed. Bounce back to the neurological ICU was defined as an unplanned readmission to the neurological ICU from a general floor service during the same hospitalization. A multivariable analysis was used to define independent variables associated with bounce back to the neurological ICU as well as association between bounce back to the neurological ICU and mortality. The significance level was set at p < 0.05. RESULTS: A total of 221 patients were included. Among those, 20 (9%) had a bounce back to the neurological ICU. Respiratory complications (n = 11) was the most common reason for bounce back to the neurological ICU, followed by neurological (n = 5) and cardiological (n = 4) complications. In a multivariable logistic regression, location of hemorrhage in the basal ganglia (odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.0-8.9, p = 0.03) and dysphagia at the time of transfer (OR: 3.9, 95% CI: 1.0-15.4, p = 0.04) were significantly associated with bounce back to the neurological ICU. After we controlled for ICH score, readmission to the ICU was also independently associated with higher mortality (OR: 14.1, 95% CI: 2.8-71.7, p < 0.01). CONCLUSIONS: Bounce back to the neurological ICU is not an infrequent complication in patients with spontaneous ICH and is associated with higher hospital length of stay and mortality. We identified relevant and potentially modifiable risk factors associated with bounce back to the neurological ICU. Future prospective studies are necessary to develop patient-centered strategies that may improve transition from the neurological ICU to the general floor.