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We propose and implement a novel scheme for dissipatively pumping two qubits into a singlet Bell state. The method relies on a process of collective optical pumping to an excited level, to which all states apart from the singlet are coupled. We apply the method to deterministically entangle two trapped ^{40}Ca^{+} ions. Within 16 pumping cycles, an initially separable state is transformed into one with 83(1)% singlet fidelity, and states with initial fidelity of âª70% converge onto a fidelity of 93(1)%. We theoretically analyze the performance and error susceptibility of the scheme and find it to be insensitive to a large class of experimentally relevant noise sources.
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Prolonged inorganic arsenic (iAs) exposure is widely associated with brain damage particularly in the hippocampus via oxidative and apoptotic pathways. Resveratrol (RES) has gained considerable attention because of its benefits to human health. However, its neuroprotective potential against iAs-induced toxicity in CA1 region of hippocampus remains unexplored. Therefore, we investigated the neuroprotective efficacy of RES against arsenic trioxide (As2O3)-induced adverse effects on neuronal morphology, apoptotic markers and oxidative stress parameters in mouse CA1 region (hippocampus). Adult female Swiss albino mice of reproductive maturity were orally exposed to either As2O3 (2 and 4 mg/kg bw) alone or in combination with RES (40 mg/kg bw) for a period of 45 days. After animal sacrifice on day 46, the perfusion fixed brain samples were used for the observation of neuronal morphology and studying the morphometric features. While the freshly dissected hippocampi were processed for biochemical estimation of oxidative stress markers and western blotting of apoptosis-associated proteins. Chronic iAs exposure led to significant decrease in Stratum Pyramidale layer thickness along with reduction in cell density and area of Pyramidal neurons in contrast to the controls. Biochemical analysis showed reduced hippocampal GSH content but no change in total nitrite (NO) levels following iAs exposure. Western blotting showed apparent changes in the expression levels of Bax and Bcl-2 proteins following iAs exposure, however the change was statistically insignificant. Contrastingly, iAs +RES co-treatment exhibited substantial reversal in morphological and biochemical observations. Together, these findings provide preliminary evidence of neuroprotective role of RES on structural and biochemical alterations pertaining to mouse hippocampus following chronic iAs exposure.
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Trióxido de Arsénico/toxicidad , Lesiones Encefálicas , Hipocampo , Células Piramidales , Resveratrol/farmacología , Animales , Arsénico/toxicidad , Lesiones Encefálicas/inducido químicamente , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Lesiones Encefálicas/prevención & control , Femenino , Hipocampo/lesiones , Hipocampo/metabolismo , Hipocampo/patología , Ratones , Células Piramidales/metabolismo , Células Piramidales/patologíaRESUMEN
Endometrial cancer is a common gynaecological cancer, is typically early stage and treated with surgery. For patients where surgery is difficult or dangerous, definitive radiation therapy is the next best option. This study included a single institution case series (step 1) and a systematic review of the literature (step 2). In step 1, all endometrial cancer cases that were treated with definitive image-guided brachytherapy at a single institution from 2008 to 2020 were retrospectively analysed. In step 2, a systematic review of Medline (PubMed) from 1975 to 2020 was carried out using the key words around endometrial cancer and brachytherapy, followed by a narrative synthesis. In total, in step 1, 31 cases were included in this study, stages I-IV, with 96.7% receiving external beam radiation. All patients received three fractions of 7.5 Gy or five fractions of 6 Gy high dose rate brachytherapy, with a median EQD2 of 75.55 (40-84.3). The 2-year Kaplan-Meier (KM) local control was 83.1% and the 2-year KM overall survival was 77.4%. There was no late toxicity ≥grade 3. In step 2, 19 articles were included in the final analysis, with between six and 280 patients. The local control ranged from 70 to 100%, with low toxicity. Definitive radiation therapy with image-guided brachytherapy seems to have good local control with low toxicity for patients who are poor surgical candidates.
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Braquiterapia , Neoplasias Endometriales , Braquiterapia/efectos adversos , Neoplasias Endometriales/radioterapia , Femenino , Humanos , Estudios RetrospectivosRESUMEN
As the demographic characteristics of the US population have changed over the past decade, the characteristics of different homeless populations have changed as well. This study tracked changes in demographic characteristics of homeless adult, veteran, and healthcare service user populations against general adult and veteran populations from 2007-2017. The results showed that changing demographics of homeless populations largely reflected broader trends in the general population, and attention is needed on the clinical needs of aging homeless populations. There may be some unique changes in the demography of some homeless populations, such as younger homeless veterans seeking healthcare services.
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Personas con Mala Vivienda , Veteranos , Adulto , Demografía , Servicios de Salud , Humanos , Estados UnidosRESUMEN
BACKGROUND: Randomised trials comparing the efficacy of standard endocrine therapy (ET) versus experimental ET + bevacizumab (Bev) in 1st line hormone receptor-positive patients with metastatic breast cancer have thus far shown conflicting results. PATIENTS AND METHODS: We pooled data from two similar phase III randomised trials of ET ± Bev (LEA and Cancer and Leukemia Group B 40503) to increase precision in estimating treatment effect. Primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Exploratory analyses were performed within subgroups defined by patients with recurrent disease, de novo disease, prior endocrine sensitivity or resistance and reported grades III-IV hypertension and proteinuria. RESULTS: The pooled sample consisted of 749 patients randomised to ET or ET + Bev. Median PFS was 14.3 months for ET versus 19 months for ET + Bev (unadjusted hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.66-0.91; p < 0.01). ORR and CBR with ET and ET + Bev were 40 versus 61% (p < 0.01) and 64 versus 77% (p < 0.01), respectively. There was no difference in OS (HR 0.96; 95% CI 0.77-1.18; p = 0.68). PFS was superior for ET + Bev for endocrine-sensitive patients (HR 0.68; 95% CI 0.53-0.89; p = 0.004). Grade III-IV hypertension (2.2 versus 20.1%), proteinuria (0 versus 9.3%), cardiovascular (0.5 versus 4.2%) and liver events (0 versus 2.9%) were significantly higher for ET + Bev (all p < 0.01). Hypertension and proteinuria were not predictors of efficacy (interaction test p = 0.33). CONCLUSION: The addition of Bev to ET increased PFS overall and in endocrine-sensitive patients but not OS at the expense of significant additional toxicity. TRIALS REGISTRATION: ClinicalTrial.Gov NCT00545077 and NCT00601900.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Estudios de Evaluación como Asunto , Femenino , Estudios de Seguimiento , Fulvestrant/administración & dosificación , Humanos , Letrozol/administración & dosificación , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/secundario , Tasa de Supervivencia , Tamoxifeno/administración & dosificaciónRESUMEN
BACKGROUND: PBSC collection using apheresis is the preferred source of hematopoietic stem cells transplantation. However, apheresis procedures fail to harvest adequate CD34 yield in 5 to 40% of patients during the first collection. Therefore, this study aimed to study both the clinical- and equipmentrelated factors influencing CD34 yield among the autologous patients and to compare the collection efficiency of two apheresis equipments(Haemonetics MCS+ and Terumo Spectra Optia). METHODS: Retrospective analysis of 69 patients underwent PBSC collection from 2015 to 2018. Frequency, clinical- and equipment-related factors responsible for adequate CD34+ cells (≥2 x106 cells/kg) yield during the first collection was studied. Factors such as collection efficiency, percentage platelet loss and percentage hemoglobin loss were considered to compare the two apheresis system. RESULTS: Two-third (72%) patients of the study population had adequate CD34 stem cells yield during the first collection. Factors such as exposure to lenalidomide-based pretreatment regimen, peripheral blood WBC count and CD34 count are associated with the adequate CD34 yield. Optia had a slightly better collection efficiency than MCS+ (50 and 44; p=0.37). Optia had lower product volume (237 vs 298 ml) and lesser procedure duration (277 vs 360 min), whereas the median Hb loss (3.0% and 2.3%) and mean platelet loss (49% and 34%) were higher with MCS. CONCLUSION: This study infers that the collection efficiency of both the equipments in collecting CD34 stem cells was similar. However, during PBSC collection, procedures using Optia can be preferred to MCS+ on the patients with risk of anemia and thrombocytopenia.
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Eliminación de Componentes Sanguíneos/instrumentación , Instituciones Oncológicas , Neoplasias/terapia , Trasplante de Células Madre de Sangre Periférica , Células Madre de Sangre Periférica , Centros de Atención Terciaria , Adulto , Autoinjertos , Femenino , Humanos , India , Masculino , Persona de Mediana Edad , Estudios RetrospectivosAsunto(s)
Anemia/tratamiento farmacológico , Darbepoetina alfa/uso terapéutico , Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Anemia/complicaciones , Darbepoetina alfa/farmacología , Eritropoyetina/farmacología , Hematínicos/farmacología , Hemoglobinas , Humanos , Fallo Renal Crónico , Proteínas Recombinantes , Diálisis Renal , Insuficiencia Renal Crónica/complicacionesRESUMEN
The stable operation of quantum computers will rely on error correction, in which single quantum bits of information are stored redundantly in the Hilbert space of a larger system. Such encoded qubits are commonly based on arrays of many physical qubits, but can also be realized using a single higher-dimensional quantum system, such as a harmonic oscillator1-3. In such a system, a powerful encoding has been devised based on periodically spaced superpositions of position eigenstates4-6. Various proposals have been made for realizing approximations to such states, but these have thus far remained out of reach7-11. Here we demonstrate such an encoded qubit using a superposition of displaced squeezed states of the harmonic motion of a single trapped 40Ca+ ion, controlling and measuring the mechanical oscillator through coupling to an ancillary internal-state qubit12. We prepare and reconstruct logical states with an average squared fidelity of 87.3 ± 0.7 per cent. Also, we demonstrate a universal logical single-qubit gate set, which we analyse using process tomography. For Pauli gates we reach process fidelities of about 97 per cent, whereas for continuous rotations we use gate teleportation and achieve fidelities of approximately 89 per cent. This control method opens a route for exploring continuous variable error correction as well as hybrid quantum information schemes using both discrete and continuous variables13. The code states also have direct applications in quantum sensing, allowing simultaneous measurement of small displacements in both position and momentum14,15.
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Quantum error correction is essential for realizing the full potential of large-scale quantum information processing devices1,2. Fundamental to its experimental realization is the repetitive detection of errors via projective measurements of quantum correlations among qubits, as well as corrections using conditional feedback3. Repetitive application of such tasks requires that they neither induce unwanted crosstalk nor impede further control operations, which is challenging owing to the need to dissipatively couple qubits to the classical world for detection and reinitialization. For trapped ions, state readout involves scattering large numbers of resonant photons, which increases the probability of stray light causing errors on nearby qubits and leads to undesirable recoil heating of the ion motion. Here we demonstrate up to 50 sequential measurements of correlations between two beryllium ion microwave qubits using an ancillary optical qubit in a calcium ion, and implement feedback that allows us to stabilize two-qubit subspaces as well as Bell states, a class of maximally entangled states. Multi-qubit mixed-species gates are used to transfer information within the register from the qubit to the ancilla, enabling readout with negligible crosstalk to the data qubits. Heating of the ion motion during detection is mitigated by recooling all three ions using light that interacts with only the calcium ion, known as sympathetic cooling. A key element of our experimental setup is a powerful classical control system that features flexible in-sequence processing for feedback control. The methods employed here provide essential tools for scaling trapped-ion quantum computing, quantum-state control and entanglement-enhanced quantum metrology4.
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PURPOSE OF REVIEW: Zoonotic influenza viruses are those that cross the animal-human barrier and can cause disease in humans, manifesting from minor respiratory illnesses to multiorgan dysfunction. They have also been implicated in the causation of deadly pandemics in recent history. The increasing incidence of infections caused by these viruses worldwide has necessitated focused attention to improve both diagnostic as well as treatment modalities. In this first part of a two-part review, we describe the structure of zoonotic influenza viruses, the relationship between mutation and pandemic capacity, pathogenesis of infection, and also discuss history and epidemiology. RECENT FINDINGS: We are currently witnessing the fifth and the largest wave of the avian influenza A(H7N9) epidemic. Also in circulation are a number of other zoonotic influenza viruses, including avian influenza A(H5N1) and A(H5N6); avian influenza A(H7N2); and swine influenza A(H1N1)v, A(H1N2)v, and A(H3N2)v viruses. Most recently, the first human case of avian influenza A(H7N4) infection has been documented. By understanding the virology and epidemiology of emerging zoonotic influenzas, we are better prepared to face a new pandemic. However, continued effort is warranted to build on this knowledge in order to efficiently combat the constant threat posed by the zoonotic influenza viruses.
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PURPOSE OF REVIEW: Zoonotic influenza viruses are those influenza viruses that cross the animal-human barrier and can cause disease in humans, manifesting from minor respiratory illnesses to multiorgan dysfunction. The increasing incidence of infections caused by these viruses worldwide has necessitated focused attention to improve both diagnostic as well as treatment modalities. In this second part of a two-part review, we discuss the clinical features, diagnostic modalities, and treatment of zoonotic influenza, and provide an overview of prevention strategies. RECENT FINDINGS: Illnesses caused by novel reassortant avian influenza viruses continue to be detected and described; most recently, a human case of avian influenza A(H7N4) has been described from China. We continue to witness increasing rates of A(H7N9) infections, with the latest (fifth) wave, from late 2016 to 2017, being the largest to date. The case fatality rate for A(H7N9) and A(H5N1) infections among humans is much higher than that of seasonal influenza infections. Since the emergence of the A(H1N1) 2009 pandemic, and subsequently A(H7N9), testing and surveillance for novel influenzas have become more effective. Various newer treatment options, including peramivir, favipiravir (T-705), and DAS181, and human or murine monoclonal antibodies have been evaluated in vitro and in animal models. Armed with robust diagnostic modalities, antiviral medications, vaccines, and advanced surveillance systems, we are today better prepared to face a new influenza pandemic and to limit the burden of zoonotic influenza than ever before. Sustained efforts and robust research are necessary to efficiently deal with the highly mutagenic zoonotic influenza viruses.
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The epidemiological pattern of acute kidney injury (AKI) in tropical countries during monsoon reflects infectious disease as the most important cause. AKI is a confounding factor and may be overlooked by primary health-care providers and underreported in health statistics. The present study prospectively helps estimate the burden of disease and analyze etiology, clinical profile, and outcome in a tertiary care hospital of a metropolitan city in a tropical country. The study period included monsoon season of 2012 and 2013, a total of 8 months. AKI staging was done as per the AKI Network (AKIN) criteria. Patients were treated for primary disease. Renal replacement therapy (RRT) was given as required. Patients were followed up during hospitalization till recovery/death. Out of a total of 9930 admissions during this period, 1740 (17.52%) were for infections and 230 (2.31%) had AKI secondary to infectious diseases during monsoon. The incidence of AKI (230/1740) in infectious diseases during monsoon was 13.21%. The study population (n = 230) comprised 79.5% of males and the mean age was 40.95 ± 16.55 years. Severe AKI: AKIN Stage III was seen in 48.26% of patients and AKIN Stage I in 41.74%. The most common etiology of AKI was malaria (28.3%) followed by acute gastroenteritis (23%), dengue (16.5%), leptospirosis (13%), undifferentiated fever (10.4%), more than one etiology (5.4%), and enteric fever (3.5%). RRT was required in 44.78% of patients. Requirement for RRT was maximum in patients with more than one etiology followed by leptospirosis, malaria, dengue, and least in typhoid. The overall mortality was 12.17%. In multivariate analysis, vasopressor support and assisted ventilation were risk factors for mortality.
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Introduction Proximal cervical internal carotid artery stenosis greater than 50% merits revascularization to mitigate the risk of stroke recurrence among large-vessel anterior circulation strokes undergoing mechanical thrombectomy. Carotid artery stenting necessitates the use of antiplatelets, and there is a theoretical increased risk of hemorrhagic transformation given that such patients may already have received intravenous thrombolytics and have a significant infarct burden. We investigate the outcomes of large-vessel anterior circulation stroke patients treated with intravenous thrombolytics receiving same-day carotid stenting or selective angioplasty compared to no carotid intervention. Materials and methods The study cohort was obtained from the National (Nationwide) Inpatient Sample database between 2006 and 2014, using International Statistical Classification of Diseases, ninth revision discharge diagnosis and procedure codes. A total of 11,825 patients with large-vessel anterior circulation stroke treated with intravenous thrombolytic and mechanical thrombectomy on the same day were identified. The study population was subdivided into three subgroups: no carotid intervention, same-day carotid angioplasty without carotid stenting, and same-day carotid stenting. Outcomes were assessed with respect to mortality, significant disability at discharge, hemorrhagic transformation, and requirement of percutaneous endoscopic gastronomy tube placement, prolonged mechanical ventilation, or craniotomy. Results This study found no statistically significant difference in patient outcomes in those treated with concurrent carotid stenting compared to no carotid intervention in terms of morbidity or mortality. Conclusions If indicated, it is reasonable to consider concurrent carotid stenting and/or angioplasty for large-vessel anterior circulation stroke patients treated with mechanical thrombectomy who also receive intravenous thrombolytics.
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Angioplastia/métodos , Estenosis Carotídea/terapia , Fibrinolíticos/uso terapéutico , Stents , Accidente Cerebrovascular/terapia , Trombectomía/métodos , Anciano , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
PURPOSE: Hormone receptor (HR)-positive breast cancer (BC) shows a poor response to neoadjuvant chemotherapy (NACT). New treatment targets like the Cyclin D1-CDK4/CDK6 complex are promising adjuvant/post-neoadjuvant therapeutic strategies. Evaluating Cyclin D1 overexpression in residual tumor could recognize those patients that benefit most from such post-neoadjuvant treatment. In this study, we determined Cyclin D1 expression in residual BC after NACT. Secondary aims were to correlate Cyclin D1 expression levels with clinicopathological parameters and to assess its prognostic value after NACT. METHODS: We retrospectively assessed the nuclear expression of Cyclin D1 on tissue microarrays with residual tumor from 284 patients treated in the neoadjuvant GeparTrio (n = 186) and GeparQuattro (n = 98) trials. Evaluation was performed with a standardized immunoreactive score (IRS) after selecting a cut-off value. RESULTS: A high expression level (IRS ≥ 6) of Cyclin D1 was found in 37.3% of the assessed specimens. An increased Cyclin D1 expression was observed in HR-positive tumors, compared to HR-negative tumors (p = 0.02). Low Cyclin D1 levels correlated with clinical tumor stage 1-3 (p = 0.03). Among patients with HR-positive/Her2-negative tumors and high Cyclin D1 expression, a better disease-free survival (DFS) was graphically suggested, but not significant (p = 0.21). CONCLUSION: Our study demonstrates a measurable nuclear expression of Cyclin D1 in post-neoadjuvant residual tumor tissue of HR-positive BC. Cyclin D1 expression was not prognostic for DFS after NACT. Our results and defined cut-off suggest that the marker can be used to stratify tumors according to protein expression levels. Based on this, a prospective evaluation is currently performed in the ongoing Penelope-B trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/terapia , Mama/patología , Ciclina D1/metabolismo , Adulto , Biomarcadores de Tumor/análisis , Mama/citología , Mama/cirugía , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Núcleo Celular/metabolismo , Ciclina D1/análisis , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Mastectomía , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Neoplasia Residual , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Análisis de Matrices Tisulares/métodosRESUMEN
The aim of this study was to determine the potential role of leukocyte telomere length as a biomarker for development of childhood obesity in a low-income Latino population. A birth cohort of Latino children (N = 201) in San Francisco (recruited May 2006-May 2007) was followed until age 9 and assessed annually for obesity and dietary intake. Leukocyte telomere length was measured at 4 and 5 years (n = 102) and assessed as a predictor for obesity at age 9, adjusting for known risk factors. Furthermore, leukocyte telomere length at age 4 and 5 was evaluated as a possible mediator of the relationship between excessive sugar-sweetened beverage consumption and obesity at age 9. Shorter leukocyte telomere length in preschoolers was associated with obesity at age 9 (adjusted odds ratio 0.35, 95% confidence interval 0.13-0.94) after adjustment for known risk factors. Telomere length mediated 11% of the relationship between excessive sugar-sweetened beverage consumption and obesity. Shorter leukocyte telomere length may be an indicator of future obesity risk in high-risk populations as it is particularly sensitive to damage from oxidative stress exposure, including those from sugar-sweetened beverages.
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Leucocitos/metabolismo , Obesidad Infantil/metabolismo , Telómero/metabolismo , Bebidas/efectos adversos , Bebidas/análisis , Niño , Estudios de Cohortes , Ingestión de Energía , Femenino , Estudios de Seguimiento , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Masculino , Obesidad Infantil/etnología , Obesidad Infantil/fisiopatología , Factores de Riesgo , San Francisco/etnología , Azúcares/análisis , Azúcares/metabolismoRESUMEN
Hypertension has been rarely reported in patients with the nutcracker phenomenon (NCP)/syndrome. We describe a case of a young adolescent female patient where a computed tomography angiography (CTA) provided evidence of left renal vein dilatation, probably due to its compression through the angle between the aorta and the superior mesenteric artery, during the evaluation of secondary hypertension. Blood levels of renin and aldosterone were within normal limits. Ultrasonography of the kidney showed minimal scarring on the left side. As there were no other signs of secondary hypertension, we proceeded with a CTA, which revealed findings compatible with the so-called NCP/syndrome.
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BACKGROUND: Tranexamic acid (TXA) has been used orally, intravenously, topically and intradermally (microinjection, microneedling) for treating melasma. However, the comparative efficacy of these different routes of administration remains underevaluated. AIM: To ascertain the comparative efficacy of different routes of administration of TXA. METHODS: In total, 100 consecutive patients with melasma (8 men, 92 women, age range 18-55 years) were randomly assigned to one of two groups comprising 50 patients each. Group A (3 men, 47 women) received oral TXA 250 mg twice daily, while group B (5 men, 45 women) received intradermal microinjections of TXA 4 mg/mL every 4 weeks. The treatment continued for 12 weeks in both groups. Percentage reduction in baseline Melasma Area and Severity Index (MASI) was assessed at 4-week intervals, and response was scored as very good (> 75% reduction), good (50% to < 75% reduction), moderate (25% to < 50% reduction), mild (< 25% reduction) or no response. RESULTS: The study was completed by 39 patients in group A and 41 patients in group B. Very good response was seen in 25 and 32 patients in groups A and B, respectively, while good response was seen in 14 and 9 patients, respectively. Both treatment methods were equally effective, with an average reduction of MASI at 12 weeks of 77.96 ± 9.39 in group A and 79.00 ± 9.64 in group B. The main adverse effects were mild epigastric discomfort, hypomenorrhea, headache and injection site pain, which did not warrant discontinuation of treatment. Two patients in group A had relapses at 24 weeks. CONCLUSION: TXA appears to be an effective and safe treatment for melasma, irrespective of its route of administration.
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Melanosis/tratamiento farmacológico , Ácido Tranexámico/administración & dosificación , Administración Oral , Adolescente , Adulto , Femenino , Humanos , Inyecciones Intradérmicas/efectos adversos , Masculino , Microinyecciones , Persona de Mediana Edad , Ácido Tranexámico/efectos adversos , Adulto JovenRESUMEN
Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose-ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition. Human simulations were performed using clinical pharmacokinetic data, literature values, and in vitro parameters for drug distribution and binding. Biological and mathematical uncertainties were included in simulations to generate expectations for dose response. The results demonstrated a minimal increase in efficacy for doses higher than 2 mg/kg. The findings of the translational model were successfully applied to select 2 mg/kg as the lowest dose for dose-ranging evaluations.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Modelos Biológicos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Investigación Biomédica Traslacional/métodos , Carga Tumoral/efectos de los fármacos , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales Humanizados/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/metabolismo , RatasRESUMEN
BACKGROUND: Hepatitis C is the major cause of end-stage liver disease and the major indication for orthotopic liver transplantation (OLTx) in individuals with haemophilia. AIM: To assess the epidemiology and outcomes of OLTx in U.S. haemophilia patients. METHODS: We investigated haemophilia liver transplant recipients between 1993 and 2012, using the Nationwide Inpatient Sample, identified by ICD9 code 50.59. RESULTS: Of the 11 267 (weighted n = 54 691) patients undergoing OLTx, 44 (0.4%; weighted n = 213) had haemophilia. Those with haemophilia were more likely than non-haemophilic OLTx recipients to have bleeding complications (45.3% vs. 31.5%, P = 0.009) and hypovolemic shock (7.0% vs. 1.1%, P < 0.0001). They also had a significantly higher incidence of HIV (24.8% vs. 0.5%, P < 0.005), hepatitis B (16.2% vs. 7.9%, P = 0.04) and vitamin K deficiency (2.1% vs. 0.02%, P < 0.001). In spite of these differences, there was no difference in in-hospital mortality between haemophilic and non-haemophilic recipients (6.8% vs. 6.2%, P = 0.9). In multivariate logistic regression, bleeding complications in haemophilia increased the risk of in-hospital mortality by more than 3-fold (P < 0.0001), and disseminated intravascular coagulation increased the risk of bleeding complications in haemophilic recipients by over 10-fold (P < 0.0001). CONCLUSIONS: Bleeding complications are common in haemophilia OLTx recipients. Thus, aggressive correction of coagulation defects in this group may be a medically sound approach to reduce complications and mortality associated with OLTx.
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Hemofilia A/complicaciones , Hemorragia/etiología , Hepatitis C/complicaciones , Femenino , Hemorragia/mortalidad , Humanos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Thyroid hormone effects on many organs including central and peripheral nervous systems. However, these hormones do not affect all systems/organs to a similar extent. Thus, we conducted this study to explore the effect of thyroid hormones on somatic nervous system assessed by Nerve conduction study and cardiac autonomic activity assessed by heart rate variability. METHODS: The study included newly diagnosed hypothyroid patients and healthy controls. In all subjects NCS were performed in median, ulnar, tibial and sural nerves using Nihonkohden machine Cardiac autonomic control was assessed using Short-term Heart Rate Variability and parameters were analyzed by Time Domain and Frequency Domain methods. RESULTS: Both the groups were comparable in term of age, Body Mass Index, Pulse Rate, Systolic Blood Pressure and Diastolic Blood Pressure. Sensory parameters of NCS showed significant decrease in left median nerve SNAP amplitude (38.24±10.23 Vs 31.59±14.06, P=0.048) and nerve conduction velocity of bilateral median nerve in hypothyroid patients. In motor parameters of NCS, onset latencies of bilateral median nerves and right ulnar nerve were significantly increased in hypothyroid patients. All Time Domain measures of HRV and Frequency Domain measures; LF Power, HF Power and Total Power were significantly decreased (P<0.05) in hypothyroid patients. These HRV parameters are indicators of parasympathetic activity. CONCLUSIONS: In newly diagnosed hypothyroid patients, especially median nerve functions (both sensory and motor) and parasympathetic activity were decreased. It reflects that in hypothyroidism both autonomic nervous system and other somatic nerves are not affected in a similar extent.