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BACKGROUND: Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1. METHODS: In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. RESULTS: A total of 48 individuals were randomly assigned to vesatolimod (nâ =â 36) or placebo (nâ =â 12). Vesatolimod was generally well tolerated, with no study drug-related serious adverse events or adverse events leading to study drug discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups, compared to placebo.Vesatolimod plasma exposures increased dose proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values. CONCLUSIONS: Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV. CLINICAL TRIALS REGISTRATION: NCT02858401.
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Infecciones por VIH , VIH-1 , Antivirales/uso terapéutico , Método Doble Ciego , Infecciones por VIH/tratamiento farmacológico , Humanos , Pteridinas/uso terapéutico , Receptor Toll-Like 7RESUMEN
BACKGROUND: Our institution has longstanding post-graduate education and training partnership programs in Emergency Medicine (EM) across India. A programmatic challenge has been the integration and uptake of evidence-based medicine and lifelong learning concepts. Formative assessment (FA) is intended to enable learners to monitor learning, identify strengths and weaknesses, and target areas of growth. As part of a program improvement initiative, we introduced an online FA tool to existing summative assessments. This study investigates how the FA tool was used and perceived by trainees. METHODS: 246 trainees across 19 sites were given access to the FA tool. Usage metrics were monitored over 12 months. Semi-structured interviews were conducted in person with trainees using a purposive sampling methodology. A hybrid thematic analysis approach was used to determine themes. Interviews were coded independently by two blinded researchers using NVivo software. The study was deemed exempt by our institutional review board. RESULTS: There was high variability in trainees' utilization of the FA tool. Trainees who used the FA tool more performed better on summative exams (r = 0.35, p < 0.001). Qualitative analysis revealed that trainees were motivated to learn for improved clinical knowledge and to be a good physician, not only passing exams. Benefits of the tool included the relationship to clinical practice and thorough explanation of answers, while disadvantages included topics unrelated to India. CONCLUSION: The integration of a FA tool has provided positive outcomes for trainees in EM education programs in India. Lessons learned may apply globally to other contexts and programs.
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PURPOSE: To describe the results of posterior conjunctival plication for the treatment of secondary eyelid ptosis after eyelid retraction repair in Graves disease. METHODS: Case series. All patients were evaluated preoperatively by routine eye examination and eyelid measurements including Margin Reflex Distance 1 and levator function. Two eyes of 2 patients who presented with ptosis following eyelid retraction repair were corrected with posterior conjunctival plication. RESULTS: Posterior conjunctival plication for secondary ptosis following eyelid retraction repair was successful in 2 eyelids of 2 patients with Graves disease. Follow up period ranged from 6-10 months over which no sign of recurrent ptosis was observed. CONCLUSIONS: Posterior conjunctival plication is an effective surgical technique for the correction of secondary ptosis following eyelid retraction repair in patients with Graves disease.
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Blefaroplastia/métodos , Blefaroptosis/cirugía , Conjuntiva/cirugía , Párpados/cirugía , Enfermedad de Graves/cirugía , Complicaciones Posoperatorias/cirugía , Adulto , Blefaroptosis/etiología , Femenino , Humanos , ReoperaciónRESUMEN
Background and Aims: Medical professionals must be able to perform life-saving skills like cardiopulmonary resuscitation (CPR) during emergency situations, even outside the hospital. The foundation course for the first-year medical students includes first aid and CPR training. This quasi-experimental study was conducted to assess the effectiveness of basic cardiac life support (BCLS) training based on Indian guidelines, on the self-confidence and knowledge regarding CPR of first-year medical students. Methods: This study was conducted during the foundation course for first-year medical students. The training included a common lecture for all the students followed by a 4 day long practical training in groups of 45-46 students, each day. BCLS training was carried out in three skill stations - airway, chest compressions and full sequence CPR. Students' skills were recorded real time on a skill assessment manikin after completion of the hands-on training. The students were asked to fill a questionnaire regarding knowledge and self-confidence, before and after the training. The outcome measures were the difference in knowledge and self-confidence with regard to CPR before and after the training. Results: Out of the 199 students, 181 were included in the analysis. There was significant improvement in the knowledge score (pre-test - 1.46 versus post-test - 8.27, P < 0.001). The overall confidence regarding first aid skills, BCLS knowledge and self-confidence for performing BCLS improved significantly. Conclusion: There is improvement in knowledge and self-confidence regarding CPR and the students develop an acceptable level of skills after the training.
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Finafloxacin is a new fluoroquinolone antibiotic with the unique property of increasing antibacterial activity at pH values lower than neutral. Whereas its antibacterial activity at neutral pH matches that of other quinolones in clinical use, it is expected to surpass this activity in tissues and body fluids acidified by the infection or inflammation processes. Pharmacokinetic parameters of oral single and multiple doses of up to 800 mg of finafloxacin and safety/tolerability observations were assessed in a phase I study including 95 healthy volunteers. Finafloxacin is well absorbed after oral administration, generating maximum concentrations (C(max)s) in plasma at least comparable to those of other fluoroquinolones, with a half-life of around 10 h. About one-third of the dose is excreted unchanged in the urine. Renal elimination appears to be a saturable process leading to slight increases of the area under the concentration-time curve extrapolated to infinity and dose normalized (AUC(∞,norm)) at dosages of 400 mg and above. Safety and tolerability data characterize finafloxacin as a drug with a favorable safety profile. In particular, adverse reactions regarded as class-typical of fluoroquinolones, such as, e.g., electrocardiogram (ECG) changes, neurotoxic effects, or hypoglycemia, were not observed in the study population.
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Fluoroquinolonas/efectos adversos , Fluoroquinolonas/farmacocinética , Administración Oral , Adulto , Método Doble Ciego , Femenino , Fluoroquinolonas/sangre , Fluoroquinolonas/orina , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We present the case of imported malaria in pregnancy to the United Kingdom (UK) from Nigeria, where a 28-year-old primigravida presented to our maternity assessment unit (MAU) with complaints of pyrexia, rigors and passing dark coloured urine. She gave a travel history of recent migration from Nigeria 10 days before presenting to our emergency department. She initially became unwell five days after her arrival with general malaise and myalgia. On day six, she developed lower abdominal pain and observed that her urine was dark in colour. This prompted her to contact her general practitioner (GP). Treatment for a urinary tract infection was initiated by the GP after a phone consultation in keeping with COVID-19 contingency guidance, and the patient was prescribed antibiotics for three days. She presented to the emergency department two days after completing the course of antibiotics where she complained of worsening pelvic pain, reduced foetal movements and passing black urine. She was treated as suspected COVID-19 and red flag sepsis. Obstetric review led to investigation and diagnosis of severe malaria in pregnancy, which was accompanied by blackwater fever (BWF). The patient recovered after three doses of artesunate. An ultrasound scan of the foetus revealed a congenital cardiac anomaly, which had not been detected in an earlier scan. There was no evidence of congenital malaria in the neonate after delivery. There are several novel aspects in this case as maternal mortality in severe Plasmodium falciparum can be significantly high. Those who survive the disease in pregnancy are also known to develop several complications such as intrauterine death and preterm labour. There was also the component of blackwater fever, which is a rare event associated with severe malaria, and it also has a mortality rate. Significant in her medical history was a diagnosis of the sickle cell trait, and we postulate that this feature gave an added protection from the complications of severe malaria in pregnancy as well as blackwater fever.
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The deep learning models for the Single Image Super-Resolution (SISR) task have found success in recent years. However, one of the prime limitations of existing deep learning-based SISR approaches is that they need supervised training. Specifically, the Low-Resolution (LR) images are obtained through known degradation (for instance, bicubic downsampling) from the High-Resolution (HR) images to provide supervised data as an LR-HR pair. Such training results in a domain shift of learnt models when real-world data is provided with multiple degradation factors not present in the training set. To address this challenge, we propose an unsupervised approach for the SISR task using Generative Adversarial Network (GAN), which we refer to hereafter as DUS-GAN. The novel design of the proposed method accomplishes the SR task without degradation estimation of real-world LR data. In addition, a new human perception-based quality assessment loss, i.e., Mean Opinion Score (MOS), has also been introduced to boost the perceptual quality of SR results. The pertinence of the proposed method is validated with numerous experiments on different reference-based (i.e., NTIRE Real-world SR Challenge validation dataset) and no-reference based (i.e., NTIRE Real-world SR Challenge Track-1 and Track-2) testing datasets. The experimental analysis demonstrates committed improvement from the proposed method over the other state-of-the-art unsupervised SR approaches, both in terms of subjective and quantitative evaluations on different reference metrics (i.e., LPIPS, PI-RMSE graph) and no-reference quality measures such as NIQE, BRISQUE and PIQE. We also provide the implementation of the proposed approach (https://github.com/kalpeshjp89/DUSGAN) to support reproducible research.
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CONTEXT: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. OBJECTIVE: To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients. DESIGN: Retrospective study. METHODS: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. RESULTS: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. CONCLUSION: This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.
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Pubertad Tardía/diagnóstico , Pubertad Tardía/genética , Adolescente , Estudios de Cohortes , Biología Computacional , Simulación por Computador , Diagnóstico Diferencial , Exoma/genética , Femenino , Pruebas Genéticas , Variación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hipogonadismo/genética , Masculino , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Secuenciación del ExomaRESUMEN
BACKGROUND: Despite fungal prophylaxis, invasive mold infections (IMIs) are a significant cause of morbidity and mortality in patients with acute myeloid leukemia (AML) receiving remission induction chemotherapy. The choice of antifungal prophylaxis agent remains controversial, especially in the era of novel targeted therapies. We conducted a retrospective case-control study to determine the incidence of fungal infections and to identify risk factors associated with IMI. METHODS: Adult patients with AML receiving anti-Aspergillus prophylaxis were included to determine the incidence of IMI per 1000 prophylaxis-days. Patients without and with IMI were matched 2:1 based on the day of IMI diagnosis, and multivariable models using logistic regression were constructed to identify risk factors for IMI. RESULTS: Of the 162 included patients, 28 patients had a possible (n = 22), probable, or proven (n = 6) diagnosis of IMI. The incidence of proven or probable IMI per 1000 prophylaxis-days was not statistically different between anti-Aspergillus azoles and micafungin (1.6 vs 5.4, P = .11). The duration of prophylaxis with each agent did not predict IMI occurrence on regression analysis. Older age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.004-1.081; P = .03) and relapsed/refractory AML diagnosis (OR, 4.44; 95% CI, 1.56-12.64; P = .003) were associated with IMI on multivariable analysis. CONCLUSIONS: In cases that preclude use of anti-Aspergillus azoles for prophylaxis, micafungin 100 mg once daily may be considered; however, in older patients and those with relapsed/refractory disease, diligent monitoring for IMI is required, irrespective of the agent used for antifungal prophylaxis.
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Chronic pancreatitis (CP), secondary to a wide variety of etiologies, is a progressive and irreversible disease. Initially, CP is managed with endoscopic interventions, long-term analgesia for its associated chronic abdominal pain syndrome and pancreatic enzyme replacement for exocrine dysfunction. As the disease advances, pancreatic drainage procedures and partial resections are considered, but they leave diseased tissue behind and usually result in short-term relief only. Total pancreatectomy alone is widely viewed as a last resort treatment option because it causes brittle diabetes mellitus. However, total pancreatectomy with islet autotransplantation (TPIAT) can prevent the development of diabetes and cure the chronic pain syndrome. One serious, albeit rare, complication of TPIAT is (partial) portal vein thrombosis. Its incidence is probably about 5%. To prevent the occurrence of portal vein thrombosis, we propose herein, and have successfully performed, continuous real-time Doppler ultrasonography during the islet infusion to study portal vein and intrahepatic flow patterns, as well as changes in Doppler signals. Flow and signal changes may allow for timely adjustment of the infusion rate, before a marked increase in portal vein pressure is noted and decrease the risk of portal vein thrombosis.
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Trasplante de Islotes Pancreáticos/métodos , Monitoreo Intraoperatorio/métodos , Pancreatectomía/métodos , Vena Porta/diagnóstico por imagen , Ultrasonografía Doppler/métodos , Drenaje/efectos adversos , Humanos , Pancreatitis Crónica/cirugía , Trasplante Autólogo/métodosRESUMEN
Human papilloma virus (HPV) infection is considered as an important aetiological factor for anal squamous cell carcinoma (ASCC) but is not sufficient for tumour progression. This carcinoma is poorly understood at the molecular level. Using the largest cohort of cases to date we investigated the molecular mechanisms underlying ASCC development, in particular the roles of TP53, MDM2 and AKT. Viral infection in our cohort occurred at high frequency (73%, 94/128) with HPV16 accounting for the majority (86%, 81/94) of infected cases. Only 4% (5/119) of ASCCs showed TP53 (exons 5-8) mutations, but a high frequency (91%, 100/110) of nuclear protein expression of TP53 was observed. There was a significant association (p < 0.001) between nuclear accumulation of TP53 and MDM2 protein although no MDM2 mutations were found, and copy number was normal. Cellular accumulation of phosphorylated-AKT was observed in 66% (82/125) of ASCCs and an association demonstrated between nuclear accumulation of MDM2 and activated AKT (p < 0.001). We observed a high frequency of copy number gain at PIK3CA (47%), and some coding sequence mutations (4%). Amplification of PIK3CA was associated with presence of phosphorylated-AKT (p= 0.008). There was no association between virus infection and TP53 nuclear accumulation (p = 0.5). However, a significant association was found between infection and MDM2 nuclear staining, and between infection and activated AKT (p = 0.04, p = 0.01, respectively). We propose that activation of AKT, possibly through the PI3K-AKT pathway, is an important component of ASCC tumorigenesis that contributes to MDM2 and TP53 accumulation in the nucleus.
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Neoplasias del Ano/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Mutación , Papillomaviridae/aislamiento & purificación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Alphapapillomavirus/aislamiento & purificación , Sustitución de Aminoácidos , Neoplasias del Ano/virología , Carcinoma de Células Escamosas/virología , Fosfatidilinositol 3-Quinasa Clase I , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutagénesis Insercional , Proteínas Nucleares/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Fosfatidilinositol 3-Quinasas/genética , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Estudios Retrospectivos , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/metabolismo , Infecciones Tumorales por Virus/complicaciones , Infecciones Tumorales por Virus/virologíaRESUMEN
AIM: To perform a systematic review and meta-analysis on post-operative complications after surgery for Crohn's disease (CD) comparing biological with no therapy. METHODS: PubMed, Medline and Embase databases were searched to identify studies comparing post-operative outcomes in CD patients receiving biological therapy and those who did not. A meta-analysis with a random-effects model was used to calculate pooled odds ratios (OR) and confidence intervals (CI) for each outcome measure of interest. RESULTS: A total of 14 studies were included for meta-analysis, comprising a total of 5425 patients with CD 1024 (biological treatment, 4401 control group). After biological therapy there was an increased risk of total infectious complications (OR = 1.52; 95%CI: 1.14-2.03, 8 studies) and wound infection (OR = 1.73; 95%CI: 1.12-2.67; P = 0.01, 7 studies). There was no increased risk for other complications including anastomotic leak (OR = 1.19; 95%CI: 0.82-1.71; P = 0.26), abdominal sepsis (OR = 1.22; 95%CI: 0.87-1.72; P = 0.25) and re-operation (OR = 1.12; 95%CI: 0.81-1.54; P = 0.46) in patients receiving biological therapy. CONCLUSION: Pre-operative use of anti-TNF-α therapy may increase risk of post-operative infectious complications after surgery for CD and in particular wound related infections.
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PURPOSE: An association between antecedent viral illness and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) has long been suspected. The authors propose dengue fever as a possible cause of APMPPE, based on three patients who travelled to or lived in endemic areas and had serologic evidence of prior exposure. METHODS: Review of case records of two patients. RESULTS: The index patient presented with APMPPE after her second confirmed dengue infection. A second patient with positive serology for dengue was subsequently identified, who had acute onset of posterior uveitis with APMPPE-like features. Dengue antibody titers were positive in both patients. CONCLUSIONS: APMPPE may be another manifestation of dengue fever. Ophthalmologists should take travel histories and consider ordering dengue serology in appropriate patients with APMPPE even if fever is absent, and especially in patients with the possibility of attenuated systemic disease and a primarily immunologic reaction to subsequent exposure.
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Coroiditis/etiología , Dengue/complicaciones , Epitelio Pigmentado Ocular/patología , Enfermedad Aguda , Coroiditis/diagnóstico , Coroiditis/patología , Femenino , Humanos , Enfermedad Relacionada con los ViajesRESUMEN
Tunneled central venous catheters (TCVCs) are used for dialysis access in 82% of new hemodialysis patients and are rapidly colonized with Gram-positive organism (e.g. Staphylococcus aureus) biofilm, a source of recurrent infections and chronic inflammation. Lipoteichoic acid (LTA), a cell wall ribitol polymer from Gram-positive organisms, mediates inflammation through the Toll-like receptor 2 (TLR2). The effect of LTA on lung endothelial permeability is not known. We tested the hypothesis that LTA from Staphylococcus aureus induces alterations in the permeability of pulmonary microvessel endothelial monolayers (PMEM) that result from activation of TLR2 and are mediated by reactive oxygen/nitrogen species (RONS). The permeability of PMEM was assessed by the clearance rate of Evans blue-labeled albumin, the activation of the TLR2 pathway was assessed by Western blot, and the generation of RONS was measured by the fluorescence of oxidized dihydroethidium and a dichlorofluorescein derivative. Treatment with LTA or the TLR2 agonist Pam((3))CSK((4)) induced significant increases in albumin permeability, IκBα phosphorylation, IRAK1 degradation, RONS generation, and endothelial nitric oxide synthase (eNOS) activation (as measured by the p-eNOS(ser1177):p-eNOS(thr495) ratio). The effects on permeability and RONS were effectively prevented by co-administration of the superoxide scavenger Tiron, the peroxynitrite scavenger Urate, or the eNOS inhibitor L-NAME and these effects as well as eNOS activation were reduced or prevented by pretreatment with an IRAK1/4 inhibitor. The results indicate that the activation of TLR2 and the generation of ROS/RNS mediates LTA-induced barrier dysfunction in PMEM.
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Catéteres Venosos Centrales/microbiología , Células Endoteliales/metabolismo , Lipopolisacáridos/toxicidad , Pulmón/citología , Permeabilidad/efectos de los fármacos , Diálisis Renal/efectos adversos , Staphylococcus aureus/metabolismo , Ácidos Teicoicos/toxicidad , Sal Disódica del Ácido 1,2-Dihidroxibenceno-3,5-Disulfónico , Western Blotting , Azul de Evans , Fluorescencia , Humanos , Immunoblotting , Pulmón/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor Toll-Like 2/metabolismoRESUMEN
Ankylosing spondylitis (AS) patients are most challenging. These patient present the most serious array of intubation and difficult airway imaginable, secondary to decrease or no cervical spine mobility, fixed flexion deformity of thoracolumbar spine and possible temporomandibular joint disease. Sound clinical judgment is critical for timing and selecting the method for airway intervention. The retrograde intubation technique is an important option when fiberoptic bronchoscope is not available, and other method is not applicable for gaining airway access for surgery in prone position. We report a case of AS with fixed flexion deformity of thoracic and thoracolumbar spine, fusion of posterior elements of cervical spine posted for lumbar spinal osteotomy with anticipated difficult intubation. An awake retrograde oral intubation with light sedation and local block is performed.
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PURPOSE: A comprehensive literature review was performed to examine the prevalence of anal cancer, anal intraepithelial neoplasia (AIN) and anal human papillomavirus (HPV) infection in renal transplant recipients who are at risk of anal cancer due to iatrogenic immunosuppression. METHODS: Pertinent articles were identified from searches performed on the National Center for Biotechnology Information database using the following keywords: anal cancer, AIN, screening, renal transplant (or kidney transplant), organ transplant recipients and post-transplant malignancies. RESULTS: The prevalence of AIN is 20% in renal transplant patients. The prevalence of anal HPV infection in established transplant patients is 47%, and the prevalence of anal HPV infection in new transplant patients is 23%. The relative risk for anal cancer in renal transplant patients is 10. CONCLUSIONS: As compared to HIV-positive male patients who practise anal intercourse, renal transplant patients showed a modest rise in relative risk for anal cancer. Screening programmes to detect AIN in HIV-positive patients who practise anal intercourse have been introduced on a preliminary basis in sexual health clinics in the US and may become standard practise in this population. The case for screening in renal transplant patients is unclear and would merit further investigation, especially with reference to the prevalence of anal HPV infection in this population. It may transpire that renal transplant patients would benefit more from HPV prophylaxis rather than screening for AIN.
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Neoplasias del Ano/etiología , Carcinoma in Situ/etiología , Rechazo de Injerto/prevención & control , Terapia de Inmunosupresión/efectos adversos , Inmunosupresores/efectos adversos , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Enfermedades del Ano/epidemiología , Enfermedades del Ano/virología , Neoplasias del Ano/epidemiología , Carcinoma in Situ/epidemiología , Rechazo de Injerto/complicaciones , Humanos , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/etiología , Prevalencia , Factores de RiesgoRESUMEN
A high-throughput and sensitive bioanalytical method using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) has been developed for the estimation of sibutramine and its two metabolites (M1 and M2). The extraction of sibutramine, its metabolites and imipramine (internal standard (IS)) from the plasma involved treatment with phosphoric acid followed by solid-phase extraction (SPE) using a hydrophilic-lipophilic balanced HLB cartridge. The SPE eluate without drying and reconstitution was analyzed by LC/MS/MS, equipped with a with turbo ion spray (TIS) source, operating in the positive and multiple reaction monitoring (MRM) acquisition mode. Sample preparation by this method yielded extremely clean extracts with quantitative and consistent mean recoveries; 95.12% for sibutramine, 92.74% for M1, 95.97% for M2 and 96.60% for the IS. The total chromatographic run time was 3.0 min with retention times of 2.51, 2.13, 2.09 min for sibutramine, M1, M2 and imipramine, respectively. The developed method was validated in human plasma matrix, with a sensitivity of 0.1 ng/mL (coefficient of variance (CV), 2.07%) for sibutramine, 0.1 ng/mL (CV, 3.59%) for M1 and 0.2 ng/mL (CV, 4.93%) for M2. Validation of the method for its accuracy, precision, recovery, matrix effect and stability was carried out especially with regard to real subject sample analysis. The response was linear over the dynamic range 0.1 to 8.0 ng/mL for sibutramine and M1, and 0.2 to 16.0 ng/mL for M2 with correlation coefficients of r > or = 0.9959 (sibutramine), 0.9935 (M1) and 0.9943 (M2). The method was successfully applied for bioequivalence studies in 40 human subjects with 15 mg capsule formulations.
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Aminas/sangre , Aminas/farmacocinética , Análisis Químico de la Sangre/métodos , Cromatografía Liquida/métodos , Ciclobutanos/sangre , Ciclobutanos/farmacocinética , Espectrometría de Masa por Ionización de Electrospray/métodos , Humanos , Equivalencia TerapéuticaRESUMEN
A rapid and sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for the determination of isosorbide-5-mononitrate (5-ISMN), used in the treatment of angina pectoris, in human plasma is described. The quantification of 5-ISMN was performed via stable acetate adduct formation with a high relative abundance. The plasma filtrate obtained after solid-phase extraction (SPE), using a polymer based, hydrophilic-lipophilic balanced (HLB) cartridge, was submitted directly to reversed-phase high-performance liquid chromatography separation followed by ESI and detection of the resulting ions using triple-quadrupole mass spectrometry in selected reaction monitoring (SRM) mode. There was no significant matrix effect on the analysis. For validation of the method, the recovery of the free analyte response was compared to that obtained from an optimized extraction method. The analyte stability was examined under conditions mimicking the sample storage, handling, and analytical procedures. The extraction procedure yielded extremely clean extracts with a recovery of 95.51% and 93.98% for iossorbide-5-mononitrate and topiramate (internal standard (IS)), respectively. The calibration curves were linear for the dynamic range of 10.0 to 1000.0 ng/mL with a correlation coefficient r > or = 0.9985. The intra-assay and inter-assay precision for the samples at the lower limit of quantification (LLOQ) were 9.02 and 13.30%, respectively. The intra-assay accuracies at LLOQ, LQC, MQC and HQC levels varied from 98.13 to 118.15, 102.34 to 105.21, 100.69 to 109.68, and 95.76 to 102.92%, respectively, while the inter-assay accuracies ranged from 93.10 to 118.15, 93.03 to 107.04, 86.97 to 109.68 and 86.18 to 105.85%, respectively, at these levels. The method is rugged and fast with a total run time of 2 min. The method was successfully applied for a bioequivalence study in 24 human subject samples after oral administration of 60 mg extended release (ER) formulations.