RESUMEN
A commonly encountered challenge with freeze-dried drug products is glass vial fogging. Fogging is characterized by a thin layer of product deposited upon the inner surface of the vial above the lyophilized cake. While considered to be a routine cosmetic defect in many instances, fogging around the shoulder and neck of the vial may potentially impact container closure integrity and reject rates during inspection. In this work, the influence of processing conditions i.e. vial pre-treatment, lyophilization cycle modifications and filling conditions on fogging was evaluated. A battery of analytical techniques was employed to investigate factors affecting glass vial fogging. A fogging score was used to quantify its severity in freeze-dried products. Additionally, a dye-based method was used to study solution upcreep (Marangoni flow) following product filling. Our lab-scale results indicate measurable improvement in fogging following the addition of an annealing step in the lyophilization cycle. Pre-freeze isothermal holding of the vials (at 5°C on the lyophilizer shelf) for an extended duration indicated a reduction in fogging whereas an increase in the freezing time exhibited no effect on fogging. Vial pre-treatment conditions were critical determinants of fogging for Type 1 vials whereas they had no impact on fogging in TopLyo® vials. The headspace relative humidity (RH) investigation also indicated sufficient increase in the water vapor pressure inside the vial to be conducive to the formulation of a hydration film - the precursor to Marangoni flow.
Asunto(s)
Embalaje de Medicamentos , Liofilización , Liofilización/métodos , Embalaje de Medicamentos/métodos , Vidrio/química , Preparaciones Farmacéuticas/química , Química Farmacéutica/métodosRESUMEN
Antimicrobial agents are essential in reducing illness and mortality brought on by infectious diseases in both humans and animals. However, the therapeutic effect of antibiotics has diminished due to an increase in antimicrobial drug resistance (AMR). This article provides a retrospective analysis of AMR in Shigella infections in India, showing a rise in resistance that has contributed to a global burden. Shigella spp. are widespread and the second-leading cause of diarrheal death in people of all ages. The frequency and mortality rates of Shigella infections are decreased by antibiotic treatment. However, the growth of broad-spectrum antibiotic resistance is making it more difficult to treat many illnesses. Reduced cell permeability, efflux pumps, and the presence of enzymes that break down antibiotics are the causes of resistance. AMR is a multifaceted and cross-sectoral problem that affects humans, animals, food, and the environment. As a result, there is a growing need for new therapeutic approaches, and ongoing surveillance of Shigella spp. infections which should definitely be improved for disease prevention and management. This review emphasizes on the epidemiological data of India, and antimicrobial resistance in Shigella spp.
Asunto(s)
Antibacterianos , Farmacorresistencia Bacteriana , Disentería Bacilar , Shigella , Humanos , India/epidemiología , Shigella/efectos de los fármacos , Disentería Bacilar/tratamiento farmacológico , Disentería Bacilar/epidemiología , Disentería Bacilar/microbiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana/efectos de los fármacos , AnimalesRESUMEN
Our retrospective cohort study assesses the survival probability and identifies the demographic and clinical predictors of mortality in HIV patients taking antiretroviral therapy using an antiretroviral therapy centre data in Western India. Secondary data on 7532 registered HIV-infected individuals between September 2006 and January 2013 were analysed. The probability of survival at 75 months was 84.9%. Significant indicators of poor chances of survival were greater age, lower occupation class, lower CD4 count, poor functional status; higher stage of disease, lower weight, the presence and type of opportunistic infections, co-trimoxazole therapy and poor adherence to antiretroviral therapy. We thus find that, in addition to pre-ART, antiretroviral therapy clinical status and treatment adherence, socioeconomic status plays an important influence on ultimate survival of HIV patients on antiretroviral therapy.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Adulto , Recuento de Linfocito CD4 , Demografía , Infecciones por VIH/mortalidad , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Factores Socioeconómicos , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Obese patients undergoing colorectal surgery are at increased risk for adverse outcomes. It remains unclear whether these risks can be further defined with more discriminatory stratifications of obesity. OBJECTIVE: The purpose of this study was to understand the association between BMI and 30-day postoperative outcomes, including surgical site infection, among patients undergoing colorectal surgery. DESIGN: This was a retrospective cohort study. SETTINGS: The 2011-2013 American College of Surgeons National Surgical Quality Improvement Program database was used. PATIENTS: Patients included those undergoing elective colorectal surgery in 2011-2013 who were assessed by the American College of Surgeons National Surgical Quality Improvement Program. MAIN OUTCOME MEASURES: BMI was categorized into World Health Organization categories. Primary outcome was 30-day postoperative surgical site infection. Secondary outcomes included all American College of Surgeons National Surgical Quality Improvement Program-assessed 30-day postoperative complications. RESULTS: Our cohort included 74,891 patients with 4.4% underweight (BMI <18.5), 29.0% normal weight (BMI 18.5-24.9), 33.0% overweight (BMI 25.0-29.9), 19.8% obesity class I (BMI 30.0-34.9), 8.4% obesity class II (BMI 35.0-39.9), and 5.5% obesity class III (BMI ≥40.0). Compared with normal-weight patients, obese patients experienced incremental odds of surgical site infection from class I to class III (I: OR = 1.5 (95% CI, 1.4-1.6); II: OR = 1.9 (95% CI, 1.7-2.0); III: OR = 2.1 (95% CI, 1.9-2.3)). Obesity class III patients were most likely to experience wound disruption, sepsis, respiratory or renal complication, and urinary tract infection. Mortality was highest among underweight patients (OR = 1.3 (95% CI, 1.0-1.8)) and lowest among overweight (OR = 0.8 (95% CI, 0.6-0.9)) and obesity class I patients (OR = 0.8 (95% CI, 0.6-1.0)). LIMITATIONS: Retrospective analysis of American College of Surgeons National Surgical Quality Improvement Program hospitals may not represent patients outside of the American College of Surgeons National Surgical Quality Improvement Program and cannot assign causation or account for interventions to improve surgical outcomes. CONCLUSIONS: Patients with increasing BMI showed an incremental and independent risk for adverse 30-day postoperative outcomes, especially surgical site infections. Strategies to address obesity preoperatively should be considered to improve surgical outcomes among this population. See Video Abstract at http://links.lww.com/DCR/A607.
Asunto(s)
Colectomía/efectos adversos , Enfermedades del Colon , Cirugía Colorrectal/estadística & datos numéricos , Obesidad , Infección de la Herida Quirúrgica , Infecciones Urinarias , Índice de Masa Corporal , Colectomía/métodos , Enfermedades del Colon/complicaciones , Enfermedades del Colon/cirugía , Bases de Datos Factuales , Procedimientos Quirúrgicos Electivos/efectos adversos , Procedimientos Quirúrgicos Electivos/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/diagnóstico , Mejoramiento de la Calidad , Medición de Riesgo , Factores de Riesgo , Infección de la Herida Quirúrgica/diagnóstico , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/etiología , Estados Unidos/epidemiología , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/epidemiología , Infecciones Urinarias/etiologíaRESUMEN
BACKGROUND AND AIM: APRI (aspartate aminotransferase [AST] to platelet ratio index) is widely used to assess fibrosis and cirrhosis risk, especially in hepatitis C virus (HCV)-infected patients. Few studies have evaluated APRI and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) risk. Prospective evidence is needed to assess whether APRI predicts HCC risk in HBV patients. METHOD: In a prospectively enrolled clinical cohort of 855 HBV patients with a 1-year exclusion window (followed for > 1 year and did not develop HCC within 1 year), the predictive value of APRI in HCC risk was evaluated by Cox proportional hazards model using univariate and multivariate analyses and longitudinal analysis. RESULTS: Higher APRI prospectively conferred a significantly increased risk of HCC in univariate analysis (quartile analysis, P trend = 2.9 × 10(-7) ). This effect remained highly significant after adjusting for common host characteristics but not cirrhosis (P trend = 7.1 × 10(-5) ), and attenuated when cirrhosis is adjusted (P trend = 0.021). The effect remained prominent when the analysis was restricted to patients with a more stringent 2-year exclusion window (P trend = 0.008 in quartile analysis adjusting all characteristics including cirrhosis), indicating that the association was unlikely due to including undetected HCC patients in the cohort, thus minimizing the reverse-causation limitation in most retrospective studies. Longitudinal comparison demonstrated a persistently higher APRI value in HBV patients who developed HCC during follow-up than those remaining cancer free. CONCLUSION: APRI might be a marker of HCC risk in HBV patients in cirrhosis-dependent and -independent manners. Further studies are warranted to validate this finding and test its clinical applicability in HCC prevention.
Asunto(s)
Aspartato Aminotransferasas/sangre , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiología , Recuento de Plaquetas , Adulto , Anciano , Biomarcadores/sangre , Carcinoma Hepatocelular/prevención & control , Estudios de Cohortes , Femenino , Humanos , Neoplasias Hepáticas/prevención & control , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Riesgo , Adulto JovenRESUMEN
Establishment of the corpus callosum involves coordination between callosal projection neurons and multiple midline structures, including the glial wedge (GW) rostrally and hippocampal commissure caudally. GW defects have been associated with agenesis of the corpus callosum (ACC). Here we show that conditional Lhx2 inactivation in cortical radial glia using Emx1-Cre or Nestin-Cre drivers results in ACC. The ACC phenotype was characterized by aberrant ventrally projecting callosal axons rather than Probst bundles, and was 100% penetrant on 2 different mouse strain backgrounds. Lhx2 inactivation in postmitotic cortical neurons using Nex-Cre mice did not result in ACC, suggesting that the mutant phenotype was not autonomous to the callosal projection neurons. Instead, ACC was associated with an absent hippocampal commissure and a markedly reduced to absent GW. Expression studies demonstrated strong Lhx2 expression in the normal GW and in its radial glial progenitors, with absence of Lhx2 resulting in normal Emx1 and Sox2 expression, but premature exit from the cell cycle based on EdU-Ki67 double labeling. These studies define essential roles for Lhx2 in GW, hippocampal commissure, and corpus callosum formation, and suggest that defects in radial GW progenitors can give rise to ACC.
Asunto(s)
Agenesia del Cuerpo Calloso/genética , Agenesia del Cuerpo Calloso/patología , Proteínas con Homeodominio LIM/genética , Mutación/genética , Neuroglía/patología , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/patología , Factores de Transcripción/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neocórtex/patología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Nestina/genética , ARN no Traducido/genética , ARN no Traducido/metabolismo , Proteínas Represoras/metabolismo , Proteínas de Dominio T Box , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Colorectal cancer (CRC) has an apparent hereditary component, as evidenced by the well-characterized genetic syndromes and family history associated with the increased risk of this disease. However, in a large fraction of CRC cases, no known genetic syndrome or family history can be identified, suggesting the presence of "missing heritability" in CRC etiology. The genome-wide association study (GWAS) platform has led to the identification of multiple replicable common genetic variants associated with CRC risk. These newly discovered genetic variations might account for a portion of the missing heritability. Here, we summarize the recent GWASs related to newly identified genetic variants associated with CRC risk and clinical outcome. The findings from these studies suggest that there is a lack of understanding of the mechanism of many single nucleotide polymorphisms (SNPs) that are associated with CRC. In addition, the utility of SNPs as prognostic markers of CRC in clinical settings remains to be further assessed. Finally, the currently validated SNPs explain only a small fraction of total heritability in complex-trait diseases like CRC. Thus, the "missing heritability" still needs to be explored further. Future epidemiological and functional investigations of these variants will add to our understanding of CRC pathogenesis, and may ultimately lead to individualized strategies for prevention and treatment of CRC.