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BACKGROUND: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. OBJECTIVE: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. RESULTS: The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. CONCLUSION: The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.
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Suplementos Dietéticos , Deficiencia de Vitamina D , Vitamina D , Humanos , Vitamina D/sangre , Vitamina D/uso terapéutico , Vitamina D/administración & dosificación , Vitamina D/análogos & derivados , Femenino , Deficiencia de Vitamina D/prevención & control , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/diagnóstico , Embarazo , Niño , Sociedades Médicas/normas , Adolescente , Adulto , Endocrinología/normas , Endocrinología/métodos , Endocrinología/organización & administración , Masculino , Vitaminas/uso terapéutico , Vitaminas/administración & dosificaciónRESUMEN
Distinguishing between alcohol-associated hepatitis (AH) and alcohol-associated cirrhosis (AC) remains a diagnostic challenge. In this study, we used machine learning with transcriptomics and proteomics data from liver tissue and peripheral mononuclear blood cells (PBMCs) to classify patients with alcohol-associated liver disease. The conditions in the study were AH, AC, and healthy controls. We processed 98 PBMC RNAseq samples, 55 PBMC proteomic samples, 48 liver RNAseq samples, and 53 liver proteomic samples. First, we built separate classification and feature selection pipelines for transcriptomics and proteomics data. The liver tissue models were validated in independent liver tissue datasets. Next, we built integrated gene and protein expression models that allowed us to identify combined gene-protein biomarker panels. For liver tissue, we attained 90% nested-cross validation accuracy in our dataset and 82% accuracy in the independent validation dataset using transcriptomic data. We attained 100% nested-cross validation accuracy in our dataset and 61% accuracy in the independent validation dataset using proteomic data. For PBMCs, we attained 83% and 89% accuracy with transcriptomic and proteomic data, respectively. The integration of the two data types resulted in improved classification accuracy for PBMCs, but not liver tissue. We also identified the following gene-protein matches within the gene-protein biomarker panels: CLEC4M-CLC4M, GSTA1-GSTA2 for liver tissue and SELENBP1-SBP1 for PBMCs. In this study, machine learning models had high classification accuracy for both transcriptomics and proteomics data, across liver tissue and PBMCs. The integration of transcriptomics and proteomics into a multi-omics model yielded improvement in classification accuracy for the PBMC data. The set of integrated gene-protein biomarkers for PBMCs show promise toward developing a liquid biopsy for alcohol-associated liver disease.
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Aims: Residual cardiovascular risk persists despite statin therapy. In REDUCE-IT, icosapent ethyl (IPE) reduced total events, but the mechanisms of benefit are not fully understood. EVAPORATE evaluated the effects of IPE on plaque characteristics by coronary computed tomography angiography (CCTA). Given the conclusion that the IPE-treated patients demonstrate that plaque burden decreases has already been published in the primary study analysis, we aimed to demonstrate whether the use of an analytic technique defined and validated in histological terms could extend the primary study in terms of whether such changes could be reliably seen in less time on drug, at the individual (rather than only at the cohort) level, or both, as neither of these were established by the primary study result. Methods and Results: EVAPORATE randomized the patients to IPE 4â g/day or placebo. Plaque morphology, including lipid-rich necrotic core (LRNC), fibrous cap thickness, and intraplaque hemorrhage (IPH), was assessed using the ElucidVivo® (Elucid Bioimaging Inc.) on CCTA. The changes in plaque morphology between the treatment groups were analyzed. A neural network to predict treatment assignment was used to infer patient representation that encodes significant morphological changes. Fifty-five patients completed the 18-month visit in EVAPORATE with interpretable images at each of the three time points. The decrease of LRNC between the patients on IPE vs. placebo at 9 months (reduction of 2â mm3 vs. an increase of 41â mm3, p = 0.008), widening at 18 months (6â mm3 vs. 58â mm3 increase, p = 0.015) were observed. While not statistically significant on a univariable basis, reductions in wall thickness and increases in cap thickness motivated multivariable modeling on an individual patient basis. The per-patient response assessment was possible using a multivariable model of lipid-rich phenotype at the 9-month follow-up, p < 0.01 (sustained at 18 months), generalizing well to a validation cohort. Conclusion: Plaques in the IPE-treated patients acquired more characteristics of stability. Reliable assessment using histologically validated analysis of individual response is possible at 9 months, with sustained stabilization at 18 months, providing a quantitative basis to elucidate drug mechanism and assess individual patient response.
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Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.
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Alcohol-associated hepatitis (AH) is a form of liver failure with high short-term mortality. Recent studies have shown that defective function of hepatocyte nuclear factor 4 alpha (HNF4a) and systemic inflammation are major disease drivers of AH. Plasma biomarkers of hepatocyte function could be useful for diagnostic and prognostic purposes. Herein, an integrative analysis of hepatic RNA sequencing and liquid chromatography-tandem mass spectrometry was performed to identify plasma protein signatures for patients with mild and severe AH. Alcohol-related liver disease cirrhosis, nonalcoholic fatty liver disease, and healthy subjects were used as comparator groups. Levels of identified proteins primarily involved in hepatocellular function were decreased in patients with AH, which included hepatokines, clotting factors, complement cascade components, and hepatocyte growth activators. A protein signature of AH disease severity was identified, including thrombin, hepatocyte growth factor α, clusterin, human serum factor H-related protein, and kallistatin, which exhibited large abundance shifts between severe and nonsevere AH. The combination of thrombin and hepatocyte growth factor α discriminated between severe and nonsevere AH with high sensitivity and specificity. These findings were correlated with the liver expression of genes encoding secreted proteins in a similar cohort, finding a highly consistent plasma protein signature reflecting HNF4A and HNF1A functions. This unbiased proteomic-transcriptome analysis identified plasma protein signatures and pathways associated with disease severity, reflecting HNF4A/1A activity useful for diagnostic assessment in AH.
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Carcinoma Hepatocelular , Hepatitis Alcohólica , Neoplasias Hepáticas , Humanos , Transcriptoma , Factor de Crecimiento de Hepatocito/genética , Proteómica , Trombina/metabolismo , Hepatitis Alcohólica/diagnóstico , Proteínas/genética , BiomarcadoresRESUMEN
Background & Aims: Liver disease carries significant healthcare burden and frequently requires a combination of blood tests, imaging, and invasive liver biopsy to diagnose. Distinguishing between inflammatory liver diseases, which may have similar clinical presentations, is particularly challenging. In this study, we implemented a machine learning pipeline for the identification of diagnostic gene expression biomarkers across several alcohol-associated and non-alcohol-associated liver diseases, using either liver tissue or blood-based samples. Methods: We collected peripheral blood mononuclear cells (PBMCs) and liver tissue samples from participants with alcohol-associated hepatitis (AH), alcohol-associated cirrhosis (AC), non-alcohol-associated fatty liver disease, chronic HCV infection, and healthy controls. We performed RNA sequencing (RNA-seq) on 137 PBMC samples and 67 liver tissue samples. Using gene expression data, we implemented a machine learning feature selection and classification pipeline to identify diagnostic biomarkers which distinguish between the liver disease groups. The liver tissue results were validated using a public independent RNA-seq dataset. The biomarkers were computationally validated for biological relevance using pathway analysis tools. Results: Utilizing liver tissue RNA-seq data, we distinguished between AH, AC, and healthy conditions with overall accuracies of 90% in our dataset, and 82% in the independent dataset, with 33 genes. Distinguishing 4 liver conditions and healthy controls yielded 91% overall accuracy in our liver tissue dataset with 39 genes, and 75% overall accuracy in our PBMC dataset with 75 genes. Conclusions: Our machine learning pipeline was effective at identifying a small set of diagnostic gene biomarkers and classifying several liver diseases using RNA-seq data from liver tissue and PBMCs. The methodologies implemented and genes identified in this study may facilitate future efforts toward a liquid biopsy diagnostic for liver diseases. Lay summary: Distinguishing between inflammatory liver diseases without multiple tests can be challenging due to their clinically similar characteristics. To lay the groundwork for the development of a non-invasive blood-based diagnostic across a range of liver diseases, we compared samples from participants with alcohol-associated hepatitis, alcohol-associated cirrhosis, chronic hepatitis C infection, and non-alcohol-associated fatty liver disease. We used a machine learning computational approach to demonstrate that gene expression data generated from either liver tissue or blood samples can be used to discover a small set of gene biomarkers for effective diagnosis of these liver diseases.
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PURPOSE: To test the benefits of Solumedrol treatment in sepsis patients with a blunted adrenocorticotropic hormone (ACTH)-cortisol response (delta <13â µg/dL) with regard to the number of days on ventilator, days on intravenous blood pressure support, length of time in an intensive care unit (ICU), 14-day mortality, and 28-day mortality. The trial was prospective, randomized, and double-blind. As part of a larger sepsis trial, 54 patients with sepsis had an intravenous ACTH stimulation test using 250â µg of ACTH, and serum cortisol was measured at times 0, 30, and 60â min. Eleven patients failed to increase their cortisol concentration above 19.9â µg/dL and were excluded from the clinical trial as they were considered to have adrenal insufficiency. The remaining 43 patients had a baseline cortisol of 32 ± 1â µg/dL increased to 38 ± 3â µg/dL at 30â min and 40 ± 3 at 60â min. All cortisol responses were <12.9â µg/dL between time 0 and time 60, which is defined as a blunted cortisol response to intravenous ACTH administration. Twenty-one were randomized to receive 20â mg of intravenous Solumedrol and 22 were randomized to receive a matching placebo every 8â h for 7-days. There was no significant difference between the two randomized groups. Data analysis was carried out bya two-tailed test and P < .05 as significant. RESULTS: The mean age was 51 ± 2 (mean ± SEM) with 61% female. Groups were well matched with regard to APACHE III score in Solumedrol versus placebo (59 ± 6 vs 59 ± 6), white blood cell count (18.8 ± 2.2 vs 18.6 ± 2.6), and incidence of bacteremia (29 vs 39%). The 28-day mortality rate was reduced in the Solumedrol treated arm (43 ± 11 vs 73 ± 10%; P < .05). There was no change in days in ICU, days on blood pressure agents, or days on ventilator. Seven days of high-dose intravenous Solumedrol treatment (20â mg every 8â h) in patients with a blunted cortisol response to ACTH was associated with an improved 28-day survival. This small study suggests that an inability to increase endogenous cortisol production in patients with sepsis who are then provided steroid treatment could improve survival.
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Hidrocortisona , Sepsis , Hormona Adrenocorticotrópica , Femenino , Humanos , Hidrocortisona/uso terapéutico , Masculino , Hemisuccinato de Metilprednisolona , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
INTRODUCTION: Coronary artery disease (CAD) is leading cause of morbidity and mortality among type 2 diabetics (T2DM). METHODS: 140 T2DM will be enrolled in randomized, double blind, placebo controlled Semaglutide Treatment On Coronary Plaque Progression (STOP) trial to determine effect of weekly subcutaneous semaglutide on coronary plaque progression. All participants will undergo Coronary Artery Calcium (CAC) Scoring and Coronary Computed Tomography Angiography (CCTA) at our center. A Fisher test, ANOVA and Kruskal Wallis were used. RESULTS: As of May 2020, 87 patients (81%) randomized (mean age 56.4 ± 8.4â¯yrs. and 62% male) with documented CAD by CCTA. Approximately 20% of screened study population were screen failed due to normal coronaries (n= 14) or HbA1C<7 (n=7). Of interest, 14 persons with diabetes with normal coronaries (no calcification) were significantly more likely to be females (21% vs 62%), have higher glomerular filtration rate (106.5 ± 19.4 vs 89.9 ± 22.6â¯mL/min/1.73m2; p= 0.006), and younger (53.4 ± 9.0 vs 56.4 ± 8.4â¯yrs.; p=0.02) than those who were randomized. CONCLUSION: Among T2DM, there is a significant portion who have normal coronary arteries and may have a better prognosis. Excluding these participants from cardiovascular studies may improve power and decrease sample size.
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Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Péptidos Similares al Glucagón/uso terapéutico , Placa Aterosclerótica , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/epidemiología , Valor Predictivo de las Pruebas , PrevalenciaRESUMEN
AIMS: Though statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular (CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4 g/day will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography than placebo in statin-treated patients. METHODS AND RESULTS: EVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography (CCTA) (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40-115 mg/dL, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9, and 18 months. Here, we present the protocol-specified interim efficacy results. A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9 months (age = 57 ± 6 years, male = 36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs. 94%, P = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque) (35% vs. 43%, P = 0.010), total plaque (non-calcified + calcified plaque) (15% vs. 26%, P = 0.0004), fibrous plaque (17% vs. 40%, P = 0.011), and calcified plaque (-1% vs. 9%, P = 0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use. CONCLUSION: EVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high triglyceride levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial. CLINICALTRIALS. GOVIDENTIFIER: NCT029226027.
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Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Reguladores del Metabolismo de Lípidos/uso terapéutico , Placa Aterosclerótica , Triglicéridos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Progresión de la Enfermedad , Método Doble Ciego , Quimioterapia Combinada , Dislipidemias/sangre , Dislipidemias/diagnóstico , Ácido Eicosapentaenoico/efectos adversos , Ácido Eicosapentaenoico/uso terapéutico , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Reguladores del Metabolismo de Lípidos/efectos adversos , Masculino , Persona de Mediana Edad , Tomografía Computarizada Multidetector , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients. METHODS AND RESULTS: A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was change in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053). CONCLUSIONS: Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.
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Enfermedad de la Arteria Coronaria , Ácido Eicosapentaenoico/análogos & derivados , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Anciano , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Ácido Eicosapentaenoico/uso terapéutico , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , TriglicéridosRESUMEN
PURPOSE: To test the benefits of Vitamin A treatment in patients with sepsis on length of time in ICU, days on ventilator, days on intravenous blood pressure support and 28-day mortality. The trial was prospective, randomized and double-blind. As part of a larger sepsis trial, 63 patients with sepsis were randomized to receive either 100,000 IU of Vitamin A intramuscular or placebo over 7-days. Data analysis was by ANOVA with two tailed test and p < 0.05 as significant. RESULTS: The mean age was 51 ± 2 (mean ± SEM) with 54% female. Groups were well matched with regards to APACHE III score, WBC count, and incidence of bacteremia. In addition, all patients had an ACTH stimulation test using 250 mcg of ACTH IV and serum cortisol was measured at time 0, 30 and 60 min. Baseline cortisol of 24.6 ± 1 mg/dl increased to 41 ± 2 mg/dl at 30 min and 49 ± 2 at 60 min. There was no significant difference between the groups. All cortisol responses were greater than 11.9 mg/dl. Serum Vitamin A level was below normal in 54% of the patients. After randomization, 100,000 IU of Vitamin A daily was given to 32 patients and blinded placebo was given daily to 32 patients for seven days. This was administered as a 1 cc injection of either medication or placebo and was blinded from all but the research pharmacist. The number of days in the ICU was slightly, but not significantly reduced (p = 0.39) by approximately 2 days in the Vitamin A treated patients. The average number of days on blood pressure agents and the day on ventilator were similar. The 28-day mortality rates were similar between the two groups (28 vs 34% placebo vs Vitamin A group). Seven days of high dose intramuscular Vitamin A treatment in patients with sepsis where approximately 50% were vitamin A deficient had no benefit in adults with sepsis.
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Sepsis/tratamiento farmacológico , Vitamina A/administración & dosificación , Vitamina A/uso terapéutico , APACHE , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Hidrocortisona/sangre , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Mortalidad , Estudios Prospectivos , Sepsis/mortalidadRESUMEN
INTRODUCTION: Cost of generic medications has risen more in the past few years than any other time in history. While medical insurance covers much of these costs, health care professionals can better provide medications that have the longest duration of action when compared to placebo-treated controls. This will save health care costs and improve prescribing accuracy. METHODS: Papers in PubMed were identified with keywords placebo. The study must be at least 2 years in length to evaluate the change in A1c over time. The primary endpoint was time to A1c neutrality (return of A1c to baseline at a maximum dose of single oral agent). A medication would be considered at neutrality if the 95% CI crossed baseline. Time to neutrality was averaged for each medication within the class and each summarized for class effect. RESULTS: Effective therapy for the DPP-4 and sulfonylurea classes of medications are 3-4 years as compared to a 5-year time to A1c neutrality for metformin usage. In comparison, the projected time to A1c neutrality was approximately 6-8 years for rosiglitazone and pioglitazone. While only a few studies have been published in the SGLT-2 class of medication, the time to A1c neutrality was also 6-8 years with Canagliflozin and full dosage of Empagliflozin. CONCLUSION: Metformin appears to have a 5-year duration of effect before the A1c returns to baseline. The sulfonylureas and DPP-4 inhibitors class of medications have one of the shortest durability which ranges between 3.3 to 4.4 years. In contrast, the SGLT-2 class of medication and the TZD class of medications has a projected time to A1c neutrality from 6-8 years. Diabetic duration of therapy as compared to placebo should be listed with those medications tested so the provider can choose wisely.
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Prandial insulin has been essential for the improved management of the type 1 diabetic patient. Interestingly, many studies have evaluated the addition of prandial insulin to the type 2 diabetic patients with improved control. The greatest drop in A1c with the use of various type of prandial insulins have resulted in the decrease of 1.3% in the A1c measurement. Interestingly, none of the published trials with goal of fasting blood glucose (FBG) have ever obtained the goal A1c. Since a drop in FBG of 28.7mg/dl is equal to a 1% drop in A1c, a simple approach to obtain a target A1c would be to focus on the FBG (per ADA: Average Blood Glucose = A1c (%) x 28.7 - 46.7mg/d). However, average blood glucose requires multiple measurements and may be less accurate then using just a FBG. Since prandial insulin clinical trials have only demonstrated a drop in A1c by 0.3-1.3% the use of only a FBG to help patients get to goal may be easier to teach and to obtain. It might save time and money. Our hypothesis is that if patient obtain a FBG <100 mg/dl for 2-3 months then 70% will be at an A1c goal <7.0%. After a few months of good fasting glucose control the provider can use this equation (FBG+80)/30 to estimate A1c. For example, a FBG of 130mg/dl would be (130 + 80)/30 = 7.0%; or a FBG of 190 would be (190+80)/30 =eA1c 9% (estimate of A1c). While type 1 diabetes has a very complex daily glucose pattern, the approach to type 2 diabetics on insulin could become simplified.
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Well-established risk factors for aspergillosis include HIV, cancer, recent corticosteroid (prednisone) therapy, chemotherapy, or thoracic surgery. Non-established risk factors may include weight loss and a history of diabetes. Twenty-three patients without the classical risk factors for IA were identified retrospectively at Harbor UCLA Medical Center by discharge diagnosis over a 20 year period (1992-2012). None of the well-known risk factors are for Invasive Apergillious (IA). A history of weight loss was seen in 66% of the patients with IA (15 of 23). The weight loss ranged from 3.3 lbs to 43 lbs. In patients with weight loss the average loss was 22±3 lbs (mean±SEM). In this small group of patients with IA, diabetes was seen in 8 of the 23 (34%), which is significantly higher than the 19% incidence of diabetes seen in 100 patients with severe sepsis (p<0.05). Likewise, the 34% incidence of diabetes was higher than the 21% incidence reported in immunocompromised patients with invasive aspergillus (IA) infection (p<0.05). A reduced serum albumin concentration was seen in 33% of the study patients, which was less common than the 87% incidence seen in patients with severe sepsis or candidaemia (54%). Seventeen of the 23 patients had pulmonary involvement. While no one had a well-established risk factor for aspergillious, four patients had alcoholism as a potential risk factor. Eleven of the 23 (48%) died during the hospital stay despite antifungal therapy. Immunocompromised patients are known to have a mortality rate of approximately 45% for pulmonary or disseminated disease. CONCLUSION: The incidence of diabetes was greater than seen in immunocompromised patients and may be considered an additional risk factor for the development of aspergillois infection. In addition, a history of weight loss should increase the suspicion for the diagnosis of IA in otherwise a non-immunocompromised patient. Early recognition and treatment of aspergillosis in the non-immunocompromised patient may improve outcome. Weight loss and diabetes should be added to the list of well-known risk factors for invasive aspergillosis and its high mortality rate.
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Therapeutic voriconazole concentrations have a narrow window of effectiveness before causing cholestatic hepatitis. After undergoing 1 year of voriconazole therapy for pulmonary aspergillosis, a 44-year-old man began treatment with 30 mg lansoprazole for gastroesophageal reflux symptoms. Within 5 days of starting treatment with lansoprazole, the patient presented with fatigue, jaundice, and cholestatic hepatitis. The hepatitis promptly resolved after stopping lansoprazole treatment. Sixteen months later, the patient was given simvastatin therapy, as recommended by the American Diabetes Association to prevent cardiovascular disease for patients with diabetes who are aged >40 years and have one additional risk factor. Within 2 weeks of taking simvastatin, a 3-hydroxy-3-methylglutaryl CoA reductase (statin) therapy, the patient redeveloped fatigue, jaundice, and cholestatic hepatitis. He described both episodes of fatigue and jaundice similarly in terms of onset and intensity. Voriconazole is metabolized by both CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is an inhibitor of the CYP2C19 isoenzyme. Competition between voriconazole and lansoprazole likely led to increased voriconazole serum concentration and acute cholestatic hepatitis in this patient. Simvastatin inhibits the CYP3A4 isoenzyme. After the patient took 10 mg simvastatin daily for 2 weeks, cholestatic hepatitis occurred. The voriconazole concentration remained elevated (4.1 µg/ml) when measured 15 days after stopping simvastatin. The patient's Naranjo Adverse Drug Reaction Probability Scale score of 7 revealed that the cholestatic hepatitis was probably precipitated by lansoprazole. Likewise, the patient's Naranjo score of 9 also revealed that cholestatic hepatitis was attributable to a definite adverse drug reaction precipitated by the addition of simvastatin to the stable baseline regimen of voriconazole. In a single patient, two different inhibitors of the cytochrome P450 pathway stimulated voriconazole-induced cholestatic hepatitis. Although the major cytochrome P450 pathways for the metabolism and clearance of lansoprazole and simvastatin are different, they both likely contributed to the reduced hepatic clearance of voriconazole in this patient.
Asunto(s)
Antifúngicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Dislipidemias/tratamiento farmacológico , Reflujo Gastroesofágico/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Lansoprazol/efectos adversos , Inhibidores de la Bomba de Protones/efectos adversos , Aspergilosis Pulmonar/tratamiento farmacológico , Simvastatina/efectos adversos , Voriconazol/efectos adversos , Adulto , Antifúngicos/farmacocinética , Biotransformación , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Citocromo P-450 CYP2C19/metabolismo , Inhibidores del Citocromo P-450 CYP2C19/efectos adversos , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/efectos adversos , Interacciones Farmacológicas , Dislipidemias/diagnóstico , Reflujo Gastroesofágico/diagnóstico , Humanos , Ictericia Obstructiva/inducido químicamente , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Polifarmacia , Aspergilosis Pulmonar/diagnóstico , Aspergilosis Pulmonar/microbiología , Voriconazol/farmacocinéticaRESUMEN
BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.
Asunto(s)
Calcinosis/genética , ADN/genética , Factores de Crecimiento de Fibroblastos/genética , Hiperostosis Cortical Congénita/genética , Hiperfosfatemia/genética , Mutación , Fosfatos/sangre , Calcificación Vascular/genética , Adulto , Alelos , Calcinosis/sangre , Calcinosis/complicaciones , Análisis Mutacional de ADN , Ensayo de Inmunoadsorción Enzimática , Exoma , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Genotipo , Humanos , Hiperostosis Cortical Congénita/sangre , Hiperostosis Cortical Congénita/complicaciones , Hiperfosfatemia/sangre , Hiperfosfatemia/complicaciones , Inmunohistoquímica , Masculino , Calcificación Vascular/sangre , Calcificación Vascular/etiologíaRESUMEN
BACKGROUND: Currently, American Diabetes Association guidelines suggest statin use among persons with diabetes mellitus aged >40 years. The presence of calcified plaque in coronary arteries is a sensitive surrogate of coronary artery disease and has been shown to be an independent predictor of mortality and cardiac events. OBJECTIVE: We aimed to assess the prevalence and severity of calcified plaque in coronary arteries in patients aged <40 years with and without diabetes. METHODS: We included 3723 asymptomatic patients aged <40 years who had undergone coronary calcium scanning. Clinical and demographic data were collected. Agatston score was categorized into Agatston score 0 as normal, 1 to 99 as low, 100 to 399 as intermediate, and ≥400 as severe; and statistical analysis was performed. RESULTS: The study population consisted of 4% persons with diabetes (n = 142) and 56% men with a mean age of 35 ± 5 years. Young persons with diabetes had greater prevalence of Agatston score > 0 than persons without diabetes (43% vs 24%; P < .0001). In addition, 12% of persons with diabetes vs 2.5% of persons without diabetes had an Agatston score ≥ 100 (P < .0001). The prevalence of calcified plaque in coronary arteries was >50% in persons with diabetes aged >35 years. After taking into account risk factors, the presence of diabetes was associated with a 4-fold higher odds of an Agatston score ≥ 100 (odds ratio, 4.19; 95% CI, 2.29-7.65; P < .0001). CONCLUSION: Our study found that 43% of young patients with diabetes have detectable coronary atherosclerosis. Given the known clinical implications of calcified plaque in coronary arteries, future studies are needed to evaluate interventions in persons aged <40 years who exhibit subclinical atherosclerosis to reduce future cardiovascular disease events in this vulnerable population.