Predictive factors of neurological complications and one-month mortality after liver transplantation.

BackgroundNeurological complications are common after orthotopic liver transplantation (OLT). We aimed to characterize the risk factors associated with neurological complications and mortality among patients who underwent OLT in the post-model for end-stage liver disease (MELD) era.MethodsIn a retrospective review, we evaluated 227 consecutive patients at the Keck Hospital of the University of Southern California before and after OLT to define the type and frequency of and risk factors for neurological complications and mortality.ResultsNeurological complications were common (n = 98), with encephalopathy being most frequent (56.8%), followed by tremor (26.5%), hallucinations (11.2%), and seizure (8.2%). Factors associated with neurological complications after OLT included preoperative dialysis, hepatorenal syndrome, renal insufficiency, intra-operative dialysis, preoperative encephalopathy, preoperative mechanical ventilation, and infection. Preoperative infection was an independent predictor of neurological complications (OR 2.83, 1.47-5.44). One-month mortality was 8.8% and was independently associated with urgent re-transplant, preoperative intubation, and intra-operative arrhythmia.ConclusionNeurological complications are common in patients undergoing OLT in the post-MELD era, with encephalopathy being most frequent. An improved understanding of the risk factors related to both neurological complications and one-month mortality post-transplantation can better guide perioperative care and help improve outcomes among OLT patients

Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality

Background: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods: A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results: In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions: In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates

Immune Activation and CD8(+) T-Cell Differentiation towards Senescence in HIV-1 Infection

Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8(+) T-cells and the use of an in vitro model of naïve CD8(+) T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8(+) T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8(+) T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8(+) and CD4(+) T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system

Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study

Background. There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)–containing ART

Predictive factors of neurological complications and one-month mortality after liver transplantation.

BackgroundNeurological complications are common after orthotopic liver transplantation (OLT). We aimed to characterize the risk factors associated with neurological complications and mortality among patients who underwent OLT in the post-model for end-stage liver disease (MELD) era.MethodsIn a retrospective review, we evaluated 227 consecutive patients at the Keck Hospital of the University of Southern California before and after OLT to define the type and frequency of and risk factors for neurological complications and mortality.ResultsNeurological complications were common (n = 98), with encephalopathy being most frequent (56.8%), followed by tremor (26.5%), hallucinations (11.2%), and seizure (8.2%). Factors associated with neurological complications after OLT included preoperative dialysis, hepatorenal syndrome, renal insufficiency, intra-operative dialysis, preoperative encephalopathy, preoperative mechanical ventilation, and infection. Preoperative infection was an independent predictor of neurological complications (OR 2.83, 1.47-5.44). One-month mortality was 8.8% and was independently associated with urgent re-transplant, preoperative intubation, and intra-operative arrhythmia.ConclusionNeurological complications are common in patients undergoing OLT in the post-MELD era, with encephalopathy being most frequent. An improved understanding of the risk factors related to both neurological complications and one-month mortality post-transplantation can better guide perioperative care and help improve outcomes among OLT patients

The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection

The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection.BackgroundWhile an understanding of the epidemiology and clinical course of HIV-associated nephropathy (HIVAN) is growing, little is known about the risk factors and clinical course of the other renal diseases that may also occur as a complication of HIV infection. This study was undertaken to compare HIVAN to the spectrum of other kidney diseases seen among HIV-infected patients.MethodsThis retrospective cohort study included all HIV-infected patients who underwent renal biopsy during the course of their clinical care at six major medical centers. Demographic and clinical information were abstracted from each patient's clinical record. Time to initiation of renal replacement therapy was compared for patients with lesions other than HIVAN to patients with HIVAN using Cox proportional hazards regression.ResultsEighty-nine patients (47 with lesions other than HIVAN and 42 with HIVAN) were available for inclusion. Patients with lesions other than HIVAN were less likely to be black (37/47 vs. 42/42, P = 0.02), more likely to have a positive hepatitis B surface antigen (10/37 vs. 4/42, P = 0.04), less likely to have the diagnosis of hypertension (24/46 vs. 31/42, P = 0.03), more likely to have a greater creatinine clearance at time of biopsy (60.6 vs. 39.0 cc/min, P = 0.008), and have a greater CD4 lymphocyte count at time of biopsy (287 vs. 187 cells/mL, P = 0.04) compared to patients with HIVAN. Lesions other than HIVAN were associated with a longer time to initiation of renal replacement therapy compared with HIVAN (HR 0.33, 95% CI 0.15-0.71, P = 0.005). Other factors associated with a longer time to renal replacement therapy included higher creatinine clearance at time of biopsy, greater CD4+ lymphocyte count, the absence of hepatitis C antibody, and the use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The type of renal disease (HIVAN vs. other) interacted significantly with HIV-1 RNA level and the use of antiretroviral therapy (P = 0.0001 and 0.006, respectively). Among patients with lesions other than HIVAN, the presence of nondetectable HIV-1 RNA was not associated with a greater risk of progression of renal disease (HR 0.27, P = 0.24). Among patients with HIVAN, because all patients had detectable virus at the time of institution of renal replacement therapy, this highly significant association could not be quantified. Among patients with lesions other than HIVAN, the use of antiretroviral therapy was not associated with the progression to renal replacement therapy (HR 3.29, P = 0.06). Among patients with HIVAN, the use of antiretroviral therapy was associated with a slower progression to renal replacement therapy (HR 0.24, P = 0.03).ConclusionAmong HIV-infected patients with renal disease other than HIVAN, viral suppression and the use of antiretroviral therapy are not associated with a beneficial effect on renal function; thus, additional therapeutic strategies may need to be utilized. Because renal histology is associated with prognostic differences, these data provide outcomes information that will improve the clinical utility of renal biopsy among HIV-infected patients with renal disease

Fetal antiepileptic drug exposure::Motor, adaptive, and emotional/behavioral functioning at age 3 years

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom that enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, valproate). In this article, we examine fetal AED exposure effects on motor, adaptive, and emotional/behavioral functioning in 229 children who completed at least one of these tests at 3years of age. Adjusted mean scores for the four AED groups were in the low average to average range for motor functioning, parental ratings of adaptive functioning, and parental ratings of emotional/behavioral functioning. A significant dose-related performance decline in motor functioning was seen for both valproate and carbamazepine. A significant dose-related performance decline in parental ratings of adaptive functioning was also seen for valproate, with a marginal performance decline evident for carbamazepine. Further, parents endorsed a significant decline in social skills for valproate that was dose related. Finally, on the basis of parent ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy appear to be at a significantly greater risk for a future diagnosis of attention-deficit/hyperactivity disorder. Additional research is needed to confirm these findings, examine risks of other AEDs, define the risks in the neonate associated with AEDs for treatment of seizures, and determine the underlying mechanisms of adverse AED effects on the immature brain. ► Children exposed in utero to higher dosages of valproate have lower motor/adaptive functioning. ► Children exposed in utero to higher dosages of carbamazepine have lower motor/adaptive functioning. ► Children exposed in utero to valproate may be at Increased risk for attention-deficit/hyperactivity disorder

Breastfeeding in children of women taking antiepileptic drugs: Cognitive outcomes at age 6 years

IMPORTANCE: Breastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities. OBJECTIVES: To examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery. MAIN OUTCOMES AND MEASURES: Differential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures. RESULTS: In total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P italic> .001 [adjusted IQ worse by 7–13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, −0.1; 95% CI, −0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2–10] points higher for folate, P = .005), and breastfeeding (adjusted IQ 4 [95% CI, 0–8] points higher for breastfeeding, P = .045). For the other cognitive domains, only verbal abilities differed between the breastfed and nonbreastfed groups (adjusted verbal index 4 [95% CI, 0–7] points higher for breastfed children, P = .03). CONCLUSIONS AND RELEVANCE: No adverse effects of AED exposure via breast milk were observed at age 6 years, consistent with another recent study at age 3 years. In our study, breastfed children exhibited higher IQ and enhanced verbal abilities. Additional studies are needed to fully delineate the effects of all AEDs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT0002186

Antiepileptic drug use in women of childbearing age

Research on antiepileptic drug (AED) teratogenesis has demonstrated an increased risk for valproate. The impact of these findings on current AED prescribing patterns for women of childbearing age with epilepsy is uncertain. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective multicenter observational investigation that enrolled pregnant women with epilepsy on the most common AED monotherapies from October 1999 to February 2004 (carbamazepine, lamotrigine, valproate, and phenytoin). A 2007 survey of AED use in women of childbearing age at eight NEAD centers found a total of 932 women of childbearing age with epilepsy (6% taking no AED, 53% monotherapy, 41% polytherapy). The most common monotherapies were lamotrigine or levetiracetam. Since 2004, prescriptions of carbamazepine, phenytoin, and valproate have decreased, whereas those for levetiracetam have increased. Except for the top two AED monotherapies, there were marked differences in other monotherapies and in polytherapies between U.S. and UK centers. Future investigations are needed to examine reasons for drug choice

Relationship of child IQ to parental IQ and education in children with fetal antiepileptic drug exposure

Clinical trial designs need to control for genetic and environmental influences when examining cognitive outcomes in children for whom clinical considerations preclude randomization. However, the contributions of maternal and paternal IQ and education to pediatric cognitive outcomes are uncertain in disease populations. The NEAD Study is an ongoing prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy to determine if differential long-term neurodevelopmental effects exist across four commonly used antiepileptic drugs (AEDs). Here, we examined the relationship of IQ and education in both parents to child IQ at age 3 years. IQ and education for both parents were statistically correlated to child IQ. However, paternal IQ and education were not significant after accounting for maternal IQ effects. Because maternal IQ and education are independently related to child cognitive outcome, both should be assessed in studies investigating the effects of fetal drug exposures or other environmental factors that could affect the child’s cognitive outcome