Timothy Hess

Effects of Simvastatin on Cerebrospinal Fluid Biomarkers and Cognition in Middle-Aged Adults at Risk for Alzheimer's Disease

BACKGROUND Statins reduce amyloid-beta (Abeta) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Abeta metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD. METHODS In a 4-month randomized, double-blind, controlled study, we evaluated the effects of simvastatin 40 mg daily vs. placebo on CSF Abeta42 levels and cognition in 57 asymptomatic middle-aged adult children of persons with AD. RESULTS Compared to placebo, individuals randomized to simvastatin for 4 months had similar changes in CSF Abeta42 (p=0.344) and total tau levels (p=0.226), yet greater improvements in some measures of verbal fluency (p=0.024) and working memory (p=0.015). APOE4 genotype, gender, and vascular risk factors were associated with CSF biomarker levels, but did not modify treatment effects. CONCLUSION In asymptomatic middle-aged adults at increased risk for AD, simvastatin use improved selected measures of cognitive function without significantly changing CSF Abeta42 or total tau levels. Further studies are needed to clarify the impact of higher dose and/or longer duration statin therapy on not only Abeta metabolism, but also other preclinical processes related to the development of AD.

Longitudinal changes in engagement in care and viral suppression for HIV-infected injection drug users

Objective:To examine temporal trends and predictors of linkage to HIV care, longitudinal retention in care and viral suppression among injection drug users (IDUs) infected with HIV. Design:Community-based, prospective cohort study. Methods:We prospectively studied 790 HIV-infected IDUs participating in the AIDS Linked to the Intravenous Experience (ALIVE) study from 1998 through 2011. IDUs were considered linked to care if they attended any HIV care visit during follow-up and retained in care if they reported HIV clinic attendance at every semi-annual study visit. We used logistic regression to identify predictors of poor retention in care and failure to achieve sustained viral suppression in response to ART. Results:Of 790 HIV-infected IDUs studied, 740 (93.6%) were ever linked to care. The majority of IDUs (76.7%) received ART at some point during observation and of these, most (85.4%) achieved viral suppression. However, over a median of 8.7 years of follow-up, only 241 (30.5%) IDUs were continuously retained with no 6-month lapses in HIV care and only 63 (10.2%) had sustained viral suppression at every study visit after first receiving ART. Suboptimal engagement in care was associated with poor access to medical care, active drug use, and incarceration. Conclusion:Compared with national estimates of retention in care and virologic suppression in the United States, IDUs are substantially less likely to remain fully engaged in HIV care. Strategies to optimize HIV care should acknowledge the elevated risk of poor engagement in care among IDUs.

fMRI activation during episodic encoding and metacognitive appraisal across the lifespan: risk factors for Alzheimer's disease.

In the present study, we used fMRI to examine the influence of age on two other known risk factors for Alzheimers disease (AD), APOE genotype and parental history of AD (FH status), during episodic encoding (ENC) and metacognitive self-appraisal (SA) paradigms. These paradigms have previously been shown to evoke activity from brain regions that are implicated in AD. First we examined the effect of age across the adult lifespan (age 18-84 years) on cerebral activity in a large sample (n=231) of cognitively healthy individuals. Next we examined a subset (n=155) on whom APOE status and FH status were known. For ENC, we found that increasing age was associated with reduced activity in the ventral temporal lobes and hippocampus. Our analysis of risk factors suggested that FH and age exerted independent effects, but APOE interacted with age such that APOE e4 carriers exhibit age-related increases in activity in the hippocampus. For the metacognitive SA task, increasing age was found to be associated with reduced activity in the medial prefrontal cortex, and increased activity in the mesial temporal lobe, posterior orbital cortex and striatum. Neither AD risk factor significantly modified age-related changes in brain activity during SA. These results suggest that FH and aging are exerting independent effects in both tasks while APOE affected the relationship with age in the hippocampus in one of the two tasks given.

Low HDL Cholesterol is Associated with Lower Gray Matter Volume in Cognitively Healthy Adults

Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimers disease (FHAD) alters this effect. T1-weighted magnetic resonance imaging was used to examine regional brain gray matter (GM) and white matter (WM) in 183 individuals (58.4 ± 8.0 years) using voxel-based morphometry. A non-parametric multiple linear regression model was used to assess the effect of high-density lipoprotein (HDL) and non-HDL cholesterol, APOE, and FHAD on regional GM and WM volume. A post hoc analysis was used to assess whether any significant correlations found within the volumetric analysis had an effect on cognition. HDL was positively correlated with GM volume in the bilateral temporal poles, middle temporal gyri, temporo-occipital gyri, and left superior temporal gyrus and parahippocampal region. This effect was independent of APOE and FHAD. A significant association between HDL and the Brief Visuospatial Memory Test was found. Additionally, GM volume within the right middle temporal gyrus, the region most affected by HDL, was significantly associated with the Controlled Oral Word Association Test and the Center for Epidemiological Studies Depression Scale. These findings suggest that adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and GM reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline.

The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET)

Invasive candidiasis (IC) is a common cause of mortality in solid organ transplant recipients (OTRs), but knowledge of epidemiology in this population is limited.

Hormone effects on fMRI and cognitive measures of encoding: Importance of hormone preparation

We compared fMRI and cognitive data from nine hormone therapy (HT)–naive women with data from women exposed to either opposed conjugated equine estrogens (CEE) (n = 10) or opposed estradiol (n = 4). Exposure to either form of HT was associated with healthier fMRI response; however, CEE-exposed women exhibited poorer memory performance than either HT-naive or estradiol-exposed subjects. These preliminary findings emphasize the need to characterize differential neural effects of various HTs.

Antibiotic resistance in non-major metropolitan skilled nursing facilities: prevalence and interfacility variation.

Skilled nursing facilities (SNFs) represent ideal environments for the emergence and spread of antibiotic resistance.1 Studies have found that residents in Veterans Administration (VA) SNFs2,3 and non-VA SNFs in major metropolitan areas4,5 are frequently colonized with antibiotic-resistant bacteria (ARB). The extent to which residents of non-urban SNFs are colonized with ARB remains poorly understood. Intrinsic differences in patient populations, referral patterns as well as other contextual factors may fuel very different patterns of antibiotic resistance in non-urban SNFs. Our group recently completed a longitudinal study to document patterns of antibiotic resistance in several SNFs located in non-urban counties of South Central Wisconsin. Herein, we present the colonization results of surveillance cultures performed at the inception of the study cohort in 2008–2009. The University of Wisconsin’s Institutional Review Board approved this study. A potential pool of 39 SNFs (size, ≥ 60 beds) located in 9 South Central Wisconsin counties was constituted from a directory of licensed facilities maintained by the State of Wisconsin. A randomly assigned number was used to determine the order in which facilities were approached by the research team. Six of the first 10 facilities approached agreed to participate. Variables describing characteristics of the facility and resident population were constructed from annual data collected during the state survey process as well as data collected from medical records of subjects at study entry. Residents of participating SNFs over the age of 18, including those with cognitive impairment, were eligible to participate. After obtaining written informed consent, multi-anatomical screening for colonization with methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant gram-negative bacteria (FQRGNB) was performed. Cultures of nares, skin of the axilla and groin, and perianal skin (or stool) were obtained from all subjects to detect MRSA colonization. Additional cultures of wounds, the insertion site of non-urinary indwelling medical devices, and urine collected from indwelling urinary device were obtained, when applicable. The same body sites, exclusive of nares and axilla/groin, were sampled to detect FQRGNB colonization. MRSA specimens were enriched in trypticase soy broth supplemented with 6.5% NaCl for 24 hours before plating onto selective media -- Mannitol Salt agar (Remel, Lenexa, KS) containing 4 µg/mL of cefoxitin. FQRGNB specimens were plated directly onto MacConkey agar (Remel, Lenexa, KS) containing 4 µg/mL of ciprofloxacin. All plates were incubated aerobically for 48 hours at 37°C and were identified to the species level using standard techniques. Cefoxitin and ciprofloxacin resistance was confirmed using the Kirby Bauer disk diffusion method. Point estimates and 95% confidence intervals of the proportion of residents colonized with MRSA and FQRGNB were calculated. Pearson chi-square tests were performed to identify if a significant difference in the proportion of subjects colonized with MRSA and FQRGNB across study locations was present. When applicable, visual inspection of confidence limits was performed to identify facility pairs accounting for those differences. The characteristics of the participating facilities, including characteristics of participating subjects in aggregate, are presented in Table 1. 449 of the 851 (53%) residents in the 6 participating SNFs were screened at baseline. An equal proportion of subjects were colonized with MRSA (22.3%; 95% CI 13.7 – 30.9%) and FQRGNB (21.3%; 95% CI 13.3 – 29.3%). Approximately 5% of participating subjects were co-colonized with MRSA and FQRGNB (95% CI 2.8 – 7.1%). Overall, 38.7% (95% CI 32.9 – 44.5%) of subjects screened were colonized with either MRSA and/or FQRGNB. Table 1 Facility Characteristics and Prevalence of Antibiotic-Resistant Bacteria for 6 Skilled Nursing Facilities in South Central Wisconsin. Significant variation in the proportion of subjects colonized with MRSA (Pearson chi-square = 14.6, P = 0.012) and FQRGNB (Pearson chi-square = 13.2, P = 0.022) was identified across the 6 facilities. Significant differences in the prevalence of MRSA were identified between Facility #3 (13.0%) and Facility #4 (33.7%). Significant differences in the prevalence of FQRGNB were identified between Facility #2 (29.1%) and Facility #6 (11.3%). The characteristics of facilities with the highest prevalence of MRSA or FQRGNB were not qualitatively different from facilities with a lower prevalence of MRSA or FQRGNB (Table 1). The generalizeability of our findings may be limited by the method in which study facilities were selected. Our study facilities, while representative of non-urban SNFs that cater to long-term stay residents requiring nursing services of low complexity, may not be representative of urban SNFs that provide a more complex level of nursing care.6 Nevertheless, the prevalence of MRSA in facilities in our study are not substantively different from those recently described for SNFs in a highly urbanized county in California.7 Comparable data on the prevalence of FQRGNB in other SNFs are not available. However, recently published studies describing sharp increases in the proportion of clinical isolates obtained from residents of Northeastern SNFs that were resistant to fluoroquinolone antibiotics8 as well as a high prevalence of FQRGNB colonization among SNF residents with an indwelling medical device9 support the generalizeability of our findings. In combination, these data suggest that a post-fluoroquinolone era has begun to emerge in U.S. SNFs. Few studies have attempted to measure the variation in antibiotic resistance across SNFs within the same geographic region.7,10 The twofold variation in FQRGNB prevalence and threefold variation in MRSA prevalence seen among SNFs in our study raise questions that require further study. Specifically, is variation being driven by differences in referral patterns, intra-facility antibiotic prescribing, intra-facility adherence to transmission-based precautions or some combination thereof? Pursuing the answers to these questions will be important for developing and implementing interventions to reduce the regional spread of antibiotic resistance. In summary, our study affirms the notion that residents of SNFs are commonly colonized with MRSA and FQRGNB, even in non-urban facilities that provide relatively low complexity of nursing care. Considerable variation in the prevalence of MRSA and FQRGNB in SNFs in the same geographic region exists. The explanations for this degree of inter-facility variation remain poorly understood and deserve further study.

Outcomes of Clostridium difficile infection in recipients of solid abdominal organ transplants

Knowledge of outcomes of Clostridium difficile infection (CDI) in solid organ transplant (SOT) recipients is limited. To evaluate this population, we undertook a retrospective cohort study of all recipients of kidney and liver transplants diagnosed with CDI at a single center over 14 yr. Data pertaining to all episodes of CDI were collected. Multivariate analysis using logistic regression was performed to determine independent predictors of clinical cure. Overall, 170 patients developed 215 episodes of CDI. Among these patients, 162 episodes (75%) were cured, and in 103 episodes (48%), patients were cured within 14 d. In a multivariate analysis, lack of clinical cure at 14 d was predicted by recurrent episode (0.21, 95% CI 0.06–0.72, p = 0.0128), treatment with vancomycin (OR 0.27, 95% CI 0.1–0.74, p = 0.011), vasopressor support (OR 0.23, 95% CI 0.07–0.76, p = 0.0161), and CDI before the year 2004 (OR 0.44, 95% CI 0.2–0.98, p = 0.0446). The latter three factors are likely markers for severity of illness. In this cohort, 13 patients (8%) died during hospitalization, and 49 patients (29%) died within one yr. No deaths were attributed to CDI. Recurrent episode was a major predictor of treatment failure, suggesting that research into development of therapeutic options for recurrent disease is needed.

Diabetic foot ulcer severity predicts mortality among veterans with type 2 diabetes

AIM Diabetic foot ulcers are associated with an increased risk of death. We evaluated whether ulcer severity at presentation predicts mortality. METHODS Patients from a national, retrospective, cohort of veterans with type 2 diabetes who developed incident diabetic foot ulcers between January 1, 2006 and September 1, 2010, were followed until death or the end of the study period, January 1, 2012. Ulcers were characterized as early stage, osteomyelitis, or gangrene at presentation. Cox proportional hazard regression identified independent predictors of death, controlling for comorbidities, laboratory parameters, and healthcare utilization. RESULTS 66,323 veterans were included in the cohort and followed for a mean of 27.7months: 1-, 2-, and 5-year survival rates were 80.80%, 69.01% and 28.64%, respectively. Compared to early stage ulcers, gangrene was associated with an increased risk of mortality (HR 1.70, 95% CI 1.57-1.83, p<0.001). The magnitude of this effect was greater than diagnosed vascular disease, i.e., coronary artery disease, peripheral arterial disease, or stroke. CONCLUSION Initial diabetic foot ulcer severity is a more significant predictor of subsequent mortality than coronary artery disease, peripheral arterial disease, or stroke. Unrecognized or under-estimated vascular disease and/or sepsis secondary to gangrene should be explored as possible causal explanations.

Impact of Probiotics for Reducing Infections in Veterans (IMPROVE): Study protocol for a double-blind, randomized controlled trial to reduce carriage of Staphylococcus aureus

BACKGROUND Staphylococcus aureus (S. aureus) is an organism of great public health importance, causing 20,000 deaths annually. Decolonization of patients with S. aureus may prevent infections, yet current options are limited to antimicrobials that promote antibiotic resistance and can cause adverse side effects. Probiotics have potential to reduce colonization of pathogenic bacteria, representing a promising alternative for S. aureus decolonization, but thus far lack rigorous evaluation. METHODS Potential subjects were recruited from inpatient and outpatient settings within a VA medical center and screened for S. aureus gastrointestinal (GI) or extra-GI colonization using swabs at multiple body sites. Positive, eligible, consenting participants were stratified by colonization site and randomized in a 1:1 ratio to 4-weeks of daily placebo or Lactobacillus rhamnosus (L. rhamnosus) HN001 probiotic treatment. Blood and stool samples, and treatment adherence reports were collected from each subject throughout the study, along with a final set of swabs at study completion to detect S. aureus carriage. The outcomes of this study are GI or extra-GI carriage by S. aureus at the end of 4weeks of therapy, change in phagocytic activity of polymorphonuclear cells from pre-intervention to post-intervention, and symptomatic S. aureus infection at any site during the study period. CONCLUSION 114 participants have been recruited for this study. Analysis of outcomes is underway. This is the first clinical trial to examine the efficacy of L. rhamnosus HN001 for decolonization of S. aureus, and investigates the mechanism by which L. rhamnosus HN001 mediates its effect on S. aureus colonization. ClinicalTrials.govIdentifier NCT01321606.