The burden of parainfluenza virus infection in patients with hematological malignancy and hematopoietic stem cell transplant (HSCT) recipients in the absence of active immunization and approved therapy: The role of infection control

Background. Community respiratory viruses, mainly RSV and influenza, are significant causes of morbidity and mortality in patients with leukemia and HSCT recipients. The data on impact of PIV infections in these patients is lacking. Methods. We reviewed the records of patients with leukemia and HSCT recipients who developed PIV infection from Oct'02–Nov'07 to determine the outcome of such infections. Results. We identified 200 patients with PIV infections including 80(40%) patients with leukemia and 120 (60%) recipients of HSCT. Median age was 55 y (17-84 y). As compared to HSCT recipients, patients with leukemia had higher APACHE II score (14 vs. 10, p<0.0001); were more likely to have ANC<500 (48% vs. 10%, p<0.0001) and ALC<200 (45% vs. 23.5%, p=0.02). PIV type III was the commonest isolate (172/200, 86%). Most patients 141/200 (70%) had upper respiratory infection (URI), and 59/200 (30%) had pneumonia at presentation. Patients in leukemia group were more likely to require hospitalization due to PIV infection (77% vs. 36% p=0.0001) and were more likely to progress to pneumonia (61% vs. 39%, p=0.002). Fifty five patients received aerosolized ribavirin and/or IVIG. There were no significant differences in the duration of symptoms, length of hospitalization, progression to pneumonia or mortality between the treated verses untreated group. The clinical outcome was unknown in 13 (6%) patients. Complete resolution of symptoms was noted in 91% (171/187) patients and 9% (16/187) patients died. Mortality rate was 17% (16/95) among patients who had PIV pneumonia, with no significant difference between leukemia and HSCT group (16% vs. 17%). The cause of death was acute respiratory failure and/or multi-organ failure in (13, 81%) patients. Conclusions. Patients with leukemia and HSCT could be at high risk for serious PIV infections including PIV pneumonia. Treatment with aerosolized ribavirin and/or IVIG may not have significant effect on the outcome of PIV infection.^

Implementation of active surveillance cultures and associated infection control practices for the reduction of methicillin resistant Staphylococcus aureus in the healthcare setting: An interrupted time series analysis

OBJECTIVE. To determine the effectiveness of active surveillance cultures and associated infection control practices on the incidence of methicillin resistant Staphylococcus aureus (MRSA) in the acute care setting. DESIGN. A historical analysis of existing clinical data utilizing an interrupted time series design. ^ SETTING AND PARTICIPANTS. Patients admitted to a 260-bed tertiary care facility in Houston, TX between January 2005 through December 2010. ^ INTERVENTION. Infection control practices, including enhanced barrier precautions, compulsive hand hygiene, disinfection and environmental cleaning, and executive ownership and education, were simultaneously introduced during a 5-month intervention implementation period culminating with the implementation of active surveillance screening. Beginning June 2007, all high risk patients were cultured for MRSA nasal carriage within 48 hours of admission. Segmented Poisson regression was used to test the significance of the difference in incidence of healthcare-associated MRSA during the 29-month pre-intervention period compared to the 43-month post-intervention period. ^ RESULTS. A total of 9,957 of 11,095 high-risk patients (89.7%) were screened for MRSA carriage during the intervention period. Active surveillance cultures identified 1,330 MRSA-positive patients (13.4%) contributing to an admission prevalence of 17.5% in high-risk patients. The mean rate of healthcare-associated MRSA infection and colonization decreased from 1.1 per 1,000 patient-days in the pre-intervention period to 0.36 per 1,000 patient-days in the post-intervention period (P<0.001). The effect of the intervention in association with the percentage of S. aureus isolates susceptible to oxicillin were shown to be statistically significantly associated with the incidence of MRSA infection and colonization (IRR = 0.50, 95% CI = 0.31-0.80 and IRR = 0.004, 95% CI = 0.00003-0.40, respectively). ^ CONCLUSIONS. It can be concluded that aggressively targeting patients at high risk for colonization of MRSA with active surveillance cultures and associated infection control practices as part of a multifaceted, hospital-wide intervention is effective in reducing the incidence of healthcare-associated MRSA.^

A RANDOMIZED TRIAL OF BILEVEL POSITIVE AIRWAY PRESSURE DEVICE AND HIGH FLOW OXYGEN FOR PERSISTENT DYSPNEA IN

Background: Dyspnea is a common and distressing symptom among patients with advanced cancer. The role of bilevel positive airway pressure (BIPAP) and Vapotherm in the relief of dyspnea have not been well defined. We aimed to determine and to compare the efficacy of BIPAP and VapoTherm for cancer related dyspnea. Methods: In this randomized, open-label, crossover study, we randomly assigned advanced cancer patients with persistent dyspnea >=3/10 to either Vapotherm for 2 hours followed by BiPAP for 2 hours, or BiPAP followed by Vaptherm. A variable washout period was instituted between interventions. The primary end point was change in numeric rating scale before and after each intervention. We planned to enroll 50 patients in total. Results: Among the 803 patients screened over the last 8 months, 62 (26%) were eligible, and 16 (2%) were enrolled so far. Five patients completed the entire study successfully, 4 discontinued the study prematurely due to prolonged relief of dyspnea, and 7 dropped out for various reasons, including inability to tolerate BiPAP (N=3), anxiety (N=2), fatigue (N=1) and pain requiring opioids (N=1). The median baseline numeric rating score for dyspnea was 7/10 (interquartile range (IQR) 5-8), and the median baseline Borg score was 4/10 (3-7). Interim analysis revealed that BiPAP was associated with a median change in numeric rating score of -3 (N=10, IQR -6.3 to -1, p=0.007) and modified Borg score of -1 (N=10, IQR -3 to 0.3, p=0.058), while Vapotherm was associated with a median change in numeric rating score of -2 (N=9, IQR -3 to -1, p=0.011) and modified Borg score of -2.5 (N=8, IQR -5.5 to -0.1, p=0.051). Among the 5 individuals who completed the entire study, 2 preferred Vapotherm, 2 favored BiPAP, and 1 liked both. The respiratory rate decreased and the oxygen saturation improved with both interventions. No significant toxicities were observed. Conclusions: We were successfully able to enroll patients onto this clinic trial. Our preliminary results suggest that BiPAP and Vapotherm are highly efficacious in providing relief for patients with persistent refractory dyspnea. A direct comparison of the two interventions will be done upon study completion. Further research is necessary to confirm our findings.

Tracking the Flow of Information through the Hippocampal Formation in the Rat

The hippocampus receives input from upper levels of the association cortex and is implicated in many mnemonic processes, but the exact mechanisms by which it codes and stores information is an unresolved topic. This work examines the flow of information through the hippocampal formation while attempting to determine the computations that each of the hippocampal subfields performs in learning and memory. The formation, storage, and recall of hippocampal-dependent memories theoretically utilize an autoassociative attractor network that functions by implementing two competitive, yet complementary, processes. Pattern separation, hypothesized to occur in the dentate gyrus (DG), refers to the ability to decrease the similarity among incoming information by producing output patterns that overlap less than the inputs. In contrast, pattern completion, hypothesized to occur in the CA3 region, refers to the ability to reproduce a previously stored output pattern from a partial or degraded input pattern. Prior to addressing the functional role of the DG and CA3 subfields, the spatial firing properties of neurons in the dentate gyrus were examined. The principal cell of the dentate gyrus, the granule cell, has spatially selective place fields; however, the behavioral correlates of another excitatory cell, the mossy cell of the dentate polymorphic layer, are unknown. This report shows that putative mossy cells have spatially selective firing that consists of multiple fields similar to previously reported properties of granule cells. Other cells recorded from the DG had single place fields. Compared to cells with multiple fields, cells with single fields fired at a lower rate during sleep, were less likely to burst, and were more likely to be recorded simultaneously with a large population of neurons that were active during sleep and silent during behavior. These data suggest that single-field and multiple-field cells constitute at least two distinct cell classes in the DG. Based on these characteristics, we propose that putative mossy cells tend to fire in multiple, distinct locations in an environment, whereas putative granule cells tend to fire in single locations, similar to place fields of the CA1 and CA3 regions. Experimental evidence supporting the theories of pattern separation and pattern completion comes from both behavioral and electrophysiological tests. These studies specifically focused on the function of each subregion and made implicit assumptions about how environmental manipulations changed the representations encoded by the hippocampal inputs. However, the cell populations that provided these inputs were in most cases not directly examined. We conducted a series of studies to investigate the neural activity in the entorhinal cortex, dentate gyrus, and CA3 in the same experimental conditions, which allowed a direct comparison between the input and output representations. The results show that the dentate gyrus representation changes between the familiar and cue altered environments more than its input representations, whereas the CA3 representation changes less than its input representations. These findings are consistent with longstanding computational models proposing that (1) CA3 is an associative memory system performing pattern completion in order to recall previous memories from partial inputs, and (2) the dentate gyrus performs pattern separation to help store different memories in ways that reduce interference when the memories are subsequently recalled.

Genes to blood pressure: The effects of variation in genes of the renin-angiotensin system on the hormonal and renal control of blood pressure

Objective. Essential hypertension affects 25% of the US adult population and is a leading contributor to morbidity and mortality. Because BP is a multifactorial phenotype that resists simple genetic analysis, intermediate phenotypes within the complex network of BP regulatory systems may be more accessible to genetic dissection. The Renin-Angiotensin System (RAS) is known to influence intermediate and long-term blood pressure regulation through alterations in vascular tone and renal sodium and fluid resorption. This dissertation examines associations between renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1) gene variation and interindividual differences in plasma hormone levels, renal hemodynamics, and BP homeostasis.^ Methods. A total of 150 unrelated men and 150 unrelated women, between 20.0 and 49.9 years of age and free of acute or chronic illness except for a history of hypertension (11 men and 7 women, all off medications), were studied after one week on a controlled sodium diet. RAS plasma hormone levels, renal hemodynamics and BP were determined prior to and during angiotensin II (Ang II) infusion. Individuals were genotyped by PCR for a variable number tandem repeat (VNTR) polymorphism in REN, and for the following restriction fragment length polymorphisms (RFLP): AGT M235T, ACE I/D, and AT1 A1166C. Associations between clinical measurements and allelic variation were examined using multiple linear regression statistical models.^ Results. Women homozygous for the AT1 1166C allele demonstrated higher intracellular levels of sodium (p = 0.044). Men homozygous for the AGT T235 allele demonstrated a blunted decrement in renal plasma flow in response to Ang II infusion (p = 0.0002). There were no significant associations between RAS gene variation and interindividual variation in RAS plasma hormone levels or BP.^ Conclusions. Rather than identifying new BP controlling genes or alleles, the study paradigm employed in this thesis (i.e., measured genes, controlled environments and interventions) may provide mechanistic insight into how candidate genes affect BP homeostasis. ^

THE RELATIONSHIP BETWEEN THE RHEOENCEPHALOGRAM AND CEREBRAL BLOOD FLOW

The rheoencephalogram (REG) is the change in the electrical impedance of the head that occurs with each heart beat. Without knowledge of the relationship between cerebral blood flow (Q) and the REG, the utility of the REG in the study of the cerebral vasculature is greatly limited. The hypothesis is that the relationship between the REG and Q when venous outflow is nonpulsatile is^ (DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)^ where K is a proportionality constant and Q is the mean Q.^ Pulsatile CBF was measured in the goat via a chronically implanted electromagnetic flowmeter. Electrodes were implanted in the ipsilateral cerebral hemisphere, and the REG was measured with a two electrode impedance plethysmograph. Measurements were made with the animal's head elevated so that venous flow pulsations were not transmitted from the heart to the cerebral veins. Measurements were made under conditions of varied cerebrovascular resistance induced by altering blood CO(,2) levels and under conditions of high and low cerebrospinal fluid pressures. There was a high correlation (r = .922-.983) between the REG calculated from the hypothesized relationship and the measured REG under all conditions.^ Other investigators have proposed that the REG results from linear changes in blood resistivity proportional to blood velocity. There was little to no correlation between the measured REG and the flow velocity ( r = .022-.306). A linear combination of the flow velocity and the hypothesized relationship between the REG and Q did not predict the measured REG significantly better than the hypothesized relationship alone in 37 out of 50 experiments.^ Jacquy proposed an index (F) of cerebral blood flow calculated from amplitudes and latencies of the REG. The F index was highly correlated (r = .929) with measured cerebral blood flow under control and hypercapnic conditions, but was not as highly correlated under conditions of hypocapnia (r = .723) and arterial hypotension (r = .681).^ The results demonstrate that the REG is not determined by mean cerebral blood flow, but by the pulsatile flow only. Thus, the utility of the REG in the determination of mean cerebral blood flow is limited. ^

Prevalence and risk factors of methicillin-resistant Staphylococcus aureus in critically-ill hospitalized patients in a tertiary care center in Houston, Texas: An active surveillance pilot project

Objective. The objective of this study is to determine the prevalence of MRSA colonization in adult patients admitted to intensive care units at an urban tertiary care hospital in Houston, Texas and to evaluate the risk factors associated with colonization during a three month active-screening pilot project. Design. This study used secondary data from a small cross-sectional pilot project. Methods. All patients admitted to the seven specialty ICUs were screened for MRSA by nasal culture. Results were obtained utilizing the BD GeneOhm™ IDI-MRSA assay in vitro diagnostic test, for rapid MRSA detection. Statistical analysis was performed using the STATA 10, Epi Info, and JavaStat. Results . 1283/1531 (83.4%) adult ICU admissions were screened for nasal MRSA colonization. Of those screened, demographic and risk factor data was available for 1260/1283 (98.2%). Unresolved results were obtained for 73 patients. Therefore, a total of 1187/1531 (77.5%) of all ICU admissions during the three month study period are described in this analysis. Risk factors associated with colonization included the following: hospitalization within the last six months (odds ratio 2.48 [95% CI, 1.70-3.63], p=0.000), hospitalization within the last 12 months, (odds ratio 2.27 [95% CI, 1.57-3.80], p=0.000), and having diabetes mellitus (odds ratio 1.63 [95% CI, 1.14-2.32], p=0.007). Conclusion. Based on the literature, the prevalence of MRSA for this population is typical of other prevalence studies conducted in the United States and coincides with the continual increasing trend of MRSA colonization. Significant risk factors were similar to those found in previous studies. Overall, the active surveillance screening pilot project has provided valuable information on a population not widely addressed. These findings can aid in future interventions for the education, control, prevention, and treatment of MRSA. ^

Emerging arboviruses in Harris County, Texas

Harris County, which includes Houston, Texas, is an endemic and epidemic area for two viruses transmitted by arthropods (arboviruses). These viruses are maintained in cycles involving mosquitoes and wild birds, and transmission to humans is accidental. The majority of human infections is asymptomatic or may result in a flu-like syndrome. However, some infections can result in meningitis or encephalitis. These neuroinvasive infections may cause death, and those who survive may experience serious neurological complications requiring costly and lengthy medical care. The most important arboviruses in terms of morbidity are St. Louis encephalitis (SLEV) and West Nile (WNV) viruses. In fact, Harris County reports more SLEV encephalitis cases than any other county in the U.S. Most arboviral human cases occur from July through September, when mosquitoes are most active. Those at risk for encephalitis and death are the elderly and those with a history of hypertension or immunosuppresion. There is no specific treatment and no human vaccines are commercially available in the U.S. The approach for control of arboviruses in Harris County during epidemics is multidisciplinary and executed by several agencies. It includes surveillance, vector control, and educational messages for the population. Prevention of outbreaks consists of elimination of the vector and its breeding grounds, and practicing personal protective measures to prevent exposure to mosquitoes. ^ Current findings indicate that mosquito-borne viruses other than SLEV and WNV could pose an additional threat for the population. Eastern equine encephalitis virus (EEEV) activity has been detected in dogs and sentinel chickens in Houston and surrounding areas. Several serotypes of dengue virus have caused recent outbreaks in south Texas, and some locally-acquired cases have been detected in Houston. Since the clinical presentation of all arboviruses that cause encephalitis is very similar, and current surveillance is focused on detecting SLEV and WNV, there is a possibility that other arboviruses could be present in the area but are not being detected. Additionally, Harris County's ample annual rainfall and flooding problems, warm weather, multiple mosquito species, local and migrating birds that are susceptible to arboviral infection, and a constant flow of goods and travelers from many parts of the world could favor the emergence or re-emergence of other arboviruses. ^ The aims of this project were to determine if other arboviruses were circulating in the county, to assess the knowledge and attitudes about mosquito-borne viruses in a sample of the population, and to conduct an analysis of the initial WNV epidemic in Harris County. Through the retrospective analysis of clinical specimens collected during the 2002-2005 epidemic seasons, serologic evidence of dengue infection was detected suggesting the possibility that this virus may be co-circulating with SLEV and WNV. A cross-sectional survey revealed high awareness about arboviruses but not a consistent use of protective measures to avoid mosquitoes. The third component for this project included a retrospective review and geographical analysis of the 2002 WNV epidemic. ^ Overall, this study documented valuable information about the dengue virus, a potentially emerging arbovirus in Texas, revealed the need for more educational preventative programs, reinforced the value of mosquito and avian surveillance, and indicated the importance of continuing to investigate the factors that contribute to the development of outbreaks. ^

Case-control study of factors associated with virologic failure in HIV-infected children on HAART in Botswana, a developing African country

According to the United Nations Program on HIV/AIDS (UNAIDS, 2008), in 2007 about 67 per cent of all HIV-infected patients in the world were in Sub-Saharan Africa, with 35% of new infections and 38% of the AIDS deaths occurring in Southern Africa. Globally, the number of children younger than 15 years of age infected with HIV increased from 1.6 million in 2001 to 2.0 million in 2007 and almost 90% of these were in Sub-Saharan Africa. (UNAIDS, 2008).^ Both clinical and laboratory monitoring of children on Highly Active Anti-Retroviral Therapy (HAART) are important and necessary to optimize outcomes. Laboratory monitoring of HIV viral load and genotype resistance testing, which are important in patient follow-up to optimize treatment success, are both generally expensive and beyond the healthcare budgets of most developing countries. This is especially true for the impoverished Sub-Saharan African nations. It is therefore important to identify those factors that are associated with virologic failure in HIV-infected Sub-Saharan African children. This will inform practitioners in these countries so that they can predict which patients are more likely to develop virologic failure and therefore target the limited laboratory monitoring budgets towards these at-risk patients. The objective of this study was to examine those factors that are associated with virologic failure in HIV-infected children taking Highly Active Anti-retroviral Therapy in Botswana, a developing Sub-Saharan African country. We examined these factors in a Case-Control study using medical records of HIV-infected children and adolescents on HAART at the Botswana-Baylor Children's Clinical Center of Excellence (BBCCCOE) in Gaborone, Botswana. Univariate and Multivariate Regression Analyses were performed to identify predictors of virologic failure in these children.^ The study population comprised of 197 cases (those with virologic failure) and 544 controls (those with virologic success) with ages ranging from 3 months to 16 years at baseline. Poor adherence (pill count <95% on at least 3 consecutive occasions) was the strongest independent predictor of virologic failure (adjusted OR = 269.97, 95% CI = 104.13 to 699.92; P < 0.001). Other independent predictors of virologic failure identified were: First Line NNRTI with Nevirapine (OR = 2.99, 95% CI = 1.19 to7.54; P = 0.020), Baseline HIV-1 Viral Load >750,000/ml (OR = 257, 95% CI = 1.47 to 8.63; P = 0.005), Positive History of PMTCT (OR = 11.65, 95% CI = 3.04-44.57; P < 0.001), Multiple Care-givers (>=3) (OR = 2.56, 95% CI = 1.06 to 6.19; P = 0.036) and Residence in a Village (OR = 2.85, 95% CI = 1.36 to 5.97; P = 0.005).^ The results of this study may help to improve virologic outcomes and reduce the costs of caring for HIV-infected children in resource-limited settings. ^ Keywords: Virologic Failure, Highly Active Anti-Retroviral Therapy, Sub-Saharan Africa, Children, Adherence.^

ASSESSMENT OF SKELETAL MUSCLE BLOOD FLOW AND GLUCOSE METABOLISM WITH POSITRON EMITTING RADIONUCLIDES

In order to evaluate factors regulating substrate metabolism in vivo positron emitting radionuclides were used for the assessment of skeletal muscle blood flow and glucose utilization. The potassium analog, Rb-82 was used to measure skeletal muscle blood flow and the glucose analog, 18-F-2-deoxy-2-fluoro-D-glucose (FDG) was used to examine the kinetics of skeletal muscle transport and phosphorylation.^ New Zealand white rabbits' blood flow ranged from 1.0-70 ml/min/100g with the lowest flows occurring under baseline conditions and the highest flows were measured immediately after exercise. Elevated plasma glucose had no effect on increasing blood flow, whereas high physiologic to pharmacologic levels of insulin doubled flow as measured by the radiolabeled microspheres, but a proportionate increase was not detected by Rb-82. The data suggest that skeletal muscle blood flow can be measured using the positron emitting K+ analog Rb-82 under low flow and high flow conditions but not when insulin levels in the plasma are elevated. This may be due to the fact that insulin induces an increase in the Na+/K+-ATPase activity of the cell indirectly through a direct increase in the Na+/H+pump activity. This suggests that the increased cation pump activity counteracts the normal decrease in extraction seen at higher flows resulting in an underestimation of flow as measured by rubidium-82.^ Glucose uptake as measured by FDG employed a three compartment mathematical model describing the rates of transport, countertransport and phosphorylation of hexose. The absolute values for the metabolic rate of FDG were found to be an order of magnitude higher than those reported by other investigators. Changes noted in the rate constant for transport (k1) were found to disagree with the a priori information on the effects of insulin on skeletal muscle hexose transport. Glucose metabolism was however, found to increase above control levels with administration of insulin and electrical stimulation. The data indicate that valid measurements of skeletal muscle glucose transport and phosphorylation using the positron emitting glucose analog FDG requires further model application and biochemical validation. (Abstract shortened with permission of author.) ^